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Eight new naphtho[1,2-c]furan derivatives (1-8) along with six known analogues (9-14) were isolated from culture medium of the basidiomycete Basidioradulum radula. The structures of these compounds were identified using spectroscopic analysis, and their absolute configurations were resolved using X-ray diffraction, ECD, and VCD. Compounds 7 and 14 inhibited the cell viability of human prostate cancer DU-145 cells with IC 50 values of 7.54 ± 0.03 μM and 5.04 ± 0.03 μM, respectively. At 8 μM, compounds 7 and 14 increased the percentage of apoptotic cells and upregulated the protein expression related to the apoptosis caspase pathways in DU-145 cells. Furthermore, the hallmarks of cells undergoing apoptosis, such as chromatin condensation, were also observed at this concentration. However, compound 7 and 14 showed no effect on the proliferation of splenocytes isolated from cyclophosphamide-induce immunosuppressed mice., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The epithelial-mesenchymal transition (EMT) of cancer cells is a crucial process in cancer cell metastasis. An Aquimarina sp. MC085 extract was found to inhibit A549 human lung cancer cell invasion, and caprolactin C ( 1 ), a new natural product, α-amino-ε-caprolactam linked to 3-methyl butanoic acid, was purified through bioactivity-guided isolation of the extract. Furthermore, its enantiomeric compound, ent -caprolactin C ( 2 ), was synthesized. Both 1 and 2 inhibited the invasion and γ-irradiation-induced migration of A549 cells. In transforming growth factor-β (TGF-β)-treated A549 cells, 2 inhibited the phosphorylation of Smad2/3 and suppressed the EMT cell marker proteins (N-cadherin, β-catenin, and vimentin), as well as the related messenger ribonucleic acid expression (N-cadherin, matrix metalloproteinase-9, Snail, and vimentin), while compound 1 did not suppress Smad2/3 phosphorylation and the expression of EMT cell markers. Therefore, compound 2 could be a potential candidate for antimetastatic agent development, because it suppresses TGF-β-induced EMT.

Three unusual polyketides with a 5/6/10-fused ring system, named colletotrichalactones A-Ca (1-3a), were isolated from cultures of the endophytic fungus, Colletotrichum sp. JS-0361, which was isolated from a leaf of Morus alba. Their structures, including their absolute stereochemistries, were completely established using extensive spectroscopic methods together with a chemical reaction utilizing competing enantioselective acylation coupled with LC/MS. Compounds possessing this ring skeleton were previously reported in three studies. Our rigorous chemical investigation revealed the complete configuration of this skeleton, which agreed with the results for glabramycin B with this ring skeleton established by computational chemistry and enantioselective synthesis in previous reports. 1 and 2 had unstable aldehyde groups that were easily converted to acetal groups in the presence of solvents. Meanwhile, compound 3a, with terminal acetal functionality, was deduced to be an artefact originating from compound 3 with a terminal aldehyde group. Compounds 1 and 3a displayed moderate-to-potent cytotoxic activities against MCF7 cells with IC 50 s of 35.06 and 25.20 µM, respectively., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Cisplatin is a platinum-based anticancer agent used for treating a wide range of solid cancers. One of the side effects of this drug is its severe nephrotoxicity, limiting the safe dose of cisplatin. Therefore, many natural products have been studied and applied to attenuate the toxicity of this compound. In this study, we found that steamed Vietnamese ginseng ( Panax vietnamensis ) could significantly reduce the kidney damage of cisplatin in an in vitro model using porcine proximal tubular LLC-PK1 kidney cells. From processed ginseng under optimized conditions (120 °C, 12 h), we isolated seven compounds (20( R,S )-ginsenoside Rh2, 20( R,S )-ginsenoside Rg3, ginsenoside Rk1, ginsenoside-Rg5, and ocotillol genin) that showed kidney-protective potential against cisplatin toxicity. By comparing the 50% recovery concentration (RC 50 ), the R form of ginsenoside, Rh2 and Rg3, had RC 50 values of 6.67 ± 0.42 µM and 8.39 ± 0.3 µM, respectively, while the S forms of ginsenoside, Rh2 and Rg3, and Rk1, had weaker protective effects, with RC 50 ranging from 46.15 to 88.4 µM. G-Rg5 and ocotillol, the typical saponin of Vietnamese ginseng, had the highest RC 50 (180.83 ± 33.27; 226.19 ± 66.16, respectively). Our results suggest that processed Vietnamese gingseng (PVG), as well as those compounds, has the potential to improve kidney damage due to cisplatin toxicity.

Anorexia is common in patients with cancer, mostly as a side effect of chemotherapy. The effect of electro-acupuncture (EA) on ameliorating cancer-related symptoms have been studied in animal models and in clinical trials. The aim of this study was to determine optimal conditions for the application of EA to alleviate anorexia, followed by the study of molecular mechanisms affecting its therapeutics. Anorexia was induced in male Wistar rats by injecting cisplatin, which was then followed by EA treatment at CV12, the acupuncture point located in the center of the abdominal midline. Body weight and food intake were measured daily throughout the duration of the study. The levels of monoamine neurotransmitters in the plasma were quantitatively analyzed by HPLC-ECD. Gastrointestinal hormone concentrations were elucidated with ELISA kits. RT-qPCR was performed to evaluate the mRNA expression of ghrelin (GHRL), neuropeptide Y (NPY), and pro-opiomelanocortin. The expression of c-Fos in the nucleus tractus solitarii was detected using western blotting analysis. The optimal conditions of EA to alleviate anorexia in rats was determined to be 1 unit for intensity and 10 Hz for frequency. EA treatment at CV12 reduced the levels of plasma monoamine neurotransmitters 5-hydroxytryptamine, 5-hydroxyindoleacetic acid, dopamine, and norepinephrine; as well as stimulated the expression of GHRL and NPY to alleviate cisplatin-induced anorexia in rats. EA stimulation at CV12 could be used to treat cisplatin-induced anorexia in rats.

Cordyceps militaris is a well-known medicinal mushroom. It is non-toxic and has clinical health benefits including cancer inhibition. However, the anticancer effects of C. militaris cultured in brown rice on breast cancer have not yet been reported. In this study, we simultaneously investigated the anticancer effects of cordycepin and an extract of C. militaris cultured in brown rice on MCF-7 human breast cancer cells using a cell viability assay, cell staining with Hoechst 33342, and an image-based cytometric assay. The C. militaris concentrate exhibited significant MCF-7 cell inhibitory effects, and its IC 50 value was 73.48 µg/mL. Cordycepin also exhibited significant MCF-7 cell inhibitory effects, and its IC 50 value was 9.58 µM. We applied network pharmacological analysis to predict potential targets and pathways of cordycepin. The gene set enrichment analysis showed that the targets of cordycepin are mainly associated with the hedgehog signaling, apoptosis, p53 signaling, and estrogen signaling pathways. We further verified the predicted targets related to the apoptosis pathway using western blot analysis. The C. militaris concentrate and cordycepin exhibited the ability to induce apoptotic cell death by increasing the cleavage of caspase-7 -8, and -9, increasing the Bax/Bcl-2 protein expression ratio, and decreasing the protein expression of XIAP in MCF-7 cells. Consequently, the C. militaris concentrate and cordycepin exhibited significant anticancer effects through their ability to induce apoptosis in breast cancer cells., Competing Interests: The authors declare no conflict of interest.

Gami-soyosan is a medicinal herbal formulation prescribed for the treatment of menopausal symptoms, including hot flashes and osteoporosis. Gami-soyosan is also used to treat similar symptoms experienced by patients with breast cancer. The incidence of breast cancer in women receiving hormone replacement therapy is a big burden. However, little is known about the components and their mechanism of action that exhibit these beneficial effects of Gami-soyosan. The aim of this study was to simultaneously analyze compounds of Gami-soyosan, and determine their cytotoxic effects on estrogen receptor (ER)-positive MCF-7 human breast adenocarcinoma cells. We established a simultaneous analysis method of 18 compounds contained in Gami-soyosan and found that, among the various compounds in Gami-soyosan, gallic acid ( 1 ), decursin ( 17 ), and decursinol angelate ( 18 ) suppressed the viability of MCF-7 cells. Gallic acid ( 1 ), decursin ( 17 ), and decursinol angelate ( 18 ) induced apoptotic cell death and significantly increased poly (ADP-ribose) polymerase (PARP) cleavage and the Bcl-2-associated X protein/ B-cell lymphoma 2 (Bax/Bcl-2) ratio. Decursin ( 17 ) increased the expression of cleaved caspases-8, -9, -7, and -3. Decursinol angelate ( 18 ) increased the expression of cleaved caspase-8 and -7. These three components altered the different apoptosis signal pathways. Collectively, gallic acid ( 1 ), decursin ( 17 ), and decursinol angelate ( 18 ) may be used to inhibit cell proliferation synergistically in patients with ER-positive breast cancer.

In recent years, investigations into the biochemistry of insect-associated bacteria have increased. When combined with analytical dereplication processes, these studies provide a powerful strategy to identify structurally and/or biologically novel compounds. Non-ribosomally synthesized cyclic peptides have a broad bioactivity spectrum with high medicinal potential. Here, we report the discovery of three new cyclic tripeptides: natalenamides A⁻C (compounds 1 ⁻ 3 ). These compounds were identified from the culture broth of the fungus-growing termite-associated Actinomadura sp. RB99 using a liquid chromatography (LC)/ultraviolet (UV)/mass spectrometry (MS)-based dereplication method. Chemical structures of the new compounds ( 1 ⁻ 3 ) were established by analysis of comprehensive spectroscopic methods, including one-dimensional (¹H and 13 C) and two-dimensional (¹H-¹H-COSY, HSQC, HMBC) nuclear magnetic resonance spectroscopy (NMR), together with high-resolution electrospray ionization mass spectrometry (HR-ESIMS) data. The absolute configurations of the new compounds were elucidated using Marfey's analysis. Through several bioactivity tests for the tripeptides, we found that compound 3 exhibited significant inhibitory effects on 3-isobutyl-1-methylxanthine (IBMX)-induced melanin production. The effect of compound 3 was similar to that of kojic acid, a compound extensively used as a cosmetic material with a skin-whitening effect.

The fruit of the white mulberry tree (Morus alba L.) is a multiple fruit with a sweet flavor commonly consumed around the world. Chemical investigation of the fruits led to the isolation of two indole acetic acid derivatives (1 -2) including a new compound, which turned out to be an isolation artifact, 3S-(β-D-glucopyranosyloxy)-2,3-dihydro-2-oxo-1H-indole-3-acetic acid butyl ester (1), along with five known compounds (3 -7). Compounds 2 and 7 were newly identified from mulberry fruit. The new isolation artifact (1) exhibited cytotoxic effect on human cervical cancer Hela cells in a dose-dependent manner. Compound 1 activated caspase-8, caspase-9, and caspase-3, followed by cleavage of PARP, a substrate of caspase-3, in a dose-dependent manner. Simultaneous alterations in protein expression of mitochondrial factors Bax, BID and Bcl-2 were also observed. A comparison between compounds 1 and 2 led to a structure-activity relationship analysis of the cytotoxic effect. These results suggest that compound 1 could be beneficial in human cervical cancer treatment, and provide a theoretical basis for further application of compound 1., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Sanguiin H-6 is a dimer of casuarictin linked by a bond between the gallic acid residue and one of the hexahydroxydiphenic acid units. It is an effective compound extracted from Rubus coreanus. It has an anticancer effect against several human cancer cells; however, its effect on breast cancer cells has not been clearly demonstrated. Thus, we aimed to investigate the anticancer effect and mechanism of action of sanguiin H-6 against two human breast carcinoma cell lines (MCF-7 and MDA-MB-231). We found that sanguiin H-6 significantly reduced cell viability in a concentration-dependent manner. It also increased the rates at which MCF-7 and MDA-MB-231 cells underwent apoptosis. Furthermore, sanguiin H-6 induced the cleavage of caspase-8, caspase-3, and poly(ADP-ribose) polymerase, which resulted in apoptosis. However, cleavage of caspase-9 was only detectable in MCF-7 cells. In addition, sanguiin H-6 increased the ratio of Bax to Bcl-2 in both MCF-7 and MDA-MB-231 cells. These findings suggest that sanguiin H-6 is a potent therapeutic agent against breast cancer cells. In addition, it exerts its anticancer effect in an estrogen-receptor-independent manner., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Pleurotus cornucopiae (Pleurotaceae) is an edible and medicinal mushroom widely distributed in Korea, China, and Japan. The MeOH extract of the fruiting bodies of P. cornucopiae showed renoprotective effects against cisplatin-induced kidney cell damage. Chemical investigation of the MeOH extract led to the isolation and identification of 12 compounds including noransine (1), uridine (2), uracil (3), (3β, 5α, 6β, 22E, 24S) -ergosta-7, 22-diene-3, 5, 6, 9-tetrol (4), (22E,24S)-ergosta-7,22-diene-3β,5α,6β-triol (5), (22E,24R)-ergosta-8(14),22-diene-3β,5α,6β,7α-tetrol (6), cerebroside B (7), (2R) -N- [(1S, 2R, 3E, 7E) -1- [(β-d-glucopyranosyloxy) methyl] -2-hydroxy-8-methyl-3, 7-heptadecadien-1-yl] -2-hydroxy-heptadecanamide (8), cerebroside D (9), nicotinamide (10), 1,2-bis(hydroxymethyl)-4,5-dimethoxybenzene (11), and benzoic acid (12). Among them, compounds 1 and 11 were isolated as naturally occurring products for the first time, though they were reported as synthetic products in previous papers. All of the compounds (except 8 and 11) abrogated cisplatin-induced LLC-PK1 cell damage in a dose-dependent manner. Of special note, compounds 2, 5, 6, and 12 ameliorated cisplatin-induced nephrotoxicity to 80% of the control value at 10μM. The protective effects of compounds 2, 5, 6, and 12 were mediated via the deactivation of JNK-caspase 3 apoptotic cascade. This study is the first to demonstrate that the chemical constituents of P. cornucopiae display renoprotective effects against anticancer drug-induced damage in kidney cells., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Eight chalcone analogues were prepared and evaluated for their cytotoxic effects in human hepatoma HepG2 cells. Compound 5 had a potent cytotoxic effect. The percentage of apoptotic cells was significantly higher in compound 5-treated cells than in control cells. Exposure to compound 5 for 24h induced cleavage of caspase-8 and -3, and poly (ADP-ribose) polymerase (PARP). Our findings suggest that compound 5 is the active chalcone analogue that contributes to cell death in HepG2 cells via the extrinsic apoptotic pathway., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Cardamonin (2',4'-dihydroxy-6'-methoxychalcone) is derived from Alpinia katsumadai Hayata (Zingiberaceae), a plant that has been used in Traditional Chinese Medicine for thousands of years. Several anticancer agents have been reported to induce autophagy, which either protects cells or further sensitizes cells to drug treatment. However, the possible autophagic and antiproliferative effects of cardamonin on the human colorectal carcinoma HCT116 cell line are unclear. In the present study, experiments were conducted to determine the effects of cardamonin on cell proliferation, cell cycle distribution, and stimulation of autophagy in cultures of the HCT116 cell line. The results showed that cardamonin inhibited cell proliferation, induced G2/M phase cell cycle arrest, and enhanced autophagy in HCT116 cells. We found evidence that cardamonin-induced autophagic and antiproliferative effects are regulated by the tumor protein p53. We also found that the enhanced activation of c-Jun N-terminal kinase (JNK) by cardamonin was partially regulated by p53 and was critical for cardamonin-induced autophagic and antiproliferative effects in HCT116 cells. These findings suggest that cardamonin or other anticancer agents that increase p53/JNK-dependent stimulation of autophagy could be used to effectively treat patients with colorectal carcinoma., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Aims: Neobavaisoflavone (NBIF), an isoflavone isolated from Psoralea corylifolia (Leguminosae), has striking anti-inflammatory and anti-cancer effects. NBIF inhibits the proliferation of prostate cancer in vitro and in vivo., Main Methods: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a key endogenous molecule that selectively induces apoptosis in cancer cells with little or no toxicity in normal cells. However, some cancer cells, including U373MG cells, are resistant to TRAIL-mediated apoptosis. We demonstrated that the cell viability, migration and invasion assay were used in U373MG glioma cells., Key Findings: In this study, we found that NBIF sensitizes human U373MG glioma cells to TRAIL-mediated apoptosis. Co-treatment of TRAIL and NBIF effectively induced Bid cleavage and activated caspases 3, 8, and 9. Importantly, DR5 expression was upregulated by NBIF. We also observed that the combination NBIF and TRAIL increased expression of BAX. We further demonstrate that NBIF induced TRAIL-mediated apoptosis in human glioma cells by suppressing migration and invasion, and by inhibiting anoikis resistance., Significance: Taken together, our results suggest that NBIF reduces the resistance of cancer cells to TRAIL and that the combination of NBIF and TRAIL may be a new therapeutic strategy for treating TRAIL-resistant glioma cells., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The aim of the present study was to verify the important role of Maillard reaction in the protective effect of heat-processed ginsenoside Re-serine mixture against oxidative stress-induced nephrotoxicity. The free radical-scavenging activity of ginsenoside Re-serine mixture was increased by heat-processing. Ginsenoside Re was transformed into less-polar ginsenosides such as Rg(2), Rg(6) and F(4) by heat-processing, and the glucose molecule at carbon-20 was separated. The improved-free radical-scavenging activity by heat-processing was mediated by the generation of antioxidant Maillard reaction products (MRPs) from the reaction of glucose with serine. Moreover, MRPs from ginsenoside Re-serine mixture showed protective effect against cisplatin-induced renal epithelial cell damage., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Cisplatin is a well-known anticancer drug frequently used for treating solid tumors, including ovarian, testicular, bladder, and cervical tumors. However, usage of cisplatin has been limited because of its adverse effects, particularly nephrotoxicity. Therefore, the present study sought to investigate the protective effect of formononetin against cisplatin-induced cytotoxicity in LLC-PK1 pig kidney epithelial cells as well as the anticancer effect of cisplatin in three different human cervical cancer cell lines, including HeLa, SiHa, and CaSKi cells. We first demonstrated that formononetin strongly prevented cisplatin-induced LLC-PK1 cell death. Although formononetin had no anticancer effect, it did not interrupt the anticancer effect of cisplatin in human cervical carcinoma cell lines. Furthermore, the treatment with formononetin reduced reactive oxygen species (ROS) accumulation and chromatin condensation. The percentage of Annexin V-positive cells also increased following cisplatin treatment. Finally, formononetin-inhibited c-Jun N-terminal kinase (JNK) phosphorylation, cleavage of caspase-8 and caspase-3, and the ratio of Bax to Bcl-2 increased with cisplatin. Taken together, these findings suggest that formononetin may be a possible option to prevent nephrotoxicity induced by cisplatin during treatment for cervical cancer. [ABSTRACT FROM AUTHOR]

Platinum-based anticancer drug therapies can cause renal damage and apoptotic kidney cell damage. The development of reno- and kidney-protective molecules is therefore urgently required. To address this challenge, we explored secondary metabolites of termite-associated Streptomyces sp. RB1 isolated fromthe cuticle of the South African termite, Macrotermes natalensis for their renoprotective ability using bioassay-guided fractionation and LLC-PK1 cells. Chemical investigation of the MeOH extract of Streptomyces sp. RB1 resulted in the isolation and identification of a renoprotectivemetabolite, 1-O-(2-aminobenzoyl)-α-L-rhamnopyranoside (ABR) (1) from the active fraction, which ameliorated cisplatin-induced cytotoxicity to 80% of the control value at 25 μM. Upregulated phosphorylation of c-Jun N-terminal kinases (JNK) and p38 following cisplatin treatment was markedly decreased after pre-treatment of cells with ABR. In addition, levels of cleaved caspase-3 and the percentage of apoptotic cells were also significantly reduced after pre-treatment with ABR. These findings provide experimental evidence that blocking the MAPK signaling cascade plays a critical role in mediating the renoprotective effect of ABR, which may inspire the development of novel therapeutic substances to prevent anticancer drug-induced nephrotoxicity. [ABSTRACT FROM AUTHOR]

The article discusses a study on the synthesis of chalcone derivatives that protect against cytotoxicity induced by the anticancer drug cisplatin in LLC-PK1 cells. Topics include the toxicities of cisplatin, the renoprotective potential of chalcone derivatives and the potential of chalcone in the development of chemotherapeutic drugs.

Cisplatin, one of the most common antitumor agents, is widely applied to treat various cancerous diseases and is included in the World Health Organization Model List of Essential Medicines. Cisplatin therapy is used to treat 10–20% of all cancerous cases, and its cure rate is especially high in testicular cancer (over 90%). However, a major side effect of this anticancer drug is nephrotoxicity, limiting treatment effect and reducing the quality of life in cancer patients. Muscone, an odoriferous constituent of musk, was confirmed to inhibit cisplatin-induced LLC-PK1 kidney proximal tubule cell death in a dose-dependent manner. In term of renal protective mechanism, muscone inhibited cisplatin oxidative toxicity by decreasing reactive oxygen species (ROS) level and stimulating HO-1 expression. Muscone also exerted anti-inflammation effect through inhibition of p38 phosphorylation. Furthermore, muscone mitigated cisplatin-induced apoptosis in LLC-PK1 cells via both intrinsic and extrinsic pathways by inhibiting pro-apoptotic protein Bax expression, and cleaved caspase-3, 7, and 8; and increase of anti-apoptotic protein Bcl-2 level. In addition, the anti-apoptotic effect of muscone also was enhanced by preventing p53 expression and its phosphorylation. Our study showed that muscone may be a potential protective agent against cisplatin-induced nephrotoxicity. [ABSTRACT FROM AUTHOR]

Abstract: Ginsenosides are the main active components of Panax ginseng. Structural changes in diol type ginsenosides along with generation of Maillard reaction products (MRPs) are strongly associated with increased free radical-scavenging activities. Ginsenoside Re, one of the major triol type ginsenosides of P. ginseng, possesses a hydrophobic four-ring steroid-like structure with hydrophilic sugar moieties at carbons-3 and -20. The aim of the present study was to identify changes in the structure, antioxidant and anticancer effects of ginsenoside Re upon Maillard reaction. Ginsenoside Re was transformed into less-polar ginsenosides, namely Rg2, Rg6 and F4 by heat-processing. Free radical-scavenging activity of the ginsenoside Re–lysine mixture increased upon heat processing. This improved free radical-scavenging activity mediated by antioxidant MRPs, which were generated through Maillard reaction of a glucosyl moiety separated from carbon-20 of ginsenoside Re and lysine. The increased anticancer effect of ginsenoside Re–lysine mixture upon heat processing was mainly derived from the generation of less-polar ginsenosides through the regulation of Bcl-2 and Bax, as well as caspase-dependent apoptotic pathway. These results reported here have shed significant new lights on the mechanism of increased antioxidant and anticancer effects of P. ginseng upon heat processing. [Copyright &y& Elsevier]