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The pandemic of acute respiratory disease in 2019 caused by highly pathogenic and infectious SARS-CoV-2 has seriously endangered human public safety. The 6-HB (HR1-HR2 complex) formation occurring in the process of spike protein-mediated membrane fusion could serve as a conserved and potential target for the design of fusion inhibitors. Based on the HR2 domain of 6-HB, we designed and synthesized 32 stapled peptides using an all-hydrocarbon peptide stapling strategy. Owing to the improved proteolytic stability and higher helical contents, the optimized stapled peptides termed SCH2-1-20 and SCH2-1-27 showed better inhibitory activities against pseudo and authentic SARS-CoV-2 compared to the linear counterpart. Of note, SCH2-1-20 and SCH2-1-27 were proved to interfere with S protein-mediated membrane fusion. Structural modeling indicated similar binding modes between SCH2-1-20 and the linear peptide. These optimized stapled peptides could serve as potent fusion inhibitors in treating and preventing SARS-CoV-2, and the corresponding SAR could facilitate further optimization.

The curcusone natural products are complex diterpenes featuring a characteristic [6-7-5] tricyclic carbon skeleton similar to the daphnane and tigliane diterpenes. Among them, curcusones A-D demonstrated potent anticancer activity against a broad spectrum of human cancer cell lines. Prior to this study, no total synthesis of the curcusones was achieved and their anticancer mode of action remained unknown. Herein, we report our synthetic and chemoproteomics studies of the curcusone diterpenes that culminate in the first total synthesis of several curcusone natural products and identification of BRCA1-associated ATM activator 1 (BRAT1) as a cellular target. Our efficient synthesis is highly convergent, builds upon cheap and abundant starting materials, features a thermal [3,3]-sigmatropic rearrangement and a novel FeCl(3)-promoted cascade reaction to rapidly construct the critical cycloheptadienone core of the curcusones, and led us to complete the first total synthesis of curcusones A and B in only 9 steps, C and D in 10 steps, and dimericursone A in 12 steps. The chemical synthesis of dimericursone A from curcusones C and D provided direct evidence to support the proposed Diels-Alder dimerization and cheletropic elimination biosynthetic pathway. Using an alkyne-tagged probe molecule, BRAT1, an important but previously “undruggable” oncoprotein, was identified as a key cellular target via chemoproteomics. We further demonstrate for the first time that BRAT1 can be inhibited by curcusone D, resulting in impaired DNA damage response, reduced cancer cell migration, potentiated activity of the DNA damaging drug etoposide, and other phenotypes similar to BRAT1 knockdown.

Whether Li–S batteries can be worked in a wider temperature range is particularly important. Here, we report micro/nanostructure CoFe2O4 rods combining both catalytic sites (Co) and adsorption sites (Fe). Under the synergistic enhancement of these two different sites, the conversion rate of polysulfides in Li–S batteries is greatly accelerated, and the “shuttle effect” is effectively suppressed. When used as the host material for Li–S batteries, the capacity, rate performance and cycling stability are promoted greatly. Most importantly, the cell achieves an excellent electrochemical performance at high temperatures. After 1000 cycles, the Li–S battery using CoFe2O4 nanorods as the cathode exhibits a high reversible capacity of about 700 mA h g−1 at a high temperature of 70 °C with a capacity attenuation of less than 0.02% per cycle. Meanwhile, the battery also shows excellent performance at −20 °C owing to the high catalytic activity.

In China, the fruits of Physalis alkekengi L. var. franchetii, which are conventionally utilized as edible berry, have attracted wide attention due to its significant biological activities. In the present study, phytochemical studies on the fruits of Physalis plants afforded six compounds, including two new withanolides (1-2) and four known agnologues (3-6). The inhibitory effects of these compounds on the formation of nitric oxide (NO) stimulated by lipopolysaccharide (LPS) in RAW264.7 macrophages were evaluated. Physapubescin M (1), with IC50 value of 1.58 μM, was selected for further study. The protein expression of COX-2 and iNOS, and LPS-induced production of cytokines (IL-6, IL-1β and TNF-α) were reduced by physapubescin M (1) in a dose-dependent way. In addition, transcriptomic analyses were conducted to profile gene expression alterations in LPS-induced RAW264.7 cells upon treatment of physapubescin M (1) and the potential antiinflammatory mechanism of withnolides was mentioned. These results provide broad view to the underlying antiinflammatory mechanism of withnolides, and give a theoretical basis for the utilization of the fruits of P. alkekengi L. var. franchetii.

Although immunotherapy has achieved impressive durable clinical responses, many cancers respond only temporarily or not at all to immunotherapy. To find novel, targetable mechanisms of resistance to immunotherapy, patient-derived melanoma cell lines were transduced with 576 open reading frames, or exposed to arrayed libraries of 850 bioactive compounds, prior to co-culture with autologous tumor-infiltrating lymphocytes (TILs). The synergy between the targets and TILs to induce apoptosis, and the mechanisms of inhibiting resistance to TILs were interrogated. Gene expression analyses were performed on tumor samples from patients undergoing immunotherapy for metastatic melanoma. Finally, the effect of inhibiting the top targets on the efficacy of immunotherapy was investigated in multiple preclinical models. Aurora kinase was identified as a mediator of melanoma cell resistance to T-cell-mediated cytotoxicity in both complementary screens. Aurora kinase inhibitors were validated to synergize with T-cell-mediated cytotoxicity in vitro. The Aurora kinase inhibition-mediated sensitivity to T-cell cytotoxicity was shown to be partially driven by p21-mediated induction of cellular senescence. The expression levels of Aurora kinase and related proteins were inversely correlated with immune infiltration, response to immunotherapy and survival in melanoma patients. Aurora kinase inhibition showed variable responses in combination with immunotherapy in vivo, suggesting its activity is modified by other factors in the tumor microenvironment. These data suggest that Aurora kinase inhibition enhances T-cell cytotoxicity in vitro and can potentiate antitumor immunity in vivo in some but not all settings. Further studies are required to determine the mechanism of primary resistance to this therapeutic intervention. Electronic supplementary material The online version of this article (10.1007/s00262-020-02748-9) contains supplementary material, which is available to authorized users.

Background: Henoch-Schonlein purpura nephritis (HSPN) is a very common secondary kidney disease of childhood. Its pathogenesis and the treatment mechanism of glucocorticoid have not been fully elucidated. The aim of this study was to determine the relationship between p300 and the pathogenesis, glucocorticoid therapy in mice with HSPN, respectively. Methods: Forty-eight C57BL/6N male mice, weighing 18 to 20 g, were selected (3–4 weeks old, n = 8 per group). The mice in the normal control group (Group I) were given normal solvent and the HSPN model group (Group II) were given sensitizing drugs. The mice in Group III were injected intraperitoneally with dexamethasone after being given sensitizing drugs. Meanwhile, mice in Groups IV, V and VI with conditional knockout of p300 were also given normal solvent, sensitizing drugs and dexamethasone. The levels of serum IgA, creatinine, and circulating immune complex (CIC) concentrations, 24 h urinary protein and urinary erythrocyte in C57 wild mice, and p300 conditional knockout mice in each group were measured. The expression of p300 in renal tissues and the expression of glucocorticoid receptor (GR) α and β, transforming growth factor (TGF)-β1, and activator protein (AP)-1 after dexamethasone treatment were determined by real-time polymerase chain reaction and Western blotting. Results: Compared with the normal solvent control group (Group I), the expression of p300 mRNA in the model group (Group II) was significantly up-regulated. Western blotting further confirmed the result. Urinary erythrocyte count, 24 h urinary protein quantification, serum IgA, CIC, and renal pathologic score in Group V were distinctly decreased compared with non-knockout mice in Group II (9.7 ± 3.8 per high-power field [/HP] vs. 18.7 ± 6.2/HP, t = 1.828, P = 0.043; 0.18 ± 0.06 g/24 h vs. 0.36 ± 0.08 g/24 h, t = 1.837, P = 0.042; 18.78 ± 0.85 mg/mL vs. 38.46 ± 0.46 mg/mL, t = 1.925, P = 0.038; 0.80 ± 0.27 μg/mL vs. 1.64 ± 0.47 μg/mL, t = 1.892, P = 0.041; 7.0 ± 0.5 vs. 18.0 ± 0.5, t = 1.908, P = 0.039). Compared with non-knockout mice (Group III), the level of urinary erythrocyte count and serum IgA in knockout mice (Group VI) increased significantly after treatment with dexamethasone (3.7 ± 0.6/HP vs. 9.2 ± 3.5/HP, t = 2.186, P = 0.024; 12.38 ± 0.26 mg/mL vs. 27.85 ± 0.65 mg/mL, t = 1.852, P = 0.041). The expression level of GRα was considerably increased in the knockout group after dexamethasone treatment compared with non-knockout mice in mRNA and protein level (t = 2.085, P = 0.026; t = 1.928, P = 0.035), but there was no statistically significant difference in the expression level of GRβ between condition knockout and non-knockout mice (t = 0.059, P = 0.087; t = 0.038, P = 1.12). Furthermore, the expression levels of glucocorticoid resistance genes (AP-1 and TGF-β1) were notably increased after p300 knockout compared with non-knockout mice in mRNA and protein level (TGF-β1: t = 1.945, P = 0.034; t = 1.902, P = 0.039; AP-1: t = 1.914, P = 0.038; t = 1.802, P = 0.041). Conclusions: p300 plays a crucial role in the pathogenesis of HSPN. p300 can down-regulate the expression of resistance genes (AP-1 and TGF-β1) by binding with GRα to prevent further renal injury and glucocorticoid resistance. Therefore, p300 is a promising new target in glucocorticoid therapy in HSPN. Key words: p300; Henoch-Schonlein purpura nephritis; Pathogenesis; Glucocorticoid treatment

Background: Rapid reversal of neuromuscular block after surgery and anesthesia is often necessary. Here, we reported the primary efficacy and safety data from a phase IIa study on adamgammadex sodium, a newly developed modified γ-cyclodextrin derivative.Methods: This was a phase IIa, single-center, randomized, open-label, and dose-finding study that enrolled 35 patients under general anesthesia who received the neuromuscular blocking agent rocuronium for induction and maintenance of neuromuscular blockade. The subjects were randomized to one of the five adamgammadex dose groups (2, 4, 6, 8, and 10 mg kg−1) and to the 4 mg kg−1 sugammadex group. Pharmacological efficacy was the recovery time from the start of adamgammadex or sugammadex administration to train-of-four (TOF) ratio ≥0.9, 0.8, and 0.7 among the different dose groups. Adverse events were recorded throughout the study.Results: The efficacy in reversing deep neuromuscular block was the same between 4 mg kg−1 sugammadex and adamgammadex. However, in the lowest dose groups of 2 and 4 mg kg−1 adamgammadex, adequate reversal could not be achieved in all subjects. The recovery time of TOF ratio to 0.9, 0.8, and 0.7 was shorter in the adamgammadex 10 mg kg−1 group than in the sugammadex 4 mg kg−1 group. The average values of the TOF ratio after 3 min of administration of adamgammadex 8 and 10 mg kg−1 and sugammadex 4 mg kg−1 were >90%. There were no serious adverse events after the use of adamgammadex, and no subjects had to be withdrawn from the trial.Conclusions: Adamgammadex enabled quick, predictable, and tolerable reversion of rocuronium-induced deep neuromuscular block in a dose-dependent manner. Adamgammadex doses of 6–10 mg kg−1 might be the recommended dose range for further exploration of efficacy. Clinical Trial Registration: This study was registered at chictr.org.cn, identifier: ChiCTR2000038391.

Mitochondria are the main powerhouse of the cell, generating ATP through the tricarboxylic acid cycle (TCA) and oxidative phosphorylation (OXPHOS), which drives myriad cellular processes. In addition to their role in maintaining bioenergetic homeostasis, changes in mitochondrial metabolism, permeability, and morphology are critical in cell fate decisions and determination. Notably, mitochondrial respiration coupled with the passage of electrons through the electron transport chain (ETC) set up a potential source of reactive oxygen species (ROS). While low to moderate increase in intracellular ROS serves as secondary messenger, an overwhelming increase as a result of either increased production and/or deficient antioxidant defenses is detrimental to biomolecules, cells, and tissues. Since ROS and mitochondria both regulate cell fate, attention has been drawn to their involvement in the various processes of carcinogenesis. To that end, the link between a prooxidant milieu and cell survival and proliferation as well as a switch to mitochondrial OXPHOS associated with recalcitrant cancers provide testimony for the remarkable metabolic plasticity as an important hallmark of cancers. In this review, the regulation of cell redox status by mitochondrial metabolism and its implications for cancer cell fate will be discussed followed by the significance of mitochondria-targeted therapies for cancer.

The toxic kernel cake of Jatropha curcas (KCakeJ) is an emerging health and environmental concern. Although phorbol esters are widely recognized as the major toxin of KCakeJ, convincing evidence is absent. Here, we show that rather than phorbol esters an isomeric mixture of 11-hydroxy-9E-octadecenoic acid, 12-hydroxy-10E-octadecenoic acid and 12-hydroxy-10Z-octadecenoic acid (hydroxy-octadecenoic acids, molecular formula C18H34O3) is the major toxic component. The toxicities of hydroxy-octadecenoic acids on experimental animals, e.g. acute lethality, causing inflammation, pulmonary hemorrhage and thrombi, allergies, diarrhea and abortion, are consistent with those on human/animals caused by Jatropha seed and/or KCakeJ. The hydroxyl group and the double bond are essential for hydroxy-octadecenoic acids’ toxicity. The main pathway of the toxicity mechanism includes down-regulating UCP3 gene expression, promoting ROS production, thus activating CD62P expression (platelet activation) and mast cell degranulation. The identification of the major toxin of KCakeJ lays a foundation for establishing an environmentally friendly Jatropha biofuel industry.

Ganoderma fungi have long been used as a famous traditional medicine and food in country of East Asia. In this work, two new farnesyl phenolic compounds, ganoduriporols A and B (1 and 2), were isolated from the fruiting bodies of Ganoderma duripora, and their structures were elucidated using various spectroscopic methods. Anti-inflammatory activities were assayed and evaluated for the two compounds. Ganoduriporols A and B exhibited dose-dependent anti-inflammatory effects in RAW 264.7 cells. Furthermore, ganoduriporol A was demonstrated to inhibit the production of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) and prostaglandin E2 (PGE2) through the suppression of COX-2, MAPK and NF-κB signaling pathway in LPS-induced macrophage cells. These results suggested that these two new farnesyl phenolic compounds and the fruiting body of G. duripora could serve as anti-inflammatory agents for medicinal use or functional food.

Signal transduction activator of transcription (STAT) 3 is a member of the STAT protein family which transduces intracellular and extracellular signals to the nucleus, controlling the expression of...

Twenty withanolides, including previously unknown nicanlodes A-M, were isolated from aerial parts of Nicandra physalodes. Their structural elucidations were unambiguously achieved through interpretation of extensive spectroscopic data (NMR and HRMS) and by comparison with literature data. Nicanlodes A and B have an unusual aromatic amine moiety. The isolated compounds were evaluated for their cytotoxicity against five human cancer cell lines.

Objective To investigate the efficacy and safety of rituximab (RTX) as first-line treatment of acquired thrombotic thrombocytopenic purpura (aTTP). Methods Twenty-five patients with acute aTTP and/or severe a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) deficiency were admitted to our centre from April 2009 to March 2015. Fourteen patients received RTX plus standard therapy (plasma exchange and corticosteroids) at acute episodes. Haemoglobin, platelet count, schistocytes, lactate dehydrogenase levels, ADAMTS13 activity and its inhibitors, and the ratio of B lymphocytes in the peripheral blood, were monitored. The number of plasma exchange (PEXs), total plasma volume, remission time, relapse ratio, and adverse effects were recorded. Results The median number of PEXs was 5 (2–17) sessions and median total plasma volume was 168.43 ml/kg (62.86–469.52 ml/kg). Patients achieved haematological remission at a median of 15 days (5–22 days), and the median time of immunological remission was 2 weeks (2–8 weeks) with a median follow-up of 13 months (3–61 months). ADAMTS13 activity significantly increased after 2 weeks. The B lymphocyte percentage in peripheral blood was reduced 1 week after the first dose of RTX infusion compared with before treatment (2.21% ± 5.23% vs 18.47% ± 7.34%, P = 0.000 [the result of statistical software]), and began to gradually increase 9 months later. Severe adverse effects and relapsing TTP were not observed during therapy and follow-up. However, one patient who had sustained immunological remission died of severe pneumonia 7 months later. Conclusion Although our study was limited by its small sample number and it was a non-controlled, clinical trial, it showed potential benefits of RTX therapy for acute aTTP. RTX may be administered as a first-line therapy for lowering patients’ relapse rate in the long term. Randomized, controlled trials of RTX for aTTP are required.

Deregulation of the Wnt signaling pathway leads to colorectal cancer progression. Natural dietary compounds serve as promising candidates for development as chemopreventive agents by suppressing the Wnt/&beta, catenin signaling pathway. Physalis peruviana-derived 4&beta, HWE showed a significant inhibitory activity with a calculated IC50 of 0.09 &mu, &Mu, in a screening of novel inhibitors of Wnt signaling with the dual-luciferase reporter assay. This study investigated the anti-tumor effect of 4&beta, HWE and the potential Wnt signaling inhibitory mechanism. Both the western blot analysis and immunofluorescence assay showed that 4&beta, HWE promoted the phosphorylation and degradation of &beta, catenin and the subsequent inhibition of its nuclear translocation to attenuate the endogenous Wnt target gene expression in colorectal cancer (CRC) cells. The cell viability assay indicated that 4&beta, HWE preferentially inhibited the proliferation of CRC compared with CCD-841-CoN, a normal human colonic epithelial cell line. 4&beta, HWE-mediated G0/G1 cell cycle arrest and apoptosis induction contributed to the suppression of the proliferation of CRC in the cell cycle and Annexin V-FITC/Propidium Iodide apoptosis analysis. Moreover, in vivo, 4&beta, HWE dramatically inhibited tumor growth in HCT116 xenografts by attenuating the Wnt/&beta, catenin signaling pathway. In conclusion, our study suggested that 4&beta, HWE could be of potential use in anti-tumor agent development as a novel Wnt signaling inhibitor.

Ganoderma duripora is widely circulated in the Chinese herbal medicine market, although the chemical constituents of this fungus are remain poorly characterized. Phytochemical investigation of the EtOH extract of the fruiting body of G.duripora resulted in the isolation of two trace triterpenoids, named ganoduritriol A and B, and their structures were determined by a combination of 1D, 2D NMR and UPLC-TOF-MS.

Dimericursones A and B (1 and 2), two unprecedented hexacyclic dimeric diterpenoids, were obtained from the root barks of Jatropha curcas. Their structures were elucidated by extensive spectroscopic analysis, electronic circular dichroism calculations, and single-crystal X-ray diffraction. Dimericursone B (2) showed significant inhibition on nitric oxide production of lipopolysaccharide-induced RAW264.7 macrophages with IC50 values of 5.65 μM.

Hepatitis disease caused by hepatitis C virus (HCV) is a severe threat to global public health, affecting approximately 3% of the world's population. Sofosbuvir (PSI-7977), a uridine nucleotide analog inhibitor targeting the HCV NS5B polymerase, was approved by FDA at the end of 2013 and represents a key step towards a new era in the management of HCV infection. Previous study identified NITD008, an adenosine nucleoside analog, as the specific inhibitor against dengue virus and showed good antiviral effect on other flaviviruses or enteroviruses. In this report, we systematically analyzed the anti-HCV profile of NITD008, which was discovered to effectively suppress the replication of different strains of HCV in human hepatoma cells with a low nanomolar activity. On genotype 2a virus, or 2a, 1a, and 1b replicon cells, EC50 values were 8.7 nM, 93.3 nM, 60.0 nM and 67.2 nM, and selective index values were >2298.9, >214.4, >333.3, >298.5 respectively. We demonstrated that resistance to NITD008 was conferred by mutation in NS5B (S282T) in the HCV infectious virus genotype 2a (JFH-1). Then, we compared the resistant profiles of NITD008 and PSI-7977, and found that the folds change of EC50 of NITD008 to full replicon cells containing mutation S282T was much bigger than PSI-7977(folds 76.50 vs. 4.52). Analysis of NITD008 cross-resistance against previously reported NS5B drug-selected mutations showed that the resistance pattern of NITD008 was not completely similar to PSI-7977, and meanwhile, S282T resistant mutation to NITD008 emerge more easily in cell culture than PSI-7977. Interestingly, NITD008 displayed significant synergistic effects with the NS5B polymerase inhibitor PSI-7977, however, only additive effects with alpha interferon (IFNα-2b), ribavirin, and an NS3 protease inhibitor. These results verify that NITD008 is an effective analog inhibitor against hepatitis C virus and a good research tool as a supplement to other types of nucleoside analogs.

Magnesium-substituted hydroxyapatite coatings have been deposited on magnesium alloy for biomedical applications by sol–gel technology. The Ca(10−x)Mgx(PO4)6(OH)2 coatings obtained, with magnesium contents up to x = 1.5, show dense and compact and with visible cracks. The results of Hydrogen (H2) evolution testing in Hank’s solution show that magnesium-substituted hydroxyapatite coatings can improve the corrosion resistance of magnesium alloy.

RO8191 represents a newly discovered small-molecule IFN-like agent that displays potent anti-HCV activity. With it as lead, a series of compounds bearing an imidazo[1,2-α][1,8]naphthyridine core and an amide bond-linked side chain were designed and synthesized. These compounds were evaluated on HCV cell culture system (HCVcc-hRluc-JFH1), and some of them exhibited remarkable anti-HCV activity (EC50 = 0.017-0.159 μM) and low toxicity (CC50 > 25 μM). Moreover, it was revealed that these newly identified anti-HCV agents exert their antiviral effect through a distinct mechanism of action from that of RO8191 by targeting the viral entry process. Thus, our study provides a starting point for the development of potential HCV entry inhibitor.

Chemical investigation of the fruiting bodies of Ganoderma hainanense resulted in isolation of fourteen lanostane triterpenoids, including nine ganoderma acids and five ganoderma alcohols, together with five known compounds. Structural elucidation was determined using extensive spectroscopic technologies, Mosher's method and X-ray single crystal diffraction. Three of the compounds showed inhibitory activities against HL-60, SMMC-7721, A-549 and MCF-7 cells with IC50 values of 15.0-40.0 mu M. (C) 2014 Elsevier Ltd. All rights reserved.

In this work, the relationship between cyclophilin A (CypA) and HCV prompted us to screen a series of small molecule CypA inhibitors which were previously reported by our group. Among them, compound 1, discovered as a non-immunosuppressive anti-HCV agent with an EC50 value of 0.67 μM in a virus assay, was selected for further study. Subsequent chemical modification by O-acylation led to a novel class of molecules, among which compound 25 demonstrated the most potent anti-HCV activity in the virus assay (EC50 = 0.19 μM), but low cytotoxicity and hERG cardiac toxicity. The following studies (a solution stability assay and a simple pharmacokinetic test together with a CypA enzyme inhibition assay) preliminarily indicated that 25 was a prodrug of 1. To the best of our knowledge, 25 is probably the most potent currently reported small molecule anti-HCV agent acting via the CypA inhibitory mechanism. Consequently, our study has provided a new potential small molecule for curing HCV infection.

Five new cucurbitacins, kuguacins II-VI (1-5), along with five known analogues (6-10), were obtained from the fruit of Momordica charantia. Structures of the new compounds were elucidated as 5 beta, 19-epoxycucurbit-23-en-7-on-3 beta, 25-diol (1), 5 beta, 19-epoxycucurbit-7,23-dion-3 beta, 25-diol (2), 5 beta, 19-epoxycucurbit-6-en-19,23-dion3 beta, 25-diol (3), 5 beta, 19-epoxy-23,24,25,26,27-pentanorcucurbit-6-en-7,19-dion-3 beta, 22-diol (4), and cucurbit-5-en-7,23-dion-3 beta, 19,25-triol (5) by extensive spectroscopic and single-crystal X-ray diffraction analyses. Some cucurbitane compounds from this species were screened for their potential antidiabetic properties in terms of antigluconeogenic activity. As a result, compounds 1, 10, 11, and 12 (at 25-100 mu M) showed concentration-dependent inhibition on glucose production from liver cells. In addition, compounds 11 and 12 (at 100 mu M) showed around 20-30% inhibition on PEPCK activity.

Two new monoterpenoid indole alkaloids, vincamajorines A (1) and B (2), were isolated from Vinca major. Their structures were elucidated by means of 1D and 2D NMR, and HREIMS spectroscopic data. The relative and absolute configurations were deduced by comparing the experimental C-13 NMR, ECD spectra, and OR data with those theoretically calculated. Vincamajorine A (1) represents a new C-20 carbon skeleton arranged compactly in seven rings, and vincamajorine B(2) is an alkaloid with an unprecedented 6/5/7/5/6 pentacyclic ring system. A possible biosynthetic pathway was also proposed for the formation of 1 and 2. (C) 2014 Elsevier Ltd. All rights reserved.

NS3/4A serine protease is a prime target for direct-acting antiviral therapies against hepatitis C virus (HCV) infection. Several NS3/4A inhibitors have been widely used in clinic, while new inhibitors with better characteristics are still urgently needed. GP205 is a new macrocyclic inhibitor of NS3/4A with low nanomolar activities against HCV replicons of genotypes 1b, 2a, 4a, and 5a, with EC(50) values ranging from 1.5 to 12.8 nmol/L. In resistance selection study in vitro, we found resistance-associated substitutions on D168: The activity of GP205 was significantly attenuated against 1b replicon with D168V or D168A mutation, similar as simeprevir. No cross resistance of GP205 with NS5B or NS5A inhibitor was observed. Combination of GP205 with sofosbuvir or daclatasvir displayed additive or synergistic efficacy. The pharmacokinetic profile of GP205 was characterized in rats and dogs after oral administration, which revealed good drug exposure both in plasma and in liver and long plasma half-life. The in vitro stability test showed ideal microsomal and hepatic cells stability of GP205. The preclinical profiles of GP205 support further research on this NS3/4A inhibitor to expand the existing HCV infection therapies.

There is evidence to implicate reactive oxygen species (ROS) in tumorigenesis and its progression. This has been associated with the interplay between ROS and oncoproteins, resulting in enhanced cellular proliferation and survival. Recent Advances: To date, studies have investigated specific contributions of the crosstalk between ROS and signaling networks in cancer initiation and progression. These investigations have challenged the established dogma of ROS as agents of cell death by demonstrating a secondary function that fuels cell proliferation and survival. Studies have thus identified (onco)proteins (Bcl-2, STAT3/5, RAS, Rac1, and Myc) in manipulating ROS level as well as exploiting an altered redox environment to create a milieu conducive for cancer formation and progression.Despite these advances, drug resistance and its association with an altered redox metabolism continue to pose a challenge at the mechanistic and clinical levels. Therefore, identifying specific signatures, altered protein expressions, and modifications as well as protein-protein interplay/function could not only enhance our understanding of the redox networks during cancer initiation and progression but will also provide novel targets for designing specific therapeutic strategies.Not only a heightened realization is required to unravel various gene/protein networks associated with cancer formation and progression, particularly from the redox standpoint, but there is also a need for developing more sensitive tools for assessing cancer redox metabolism in clinical settings. This review attempts to summarize our current knowledge of the crosstalk between oncoproteins and ROS in promoting cancer cell survival and proliferation and treatment strategies employed against these oncoproteins. Antioxid. Redox Signal.

Chemical investigation on ethyl acetate extract of the calyces of Nicandra physaloides resulted in the isolation of three new withanolides named as nicphysatone A (1), nicphysatone B (2), nicphysatone C (3), together with five known withanolides, nic 17 (4), nic 7 (5), nic 2 (6), withahisolide G (7) and nicaphysalin B (8). The structures were determined by comprehensive spectroscopic experiments. The discovery enriched the diversity of natural withanolides and could serve as scaffolds for the synthesis of more potent modified withanolides.

Enterovirus 71 (EV71), one of the major causative agents of Hand-Foot-Mouth Disease (HFMD), causes severe pandemics and hundreds of deaths in the Asia-Pacific region annually and is an enormous public health threat. However, effective therapeutic antiviral drugs against EV71 are rare. Nucleoside analogues have been successfully used in the clinic for the treatment of various viral infections. We evaluated a total of 27 nucleoside analogues and discovered that an adenosine nucleoside analogue NITD008, which has been reported to be an antiviral reagent that specifically inhibits flaviviruses, effectively suppressed the propagation of different strains of EV71 in RD, 293T and Vero cells with a relatively high selectivity index. Triphosphorylated NITD008 (ppp-NITD008) functions as a chain terminator to directly inhibit the RNA-dependent RNA polymerase activity of EV71, and it does not affect the EV71 VPg uridylylation process. A significant synergistic anti-EV71 effect of NITD008 with rupintrivir (AG7088) (a protease inhibitor) was documented, supporting the potential combination therapy of NITD008 with other inhibitors for the treatment of EV71 infections.

Four new 5 beta,19-epoxycucurbitacins, kuguacins T-W (1-4, resp.), along with nine known cucurbitane derivatives, 5-13, were obtained from the fresh fruit of Momordica chrantia. Structures of the new metabolites were elucidated as 5 beta,19-epoxy-25-hydroxycucurbitane-3,7,23-trione (1), 5 beta,19-epoxy-3,7-dioxo-23,24,25,26,27-pentanorcucurbitan-22-oic acid (2), 5 beta,19-epoxy-3 beta-hydroxycucurbit-24-ene-7,23-dione (3), and 5 beta, 19-epoxy-25-hydroxycucurbit-23-ene-3,7-dione (4), by extensive spectroscopic investigations, which were confirmed by a single-crystal X-ray diffraction analyses in the case of compound 4.

Three new limonoids, azadiraindins E-G (1-3, respectively), together with six known analogs, were isolated from the fresh fruit coats of Azadirachta indica. The structures of these compounds were elucidated by spectroscopic methods (IR, MS, HR-ESI-MS, 1D NMR, and 2D NMR).

Four pairs of new polycyclic-meroterpenoid enantiomers, ganocins A-C (1-3) possessing a spiro[4,5]decane ring system, along with ganocin D (4) with an eight-membered ring, were isolated from the fruiting bodies of Ganoderma cochlear. Their structures were determined by spectroscopic data and X-ray diffraction crystallography. Their anti-AChE activities were evaluated, and a possible biogenetic pathway was also proposed.

In this paper, the desorption temperature of adsorption bed in typical weather condition is studied though the solar adsorption refrigeration experiment with conditions of different weather. The results showed that: the better the weather condition is, the higher the highest temperature of the adsorption bed is, so the better the effect of desorption is. No matter in cloudless sunny or partly cloudy sunny conditions, the desorption temperature of adsorption bed can reach 93.4°C, and the amount of desorption also will be larger; however, in cloudy weather conditions, desorption temperature can reach 88.5°C, and desorption quantity is relatively fewer than it in cloudless sunny days.

Six new cucurbitane-type triterpenoids, karavilagenin F (1), karavilosides XII and XIII (2, 3), momordicines VI, VII, and VIII (4, 5 and 6), along with four known ones, 5 beta,19-epoxy-25-methoxycucurbita-6,23-diene-3 beta,19-diol (7), 5 beta,19-epoxycucurbita-6, 23-diene-3 beta,19,25-triol (8), kuguacin R (9), and (19R,23E)-5 beta,19-epoxy-19-methoxycucurbita-6,23,25-trien-3 beta-ol (10), were isolated from the stems and leaves of Momordica charantia L. Their chemical structures were elucidated by extensive 1D NMR and 2D NMR (HSQC, HMBC, COSY, and ROESY), MS experiments, and CD spectrum. Compound 6 showed weak cytotoxicity against five human cancer cells lines with IC50 values of 143-20.5 mol/L. (C) 2014 Elsevier B.V. All rights reserved.

Two new triterpenoids (1 and 2) and a new sterol (3), together with six known constituents (4–9), were isolated from the leaves and twigs of Melia azedarach. Their chemical structures were elucidated on the basis of spectroscopic analysis. Electronic supplementary material The online version of this article (doi:10.1007/s13659-014-0019-1) contains supplementary material, which is available to authorized users.

High contents of curcusones A and B and trace amounts of spirocurcasone exist in the roots of Jatropha curcas. Here, a one-step semisynthesis method of spirocurcasone and pyracurcasone was built, not only resulted an increased yield of spirocurcasone but also produced pyracurcasone, which exhibited greater cytotoxicity compared to curcusones A and B. The plausible mechanism of the formation of pyracurcasone was proposed, and the proposed biogenetic origin for spirocurcasone by Taglialatela-Scafati was confirmed.

Reactive oxygen/nitrogen species generated in the human body can cause oxidative damage associated with many degenerative diseases such as atherosclerosis, dementia, coronary heart diseases, aging, and cancer. There is a great interest in developing new antioxidants from Ganoderma fungus due to its low toxicity. As part of our ongoing search for antioxidative constituents from the fruiting bodies of Ganoderma ludicum, the chemical constituents were investigated and seven secondary metabolites, including one new lanostane triterpene (1), two known aromatic meroterpenoids (6&ndash, 7), and four known triterpenes (2&ndash, 5), were isolated by a series of chromatographic methods. The structures of the seven compounds were elucidated by spectroscopic techniques. The isolated compounds were tested in vitro for antioxidant potencies and neuroprotective activities against H2O2 and aged A&beta, induced cell death in SH-SY5Y cells. As a result, compounds 1, 6, and 7 exhibited potent antioxidant and neuroprotective activities. Additionally, all isolated compounds were tested for radical scavenging activities. Compounds 6 and 7 showed the comparable free radical scavenging activities with the standard drug in both ABTS (2, 2&rsquo, azobis (3-ethylbenzothiazole-6-sulfonaic acid)) and ORAC (oxygen radical absorbance capacity) experiments. The results from this study suggested that G. lucidum and its metabolites (especially the meroterpenoids) may be potential functional food ingredients for the antioxidation and prevention of neurogenerative diseases.

Drug resistance invariably limits the response of oncogene-addicted cancer cells to targeted therapy. The upregulation of signal transducer and activator of transcription 3 (STAT3) has been implicated as a mechanism of drug resistance in a range of oncogene-addicted cancers. However, the development of inhibitors against STAT3 has been fraught with challenges such as poor delivery or lack of specificity. Clinical experience with small molecule STAT3 inhibitors has seen efficacy signals, but this success has been tempered by drug limiting toxicities from off-target adverse events. It has emerged in recent years that, contrary to the Warburg theory, certain tumor types undergo metabolic reprogramming towards oxidative phosphorylation (OXPHOS) to satisfy their energy production. In particular, certain drug-resistant oncogene-addicted tumors have been found to rely on OXPHOS as a mechanism of survival. Multiple cellular signaling pathways converge on STAT3, hence the localization of STAT3 to the mitochondria may provide the link between oncogene-induced signaling pathways and cancer cell metabolism. In this article, we review the role of STAT3 and OXPHOS as targets of novel therapeutic strategies aimed at restoring drug sensitivity in treatment-resistant oncogene-addicted tumor types. Apart from drugs which have been re-purposed as OXPHOS inhibitors for-anti-cancer therapy (e.g., metformin and phenformin), several novel compounds in the drug-development pipeline have demonstrated promising pre-clinical and clinical activity. However, the clinical development of OXPHOS inhibitors remains in its infancy. The further identification of compounds with acceptable toxicity profiles, alongside the discovery of robust companion biomarkers of OXPHOS inhibition, would represent tangible early steps in transforming the therapeutic landscape of cancer cell metabolism., Highlights • Metabolic reprogramming of cancer cells is one of the hallmarks of cancer. • STAT3 and OXPHOS upregulation are resistance mechanisms in oncogene-addicted tumors. • mSTAT3 has a role in the direct, non-transcriptional regulation of OXPHOS. • Combining OXPHOS inhibitors with TKIs reverses resistance to targeted therapy.

Two novel trinorlanostanes, cochlates A and B (1 and 2), with a 3,4-seco-9,10-seco-9,19-cyclo skeleton, as well as six new triterpenoids, fornicatins D-F (3-5) and ganodercochlearins A-C (6-8), together with five known triterpenoids (9-13), were obtained from the fruiting bodies of Ganoderma cochlear. The structural elucidation was achieved by interpretation of spectroscopic data, and compounds 2 and 7a were further characterized by X-ray crystallographic analysis. Fornicatins A, D, and F (10, 3, and 5) and fredelin (13) lowered the ALT and AST levels in HepG2 cells treated with H2O2, suggesting that they could display in vivo hepatoprotective activities.

Twelve rhamnofolane diterpenoids, including curcusecons A-E with unusual seco-rhamnofolane skeletons, curcusones F-J, 4-epi-curcusone E, and 3-dehydroxy-2-epi-caniojane, together with seven known analogues, curcusones A-E, jatrogrossidione, and 2-epi-jatrogrossidione, were isolated from the roots of Jatropha curcas. Their structures were determined by extensive spectroscopic methods, and the relative stereochemistry of curcusecon B was further confirmed by X-ray crystallographic data. Their cytotoxity against five human cancer cells was studied and the results indicated that the dienone system in ring B was essential for cytotoxicity of these compounds. (C) 2013 Elsevier Ltd. All rights reserved.

Ganoderma resinaceum Boud. (Polyporeseae) has long been used for antioxidant, immunoregulation and liver protection. From the fruiting bodies of G. resinaceum, eight new lanostanoids, lucidones D-G (1-4), 7-oxo-ganoderic acid Z(2) (5), 7-oxo-ganoderic acid Z(3) (6), ganoderesin A (7), and ganoderesin B (8), together with six known lanostanoids (9-14) were isolated. The structures of new compounds were elucidated through extensive spectroscopic analysis. In an in vitro model, ganoderesin B (8), ganoderol B (10) and lucidone A (11) showed inhibitory effects against the increase of ALT and AST levels in HepG2 cells induced by H2O2 compared to a control group in the range of their maximum non-toxic concentration (MNTC). However, compounds 8, 10 and 11 displayed no anti-oxidant activities by DPPH assay. Mean-while, activation for PXR (Pregnane X Receptor) of ganoderesin B (8), ganoderol B (10) and lucidone A (11) was evaluated; ganoderol (10) exhibited a vital activation for PXR-induced CYP3A4 expression. These results suggested that GTs (Ganoderma triterpenoids) exhibited hepatoprotective activities by lowering ALT and AST levels. (C) 2013 Elsevier Ltd. All rights reserved.

Four new phragmalin limonoids (chukfuransins A-D) were isolated from the twigs and leaves of Chukrasia tabularis. Chukfuransins A (1) and B (2) feature a unique C-15/C-20 linkage proposed to be built by a biogenetic pathway involving Michael addition. Chukfuransins C (3) and D (4) feature the C-15/C-21 linkage. Their structures and absolute configurations were established by NMR techniques and X-ray crystallographic analysis.

The six new cucurbitane-type triterpenoids 1-6, along with the ten known triterpenoids 7-16, were isolated from the vines and leaves of Momordica charantia. The structures of the new compounds were elucidated as (3,7,15,23E)-3,7,15,25-tetrahydroxycucurbita-5,23-dien-19-al (1), (3,7)-3,7,22,23-tetrahydroxycucurbita-5,24-dien-19-al (2), (3,7)-3,7,23,24-tetrahydroxycucurbita-5,25-dien-19-al (3), (3,7,23S)-3,7,23-trihydroxycucurbita-5,24-dien-19-al 7--D-glucopyranoside (4), (3,7,23E)-cucurbita-5,23-diene-3,7,19,25-tetrol 7--D-glucopyranoside (5), and (3,7,23E)-3,7-dihydroxy-25-methoxy-cucurbita-5,23-dien-19-al 3--D-allopyranoside (6), by extensive analyses of their spectral data, as well as by chemical methods.

Three new physalin steroids, physalin III (1), physalin IV (2), 3-O-methylphysalin X (3), together with five known physalins (4–8) were isolated from the 80% EtOH extract of calyces of Physalis alkekengi var. franchetii. The structures of the new compounds were revealed through 1D and 2D NMR and mass spectroscopic studies. Electronic Supplementary Material Supplementary material is available for this article at 10.1007/s13659-013-0021-z and is accessible for authorized users.

Three new jatropholane-type diterpenoids, jatropholones C-E (1–3), along with seven other known compounds, including sikkimenoid B (4), jatrophaldehyde (5), epi-jatrophaldehyde (6), epi-jatrophol (7), jatrophol (8), jatropholone A (9), and jatropholone B (10), were isolated from the roots of a natural cultivar of Jatropha curcas (J. curcas cv. Multiflorum CY Yang). The structural elucidations of 1–3 were accomplished by extensive NMR analysis. Compounds 4, 6, and 8 demonstrated inhibition activity against the microorganisms with the MIC values from 0.10 to 0.18 mg/mL. Electronic Supplementary Material Supplementary material is available for this article at 10.1007/s13659-013-0031-x and is accessible for authorized users.

Three novel norfriedelanes, A-C (1-3), were isolated from the branches and roots of Malpighia emarginata. Their structures and absolute configurations were determined by 1D and 2D NMR techniques and X-ray crystallographic analysis. Norfriedelin A (possessing an alpha-oxo-beta-lactone group) and norfriedelin B (with a keto-lactone group) showed acetylcholinesterase inhibitory effects with the IC50 values of 10.3 and 28.7 mu m, respectively.

Three new limonoids (1–3) and a new intact triterpenoid (4), along with three known constituents (5–7), were isolated from the dried kernels (after extracting azadirachtin) of Azadirachta indica. The structures of the new compounds 1-benzoyl-3-deacetyl-1-detigloyl salannin (1), 7-tigloyl-12-oxo vilasini (2), azadiralactone (3) and azadirahemiacetal (4) were elucidated by means of spectroscopic analysis. The cytotoxities of these isolated constituents were assayed.

Two new sesquiterpenoids, (1S,2R)-dihydroxycycloax-4(15)-ene (1), 14-dehydroxyl daucucarotol (2), and one new rhamnofalane diterpenoid, 2-hydroxy-3-dehydroxycaniojane (3), together with two known compounds, curcusone D (4) and curcusone C (5), were isolated from the roots of Jatropha curcas. The chemical structures of these compounds were established by chemical methods and extensive 1D- and 2D-NMR spectroscopic data analyses.

We have investigated comprehensively the effects of thyroid function on gallstone formation in a mouse model. Gonadectomized gallstone-susceptible male C57BL/6 mice were randomly distributed into three groups each of which received an intervention to induce hyperthyroidism, hypothyroidism, or euthyroidism. After 5 weeks of feeding a lithogenic diet of 15% (w/w) butter fat, 1% (w/w) cholesterol, and 0.5% (w/w) cholic acid, mice were killed for further experiments. The incidence of cholesterol monohydrate crystal formation was 100% in mice with hyperthyroidism, 83% in hypothyroidism, and 33% in euthyroidism, the differences being statistically significant. Among the hepatic lithogenic genes, Trβ was found to be up-regulated and Rxr down-regulated in the mice with hypothyroidism. In contrast, Lxrα, Rxr, and Cyp7α1 were up-regulated and Fxr down-regulated in the mice with hyperthyroidism. In conclusion, thyroid dysfunction, either hyperthyroidism or hypothyroidism, promotes the formation of cholesterol gallstones in C57BL/6 mice. Gene expression differences suggest that thyroid hormone disturbance leads to gallstone formation in different ways. Hyperthyroidism induces cholesterol gallstone formation by regulating expression of the hepatic nuclear receptor genes such as Lxrα and Rxr, which are significant in cholesterol metabolism pathways. However, hypothyroidism induces cholesterol gallstone formation by promoting cholesterol biosynthesis.

Four new 9,19-cyclolanostane-type triterpenes (14), were isolated from the rhizomes of Cimicifuga foetida. On the basis of spectroscopic analysis, their chemical structures were elucidated as 1,7-dien-cimigenol-3,12-dione (1), 1-en-cimigenol-3,11-dione (2), 11(-hydroxy-7-en-cimigenol-3-one (3), and (20R,24R)-24,25-epoxy-11(-hydroxy-7-en-9,19-cyclolanost-3,16,23-trione (4).