scholarly journals Steroids from the Deep-Sea-Derived Fungus Penicillium granulatum MCCC 3A00475 Induced Apoptosis via Retinoid X Receptor (RXR)-α Pathway

Marine Drugs ◽  
2019 ◽  
Vol 17 (3) ◽  
pp. 178 ◽  
Author(s):  
Chun-Lan Xie ◽  
Duo Zhang ◽  
Jin-Mei Xia ◽  
Chao-Chao Hu ◽  
Ting Lin ◽  
...  
Keyword(s):  
Deep Sea ◽  
2D Nmr ◽  
Retinoid X Receptor ◽  
Parp Cleavage ◽  
Antiproliferative Effects ◽  
X Ray Crystallography ◽  
Cycle Arrest ◽  
Kd Values ◽  
Ic50 Values ◽  
Induced Apoptosis

Five new ergostanes, penicisteroids D−H (1−5), were isolated from the liquid culture of the deep-sea-derived fungus Penicillium granulatum MCCC 3A00475, along with 27 known compounds. The structures of the new steroids were established mainly on the basis of extensive analysis of 1D and 2D NMR as well as HRESIMS data. Moreover, the absolute configurations of 1 were confirmed unambiguously by the single-crystal X-ray crystallography. Compounds 2 and 4–7 showed moderate antiproliferative effects selectively against 12 different cancer cell lines with IC50 values of around 5 μM. Compounds 2 and 6, potent RXRα binders with Kd values of 13.8 and 12.9 μM, respectively, could induce apoptosis by a Retinoid X Receptor (RXR)-α-dependent mechanism by regulating RXRα transcriptional expression and promoting the poly-ADP-ribose polymerase (PARP) cleavage. Moreover, they could inhibit proliferation by cell cycle arrest at the G0/G1 phase.

scholarly journals Phenylhydrazone and Quinazoline Derivatives from the Cold-Seep-Derived Fungus Penicillium oxalicum

Marine Drugs ◽  
2020 ◽  
Vol 19 (1) ◽  
pp. 9
Author(s):  
Ya-Ping Liu ◽  
Sheng-Tao Fang ◽  
Zhen-Zhen Shi ◽  
Bin-Gui Wang ◽  
Xiao-Nian Li ◽  
...  
Keyword(s):  
Deep Sea ◽  
Spectroscopic Data ◽  
2D Nmr ◽  
Penicillium Oxalicum ◽  
Marine Phytoplankton ◽  
Cold Seep ◽  
Phytoplankton Species ◽  
X Ray ◽  
X Ray Crystallography ◽  
Quinazoline Derivatives

Three new phenylhydrazones, penoxahydrazones A–C (compounds 1–3), and two new quinazolines, penoxazolones A (compound 4) and B (compound 5), with unique linkages were isolated from the fungus Penicillium oxalicum obtained from the deep sea cold seep. Their structures and relative configurations were assigned by analysis of 1D/2D NMR and mass spectroscopic data, and the absolute configurations of 1, 4, and 5 were established on the basis of X-ray crystallography or ECD calculations. Compound 1 represents the first natural phenylhydrazone-bearing steroid, while compounds 2 and 3 are rarely occurring phenylhydrazone tautomers. Compounds 4 and 5 are enantiomers that feature quinazoline and cinnamic acid units. Some isolates exhibited inhibition of several marine phytoplankton species and marine-derived bacteria.

scholarly journals Fusarins G–L with Inhibition of NO in RAW264.7 from Marine-Derived Fungus Fusarium solani 7227

Marine Drugs ◽  
2021 ◽  
Vol 19 (6) ◽  
pp. 305
Author(s):  
Guangyuan Luo ◽  
Li Zheng ◽  
Qilin Wu ◽  
Senhua Chen ◽  
Jing Li ◽  
...  
Keyword(s):  
Fusarium Solani ◽  
2D Nmr ◽  
Inflammatory Activity ◽  
Raw264.7 Cells ◽  
Spectroscopic Methods ◽  
X Ray ◽  
X Ray Crystallography ◽  
Structure Activity ◽  
Ic50 Values ◽  
New Compounds

Six new fusarin derivatives, fusarins G–L (1–6), together with five known compounds (5–11) were isolated from the marine-derived fungus Fusarium solani 7227. The structures of the new compounds were elucidated by means of comprehensive spectroscopic methods (1D and 2D NMR, HRESIMS, ECD, and ORC) and X-ray crystallography. Compounds 5–11 exhibited potent anti-inflammatory activity by inhibiting the production of NO in RAW264.7 cells activated by lipopolysaccharide, with IC50 values ranging from 3.6 to 32.2 μM. The structure–activity relationships of the fusarins are discussed herein.

scholarly journals Secondary Metabolites with Nitric Oxide Inhibition from Marine-Derived Fungus Alternaria sp. 5102

Marine Drugs ◽  
2020 ◽  
Vol 18 (8) ◽  
pp. 426 ◽  
Author(s):  
Senhua Chen ◽  
Yanlian Deng ◽  
Chong Yan ◽  
Zhenger Wu ◽  
Heng Guo ◽  
...  
Keyword(s):  
Secondary Metabolites ◽  
2D Nmr ◽  
X Ray ◽  
X Ray Crystallography ◽  
Spectroscopic Analyses ◽  
Structure Activity ◽  
Ic50 Values ◽  
Alternaria Sp ◽  
Modified Mosher’S Method ◽  
Oxide Inhibition

Two new benzofurans, alternabenzofurans A and B (1 and 2) and two new sesquiterpenoids, alternaterpenoids A and B (3 and 4), along with 18 known polyketides (5−22), were isolated from the marine-derived fungus Alternaria sp. 5102. Their structures were elucidated on the basis of extensive spectroscopic analyses (1D and 2D NMR, HR-ESIMS, and ECD) and X-ray crystallography, as well as the modified Mosher’s method. Compounds 2, 3, 5, 7, 9–18, and 20–22 exhibited potent anti-inflammatory activity by inhibiting the production of NO in RAW264.7 cells activated by lipopolysaccharide with IC50 values in the range from 1.3 to 41.1 μM. Structure-activity relationships of the secondary metabolites were discussed.

The Bioactive Polyphenol Curcumin (diferuloylmethane) In Human Apolipoprotein A-1 Nanodisks Enhances Apoptosis and G1 Cell Cycle Arrest In Mantle Cell Lymphoma Compared with Free Curcumin

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3934-3934
Author(s):  
Amareshwar T.K. Singh ◽  
Mistuni Ghosh ◽  
C. Shad Thaxton ◽  
Trudy M. Forte ◽  
Robert O. Ryan ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Drug Delivery ◽  
Cyclin D1 ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
Parp Cleavage ◽  
Cycle Arrest ◽  
Mantle Cell ◽  
Induced Apoptosis

Abstract Abstract 3934 Background: Mantle cell lymphoma (MCL) is a pre–germinal center neoplasm characterized by cyclin D1 overexpression resulting from translocation of the cyclin D1 gene on 11q13 to the promoter of the immunoglobulin heavy chain locus on 14q32. Since MCL is incurable with standard lymphoma therapies, new treatment approaches are needed that target specific biologic pathways. The bioactive polyphenol curcumin (Curc), derived from the rhizome of Curcuma longa Linn, has been shown to have pleiotropic activities related to its complex chemistry and its influence on multiple signaling pathways including NF-kB, Akt, Nrf2 and pathways involved in metastasis and angiogenesis. Curc has been shown to cause growth arrest and apoptosis of BKS-2 immature B-cell lymphoma by downregulating growth and survival promoting genes (Clin Immunol 1999; 93:152). However, because of poor aqueous solubility Curc has had limited clinical utility, so investigators have explored nanoparticle drug delivery approaches (J Nanobiotech 2007, 5:3, MCT 2010; 9:2255). We reasoned that effective and targeted drug delivery by nanoparticles required appropriate receptors to facilitate binding. We therefore screened lymphoma cell lines for receptors that recognize apolipoprotein (apo) A-1. We hypothesized that a novel discoidal nanoparticle (ND) consisting of apoA-1, phospholipid and Curc (Curc ND) would bind to such receptors to facilitate drug delivery. Methods: We compared biologic activity of free Curc vs. Curc-ND in MCL cell lines expressing receptors for apoA-1. Cell lines were grown and maintained in culture, treated, and apoptosis and cell cycle progression was measured by flow cytometry. Relevant signaling intermediates and presence of apoA-1 receptors were measured by immunoblotting using specific antibodies. Results: Granta and Jeko cells (both MCL cell lines) expressed apoA-1 receptors including class B scavenger receptor (SR-B1) and the ATP-binding cassette transporter of the sub-family G1 (ABCG1). To compare the pro-apoptotic effect of free Curc and Curc-ND, Granta cells were incubated with free Curc, Curc-ND, empty ND, and medium alone (untreated). Compared to medium alone, empty ND had no effect while free Curc (20 μM) induced apoptosis. Curc-ND produced a dose-dependent increase in apoptosis, with ∼70% apoptosis at 20 μM. To investigate the mechanism of Curc-ND induced apoptosis, apoptosis-related proteins were studied in cultured Granta cells. A time-dependent decrease in caspase-9 levels was observed following incubation with Curc-ND or free Curc. The decrease in caspase-9 seen with Curc-ND, however, occurs much earlier (between 2–4 h of incubation) than for free-Curc. Caspase-3 was undetectable after 16 h with either treatment. Loss of this band implies activation of caspase-3, which was confirmed by PARP cleavage, wherein a decrease in the 116 kD band was accompanied by an increase in the 85 kD cleavage product. Unlike free Curc, Curc-ND induced PARP cleavage even at 16 h of incubation, suggesting sustained drug release. Curc-ND downregulated cyclin D1, decreased Akt phosphorylation and enhanced cleavage of caspases-9 and -3, and PARP. In addition, Curc-ND induced G1 cell cycle arrest to a greater extent than free Curc in Granta and Jeko cells (Granta: Control 34% G1, Curc 37% G1, Curc-ND 46% G1; Jeko: Control 39% G1, Curc 49% G1, Curc-ND 54% G1). Conclusion: We have shown that the MCL cell lines Granta and Jeko express apoA-1 receptors, making them likely targets for discoidal nanoscale delivery vehicles stabilized with Apo-A1. These nanodisks, when carrying the polyphenol Curc, can result in increased caspase -dependent apoptosis, cell cycle arrest, downregulation of cyclin-D1 and decreased p-Akt. These data suggest that the pleiotropic polyphenol Curc has cell killing/arrest activity in MCL and that Curc-ND may be a potential therapeutic with drug targeting ability. Disclosures: Forte: Lypro Biosciences: Employment.

scholarly journals Angucycline Glycosides from an Intertidal Sediments Strain Streptomyces sp. and Their Cytotoxic Activity against Hepatoma Carcinoma Cells

Marine Drugs ◽  
2018 ◽  
Vol 16 (12) ◽  
pp. 470 ◽  
Author(s):  
Aihong Peng ◽  
Xinying Qu ◽  
Fangyuan Liu ◽  
Xia Li ◽  
Erwei Li ◽  
...  
Keyword(s):  
Cytotoxic Activity ◽  
Fermentation Broth ◽  
Morphological Characteristics ◽  
2D Nmr ◽  
Carcinoma Cells ◽  
Intertidal Sediments ◽  
Dapi Staining ◽  
Streptomyces Sp ◽  
Ic50 Values ◽  
Induced Apoptosis

Four angucycline glycosides including three new compounds landomycin N (1), galtamycin C (2) and vineomycin D (3), and a known homologue saquayamycin B (4), along with two alkaloids 1-acetyl-β-carboline (5) and indole-3-acetic acid (6), were isolated from the fermentation broth of an intertidal sediments-derived Streptomyces sp. Their structures were established by IR, HR-ESI-MS, 1D and 2D NMR techniques. Among the isolated angucyclines, saquayamycin B (4) displayed potent cytotoxic activity against hepatoma carcinoma cells HepG-2, SMMC-7721 and plc-prf-5, with IC50 values 0.135, 0.033 and 0.244 μM respectively, superior to doxorubicin. Saquayamycin B (4) also induced apoptosis in SMMC-7721 cells as detected by its morphological characteristics in 4′,6-diamidino-2-phenylindole (DAPI) staining experiment.

Dual AKT inhibition with perifosine and GCP enhances apoptosis in prostate cancer: Clinical implications

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14096-14096
Author(s):  
R. L. Vinall ◽  
K. Hwa ◽  
C. Pan ◽  
P. Ghosh ◽  
P. N. Lara ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Western Blot ◽  
Cell Lines ◽  
Combination Treatment ◽  
Flow Cytometric Analysis ◽  
Fold Increase ◽  
Parp Cleavage ◽  
Clonogenic Potential ◽  
Ic50 Values ◽  
Induced Apoptosis

14096 Background: Genistein combined polysaccharide (GCP) has been shown to exhibit anti-cancer properties in both experimental and clinical models of prostate cancer (CaP). Perifosine is an alkylphospholipid with clinical anti-neoplastic activity. Both agents inhibit the AKT signaling pathway. Methods: Prostate cancer cell lines (LNCaP, LNCaP stably transfected with R273H or P151S p53 mutant allele, cds1, and PC3) were treated with GCP, perifosine, or both. IC50 values were established using the MTT assay. Apoptosis was assessed by flow cytometry, Western blot of PARP cleavage, and caspase activity. Clonogenic potential was assessed by colony assay. Status of AKT, p53, p21, AR and PSA was determined by Western blot. All experiments were performed in triplicate. Results: Perifosine inhibited AKT activity in all the cell lines. GCP had little or no effect on AKT activity but reduced AR and PSA levels. The combination of GCP and perifosine further increased the level of AKT inhibition and maintained inhibition for longer when compared to treatment with perifosine alone. Flow cytometric analysis of LNCaP revealed that combination treatment dramatically increased SubG1 levels (23-fold increase versus a 4.4-fold increase for GCP alone and a 6.5% increase for perifosine alone). Apoptosis was confirmed by PARP and caspase analysis. As single agents, the main effect of GCP or perifosine was to induce growth arrest as shown by a decrease in S-phase and increased p21. The cds1 cell line responded similarly to LNCaP, however, cell lines that expressed mutant p53 or were p53 null were not susceptible to GCP/perifosine-induced apoptosis. Combination treatment further decreased the clonogenic potential in all of the cell lines assessed when compared to treatment with the single agents alone. Conclusions: Treatment with a combination of the AKT inhibitors GCP and perifosine dramatically increases apoptosis and/or inhibits clonogenic potential in several CaP cell lines. The effect of the combination treatment on apoptosis appears to be dependent on p53 status. Clinical validation of these findings is warranted. A clinical trial of hormone therapy with or without GCP/perifosine is presently in development. No significant financial relationships to disclose.

scholarly journals Chemical Constituents of the Deep-Sea-Derived Penicillium solitum

Marine Drugs ◽  
2021 ◽  
Vol 19 (10) ◽  
pp. 580
Author(s):  
Zhi-Hui He ◽  
Jia Wu ◽  
Lin Xu ◽  
Man-Yi Hu ◽  
Ming-Ming Xie ◽  
...  
Keyword(s):  
Deep Sea ◽  
Chemical Constituents ◽  
A549 Cells ◽  
Acid Methyl Ester ◽  
2D Nmr ◽  
Positive Control ◽  
Ic50 Values ◽  
Penicillium Solitum ◽  
New Compounds

A systematic chemical investigation of the deep-sea-derived fungus Penicillium solitum MCCC 3A00215 resulted in the isolation of one novel polyketide (1), two new alkaloids (2 and 3), and 22 known (4–25) compounds. The structures of the new compounds were established mainly on the basis of exhaustive analysis of 1D and 2D NMR data. Viridicatol (13) displayed moderate anti-tumor activities against PANC-1, Hela, and A549 cells with IC50 values of around 20 μM. Moreover, 13 displayed potent in vitro anti-food allergic activity with an IC50 value of 13 μM, compared to that of 92 μM for the positive control, loratadine, while indole-3-acetic acid methyl ester (9) and penicopeptide A (10) showed moderate effects (IC50 = 50 and 58 μM, respectively).

scholarly journals Broad-Spectrum Antiviral Natural Products from the Marine-Derived Penicillium sp. IMB17-046

Molecules ◽  
2019 ◽  
Vol 24 (15) ◽  
pp. 2821 ◽  
Author(s):  
Jiao Li ◽  
Yujia Wang ◽  
Xiaomeng Hao ◽  
Shasha Li ◽  
Jia Jia ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Influenza A ◽  
2D Nmr ◽  
Antibacterial Activities ◽  
Gastric Diseases ◽  
X Ray Crystallography ◽  
Penicillium Sp ◽  
Ic50 Values ◽  
Antiviral Activities ◽  
New Compounds

A new pyrazine derivative, trypilepyrazinol (1), a new α-pyrone polyketide, (+)-neocitreoviridin (2), and a new ergostane analogue, 3β-hydroxyergosta-8,14,24(28)-trien-7-one (3), were isolated and characterized along with five known compounds from the marine-derived fungus Penicillium sp. IMB17-046. The structures of these new compounds were determined using spectroscopic data analyses (HRESIMS, 1D- and 2D-NMR), X-ray crystallography analysis, and TDDFT ECD calculation. Compounds 1 and 3 exhibited broad-spectrum antiviral activities against different types of viruses, including human immunodeficiency virus (HIV), hepatitis C virus (HCV), and influenza A virus (IAV), with IC50 values ranging from 0.5 to 7.7 μM. Compounds 1 and 2 showed antibacterial activities against Helicobacter pylori, a causative pathogen of various gastric diseases, with minimum inhibitory concentration (MIC) values of 1–16 μg/mL.

scholarly journals G1 Cell Cycle Arrest and Extrinsic Apoptotic Mechanisms Underlying the Anti-Leukemic Activity of CDK7 Inhibitor BS-181

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3845
Author(s):  
Shin Young Park ◽  
Ki Yun Kim ◽  
Do Youn Jun ◽  
Su-Kyeong Hwang ◽  
Young Ho Kim
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Jurkat Cells ◽  
Parp Cleavage ◽  
Caspase 8 ◽  
Down Regulation ◽  
Blocking Antibody ◽  
Cycle Arrest ◽  
G1 Cell Cycle Arrest ◽  
Induced Apoptosis

In vitro antitumor activity of the CDK7 inhibitor BS-181 against human T-ALL Jurkat cells was determined. Treatment of Jurkat clones (JT/Neo) with BS-181 caused cytotoxicity and several apoptotic events, including TRAIL/DR4/DR5 upregulation, c-FLIP down-regulation, BID cleavage, BAK activation, ΔΨm loss, caspase-8/9/3 activation, and PARP cleavage. However, the BCL-2-overexpressing Jurkat clone (JT/BCL-2) abrogated these apoptotic responses. CDK7 catalyzed the activating phosphorylation of CDK1 (Thr161) and CDK2 (Thr160), and CDK-directed retinoblastoma phosphorylation was attenuated in both BS-181-treated Jurkat clones, whereas only JT/BCL-2 cells exhibited G1 cell cycle arrest. The G1-blocker hydroxyurea augmented BS-181-induced apoptosis by enhancing TRAIL/DR4/DR5 upregulation and c-FLIP down-regulation. BS-181-induced FITC–annexin V-positive apoptotic cells were mostly in the sub-G1 and G1 phases. BS-181-induced cytotoxicity and mitochondrial apoptotic events (BAK activation/ΔΨm loss/caspase-9 activation) in Jurkat clones I2.1 (FADD-deficient) and I9.2 (caspase-8-deficient) were significantly lower than in A3 (wild-type). Exogenously added recombinant TRAIL (rTRAIL) markedly synergized BS-181-induced apoptosis in A3 cells but not in normal peripheral T cells. The cotreatment cytotoxicity was significantly reduced by the DR5-blocking antibody but not by the DR4-blocking antibody. These results demonstrated that the BS-181 anti-leukemic activity is attributed to extrinsic TRAIL/DR5-dependent apoptosis preferentially induced in G1-arrested cells, and that BS-181 and rTRAIL in combination may hold promise for T-ALL treatment.

scholarly journals Potent Quinoline-Containing Combretastatin A-4 Analogues: Design, Synthesis, Antiproliferative, and Anti-Tubulin Activity

2020 ◽  
Vol 13 (11) ◽  
pp. 393
Author(s):  
Tarek S. Ibrahim ◽  
Mohamed M. Hawwas ◽  
Azizah M. Malebari ◽  
Ehab S. Taher ◽  
Abdelsattar M. Omar ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Tubulin Polymerization ◽  
Design Synthesis ◽  
Cycle Arrest ◽  
M Phase ◽  
Ic50 Values ◽  
Low Cytotoxicity ◽  
Induced Apoptosis ◽  
Derivatives Of ◽  
Mcf 7

A novel series of quinoline derivatives of combretastatin A-4 incorporating rigid hydrazone and a cyclic oxadiazole linkers were synthesized and have demonstrated potent tubulin polymerization inhibitory properties. Many of these novel derivatives have shown significant antiproliferative activities in the submicromolar range. The most potent compound, 19h, demonstrated superior IC50 values ranging from 0.02 to 0.04 µM against four cancer cell lines while maintaining low cytotoxicity in MCF-10A non-cancer cells, thereby suggesting 19h’s selectivity towards proliferating cancer cells. In addition to tubulin polymerization inhibition, 19h caused cell cycle arrest in MCF-7 cells at the G2/M phase and induced apoptosis. Collectively, these findings indicate that 19h holds potential for further investigation as a potent chemotherapeutic agent targeting tubulin.

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