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In this study, a new flavonolignan vernicilignan A was isolated from Toxicodendron vernicifluum. The neuroprotective effects of this compound against H 2 O 2 induced cell injury in SH-SY5Y cells were evaluated by MTT assay and LDH release assay. Vernicilignan A dose-dependently attenuated the cell injury and LDH release induced by H 2 O 2 in SH-SY5Y cells. Further study indicated that vernicilignan A reduced cell apoptosis caused by H 2 O 2 treatment via regulation of some apoptotic related proteins including Bax, Bcl-2, caspase 3 and caspase 9. Also, vernicilignan A increase the cell viability of H 2 O 2 treated cells via the activation of Akt and GSK3β. Base on the findings, vernicilignan A exhibited neuroprotective effects through the activation of PI3K/Akt signaling and inhibition of mitochondria apoptosis pathway. Vernicilignan A might be a promising therapeutic agent for oxidative stress induced neurodegenerative diseases. Unlabelled Image [ABSTRACT FROM AUTHOR]

[Display omitted] • Three series of novel 6-(imidazo[1,2-a] pyridin-6-yl)-quinazolin-4(3H)-one derivatives were designed and synthesized. • Compound 12d exhibited potent anti-tumor activity in vitro and in vivo. • Compound 12d induced mitotic catastrophe and cell apoptosis in SH-SY5Y cells. • Compound 12d was identified as a novel dual ROR1/Aurora kinase inhibitor. ROR1 and Aurora kinase were overexpressed in various cancers and essential for cell proliferation, survive and metastasis. Pharmaceutical inhibition of ROR1 and Aurora kinase abrogated the activation of downstream signaling and induced cancer cell apoptosis. Hence, ROR1 and Aurora kinase considered as attractive therapeutic targets for the development of anticancer drugs. In the present work, three series of novel 6-(imidazo[1,2- a ] pyridin-6-yl)-quinazolin-4(3 H)-one derivatives were designed and synthesized via bioisosterism and scaffold-hopping strategies guided by FLF-13, an Aurora kinase inhibitor we discovered earlier. Most of compounds in series 2 and series 3 showed submicromolar to nanomolar inhibitory activity against multiple cancer cell lines. More importantly, compounds 12d and 12f in series 3 showed nanomolar inhibitory activity against all test cancer cells. The most promising compound 12d exhibited potent inhibitory activity against Aurora A and Aurora B with IC 50 values of 84.41 nM and 14.09 nM, respectively. Accordingly, compounds 12d induced G2/M phase cell cycle arrest at 24 h and polyploidy at 48 h. It's worth noting that 12d also displayed inhibitory activity against ROR1 and induce cell apoptosis. Furthermore, 12d could significantly inhibit the tumor growth in SH-SY5Y xenograft model with tumor growth inhibitory rate (IR) up to 46.31 % at 10 mg/kg and 52.66 % at 20 mg/kg. Overall, our data suggested that 12d might serve as a promising candidate for the development of therapeutic agents for cancers with aberrant expression of ROR1 and Aurora kinases by simultaneously targeting ROR1 and Aurora kinase. [ABSTRACT FROM AUTHOR]

Coumalamide derivatives are one of 2-pyrones derivatives, exerting multifunctional bioactivity. An array of coumalamide derivatives have been developed and presented good antiproliferative properties on cancer cells. However, the synthesis of 5-substituted coumalamide derivatives has not yet been published. Resistance to chemotherapeutic drugs is a major obstacle in hepatocellular carcinoma therapy. Recent evidence suggests that overexpression of constitutively active Akt confers on cancer cells resistance to chemotherapy. In this study, we report the synthesis and biological evaluation of a novel N -substituted coumalamide derivative (NSCA-1). The results indicated that NSCA-1 exerts synergistic cytotoxicity with Adriamycin in HepG2/ADR (HepG2/adriamycin) cells. Furthermore, both of the Akt kinase activity and phosphorylated Akt (Ser473) were found to be inhibited by NSCA-1 and subsequently resulting in decreased phosphorylation of GSK-3β. The intracellular accumulation of Adriamycin was also boosted by NSCA-1 via reducing the expression of p-gp. In addition, we found that combined treatment with NSCA-1 enhance cell apoptosis induced by Adriamycin via p53-dependant apoptotic pathway. [ABSTRACT FROM AUTHOR]

The ent-kaurane diterpenoid enriched fraction (EDEF) of maize root was isolated and purified, and 10 compounds, including 4 ent-kaurane diterpenoids, were isolated and identified. We evaluated their neuroprotective properties in vitro for the first time using an H 2 O 2 -induced oxidative damage model in SH-SY5Y cells. The results showed that pretreatment with maizediterpene D, a new ent-kaurane diterpenoid isolated from the EDEF, significantly attenuated H 2 O 2 -induced apoptosis by improving cell survival, reducing ROS production and increasing mitochondrial membrane potential. Mechanistically, the neuroprotective effect of maizediterpene D was confirmed to be related to the dual activation of IGF-1R and BDNF/TrkB crosstalk pathways. Our findings suggest that the EDEF and its active constituent maizediterpene D had good neuroprotective properties and could serve as potential candidates for the development of therapeutic drugs for oxidative stress-related diseases. [Display omitted] • EDEF and Maizediterpene D were isolated from maize roots. • EDEF showed good antioxidant activity against H 2 O 2 induced oxidative stress. • D showed better cytoprotective activity against H 2 O 2 triggered oxidative stress. • M-D attenuated H 2 O 2 induced oxidative stress by BDNF/TrkB and BDNF/TrkB crosstalk pathways [ABSTRACT FROM AUTHOR]

Eriocaulon sieboldianum (Sieb. & Zucc. ex Steud.), a genus of Eriocaulon in the Eriocaulaceae family, is an edible and medicinal plant used in traditional Chinese medicine. It was processed into healthcare beverages for expelling wind-heat, protecting eyes, and reducing blood fat. Also, it has been used with other herbs as Traditional Chinese herbal compound to treat cancer as adjuvants in tumor therapy in China. However, the active fractions and precise cellular mechanisms of E. sieboldianum extract remain to be illustrated. The goal of this study was to investigate the effects of the active fraction of E. sieboldianum on the growth of K562 cells and understand the possible mechanisms of its action. Our findings suggested that the fraction E3 of E. sieboldianum could effectively inhibit the activity of Aurora kinase and induce apoptosis via blocking cell cycle, up-regulating the expression of proapoptotic proteins including p53 and Bax and reducing the expression of Bcl-2. The levels of Cytochrome C, cleaved caspase-9, cleaved caspase-3 and cleaved PARP were also found to be increased after treatment with fraction E3 of E. sieboldianum . This study could improve the development of E. sieboldianum and raise its application value in cancer adjuvant therapy. Considering it is both a dietary supplement and a traditional Chinese herbal medicine which exhibits anticancer activities, it can be developed into functional food. [ABSTRACT FROM AUTHOR]

Abstract: White-line-inducing principle (WLIP), a lipodepsipeptide isolated from Lasiosphaera fenzlii Reich., which is one of the puffballs, for the first time, has been reported to exhibit anti-microbial activity. However, there are no reports regarding the anti-tumor effects of WLIP. In this study, we reported the anti-cancer effects of WLIP on K562 cells, and its potential effect on the PPAR-γ activation pathway. The obtained results showed that WLIP exerted strong anti-proliferative effect on K562 cells. Moreover, WLIP was found to increase apoptosis and induce G0/Gl arrest. Modeling results from the Surflex-Dock program suggested that PPAR-γ might be the potential anti-tumor target of WLIP, which was confirmed by the experiments that WLIP increased the activity in luciferase reporter assay and the expression of PPAR-γ in Western blot. Besides, WLIP was able to down-regulate the expression of Bcl-xL, Cyclin-D1 in K562 cells. In summary, our novel observations suggested that WLIP might have a potential implication in cancer prevention and treatment, and also showed for the first time that the anti-tumor effect of WLIP might be mediated through modulation of the PPAR-γ activation pathway. [Copyright &y& Elsevier]

Anhua dark tea known as the earliest produced Chinese dark tea, has been commercially available and famous for its unique flavor and health care effect. NMDA receptors are glutamate-coupled ion channels that critically involved in survival of neuronal cells and neurodegenerative diseases. Thus, it is considered a promising target for the therapy of neurodegenerative disease. In this study, four catechins including two new catechins derivatives (1 – 2), together with thirteen known flavonoids were isolated from Anhua dark tea. The structures of compounds 1 – 2 [2 S ,3 R -6-methoxycarbonylgallocatechin (1) and 2 R ,3 R -6-methoxycarbonylgallocatechin (2)] were determined on the basis of their spectroscopic data. The preliminary bioassay indicated that compound 1 showed the best neuroprotective effects via N -methyl- d -aspartate (NMDA) receptors inhibition. Compound 1 protected SH-SY5Y cells against NMDA-induced injury and cell apoptosis via the modulation of NR2B expression, the activation of PI3K/Akt signaling and caspase-dependent pathway. The results suggested compound 1 would be a potent dietary therapy reagent for prevention of excitable brain injury. Unlabelled Image [ABSTRACT FROM AUTHOR]

Background: MAPK/ERK kinases transmit signals from many growth factors/kinase receptors during normal cell growth/differentiation, and their dysregulation is a hallmark of diverse types of cancers. A plethora of drugs were developed to block this kinase pathway for clinical application. With the exception of a recently identified agent, EQW, most of these inhibitors target upstream factors but not ERK1/2; no activator of ERK1/2 is currently available.Method: A library of compounds isolated from medicinal plants of China was screened for anti-cancer activities. Three limonoid compounds, termed A1541-43, originally isolated from the plant Melia azedarach, exhibiting strong anti-leukemic activity. The anti-neoplastic activity and the biological target of these compounds were explored using various methods, including western blotting, flow cytometry, molecular docking and animal model for leukemia.Results: Compounds A1541-43, exhibiting potent anti-leukemic activity, was shown to induce ERK1/2 phosphorylation. In contrast, the natural product Cedrelone, which shares structural similarities with A1541-43, functions as a potent inhibitor of ERK1/2. We provided evidence that A1541-43 and Cedrelone specifically target ERK1/2, but not the upstream MAPK/ERK pathway. Computational docking analysis predicts that compounds A1541-43 bind a region in ERK1/2 that is distinct from that to which Cedrelone and EQW bind. Interestingly, both A1541-43, which act as ERK1/2 agonists, and Cedrelone, which inhibit these kinases, exerted strong anti-proliferative activity against multiple leukemic cell lines, and induced robust apoptosis as well as erythroid and megakaryocytic differentiation in erythroleukemic cell lines. These compounds also suppressed tumor progression in a mouse model of erythroleukemia.Conclusions: This study identifies for the first time activators of ERK1/2 with therapeutic potential for the treatment of cancers driven by dysregulation of the MAPK/ERK pathway and possibly for other disorders. [ABSTRACT FROM AUTHOR]

Aberrant activation of hepatocyte growth factor (HGF)/c-Met signaling pathway caused by gene amplification or mutation plays an important role in tumorigenesis. Therefore, c-Met is considered as an attractive target for cancer therapy and c-Met inhibitors have been developed with great interests. However, cancers treated with c-Met inhibitors inevitably develop resistance commonly caused by the activation of PI3K/Akt signal transduction pathway. Therefore, the combination of c-Met and PI3Kα inhibitors showed synergistic activities, especially, in c-Met hyperactivated and PIK3CA-mutated cells. In our previous study, we rationally designed and synthesized DFX117(6-(5-(2,4-difluorophenylsulfonamido)-6-methoxypyridin-3-yl)-N-(2-morpholinoethyl) imidazo[1,2-a]pyridine-3-carboxamide) as a novel PI3Kα selective inhibitor. Herein, the antitumor activity and underlying mechanisms of DFX117 against non-small cell lung cancer (NSCLC) cells were evaluated in both in vitro and in vivo animal models. Concurrent targeted c-Met and PI3Kα by DFX117 dose-dependent inhibited the cell growth of H1975 cells (PIK3CA mutation and c-Met amplification) and A549 cells (KRAS mutation). DFX117 subsequently induced G0/G1 cell cycle arrest and apoptosis. These data highlight the significant potential of DFX117 as a feasible and efficacious agent for the treatment of NSCLC patients. [ABSTRACT FROM AUTHOR]

[Display omitted] • A series of novel 3-(6-aminopyridin-3-yl)benzamide derivatives were synthesized. • Compound 7l displayed the optimal activity as an antiproliferative agent, with an IC 50 value of 0.04 ± 0.01 μM in A549 cells in vitro. • Compound 7l induced G2/M phase arrest by AURKB transcription inhibition and resulted in cell apoptosis via the p53 signaling pathway. • Compound 7l significantly inhibited the tumor growth in A549 xenograft model with tumor growth inhibitory rate (IR) up to 51.11 % at 15 mg/kg and 76.60 % at 30 mg/kg. Here, a series of 3-(6-aminopyridin-3-yl) benzamide derivatives were designed and synthesized. Cell viability assay indicated that most compounds exhibited potent antiproliferative activity against all the tested cancer cells. Among them, compound 7l displayed the best antiproliferative activity particularly in A549 cells, with an IC 50 value of 0.04 ± 0.01 μM. RNA-seq analysis was employed to explore the potential pathways related to the antiproliferative activity of compound 7l. The data revealed that 7l exerted antiproliferative activity mainly by regulating cell cycle, DNA replication and p53 signaling pathway. Indeed, compound 7l induced G2/M phase arrest by AURKB transcription inhibition and resulted in cell apoptosis via p53 signaling pathway. Most importantly, compound 7l demonstrated potent antitumor activity in A549 xenograft tumor model. Collectively, 7l might be a promising lead compound for the development of new therapeutic agents for AURKB overexpressed or mutated cancers. [ABSTRACT FROM AUTHOR]

Twenty-one new schisanhenol derivatives were synthesized, and their hepatoprotective effects against liver injury induced by concanavalin A (Con A) were evaluated in vitro using an MTT assay. The data indicated that most derivatives exhibited equivalent or better protective activity than the positive control (dimethyl dicarboxylate biphenyl, DDB) under the same conditions. Among them, compound 1b showed the most potent hepatoprotective activity against Con A-induced immunological injury. Mechanistic studies in vitro revealed that 1b inhibited cell apoptosis and inflammatory responses caused by Con A treatment via IL-6/JAK2/STAT3 signaling pathway. Consistently, it also exhibited significant hepatoprotective activity in mice with Con A-induced immunological liver injury. These results clearly indicated that 1b might be a highly potent hepatoprotective agent targeting IL-6/STAT3 signaling pathway. Twenty-one new schisanhenol derivatives were synthesized, and their hepatoprotective effects against liver injury induced by concanavalin A (Con A) were evaluated in vitro using an MTT assay. The data indicated that most derivatives exhibited equivalent or better protective activity than the positive control (dimethyl dicarboxylate biphenyl, DDB) under the same conditions. Among them, compound 1b showed the most potent hepatoprotective activity against Con A-induced immunological injury. Mechanistic studies in vitro revealed that 1b inhibited cell apoptosis and inflammatory responses caused by Con A treatment via the IL-6/JAK2/STAT3 signaling pathway. Consistently, it also exhibited significant hepatoprotective activity in mice with Con A-induced immunological liver injury. These results clearly indicated that 1b might be a highly potent hepatoprotective agent targeting the IL-6/STAT3 signal pathway. [Display omitted] • 21 novel schisanhenol derivatives were designed and synthesized firstly. • Their hepatoprotective effects against liver injury induced by Con A were firstly evaluated in vitro. • The protection of 1b in Con A-treated mice was much stronger than DDB, which could inhibit the increase of IL-6 in cell culture supernatants. • 1b could also decrease the AST and ALT levels and the increase of IL-6 after induction by Con A. • 1b had might be by reducing the actions of the IL-6/JAK2/STAT3 signaling pathway to prevent the inflammatory response. [ABSTRACT FROM AUTHOR]

The acquired resistance to gefitinib limits its clinical application. Epigallocatechin-3-gallate (EGCG) has been found to enhance the efficacy of gefitinib against resistant. However, the cellular and molecular mechanisms have not been completely illuminated in NSCLC. In this study, a new epigallocatechin gallate derivative (2R,3R-6-methoxycarbonylgallocatechin-3- O -gallate, the following referred to as EGCGD) (1) and three known epigallocatechin gallate compounds including epicatechin-3- O -gallate (2), gallocatechin-3- O -gallate (3) and epigallocatechin-3- O -gallate (4 , EGCG) were isolated and identified from Anhua dark tea. The pharmacological studies showed EGCGD was more effective against gefitinib-resistant HCC827-Gef cells compared to that of other three epigallocatechin gallate compounds including EGCG, suggesting that introduction of 6-methoxycarbonyl to EGCG might enhance its antitumor activities. Further study on molecular mechanism showed EGCGD increased the potency of gefitinib against HCC827-Gef cells via suppression of epithelial-Mesenchymal transition (EMT) and dual inhibition of PI3K/mTOR. Unlabelled Image [ABSTRACT FROM AUTHOR]

Fangchinoline, a bisbenzylisoquinoline alkaloid extracted from Stephania tetrandra S. Moore, is known to exert anti-cancer activity. A series of new fangchinoline derivatives have been synthesized and evaluated for their anti-cancer activity. In cell viability assay, these fangchinoline derivatives displayed higher proliferation inhibitory activity on leukemia and breast cancer cell lines than the parental compound. Among them, 3e exhibited strongest cell growth inhibitory activity in a dose- and time-dependent manner on leukemia cell line HEL through induction of G0/G1 cell cycle arrest and apoptosis. Treatment of HEL cells with 3e also resulted in significant suppression of the MAPK and PI3K/AKT pathway as well as c-MYC downregulation, which may responsible for induction of apoptosis and cell cycle arrest. In docking analysis, high affinity interaction between 3e and Akt1 was responsible for drastic kinase inhibition by the compound. This derivative compound may be useful as a potent anti-cancer agent for treatment of leukemia. Image 1 • Twenty-five fangchinoline derivatives displayed higher anti-neoplastic activity than the parental compound on 4 cell lines. • The compound 3e induced G0/G1 cell cycle arrest and apoptosis of HEL leukemia cell line in a dose- and time-dependent manner. • Induction of apoptosis by 3e was associated with the inhibition of p-AKT, p-ERK, and activation of p-JNK, JNK. • Molecular docking study revealed high affinity interaction between 3e and Akt1, confirmed by Akt kinase inhibition assay. [ABSTRACT FROM AUTHOR]