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Daphnane-type diterpenenoids are the major biologically active constituents in the genus Daphne. We find that there are about 101 Daphnane-type diterpenes in this genus, most of those compounds show different degrees of inhibitory effect on various cancer cell. Some of them have been studied in depth and the potent molecular mechanisms might be associated with modulation of different cell-signaling pathways. In addition, some compounds of this type also can inhibit the synthesis of protein and DNA. Absolutely, the anti-tumor activity of Daphnane-type diterpenes is worthy of attention. Unfortunately, most of the current research on the activity of these compounds is focused on simple drug efficacy, and its in-depth mechanism research is far from enough. On the other point of view, there still exists wide growing space on the depth of these compounds.

Brusatol, a triterpene lactone compound mainly from Brucea javanica, sensitizes a broad spectrum of cancer cells. It is known as a specific inhibitor of nuclear factor-erythroid 2-related factor 2 (Nrf2) pathway. In this review, we provide a comprehensive overview on the antitumor effect and molecular mechanisms of brusatol in vitro and in vivo. This review also covers pharmacokinetics studies, modification of dosages forms of brusatol. Increasing evidences have validated the value of brusatol as a chemotherapeutic agent in cancers, which may contribute to drug development and clinical application.

(±)-Crataegusnorin A (1a/1b) and B (2a/2b), two pairs of rare 8,9′-epoxy-type norlignan enantiomers featuring a γ-butyrolactone ring, were isolated from the fruit of Crataegus pinnatifida. Their structures were determined via extensive spectroscopic analyses. Gauge-independent atomic orbital (GIAO) NMR chemical shift calculations, combined with the advanced statistical method DP4+ were employed to establish the relative configurations of four compounds. Next, chiral separation was accomplished by chiral chromatographic column and the absolute configurations of the four compounds were unambiguously assigned by comparison between their experimental electronic circular dichroism curves with the quantum-mechanically calculated curves based on time-dependent density functional theory (TDDFT). All the isolates were evaluated for their neuroprotective activities against H2O2-induced cell injury in human neuroblastoma SH-SY5Y cells. The results showed that two pairs of enantiomers 1a/1b and 2a/2b displayed diff ;erent effect on neuroprotective activity. Among them, compound 2a displayed the most potent neuroprotective effect. Further flow cytometry analysis indicated that 2a could protect SH-SY5Y cells from oxidative damage through inhibiting cell apoptosis.

Using liquid chromatography with tandem mass spectrometry guided molecular networking, 12 undescribed guaiane-type sesquiterpenoids, namely tanguticatins A-L, 19 known analogs and a previously undescribed triterpene (tanguticatin M) were obtained from Daphne tangutica Maxim and characterized. Their planar structures and configurations were elucidated and unequivocally assigned by detailed spectroscopic analyses, electronic circular dichroism spectral calculations and single single-crustal X-ray diffraction analysis. All the isolated compounds were evaluated for lipopolysaccharide-induced nitric oxide production in murine microglial BV2 cells. Tanguticatin E and K exhibited more potent inhibitory effects than minocycline (positive control).

Elephantopus tomentosus L. is a perennial herb taxonomically belonging to the family Asteraceae, which has been used as a folk medicine for the treatment of hepatobiliary diseases. Sesquiterpenoids from this plant have broad biological activities, including anti-tumor, anti-inflammatory, and antibacterial effects. In this study, fifteen structurally diverse sesquiterpenoids comprised 11 germacrane-type and 4 eudesmane-type sesquiterpenoids were prioritized to isolated from Elephantopus tomentosus L. based on the HSQC-based Small Molecule Accurate Recognition Technology (SMART) strategy. Among them, ten sesquiterpenoids were previously unreported, and their structures were elucidated by spectroscopic data, computational methods, single-crystal X-ray diffraction crystallographic data or electronic circular dichroism calculations. In addition, the structures of two known sesquiterpenoids, molephantin A and B, which were reported to possess E-geometry for the Δ

Four new steroids, chouchunsteride A-D (1-4), together with four known steroids (5-8), were isolated from the leaves of Ailanthus altissima (Mill.) Swingle. Their structures were elucidated based on spectroscopic data analysis, while the relative and absolute configurations were determined via acetonide analysis and quantum chemical ECD calculations. All isolated steroids were evaluated for their cytotoxic activity against two hepatoma carcinoma cell lines (HepG2, Hep3B). Among them, 1 exhibited the most potent cytotoxicity against HepG2 cells with an IC

Sesquiterpene lactones possess excellent anti-tumor activity in multiple cancer cell lines, including glioma, the most common type of malignant brain tumor with high mortality. However, the detailed mechanism of this type of constituent, especially the potential target for anti-glioma effect, is still unclear. Here, we collected 52 sesquiterpene lactones from Elephantopus scaber Linn. for network pharmacology analysis. The results demonstrated that the targets of the active components were markedly enriched on the pathways in cancer, which were closely related to cell proliferation regulation. Next, the Gene Expression Omnibus (GEO) and DisGeNET were analyzed by bioinformatics, and 429 glioma-related targets were obtained. Furtherly, 34 common targets of compounds and glioma were revealed, and they were significantly enriched in MAPK signaling pathway. Subsequently, we constructed a common target-compound network, and glutathione S-transferase Pi 1 (GSTP1) had the highest degree value, which explained its significance in the network. Therefore, we speculated that the compounds might exert an anti-glioma effect by targeting GSTP1. To verify the above results, we obtained part of sesquiterpene lactones isolated from E. scaber in our laboratory and evaluated their activities against glioma U87 cells. Among these sesquiterpene lactones (1-27), compounds 1 (elephantopinolide A), 2 (cis-scabertopin) and 3 (elephantopinolide F) exhibited the strongest inhibitory effect, and the ICsub50/subvalues were 4.22 ± 0.14 µM, 4.28 ± 0.21 µM and 1.79 ± 0.24 µM, respectively. The results from molecular docking, cellular thermal shift assay (CETSA), as well as RT-PCR and Western blot analysis suggested that the compounds exerted an inhibitory effect by targeting GSTP1. Meanwhile, the compounds also activated JNK/STAT3 signaling pathway. Furthermore, we found that 1, 2 and 3 could suppress cell proliferation and also induce mitochondrial dysfunction as well as oxidative stress, eventually leading to cellular apoptosis. Taken together, this study revealed that sesquiterpene lactones from E. scaber could be a promising therapeutic strategy for the treatment of glioma by targeting GSTP1.

Ten undescribed phenylpropanoid derivatives including four pairs of enantiomers and two 8-9' linked neolignans, together with fifteen known ones were isolated from the fruit of Crataegus pinnatifida Bunge. Their structures were established by comprehensive spectroscopic analyses. Enantiomers were separated successfully by chiral chromatographic column and their absolute configurations were determined by comparison of the experimental and calculated electronic circular dichroism (ECD) spectra. The in vitro cytotoxicity of the isolates were evaluated against two human hepatocellular carcinoma, HepG2 and Hep3B cells. Among them, (±)-crataegusanoid A, (±)-crataegusanoid B and crataegusanoid F exhibited moderate cytotoxicity. Interestingly, the different absolute configurations of (±)-crataegusanoid A and B demonstrated enantioselective cytotoxicity in HepG2 cells. Further flow cytometry analysis indicated that both (-)-crataegusanoid A and (-)-crataegusanoid B performed more significant effects on cell apoptosis, autophagy, and cell cycle progression compared with their enantiomers (+)-crataegusanoid A and (+)-crataegusanoid B. In addition, the results revealed that these two pairs of enantiomers induced protective autophagy in HepG2 cells.

Timosaponin AIII (TAIII), a steroidal saponin isolated from the rhizome of Anemarrhena asphodeloides, exerted cytotoxic effect in many cancer cell lines. However, the effect of TAIII on resistant tumor cancer cells was unclear. In this study, MTT assay showed that TAIII exhibited significant cytotoxicity against A549/Taxol and A2780/Taxol cells in vitro. Annexin V-FITC/PI staining revealed that TAIII induced apoptosis in A549/T and A2780/T cells. Furthermore, Western blot analysis demonstrated that TAIII inhibited the expressions of phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), mammalian target of rapamycin (mTOR) as well as Ras, Raf, mitogen-activated protein kinase (MEPK), extracellular regulated protein kinases (ERK) in two taxol-resistant cancer cell lines. Besides, in vivo studies demonstrated that TAIII inhibited tumor growth in a nude mouse xenograft model. Additionally, TAIII (2.5 and 5 mg/kg) also down-regulated the protein expressions of PI3K/AKT/mTOR and Ras/Raf/MEK/ERK pathways in vivo. Taken together, these findings demonstrated that TAIII exhibited significant anti-tumor effect on taxol-resistant cells.

Five pairs of enantiomeric lignanamides including nine undescribed compounds along with a known one were obtained from Solanum nigrum L. (Solanaceae). Their structures with absolute configurations were elucidated based on comprehensive spectroscopic analyses and quantum chemical calculations of electronic circular dichroism (ECD) curves. Additionally, all isolates were evaluated for their neuroprotective activity against MPP+ (1-methyl-4-phenylpyridinium)-induced SH-SY5Y cells injury. Among them, cannabisin F showed the most significant neuroprotective effects at different concentrations (12.5, 25, 50 μM). Further studies by Hoechst 33258 staining, monodansylcadaverine (MDC) staining and Annexin V/PI analysis demonstrated that cannabisin F could induce protective autophagy to protect SH-SY5Y cells from MPP+-induced apoptosis.

Three pairs of enantiomeric dihydrobenzofuran neolignans (1a/1b-3a/3b) including four new compounds (1a/1b and 2a/2b) were isolated from the fruit of Crataegus pinnatifida. Their structures including the absolute configurations were elucidated by extensive spectroscopic analyses and comparison between the experimental measurements of electronic circular dichroism (ECD) and the calculated ECD spectra. Additionally, all the enantiomeric neolignans were investigated for their neuroprotective activities against H2O2-induced cell injury in human neuroblastoma SH-SY5Y cells. It was found that enantiomers 1a and 1b displayed different degrees of neuroprotective activities, and the results showed enantioselectivity, in which that 1b exhibited noticeable neuroprotective activity, while its enantiomer 1a only exhibited obvious protective effect at lower concentration. Further study demonstrated that the potential protective activities of compounds appeared to be mediated via suppressing cell apoptosis.

Seven new tirucallane-type triterpenoids (1-7), kumuquassin A-G, along with 20 known analogues (8-27) were isolated from the stems of Picrasma quassioides. The structures and the absolute configurations of new compounds were elucidated by spectroscopic data, electronic circular dichroism (ECD) spectroscopic analyses and quantum ECD calculations. Notably, kumuquassin A (1) contains a rare Δ17, 20 double bond, kumuquassin B (2) is the first example of tirucallane triterpenoid possessing a 5/3 biheterocyclic ring system at the side chain. All the compounds were screened for the cytotoxicity against two human hepatoma cell lines, HepG2 and Hep3B, and several compounds exhibited promising activity. The most potential compound 3 was selected for cell cycle analysis, which showed that 3 could cause an accumulation of HepG2 cells at subG1 peak. Annexin V-FITC/PI staining further confirmed that compound 3 caused death of hepatoma cells through apoptosis induction.

Seven lignans (1a/1b-2a/2b and 3-5), including six new compounds (1b, 2a/2b, 3-5), were isolated from the fruits of Crataegus pinnatifida. Their structures were elucidated by comprehensive spectroscopic analyses. Compounds 1b/1b-2a/2b were two pairs of enantiomers and the absolute configurations were determined by comparison of their experimental and calculated ECD spectra. Moreover, bioinformatics analysis suggested that more than a third of diseases were related to the nervous system. Therefore, all compounds were evaluated for neuroprotective effects toward human neuroblastoma SH-SY5Y cells injury induced by H

Scabertopin (SCP), an abundant germacrane-type sesquiterpene lactone (SLC) isolated from Elephantopus scaber, was selected as a reference compound for modification and evaluation as anticancer agents for non-small cell lung cancer (NSCLC) treatment. All derivatives (SCP-1-SCP-13) except for SCP-3 showed potential inhibitory effect (IC

Hepatocellular carcinoma (HCC), the most prevalent liver cancer, is considered one of the most lethal malignancies with a dismal outcome. There is an urgent need to find novel therapeutic approaches to treat HCC. At present, natural products have served as a valuable source for drug discovery. Here, we obtained five known biflavones from the root of Stellera chamaejasme and evaluated their activities against HCC Hep3B cells in vitro. Chamaejasmenin E (CE) exhibited the strongest inhibitory effect among these biflavones. Furthermore, we found that CE could suppress the cell proliferation and colony formation, as well as the migration ability of HCC cells, but there was no significant toxicity on normal liver cells. Additionally, CE induced mitochondrial dysfunction and oxidative stress, eventually leading to cellular apoptosis. Mechanistically, the potential target of CE was predicted by database screening, showing that the compound might exert an inhibitory effect by targeting at c-Met. Next, this result was confirmed by molecular docking, cellular thermal shift assay (CETSA), as well as RT-PCR and Western blot analysis. Meanwhile, CE also reduced the downstream proteins of c-Met in HCC cells. In concordance with above results, CE is efficacious and non-toxic in tumor xenograft model. Taken together, our findings revealed an underlying tumor-suppressive mechanism of CE, which provided a foundation for identifying the target of biflavones.

Timosaponin AIII, a major steroidal saponin found in Anemarrhena asphodeloides Bge., which has been widely used as anti-pyretic, anti-diabetic, anti-inflammatory, anti-platelet aggregator and anti-depressant agents in traditional Chinese medicine. Recent pharmacological study showed that timosaponin AIII had potent cytotoxicity, which was potential to be developed as an anticancer agent, however the molecular mechanism underlying the anticancer activity has not been fully elucidated. This review aims to give a systematic summary of the study of timosaponin AIII to reveal its anti-tumor activities by investigating invasion and migration, apoptosis, autophagy and reversing multi-drug resistance. Furthermore, we also make an overview of the mechanisms identified till now. These meaningful findings may provide novel insights on exploiting timosaponin AIII as a new anti-tumor agent.

Industrial processing of licorice (Glycyrrhiza glabra L.) leads to a considerable quantity of residues which are normally discarded randomly or treated by landfill. Therefore, the aim of this study was to develop licorice residues as a source of bioactive compounds with potentially applications. Chemical investigation of licorice residues led to the isolation of four new triterpenoid saponins (1–3, 12), along with ten known saponins (4–11, 13–14) and five flavonoids (15–19). The structures were established by comprehensive spectroscopic analyses. All the isolated compounds were tested for their inhibitory effects on nitric oxide (NO) production induced by lipopolysaccharide (LPS) in RAW 264.7 cells. Among the results, compound 18 displayed the most potent NO inhibitory effect (IC50 9.89 μM) compared with the positive control drug minocycline (IC50 33.20 μM). Further studies showed that the levels of pro-inflammatory cytokines interleukin (IL)-1β and interleukin (IL)-6 and inducible enzymes inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were markedly down-regulated by compound 18. In addition, the Western blotting assay showed that compound 18 might reduce the inflammatory effect by down-regulating autophagy level. Overall, this study suggest that licorice residues are a promising waste and a valuable source of bioactive compounds for the pharmaceutical industry.

Daphnegiravone D (DGD), a prenylated flavonoid from Daphne giraldii Nitsche, significantly inhibited cell growth of several cancer cell lines without cytotoxicity on human normal cells. Our previous study showed that DGD could induce apoptosis in hepatocellular carcinoma Hep3B and HepG2 cells, but the detailed mechanism was still unclear. The present study provides that DGD-induced oxidative and nitrosative stress contribute to apoptotic cell death in Hep3B and HepG2 cells. Furthermore, there is a positive loop between oxidative stress and p38 activation, similar result is observed between nitrosative stress and p38. N-Acetylcysteine (NAC), a reactive oxygen species scavenger, could relieve DGD-induced oxidative stress, but exerts little effect on nitrosative stress. In addition, carboxy-PTIO (PTIO, a well-known scavenger of reactive nitrogen species) down-regulates the induction of nitrosative stress without obvious effect on oxidative stress in DGD-treated cells. In conclusion, the induction of oxidative and nitrosative stress could enhance p38-mediated apoptosis in DGD-treated Hep3B and HepG2 cells. Moreover, we speculated that OS and NS could not ultimately affect each other in DGD-treated HCC cells. This study gives a new insight on the mechanism of DGD-induced apoptotic cell death via oxidative and nitrosative stress in HCC cells.

Four pairs of racemic phenylpropanoids (1a/1b-4a/4b), including five new compounds (1a/1b, 2a, 3a, and 4a) were obtained from the root barks of Ailanthus altissima (Mill.) Swingle. Their structures were determined by comprehensive spectroscopic analyses. The absolute configurations of the enantiomers were determined by comparison of the experimental ECD and OR with the calculated data. The antitumor activity of all isolates was evaluated against two human hepatoma carcinoma cells (HepG2 and Hep3B) in vitro. It was demonstrated that 1a/1b showed potent selective cytotoxicity against HepG2 cells. Additionally, 1a/1b could also induce apoptosis enantioselectively as demonstrated by Hoechst staining experiment.

β-Carboline alkaloids in Picrasma quassioides (D. Don) Benn. have been proven to possess inhibitory activity against various cancer cells. However, their effect on hepatocellular carcinoma and structure-activity relationships (SAR) have not been systematically reported. In this work, bioactivity-directed fractionation of P. quassioides led to the separation of active fraction A2-2. A total of 39 β-carbolines, including 4 new ones (1-4), were obtained from the active fraction. Moreover, all the isolated compounds were identified in the active fraction A2-2 by LC-MS. The cytotoxicity on HepG2 and Hep3B cells of all compounds was screened by MTT assay, and the SAR were established. The SAR were also supported by the apoptosis ratio of HepG2 cells using flow cytometry analysis after treatment with potential compounds 1, 2, 9, 10, 12, 29, 36 and 38. It suggested that these active compounds caused death of hepatoma cells through apoptosis induction. In addition, further study revealed that compounds 12, 29, 36 significantly activated caspase-3 in HepG2 cells.

Chemical investigation of the roots of Croton crassifolius led to the isolation of five pyran-2-one derivatives, including two brand new compounds (1–2), one new natural product (3) and two known compounds (4–5). Their structures and absolute configurations were established by spectroscopic analyses as well as comparison between the calculated optical rotation (OR) values with the experimental data. Interestingly, the new compound 1 showed an unusual negative chemical shift at H-11. It is well known that negative chemical shift values of 1H NMR spectrum are extremely rare in natural products. Such a negative chemical shift of 1H NMR spectrum was reproduced by density functional theory (DFT) calculations and explained by the shielding effect from the pyran-2-one ring over the hydrogen atom in the 3D conformations. Then, MTT assay was applied to evaluate the cytotoxicity of the isolated compounds (1–5) against two liver cancer cell lines (HepG2 and MHCC97H). The results suggested that compound 1 displayed the highest cytotoxicity with an IC50 value of 9.8 μM against HepG2 cells. Moreover, there was no obvious cytotoxicity of compounds 1–5 on normal liver cell line LO2. Furthermore, the mechanism of apoptosis induction in compound 1-treated HepG2 cells was investigated. The results showed that compound 1 could induce apoptosis via p53-mediated Ras/Raf/ERK suppression in HepG2 cells.

Silibinin has dual effects on bacteria, depending on the concentrations or living contexts. The mechanism of either action has not yet been elucidated. Present study suggests that silibinin has yinyang impacts on the growth of Staphylococcus aureus depending on doses. S. aureus treated with low concentration of silibinin (L, 6.2 μM) showed enhanced resistance to kanamycin through increased level of hydrogen peroxide (H2O2). However, S. aureus treated with medium concentration of silibinin (M, 50 μM) showed increased susceptibility to kanamycin through reduced level of H2O2. These findings suggested that dual effects of silibinin were concentration-dependent and apparently related to the levels of H2O2 that assist bacterial survival at higher concentrations. Interestingly, treatment with high concentration of silibinin (H, 400 μM) alone without kanamycin exhibited cytotoxicity to S. aureus regardless of H2O2 levels. Based on the findings in vitro, we moved to examine the influence of silibinin on S. aureus-induced mouse peritonitis model. Silibinin at high concentration was shown to enhance the survival of peritonitis mice and protected them from S. aureus-induced tissue injury presumably by antibacterial effect of high concentration of silibinin. When the infected mice were co-treated with kanamycin, bacterial burden and H2O2 levels in lung, liver and spleen were all increased by treatment with a low dose of silibinin, while decreased with a medium dose of silibinin. Thus, the findings highlighted the potential of silibinin to be as a modifying agent in case of antibiotic resistance.

PGE2 is found to attenuate the bactericidal effects of kanamycin or ampicillin in Staphylococcus aureus, as well as the methicillin-resistant S. aureus (MRSA). Co-treatment with cyclooxygenase (COX) inhibitors (celecoxib, aspirin or naproxen) synergistically enhances kanamycin or ampicillin-induced cell death of S. aureus and MRSA. COX inhibitors repressed bacterial multidrug resistance through down-regulating efflux pump activity in antibiotics-treated S. aureus and MRSA. However, this synergistic bactericidal effects are reduced by the treatment with PGE2. PGE2 restores the efflux pump activity as well as increases biofilm formation in S. aureus and MRSA. Collectively, the enhancement of efflux pump activity and biofilm formation with PGE2 might partially explain the resistance to synergistic bactericidal effects between COX inhibitors and antibiotics in PGE2-treated S. aureus.

Eight new phenylpropanoids (1a/1b, 2-4, 5a/5b and 6) including two pairs of enantiomers (1a/1b and 5a/5b), along with a known analogue (7) were isolated from the fruit of Crataegus pinnatifida. Their structures were elucidated using comprehensive spectroscopic methods. Compounds 1a/1b and 5a/5b were separated successfully by chiral chromatographic column. The absolute configurations of enantiomers were determined by comparison between the experimental and calculated electronic circular dichroism (ECD) spectra. The in vitro antitumor activities of the isolates were evaluated against two human hepatocellular carcinoma HepG2 and Hep3B cells. Five compounds (1a/1b, 2-4) exhibited more potent cytotoxicity and their structure-activity relationships were also discussed. Annexin V-FITC/PI staining using flow cytometry was carried out to examine cell apoptosis, and the results showed that compounds 3-4 with the presence of two methoxy groups substituted at C-3' significantly induced apoptosis in HepG2 cells.

Three pairs of enantiomeric neolignans 1a/1b–3a/3b were isolated from the stems of Picrasma quassioides, and separated successfully by chiral-phase HPLC. Their structures were established by comprehensive spectroscopic analyses as well as ECD spectroscopy. The in vitro cytotoxicity of the isolates was evaluated against human hepatocellular carcinoma HepG2 and Hep3B cells. Among them, 1 and its enantiomers 1a/1b, 3 and 3a/3b displayed similar cytotoxicity in pair-wise comparison against HepG2 and Hep3B cells, and the similar effects of 2 and 2a/2b were found in Hep3B cells. Interestingly, 2a and 2b had different cytotoxic activities on HepG2 cells with IC50 values of 35.6 μM and 104.4 μM, respectively. In addition, 2 exerted middle cytotoxicity against HepG2 cells with an IC50 value of 78.6 μM. The different cytotoxicity between enantiomers 2a and 2b attracted our interest. To investigate the underlying mechanisms responsible for the distinct cytotoxicity, we further assessed the effects of 2a and 2b on cell cycle distribution, cell apoptosis and reactive oxygen species (ROS) generation. The results indicated that 2a had more significant effect than 2b on apoptosis induction and ROS generation, but both had no obvious effect on cell cycle of HepG2 cells. It is concluded that the different configurations of 2a/2b determined the enantioselective cytotoxicity on HepG2 cells through apoptosis induction and ROS generation.

Sarsasapogenin, a kind of mainly effective component of Anemarrhena asphodeloides Bunge, possesses good antitumor properties. Two series of new sarsasapogenin derivatives were synthesized and evaluated for their cytotoxicities against three human cancer cell lines (HepG2, A549, MCF-7) using the MTT assay. The structure-activity relationship revealed that the N, N-dimethylamino, pyrrolidinyl, and imidazolyl substituted at the C26 position could increase the antitumor efficacy of the 3-oxo sarsasapogenin series of compounds. Compound 4c with pyrrolidinyl substituted at the C26 position exhibited the greatest cytotoxic activity against MCF-7 cell line (IC50 = 10.66 μM), which was 4.3-fold more potent than sarsasapogenin. Action mechanism investigations showed that 4c could inhibit the colony formation and induce the apoptosis of MCF-7 cells. Further researches showed that a decrease in mitochondrial membrane potential and increases in the expression level of cleaved-PARP and the ratio of Bax/Bcl-2 were observed in MCF-7 cells after treatment with 4c, suggesting that the mitochondrial pathway was involved in the 4c-mediated apoptosis. These results show that compound 4c may serve as a lead for further optimization.

Oxidative stress has been proposed to contribute to DNA damage and is involved in many neurodegenerative diseases. It has been reported that Aralia elata (Miq.) Seem. (A. elata) exhibits an anti-oxidative effect but the mechanisms underlying this protective effect are still unclear. In this study, six known triterpene saponins were isolated from the buds of A. elata, a well-known medicinal and edible plant in Northeast China. Subsequently, the anti-oxidative effects of all six triterpene saponins were screened by H2O2-induced damage in human neuronblastoma SH-SY5Y cells. Compound 6, also known as Eclalbasaponin I (EcI), was the most potent. Furthermore, the mechanism by which EcI combats H2O2-induced oxidative stress was investigated. The data suggested that EcI could down-regulate apoptosis induction and the generation of reactive oxygen species (ROS) induced by 200 μM H2O2 in SH-SY5Y cells. Moreover, EcI increased the activities of antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxides (GSH-Px), reduced the levels of malondialdehyde (MDA) to restore the antioxidant defense system, and activated the nuclear factor E2-related factor (Nrf2)/heme oxygenase 1 (HO-1) pathway to combat oxidative stress. In addition, EcI also promoted autophagy during this process. Interestingly, the protective effect was remarkably reversed by autophagy inhibitors, bafilomycin A1 (Baf) or 3-Methyladenine (3-MA). These results demonstrate that autophagy is contribute to the protective effect of EcI. Collectively, our findings provide a new insight into the potential protective effect of EcI by focusing on the role of autophagy.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer, and treatment options for HCC are limited. In addition, the discovery of new natural compounds with anti-hepatocarcinoma activity is attracting increasing attention. For this reason, phytochemical investigation of Croton crassifolius led to the isolation of 17 diterpenoids, including three new clerodane diterpenoids, named crassifolius A-C (1-3), along with 14 known ones (4-17). Their structures were established by 1D, 2D NMR, HR-ESI-MS, detailed calculated electronic circular dichroism (ECD) spectra and the assistance of quantum chemical predictions (QCP) of 13C NMR chemical shifts. The cytotoxicities of all these compounds against human liver cancer lines (HepG2 and Hep3B) were determined. Among them, compound 1 exhibited good cytotoxicity with IC50 value of 17.91μM against human liver tumor cells Hep3B. Following further studies of the anti-tumor mechanism of compound 1-induced cell growth inhibition, we found that compound 1 caused apoptotic cell death in Hep3B cells by detecting morphologic changes and Western blotting analysis.

Three new phenylpropanoids (1–3) together with six known congeners (4–9) were isolated from the bark of Juglans mandshurica Maxim using anti-hepatoma activity as a guide. Their structures were determined by comprehensive NMR and HRESIMS spectroscopic data analyses. All the isolated compounds were evaluated for their growth inhibitory activities against two kinds of liver cancer cell lines (HepG2 and Hep3B). Among them, compound 4 showed moderate cytotoxic activities against HepG2 and Hep3B cell lines with IC50 values of 58.58 and 69.87 μM. Compound 5 exhibited 50% cell death rate in HepG2 and Hep3B cell lines at 63.70 and 46.45 μM, respectively. Further observation of morphological changes and Western blot demonstrated that compounds 4 and 5 exhibited their cytotoxic activities through the induction of apoptosis. A structure-activity relationship study suggested that an α, β-unsaturated aldehyde might be the most important functional group.

Compound 8 (C8) is a newly synthesized bis-benzimidazole derivative and exerts significant anti-tumor activity in vitro. Previous studies demonstrated that C8 induced apoptosis and autophagy in human promyelocytic leukemia HL60 cells. However, cytotoxicity study on human peripheral blood mononuclear cells (hPBMC) showed that C8 exhibited less toxicity in normal cells. In this study, the molecular mechanism of C8 on human cervical carcinoma HeLa cells was investigated. The results showed that C8 inhibited the growth of HeLa cells and triggered both apoptotic and autophagic cell death. Subsequent experiment also indicated that reactive oxygen species (ROS) generation was induced in C8-treated HeLa cells. Since ROS scavenger decreased the ratio of apoptotic and autophagic cells, ROS generation contributed to C8-induced apoptosis and autophagy. Furthermore, inhibitors of apoptosis and autophagy also reduced ROS generation, respectively. Autophagy inhibition increased cell growth compared to C8-treated group and attenuated apoptotic cell death, indicating that C8-induced autophagy promoted apoptosis for cell death. However, the percentage of autophagic cells was enhanced when limiting apoptosis process. Taken together, C8 induced ROS-mediated apoptosis and autophagy in HeLa cells, autophagy promoted apoptosis but the former was antagonized by the latter. The data also gave us a new perspective on the anti-tumor effect of C8.

Seven new diterpenoids (1–7), including five 7-membered ring vibsane-type diterpenoids, vibsanolide A-E (1–5) and a pair of epimers of 14,15,16,17-tetranorvibsane-type diterpenoids possessing bicyclo[4.2.1]nonane moiety, vibsanolide F-G (6–7), together with twelve known analogues (8–19) were isolated from the crude extracts of the leaves of Viburnum odoratissimum using Small Molecule Accurate Recognition Technology (SMART). These structures including absolute configurations were elucidated by means of comprehensive analyses of spectroscopic data, as well as comparison of the experimental and calculated electronic circular dichroism (ECD) spectra. These compounds were evaluated for their cytotoxic activities against A549 and HepG2 cells by MTT assay. The results showed that compound 2 exhibited potent cytotoxic activity against A549 cells with IC50 value of 1.11 μM. Further staining experiments indicated that 2 could promote apoptosis induction, enhance reactive oxygen species (ROS) level and attenuate mitochondrial membrane potential (MMP) in A549 cells. Taken together, these findings provided new insights into understanding the cytotoxic activity of vibsane-type diterpenoids and it is meaningful to further investigate the application potential of V. odoratissimum.

Six undescribed lanostane triterpenoids (1-6), together with three known compounds (7-9) were isolated from Inonotus obliquus. Compounds 3-5 are the rare natural compounds featuring a 4,5-seco-lanostane core with a 5,7,9-trien-21,24-cyclopentane moiety. The structure elucidation of the compounds was conducted by spectroscopic techniques and the ECD method. The absolute configuration of compound 1 was confirmed by single-crystal X-ray diffraction analysis. All isolated compounds were assayed for their neuroprotective activity against H2O2-induced cell injury using human neuroblastoma SH-SY5Y cells. Compound 9 exhibited the most potent neuroprotective activity and the flow cytometry analysis indicated that 9 could protect SH-SY5Y cells from oxidative damage by inhibiting cell apoptosis.

Small molecule accurate recognition technology (SMART) is an emerging method for the rapid structural prediction of major constituents from crude extracts and fractions. In the present study, a targeted isolation of an Elephantopus scaber extract by SMART resulted in the obtention of 15 new (1–15) and five known germacranolide sesquiterpenes (16–20). Their structures were assigned by extensively analyzing HRESIMS, NMR, X-ray crystallographic analyses, modified Mosher’s method results, and quantum chemical calculate electronic circular dichroism (ECD) spectra. All germacranolide sesquiterpenes were screened to determine their inhibitory effects with two hepatoma cell lines (HepG2 and Hep3B), and compounds 14, 16, 18, 19 and 20 showed significant cytotoxic activities against the HepG2 (IC50, 3.3–9.9 μM) and Hep3B (IC50, 4.5–8.6 μM) cell lines. Further study suggested that 18 can induce the apoptosis of hepatoma cells via mitochondrial dysfunction.

Eight pairs of enantiomeric lignans and neolignans including thirteen undescribed compounds, along with an undescribed meso compound, were isolated from the herbs of Solanum lyratum Thunb.(Solanaceae). Their structures and relative configurations were determined by extensive spectroscopic analyses of HRESIMS and nuclear magnetic resonance. The absolute configurations of the pure isomers were established based on the cooperative comparison between the experimental and calculated electronic circular dichroism (ECD) and optical rotation (OR). It is interesting that we obtained several naturally occurring stereoisomers with the identical gross structure possessing several stereogenic carbons from S. lyratum. Additionally, all isolates were assessed for neuroprotective effects toward human neuroblastoma SH-SY5Y cells injury induced by H2O2.

Five terpenoids (1-5), including three new ent-kaurane diterpenoids (1-3), one new ent-rosane type diterpenoid (4) and one known triterpenoid (5), were isolated from stigma maydis (Zea mays L.). The structures of the compounds were elucidated by comprehensive spectroscopic analyses. The relative configurations of stigmanes A-D (1-4) were determined by NOESY experiments. In addition, the relative configuration of stigmane D (4) was further established by NMR calculations. The absolute configurations of these compounds were identified by a comparison of experimental and calculated specific rotations. The neuroprotective effects of these compounds against H2O2-induced injury in human neuroblastoma SH-SY5Y cells were evaluated, and the results showed that among the compounds, 2 exhibited the most significant neuroprotection. Further study demonstrated that 2 could activate nuclear factor E2-related factor (Nrf2), downregulate apoptosis and reactive oxygen species (ROS) generation, and increase antioxidant enzyme activities in SH-SY5Y cells. However, the neuroprotective effect was reversed when Nrf2 was silenced. In conclusion, this study suggested that terpenoids from stigma maydis exerted neuroprotective effects through Nrf2 activation.

7-O-galloyltricetiflavan (GTF), a natural flavonoid, is known to exert anti-oxidation and neuroprotective activity, which are related to the prevention of Alzheimer's disease (AD). In this study, three series of GTF hybrids have been designed, synthesized and evaluated as multifunctional agents for treatment AD. The biological assays indicated that most of them showed strong inhibitory effect on self-induced β-amyloid (Aβ) aggregation, and a significant ability to inhibit ChEs. Among them, compound A15 exhibited best inhibition of Aβ aggregation (78.81% at 20 μM), potent AChE inhibitory potencies (IC50, 0.56 μM), and compound C4 presented the highest ability to inhibit BuChE (IC50, 5.77 μM). Furthermore, kinetic, molecular modeling and molecular dynamics studies revealed that A15 and C4 could interact with the catalytic active site of AChE and BuChE, respectively. In addition, compounds A15 and C4 could cross the blood-brain barrier in vitro. More importantly, A15 and C4 also showed excellent neuroprotective activities against H2O2-induced human neuroblastoma SH-SY5Y cells damage and nearly no toxicity on SH-SY5Y cells. All of these outstanding in vitro results indicated A15 and C4 as the leading structure worthy of further investigation.

Chromatographic purification of Elephantopus scaber led to 16 new germacrane-type sesquiterpene lactones (1–16), named elephantopinolide A-P, along with a known analogue (17). Their structures were confirmed by comprehensive spectroscopic analyses, single-crystal X-ray diffraction, and comparison between the experimental and calculated ECD spectra. Their hepatocellular inhibition activities against Hep3B and HepG2 cells were screened by MTT assay, and the structure-activity relationships were examined. The results revealed that 10 (IC50 value of 2.83 μM and 1.98 μM) is more potent than sorafenib. The underlying mechanism study demonstrated that 10 could markedly induce apoptosis accompanied by increased ROS production and decreased mitochondrial membrane potential, resulting in the autophagy and G2/M phase cell arrest in Hep3B and HepG2 cells. Furthermore, signal pathways including MAPKs and AKT may play important roles in 10-induced hepatocellular carcinoma cells death.

In the current study, four pairs of new enantiomeric alkaloids (1a/1b-4a/4b) were obtained from the leaves of Isatis indigotica Fortune Ex Land. Their structures were elucidated through spectroscopic methods and quantum mechanical calculations. Biologically, all isolates were evaluated for their neuroprotective effects against H2O2-induced SH-SY5Y cell injury. As a result, 1a and 1b exhibited enantioselective neuroprotective effects, further Annexin V-FITC/PI analysis showed that apoptosis ratios of 1a and 1b were reduced to 20.93% and 17.87%, respectively.

An efficient conversion of cellulose to CH 4 over porous Ni catalyst under hydrothermal conditions has been investigated. The results indicated that porous Ni catalyst showed significant catalytic activity and selectivity for the cellulose conversion to methane. Porous Ni catalyst still remained good activity with gaseous hydrogen after three runs for the transformation. The maximum CH 4 yield of 73.8% from cellulose was achieved in the presence of Zn as a reductant over porous Ni at 325 °C for 2 h. This value obtained is the highest yield for the formation of CH 4 from cellulose to date. The mechanistic studies for this transformation proposed three possible pathways for the formation of CH 4 from cellulose: (1) pyrolysis, (2) hydrogenation of intermediates, and (3) methanation. The present work provides an environmentally benign and efficient route for the conversion of cellulose to CH 4 with high efficiency and high selectivity and has great significance for both academia and industry.

Eleven aromatic compounds, including four pairs of undescribed phenylpropanoids and two undescribed dibenzofurans (1a/1b-4a/4b and 5-6), were isolated from the fruits of C. pinnatifida. Their structures were established by extensive spectroscopic analyses. Their relative and absolute configurations were determined by the assistance of quantum chemical calculations of NMR chemical shifts and electronic circular dichroism (ECD). All isolates were screened for the cytotoxicity against two human hepatoma cell lines, HepG2 and Hep3B. It was found that compound 7 exhibited noticeable cytotoxicity against both cells with the IC50 values of 12.24 (HepG2) and 24.90 (Hep3B) μM. Further Annexin VFITC/ PI staining assay suggested that 7 could induce apoptosis in a concentration-dependent manner to exert antiproliferative activities on hepatoma cells.

Four new sesquiterpenes (1–2, 6–7), a new pyranone glycoside (10) along with six known compounds, were isolated from the whole plant of Erigeron breviscapus. Their planar structures were elucidated using extensive spectroscopic analyses. Brevisterpene A (1) and brevisterpene B (2) were proved to be a pair of diastereomer followed by mixtures resolution using chiral HPLC. Their absolute configurations were determined by ECD calculation. The relative configuration of brevisnoside B (7) was elucidated by a combined analysis of NOESY spectrum and computation of 13C NMR chemical shifts, and determination of the absolute configurations of 6 and 7 assisted by optical rotation calculations. Compounds 1 and 2 displayed moderate neuroprotective effects against H2O2-induced damage in SH-SY5Y cells.

A pair of new cycloneolignan enantiomers (1a and 1b) were isolated from the leaves of Isatis indigotica Fortune. Their structures were elucidated by extensive spectroscopic data analysis, including 1D and 2D NMR, HRESIMS, MS/MS analysis, together with theoretical electronic circular dichroism (ECD) calculations. Compounds 1a and 1b were then evaluated for their neuroprotective effects against MPP+-induced SH-SY5Y cell injury. As a result, compounds 1a (77.64%) and 1b (78.62%) exhibited moderate neuroprotective activity at the concentration of 12.5 µM compared with that of MPP+ treated group (62.00% at 1 mM) by MTT assay. Furthermore, Annexin V-FITC/PI analysis showed that apoptosis ratios of 1a and 1b were reduced to 10.99% and 9.31%, respectively.