Anti-inflammatory Polyketides from an Endophytic Fungus Chaetomium sp. UJN-EF006 of Vaccinium bracteatum.

Seven new polyketides including three chromone derivatives (1-3) and four linear ones incorporating a tetrahydrofuran ring (4-7), along with three known compounds (8-10), were obtained from the fermentation of an endophytic fungus (Chaetomium sp. UJN-EF006) isolated from the leaves of Vaccinium bracteatum. The structures of these fungal metabolites have been elucidated by spectroscopic means including MS, NMR and electronic circular dichroism. A preliminary anti-inflammatory screening with the lipopolysaccharide (LPS) induced RAW264.7 cell model revealed moderate NO production inhibitory activity for compounds 1 and 4. In addition, the expression of three LPS-induced inflammatory factors IL-6, iNOS and COX-2 was also blocked by 1 and 4.

Bioactive neolignan, iridoid and flavonoid glycosides from the leaves of Vaccinium bracteatum.

Two neolignan glycosides including a new one (1), along with seven iridoid glycosides (3 - 9) and nine flavonoid glycosides (10 - 18), were isolated from the leaves of Vaccinium bracteatum. Their structures were established mainly on the basis of 1D/2D NMR and ESIMS analyses, as well as comparison to known compounds in the literature. The structure of 1 with absolute stereochemistry was also confirmed by chemical degradation and ECD calculation. Selective compounds showed antiradical activity against ABTS and/or DPPH. Moreover, several isolates also suppressed the production of ROS in RAW264.7 cells and exerted neuroprotective effect toward PC12 cells.

Structurally Diverse Sesquiterpenoids with NO Production and α-Glucosidase Inhibitory Activities from the Fruits of Schisandra chinensis.

Chemical fractionation of the AcOEt partition, generated from the EtOH extract of the fruits of Schisandra chinensis, afforded a series of sesquiterpenyl constituents including two new cadinanes, a new eudesmane, two new widdranes (a handling artefact and a new natural product), a new bisabolane and two new natural cuparane enantiomers, along with 15 known structurally related analogs. Structures of the new compounds were unambiguously characterized by interpretation of detailed spectroscopic data including ESI-MS and 1D/2D NMR, with their absolute configurations being established by electronic circular dichroism (ECD) calculation and induced ECD experiment. The inhibitory effects of all the isolates against α-glucosidase and lipopolysaccharide (LPS) induced nitric oxide (NO) production in murine RAW264.7 macrophages, as well as their antibacterial and cytotoxic potential, were evaluated, with selective compounds showing moderate α-glucosidase and NO inhibitory activity. Notably, canangaterpene III exhibited the most significant NO inhibitory effect with an IC50 value of 31.50±1.49 µM.

Identification of Small-Molecule Bioactive Constituents from the Leaves of Vaccinium bracteatum Confirms It as a Potential Functional Food with Health Benefits.

The health benefits of Vaccinium bracteatum are well recorded in ancient Chinese medical books and were also demonstrated by modern researches. However, the relationship between its beneficial functions and specific chemical constituents has not been fully characterized. This study investigated the bioactive small-molecule constituents in the leaves of V. bracteatum, which afforded 32 compounds including ten new ones (1-9) and ten pairs of enantiomers (9-18). Their structures with absolute configurations were elucidated by spectroscopic methods, especially nuclear magnetic resonance (NMR) and electronic circular dichroism (ECD) analyses, with 1-4 bearing a novel revolving-door shaped scaffold. While half-compounds exhibited decent antioxidant activity by scavenging 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals, all except 19 and 20 exerted significant capturing activity against diammonium 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonate) (ABTS) radicals. In addition, the new iridoids 1, 5, 6, and 7 exerted apparent neuroprotective activity toward PC12 cells, with 1 being comparable to the positive control, and selective compounds also displayed anti-diabetic and anti-inflammatory properties by inhibiting α-glucosidase and NO production, respectively. The current work revealed that the bioactive small-molecule constituents could be closely related to the functional food property of the title species.

Clerodane furanoditerpenoids from the stems of Tinospora sinensis.

One new clerodane-type furanoditerpenoid tinosinoid A (1) and nine new nor-clerodane analogs tinosinoids B-J (2-10) have been isolated from the stems of Tinospora sinensis. The structures of the new compounds with absolute configurations have been elucidated by spectroscopic means, including MS, NMR and ECD techniques, as well as chemical correlation. Compound 1 is a rare sulfur-containing clerodane diterpenoid incorporating a 2-mercaptoethanol unit via a thioether bond, while compounds 4/5 and 9 represent two pairs of unusual equilibrium regioisomers through an interesting intramolecular transesterification. Our bioassays established that 1 and 8 displayed moderate antiproliferative effects against two human tumor cell lines, and 9 and 10 showed significant α-glucosidase inhibitory activities. A kinetics study revealed that compound 10 was a noncompetitive α-glucosidase inhibitor, and its possible binding mode to the enzyme was further probed by molecular docking experiments.

Lignans with NO inhibitory activity from Tinospora sinensis.

Two new lignan glucosides, tinsinlignans A and B (1 and 2), two new oxyneolignans, tinsinlignans C and D (3 and 4), along with one known analogue (5), were isolated from the stems of Tinospora sinensis. The structures of the new compounds were elucidated based on analysis of spectroscopic data, and the absolute configuration of 1 was determined through electronic circular dichroism (ECD) calculation based on the time-dependent density functional theory (TD-DFT). Compounds 1-4 were evaluated for their inhibitory effects on nitric oxide (NO) production induced by lipopolysaccharide (LPS) in murine RAW264.7 macrophage cells and compounds 1 and 2 exhibited moderate inhibitory activities with IC50 values of 18.5 ± 2.0 and 28.8 ± 1.2 µmol·L-1, respectively.

Chemical constituents from Tinospora sagittata and their biological activities.

Six undescribed low-polarity compounds including three rare 14-methylergostane steroids (1-3), one euphane triterpenoid (4) and two octadecanoic acid ethyl esters (5 and 6), along with ten previously reported terpenyl cometabolites (7-16), were isolated from the stems of Tinospora sagittata. Their structures were determined by detailed spectroscopic analyses and comparison with structurally related known compounds, and all of them have been reported from T. sagittata for the first time. Compounds 4-6 and 16 showed potent in vitro inhibitory activity against the diabetes target α-glucosidase, while compounds 10 and 14 displayed promising antibacterial effect toward Staphylococcus aureus ATCC 25923.

Bioactive aromatic butenolides from a mangrove sediment originated fungal species, Aspergillus terreus SCAU011.

Seven new compounds including five aromatic butenolide analogues (1-5), one quinazolinone alkaloid (6) and one benzoic acid derivative (7), along with eleven known co-metabolites (8-18), were isolated from Aspergillus terreus SCAU011, a fungus from the rhizosphere sediment of a mangrove plant Rhizophora stylosa. The structures of these isolates were established by a combination of MS, NMR and ECD data analyses, as well as chemical method. Compound 3 is a rare ring-open aromatic butenolide, while 6 represents the first natural ring-open benzomalvin-type quinazolinone alkaloid. Also, the previously reported structures for asperlides A-C were proposed to be revised in the present work. The COX-2 inhibitory, α-glucosidase inhibitory, antioxidant and antibacterial activities of all the compounds were assessed. While compounds 4, 6, 11 and 18 exhibited better COX-2 inhibitory activity than the positive control celecoxib, compounds 9 and 10 showed significant α-glucosidase inhibitory activity with IC50 values of 56.1 and 12.9 µM, respectively. Meanwhile, half of the tested samples (1, 8-11 and 15-17) exerted similar or better antioxidant activity compared with the reference drug curcumin, and compounds 3, 9, 17 and 18 displayed moderate antibacterial effect against Staphylococcus aureus.

New antibacterial thiophenes from Eclipta prostrata.

Three new thiophene derivatives, ecliprostins A-C (1-3), have been isolated from the aerial parts of a Compositae medicinal plant Eclipta prostrata, and structures of them have been elucidated by comprehensive spectroscopic analyses. Both ecliprostins A (1) and B (2) feature an acetylenic bithiophenyl backbone and also incorporate an isovalerate moiety, while ecliprostin C (3) is a symmetrical dimer of compound 1 and represents the first example bonded via an ether bridge among the very limited natural dimers. All three compounds show antibacterial activity against Staphylococcus aureus.

Structural characterization and biological evaluation of chemical constituents from Ilex cornuta.

One new ursane-type triterpenoid (1), one new ursane-type triterpenoid glycoside (2), and one new oleanane-type triterpenoid glycoside (3), along with 20 known compounds, were isolated from the leaves of Ilex cornuta. The structures of these natural products were elucidated on the basis of detailed spectroscopic analyses and chemical derivation. Our biological evaluation established that selective compounds showed moderate to significant antioxidant activities in the 1,1-diphenyl-2-picrylhydrazyl and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) methods.

Preoperative insomnia and its association with psychological factors, pain and anxiety in Chinese colorectal cancer patients.

PURPOSE: Sleep disturbances are common in cancer patients, but little is known about preoperative insomnia and its associated factors in colorectal cancer (CRC) patients. The aim of this study was to clarify the relationship between preoperative insomnia and its associated factors (i.e., pain, anxiety, self-esteem, and coping styles) in CRC patients. METHODS: A cross-sectional study was conducted in consecutive CRC inpatients (N = 434), who were required to complete the questionnaires about insomnia, pain, anxiety, self-esteem, and coping styles (acceptance/resignation, confrontation, avoidance) before the day of surgery. Hierarchical regression analyses were conducted to explore the relationships between preoperative anxiety and its associated factors. RESULTS: Based on the cutoff value of Athens Insomnia Scale (scores ≥ 6) in Chinese cancer patients, the prevalence of insomnia was 38.2% before surgery. Pain (ß = 0.087, p = 0.015) and anxiety (ß = 0.372, p < 0.001) were positively associated with preoperative insomnia, while self-esteem (ß = - 0.479, p < 0.001) and confrontation coping (ß = - 0.124, p = 0.003) showed protective effects on preoperative insomnia when putting them together into hierarchical regression. The associated factors together accounted for an additional variance of preoperative insomnia (47.6%). CONCLUSIONS: In line with previous findings, the detrimental effects of pain and anxiety on preoperative insomnia were also observed in our study. More importantly, our main new findings were that self-esteem and confrontation coping played important roles in alleviating preoperative insomnia among CRC patients. Clinicians should take these results into account when developing cancer care management to relieve preoperative insomnia.

New cinnamic acid-pregenolone hybrids as potential antiproliferative agents: Design, synthesis and biological evaluation.

A series of new cinnamic acid-pregenolone hybrids (5a-5o) was designed, synthesized and evaluated for their in vitro antiproliferative activity. Some of them showed potential antiproliferative activity and selectivity towards a panel of cancer cell lines, including A549, H157, HepG2, MCF-7, and HL-60. Among these analogs, compound 5f showed the most promising activity with IC50 values ranging from 3.2 to 6.8 µM, and it was taken as a model compound in the following antiproliferative mechanism study. In Hoechst 33258 staining assay, 5f-treated A549 cells displayed significant apoptosis characteristics. Flow cytometry analysis revealed that 5f showed the antiproliferative activity against A549 via G1 cell cycle arrest and inducing apoptosis. Western blotting analysis demonstrated that 5f enhanced apoptosis of A549 cells by down-regulating Bcl-2 and up-regulating Bax protein expression. The present study highlighted this series of cinnamic acid-pregenolone hybrids as a new antiproliferative lead prototype.

New e:b-Friedo-Hopane Type Triterpenoids from Euphorbia peplus with Simiarendiol Possessing Significant Cytostatic Activity against HeLa Cells by Induction of Apoptosis and S/G2 Cell Cycle Arrest.

Seven rare e:b-friedo-hopane-type triterpenoids including four new (1-4) and three known (5-7) ones with 5 being first reported as a natural product, together with five other known triterpenoids (8-12), were isolated from the nonpolar fractions of the ethanolic extract of Euphorbia peplus. Structural assignments for these compounds were based on spectroscopic analyses and quantum chemical computation method. The structural variations for the C-21 isopropyl group, including dehydrogenation (1 and 3) and hydroxylation at C-22 (simiarendiol, 2), were the first cases among e:b-friedo-hopane-type triterpenoids. Simiarendiol (2) bearing a 22-OH showed significant cytostatic activity against HeLa and A549 human tumor cell lines with IC50 values of 3.93 ± 0.10 and 7.90 ± 0.31 µM, respectively. The DAPI staining and flow cytometric analysis revealed that simiarendiol (2) effectively induced cell apoptosis and arrested cell cycle at the S/G2 phases in a dose-dependent manner in HeLa cells.

Discovery of New Selective Butyrylcholinesterase (BChE) Inhibitors with Anti-Aß Aggregation Activity: Structure-Based Virtual Screening, Hit Optimization and Biological Evaluation.

In this study, a series of selective butyrylcholinesterase (BChE) inhibitors was designed and synthesized from the structural optimization of hit 1, a 4-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)benzoic acid derivative identified by virtual screening our compound library. The in vitro enzyme assay results showed that compounds 9 ((4-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)phenyl)(pyrrolidin-1-yl)methanone) and 23 (N-(2-bromophenyl)-4-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)benzamide) displayed improved BChE inhibitory activity and good selectivity towards BChE versus AChE. Their binding modes were probed by molecular docking and further validated by molecular dynamics simulation. Kinetic analysis together with molecular modeling studies suggested that these derivatives could target both the catalytic active site (CAS) and peripheral anionic site (PAS) of BChE. In addition, the selected compounds 9 and 23 displayed anti-Aß1-42 aggregation activity in a dose-dependent manner, and they did not show obvious cytotoxicity towards SH-SY5Y neuroblastoma cells. Also, both compounds showed significantly protective activity against Aß1-42-induced toxicity in a SH-SY5Y cell model. The present results provided a new valuable chemical template for the development of selective BChE inhibitors.

Cuceolatins A-D: New Bioactive Diterpenoids from the Leaves of Cunninghamia lanceolata.

Four new diterpenoids named cuceolatins A-D, including three labdane-type (1-3) and one abietane-type (4) as well as three known labdane analogs (5-7), were reported from the leaves of Cunninghamia lanceolata. Structural assignments for these compounds were conducted by analyses of spectroscopic data, and their absolute configurations were determined by time-dependent density functional theory (TD-DFT) based electronic circular dichroism (ECD) calculations. Among them, the abietane-type diterpenoid (11-hydroxy-12-methoxyabieta-8,11,13-trien-3-one (4)) showed significant cytotoxicity against human MDA-MB-231, MCF-7, and HeLa tumor cell lines with IC50 measurements of 4.3, 2.8 and 4.5 µm, respectively, while the labdane-type diterpenoids with a 4α-carboxy group (1-3 and 5) exhibited moderate antibacterial activity towards Bacillus subtilis and Staphylococcus aureus with IC50 values all below 25 µm.

Absolute structure assignment of an iridoid-monoterpenoid indole alkaloid hybrid from Dipsacus asper.

Iridoid-monoterpenoid indole alkaloid hybrids (IMIAHs) represent a rare class of natural products reported from only several plants of Rubiaceae and Dipsacaceae families, while their structural assignments remain a very challenging work due to complexity and flexibility. In the current study, a new IMIAH (1) was isolated from the roots of Dipsacus asper and its structure with absolute configuration was unambiguously established by a combination of spectroscopic analyses, chemical degradation and ECD calculation. A new oleanane-type triterpenoid saponin (2) and 15 known co-metabolites were also obtained and structurally characterized. Our biological evaluations showed that compound 2 exhibited moderate inhibition against acetylcholine esterase (AChE) with an IC50 value of 15.8 ±â€¯0.56 µM, and compound 15 displayed potent cytotoxicity selectively against human A549 and H157 lung cancer cells with IC50 values of 6.94 ±â€¯0.24 and 9.06 ±â€¯0.12 µM, respectively.

Secondary metabolites from the mangrove sediment-derived fungus Penicillium pinophilum SCAU037.

Five new funicone derivatives, pinophilones A-E (1a/1b and 2-4), along with 18 biosynthetically related known analogues (5-22), were obtained from the culture of a mangrove sediment-derived fungus Penicillium pinophilum SCAU037. Their structures were established by analysis of 1D/2D NMR and MS data, while the absolute configurations of the new compounds were determined by ECD calculation based on time-dependent density functional theory (TD-DFT). The dihydrofuran moiety in 1a and 1b was first reported for funicone derivatives. Compound 22 exhibited antibacterial activity against Mycobacterium smegmatis and Staphylococcus aureus with IC50 of 23.5 and 2.6 µM, respectively, while 16, 18 and 22 showed significant α-glucosidase inhibitory activity with IC50 of 51.9, 78.4 and 33.8 µM, respectively.

Triterpenoids and triterpenoid saponins from Dipsacus asper and their cytotoxic and antibacterial activities.

Phytochemical investigation of the ethyl acetate soluble part, generated from the ethanol extract of the roots of Dipsacus asper, led to the separation and identification of three undescribed triterpenoids including one arborinane type, one ursane type and one oleanane type, two unreported oleanane type triterpenoid arabinoglycosides, and 18 known analogues. Structures of these compounds were determined by comprehensive spectroscopic analyses, with the absolute configurations of 25-acetoxy-28-dehydroxyrubiarbonone E and 2α,3ß-dihydroxy-23-norurs-4(24),11,13(18)-trien-28-oic acid being established by evaluation of their experimental and calculated ECD spectra. 25-Acetoxy-28-dehydroxyrubiarbonone E features an oxygenated C-25 that is the first case among arborinane type triterpenoids, while 2α,3ß,24-trihydroxy-23-norurs-12-en-28-oic acid incorporates a sp3 C-24 that is a rare structural feature of 23-norursane type triterpenoids. Of these isolates, 2',4'-O-diacetyl-3-O-α-l-arabinopyranosyl-23-hydroxyolea-12-en-28-oic acid and hederagonic acid exhibited moderate antibacterial activity against Staphylococcus aureus with IC50 values of 12.3 and 10.3 µM, respectively, while those with either a feruloyloxy group or an arabinosyl moiety at C-3 displayed potent cytotoxic activities against four tumor cell lines A549, H157, HepG2 and MCF-7.

Discovery of new multifunctional selective acetylcholinesterase inhibitors: structure-based virtual screening and biological evaluation.

Although the mechanism of Alzheimer's disease (AD) is still not fully understood, the development of multifunctional AChE inhibitors remains a research focus for AD treatment. In this study, 48 AChE candidate inhibitors were picked out from SPECS database through a pharmacophore- and molecular docking-based virtual screening. The biological evaluation results indicated that four compounds 7, 29, 41 and 48 with different scaffolds exhibited potent and selective AChE inhibitory activity, with the best IC50 value of 1.62 ± 0.11 µM obtained for 48. Then their mechanism of action, the inhibition on Aß aggregation, neurotoxicity, and neuroprotective activity against Aß-induced nerve cell injury were well studied. The binding mode of 48 with AChE was also proposed. The present bioassay results indicated that these multifunctional AChE inhibitors were worth for further structural derivatization to make them the anti-AD lead compounds.

Loss of PTPN4 activates STAT3 to promote the tumor growth in rectal cancer.

Colorectal cancer (CRC) is one of the most common types of malignant tumor. Many genetic factors have been proved to show high association with the occurrence and development of CRC and many mutations are detected in CRC. PTPN4/PTP-MEG1 is a widely expressed non-receptor protein tyrosine phosphatase. Over the past three decades, PTPN4 has been demonstrated in the literature to participate in many biological processes. In this study, we identified a nonsense mutation of PTPN4 with a mutation ratio of 90.90% from 1 case of rectal cancer, leading to loss of function in PTPN4 gene. Several somatic mutations occurred in 5/137 rectal cancer samples from The Cancer Genome Atlas Rectum Adenocarcinoma (TCGA READ) database. Interestingly, we found that PTPN4 negative cytoplasm staining was more prone to lymphatic metastasis (N = 50, P = 0.0153) and low expression of PTPN4 in rectal cancer was highly associated with poor prognosis. Overexpression of PTPN4 suppressed the cell growth, and moreover, the loss of PTPN4 accelerated cell growth and boosted clonogenicity of CRC cells. Furthermore, we revealed that the deletion of PTPN4 promoted the tumor formation of NCM460 cells in vivo. In terms of the molecular mechanism, we demonstrated that PTPN4 dephosphorylates pSTAT3 at the Tyr705 residue with a direct interaction and suppresses the transcriptional activity of STAT3. In summary, our study revealed a novel mechanism that the tumorigenesis of colorectal cancer might be caused by the loss of PTPN4 through activating STAT3, which will broaden the therapy strategy for anti-rectal cancer in the future.