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Hyphenrones R-X （1-7）, seven new polyprenylated acylphloroglucinols derivatives, were isolated from the fruits of Hypericum henryi, together with eight know analogues. Compounds 1 and 2 were elucidated to possess complex caged skeleton, while compounds 3-6 shared a common 3,9-epoxy moiety deriving from the normal polyprenylated acylphloroglucinols with a bicyclo[3.3.1]nonane-2,4,9-trione core. The new structures were elucidated on the basis of the interpretation of nuclear magnetic resonance （NMR） data, circular dichroism （CD） comparison, and single-crystal X-ray diffraction. In the bioassay, several compounds exhibited inhibitory activities against human tumor cell lines in vitro.

Aim： Urea transporters （UT） are a family of transmembrane proteins that specifically transport urea. UT inhibitors exert diuretic activity without affecting electrolyte balance. The purpose of this study was to discover novel UT inhibitors and determine the inhibition mechanism. Methods： The primary screening urea transporter B （UT-B） inhibitory activity was conducted in a collection of 10000 diverse small molecules using mouse erythrocyte lysis assay. After discovering a hit with a core structure of 1-phenylamino-4-phenylphthalazin, the UT-B inhibitory activity of 160 analogs were examined with a stopped-flow light scattering assay and their structure-activity relationship （SAR） was analyzed. The inhibition mechanism was further investigated using in silico assays. Results： A phenylphthalazine compound PU1424, chemically named 5-（4-（（4-methoxyphenyl） amino） phthalazin-l-yl）-2-methylbenzene sulfonamide, showed potent UT-B inhibition activity, inhibited human and mouse UT-B-mediated urea transport with IC5o value of 0.02 and 0.69 IJmol/L, respectively, and exerted 100% UT-B inhibition at higher concentrations. The compound PU1424 did not affect membrane urea transport in mouse erythrocytes lacking UT-B. Structure-activity analysis revealed that the analogs with methoxyl group at R4 and sulfonic amide at R2 position exhibited the highest potency inhibition activity on UT-B. Furthermore, in silico assays validated that the R4 and R2 positions of the analogs bound to the UT-B binding pocket and exerted inhibition activity on UT-B. Conclusion： The compound PU1424 is a novel inhibitor of both human and mouse UT-B with ICso at submicromolar ranges. Its binding site is located at the So site of the UT-B structure.

Tolerogenic dendritic cells （DCs） are widely studied for their possible use in the treatment of inflammatory disorders, such as autoimmune diseases. One of the obstacles for the use of this cell-based therapy is the characterization of drugs that are able to modulate DCs. We have previously shown that chloroquine （CQ）, an antimalarial agent, has the ability to modulate DCs towards a tolerogenic phenotype.1 These tolerogenic DCs are able to suppress the development of experimental autoimmune encephalomyelitis （EAE）, a T cell-driven mouse model of human multiple sclerosis. In addition, several studies have proposed that nitric oxide （NO） plays a major role in the dif- ferentiation of regulatory T cells （Tregs） and the suppression of Thl/Th17 cells.2＂3 However, little is known about the role of DC-derived NO in the modulation of inflammatory auto- immune responses. Thus, we aimed to evaluate whether NO plays a role in the tolerogenic activity of CQ-treated DCs （CQ- DCs）. We found that CQ induces DC production of NO and expression of indoleamine 2,3-dioxygenase （IDO）, as well as inducible nitric oxide syrtthase （iNOS）.

Malignant melanoma, characterized by invasive local growth and early formation of metastases, is the most aggressive type of skin cancer. Melanoma inhibitory activity （MIA）, secreted by malignant melanoma cells, interacts with the cell adhesion receptors, integrins a4131 and 05131, facilitating cell detachment and promoting formation of me- tastases. In the present study, we demonstrate that MIA secretion is confined to the rear end of migrating cells, while in non-migrating cells MIA accumulates in the actin cortex. MIA protein takes a conventional secretory pathway including coat protein complex I （COPI）- and coat protein complex II （COPII）-dependent protein transport to the cell periphery, where its final release depends on intracellular Ca2＋ ions. Interestingly, the Ca2＋-activated K＋-channel, subfamily N, member 4 （KCa3.1）, known to be active at the rear end of migrating cells, was found to support MIA secretion. Secretion was diminished by the specific KCa3.1 channel inhibitor TRAM-34 and by expression of dominant- negative mutants of the channel. In summary, we have elucidated the migration-associated transport of MIA protein to the cell rear and also disclosed a new mechanism by which KCa3.1 potassium channels promote cell migration.

The tumor-suppressive activity of PTEN has always been attributed to its endogenous intracellular function. Recently two different groups have demonstrated that PTEN is secreted/ exported into the extracellular envi- ronment for uptake by recipient cells, and functions as a tumor suppressor in a cell non-autonomous manner.

Aim： To discover novel hepatitis C virus （HCV） inhibitors and elucidate the mechanism of action of the active compounds. Methods： HCV subgenomic replicon-based luciferase reporter cell line was used to screen 1200 synthetic compounds with novel structures. HuhT.5.1 cell line stably transfected with HCV NS3/4A protease reporter was established to investigate the anti-HCV mechanism of the active compounds. The active compounds were further examined in an in vitro HCV infection assay to confirm their anti-HCV activity. Results： After two-round screening in the anti-HCV replicon assay, some 2,4-diaminoquinazoline derivatives and carboxamide analogues were found to possess anti-HCV replicon activities （the IC50 values were less than 5 μmol/L）. Among them, two representative compounds HZ-1157 and LZ-110618-6 inhibited HCV NS3/4A protease with IC50 values of 1.0 and 0.68 μmol/L, respectively. Furthermore, HZ-1157 and LZ-110618-6 inhibited HCV infection in vitro with IC50values of 0.82 and 0.11 μmol/L, respectively. Conclusion： Some 2,4-diaminoquinazoline derivatives and carboxamide analogues have been identified as novel anti-HCV compounds.

Nanoparticles can be involved in biological activities such as apoptosis, angiogenesis, and oxidative stress by themselves. In particular, inorganic nanoparticles such as gold and silica nanoparticles are known to inhibit vascular endothelial growth factor （VEGF）-mediated pathological angiogenesis. In this study, we show that anti-angiogenic effect of inorganic nanospheres is determined by their sizes. We demonstrate that 20 nm size gold and silica nanospheres suppress VEGF-induced activation of VEGF receptor-2, in vitro angiogenesis, and in vivo pathological angiogenesis more efficiently than their 100 nm size counterparts. Our results suggest that modulation of the size of gold and silica nanospheres determines their inhibitory activity to VEGF-mediated angiogenesis.

Three angiotensin I converting enzyme（ACE） inhibition peptides were isolated from sandworm Sipunculus nudus protein hydrolysate prepared using protamex. Consecutive purification methods, including size exclusion chromatography and reverse-phase high performance liquid chromatography（RP-HPLC）, were used to isolate the ACE inhibition peptides. The amino acid sequences of the peptides were identified as Ile-Asn-Asp, Val-Glu-Pro-Gly and Leu-Ala-Asp-Glu-Phe. The IC_（50） values of the purified peptides for ACE inhibition activity were 34.72 μmol L^-1, 20.55 μmol L^-1 and 22.77 μmol L^-1, respectively. These results suggested that S. nudus proteins contain specific peptides that can be released by enzymatic hydrolysis. This study may provide an experimental basis for further systematic research, rational development and clinical utilization of sandworm resources.

A chemical investigation of the ethyl acetate extract of the fermentation broth of Alternariatenuissima EN-192, an endophytic fungus obtained from the stems of the marine mangrove plant Rhizophorastylosa, resulted in the isolation of nine known secondary metabolites, including four indole-diterpenoids: penijanthine A (1), paspaline (2), paspalinine (3), and penitrem A (4); three tricycloalternarene derivatives: tricycloalternarene 3a (5), tricycloalternarene 1b (6), and tricycloalternarene 2b (7); and two alternariol congeners: djalonensone (8) and alternariol (9). The chemical structures of these metabolites were characterized through a combination of detailed spectroscopic analyses and their comparison with reports from the literature. The inhibitory activities of each isolated compound against four bacteria were evaluated and compounds 5 and 8 displayed moderate activity against the aquaculture pathogenic bacterium Vibrioanguillarum, with inhibition zone diameters of 8 and 9 mm, respectively, at 100 μg/disk. To the best of our knowledge, this is the first report on the secondary metabolites of mangrove-derived A lternaria tenuissima and also the first report of the isolation of indole-diterpenoids from fungal genus A lternaria.

Previously, we had characterized several structurally interesting brominated phenols from the marine red alga Symphyocladia latiuscula collected from various sites. However, Phytochemical investigations on this species collected from the Weihai coastline of Shandong Province remains blank. Therefore, we characterized the chemical constituents of individuals of this species collected from the region. Eight bromophenols were isolated and identified. Using detailed spectroscopic techniques and comparisons with published data, these compounds were identified as 2,3-dibromo-4,5-dihydroxybenzyl methyl ether (1), 3,5-dibromo-4-hydroxybenzoic acid (2), 2,3,6-tribromo-4,5-dihydroxymethylbenzene (3), 2,3,6-tribromo-4,5-dihydroxybenzaldehyde (4), 2,3,6-tribromo-4,5-dihydroxybenzyl methyl ether (5), bis(2,3,6-tribromo-4,5-dihydroxyphenyl)methane (6), 1,2-bis(2,3,6-tribromo-4,5-dihydroxyphenyl)-ethane (7), and 1-(2,3,6-tribromo-4,5-dihydroxybenzyl)-pyrrolidin-2-one (8). Among these compounds, 1 and 2 were isolated for the first time from S. latiuscula. Each compound was evaluated on the ability to inhibit protein tyrosine phosphatase 1B (PTP1B), which is a potential therapeutic target in the treatment of type 2 diabetes. Bromophenols 5, 6, and 7 showed strong activities with IC50 values of 3.9, 4.3, and 3.5 μmol/L, respectively. This study provides further evidence that bromophenols are predominant among the chemical constituents of Symphyocladia, and that some of these compounds may be candidates for the development of anti-diabetes drugs.