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1.
Biochem Biophys Res Commun ; 636(Pt 2): 1-9, 2022 12 25.
Artículo en Inglés | MEDLINE | ID: mdl-36335857

RESUMEN

Edible mushrooms are known to exert anti-inflammatory effects. In this study, the effects of ethanol extracts from edible mushrooms, such as Hericium erinaceus, and other edible mushrooms on inflammatory responses were investigated. Experiments were conducted using the inflammatory responses of human monocytes induced by lipopolysaccharide (LPS), a bacterial component, that provokes inflammation. Notably, we demonstrated that LPS mixed with ethanol and hot water extracts derived from edible mushrooms attenuated the production of inflammatory cytokines, such as interleukin (IL)-1ß, -6, and -8, induced by LPS in human monocytic cell cultures. Moreover, we found that the ethanol extract of H. erinaceus contained ergosterol, which attenuated IL-8 production in LPS-stimulated cells. Subsequent component analysis of the ethanol extract of H. erinaceus revealed that ergosterol binds to lipid A to attenuate LPS-induced inflammation. Together, our findings suggest that ergosterol in ethanol extracts from edible mushrooms can prevent the induction of inflammation by binding to LPS.


Asunto(s)
Agaricales , Lipopolisacáridos , Humanos , Lipopolisacáridos/uso terapéutico , Ergosterol/farmacología , Etanol , Monocitos/metabolismo , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Agaricales/metabolismo , Inflamación/tratamiento farmacológico , Citocinas/metabolismo
2.
Chemistry ; 28(52): e202201426, 2022 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-35729456

RESUMEN

A novel neutral diradical of π-extended phenalenyl derivative having three oxo-groups, tri-tert-butyl-1,4,7-trioxophenalenyl, and two types of the corresponding σ-dimers were investigated. Quantum chemical calculations showed that the neutral diradical is in triplet ground state having doubly degenerate singly occupied molecular orbitals. The neutral diradical undergoes a σ-dimerization, generating two types of σ-dimers immediately after the preparation. One of the σ-dimers, which was selectively generated in the crystalline state, was a close-shell dimer linked through double-σ-bonds on the phenalenyl skeleton with a long C-C bond length of 1.66 Å. The other σ-dimer, which existed only in the solution state, was a peroxy-linked open-shell dimer in which one σ-bond was formed between two oxygen atoms. Furthermore, the temperature-dependent 1 H NMR and ESR spectra revealed that these σ-dimers are in equilibrium in the solution state by the reversible σ-bond formation/cleavage via the neutral diradical as a key intermediate.

3.
Biochem Biophys Res Commun ; 584: 7-14, 2021 12 20.
Artículo en Inglés | MEDLINE | ID: mdl-34753066

RESUMEN

Patients with triple-negative breast cancer have a poor prognosis as only a few efficient targeted therapies are available. Cancer cells are characterized by their unregulated proliferation and require large amounts of nucleotides to replicate their DNA. One-carbon metabolism contributes to purine and pyrimidine nucleotide synthesis by supplying one carbon atom. Although mitochondrial one-carbon metabolism has recently been focused on as an important target for cancer treatment, few specific inhibitors have been reported. In this study, we aimed to examine the effects of DS18561882 (DS18), a novel, orally active, specific inhibitor of methylenetetrahydrofolate dehydrogenase (MTHFD2), a mitochondrial enzyme involved in one-carbon metabolism. Treatment with DS18 led to a marked reduction in cancer-cell proliferation; however, it did not induce cell death. Combinatorial treatment with DS18 and inhibitors of checkpoint kinase 1 (Chk1), an activator of the S phase checkpoint pathway, efficiently induced apoptotic cell death in breast cancer cells and suppressed tumorigenesis in a triple-negative breast cancer patient-derived xenograft model. Mechanistically, MTHFD2 inhibition led to cell cycle arrest and slowed nucleotide synthesis. This finding suggests that DNA replication stress occurs due to nucleotide shortage and that the S-phase checkpoint pathway is activated, leading to cell-cycle arrest. Combinatorial treatment with both inhibitors released cell-cycle arrest, but induced accumulation of DNA double-strand breaks, leading to apoptotic cell death. Collectively, a combination of MTHFD2 and Chk1 inhibitors would be a rational treatment option for patients with triple-negative breast cancer.


Asunto(s)
Aminohidrolasas/antagonistas & inhibidores , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/antagonistas & inhibidores , Inhibidores Enzimáticos/uso terapéutico , Metilenotetrahidrofolato Deshidrogenasa (NADP)/antagonistas & inhibidores , Enzimas Multifuncionales/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Administración Oral , Aminohidrolasas/metabolismo , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/metabolismo , Quimioterapia Combinada , Inhibidores Enzimáticos/administración & dosificación , Femenino , Humanos , Metilenotetrahidrofolato Deshidrogenasa (NADP)/metabolismo , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Enzimas Multifuncionales/metabolismo , Puntos de Control de la Fase S del Ciclo Celular/efectos de los fármacos , Neoplasias de la Mama Triple Negativas/enzimología , Neoplasias de la Mama Triple Negativas/patología , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
4.
Biosci Biotechnol Biochem ; 83(12): 2280-2287, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31412751

RESUMEN

The increasing number of patients suffering from allergic diseases is a global health problem. Grifola frondosa is an edible mushroom consumed as a health food in Asia, and has recently been reported to have anti-allergic effects. We previously reported that G. frondosa extract (GFE) and its active components, ergosterol and its derivatives, inhibited the antigen-induced activation of RBL-2H3 cells. Here, we demonstrated that GFE and ergosterol also had an inhibitory effect on the degranulation of bone marrow-derived mast cells (BMMCs) and alleviated anaphylactic cutaneous responses in mice. Using an air pouch-type allergic inflammation mouse model, we confirmed that oral administration of GFE and ergosterol suppressed the degranulation of mast cells in vivo. Our findings suggest that G. frondosa, including ergosterol as its active component, reduces type I allergic reactions by suppressing mast cell degranulation in mice, and might be a novel functional food that prevents allergic diseases.


Asunto(s)
Degranulación de la Célula/efectos de los fármacos , Ergosterol/farmacología , Grifola/química , Hipersensibilidad/prevención & control , Mastocitos/efectos de los fármacos , Extractos Vegetales/farmacología , Animales , Permeabilidad Capilar/efectos de los fármacos , Línea Celular , Modelos Animales de Enfermedad , Alimentos Funcionales , Liberación de Histamina/efectos de los fármacos , Hipersensibilidad/patología , Masculino , Ratones , Ratones Endogámicos ICR , beta-N-Acetilhexosaminidasas/antagonistas & inhibidores
5.
Biosci Biotechnol Biochem ; 82(10): 1803-1811, 2018 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-29968517

RESUMEN

Grifola frondosa is an edible mushroom consumed as a health food and/or traditional medicine in Asia. However, the anti-allergic effects of G. frondosa are not yet understood. In this study, we demonstrated the effects of G. frondosa extract (GFE) on IgE-mediated allergic responses, using antigen-stimulated RBL-2H3 cells. Three active compounds: ergosterol, 6ß-methoxyergosta-7,22-dien-3ß,5α-diol (MEDD), and 6-oxoergosta-7,22-dien-3ß-ol (6-OXO) were isolated from GFE and shown to inhibit the antigen-induced release of ß-hexosaminidase and histamine. Among the three active components, we focused on ergosterol because of its high content in GFE. Ergosterol inhibited the aggregation of high-affinity IgE receptor (FcεRI), which is the first step in the activation of mast cells and antigen-induced tyrosine phosphorylation. Furthermore, ergosterol suppressed antigen-increased IL-4 and TNF-α mRNA. Taken together, our findings suggest that G. frondosa, including ergosterol and its derivatives as active components, has the potential to be a novel functional food that prevents type I allergies.


Asunto(s)
Antígenos/inmunología , Degranulación de la Célula/efectos de los fármacos , Degranulación de la Célula/inmunología , Ergosterol/farmacología , Grifola/química , Mastocitos/efectos de los fármacos , Receptores de IgE/efectos de los fármacos , Animales , Espectroscopía de Resonancia Magnética con Carbono-13 , Línea Celular , Ergosterol/química , Alimentos Funcionales , Liberación de Histamina/efectos de los fármacos , Mastocitos/inmunología , Espectroscopía de Protones por Resonancia Magnética , Ratas , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores de IgE/inmunología , Espectrometría de Masa por Ionización de Electrospray
6.
Chemistry ; 22(44): 15819-15825, 2016 Oct 24.
Artículo en Inglés | MEDLINE | ID: mdl-27624861

RESUMEN

Many natural terpenoid alkaloid conjugates show biological activity because their structures contain both sp3 -rich terpenoid scaffolds and nitrogen-containing alkaloid scaffolds. However, their biosynthesis utilizes a limited set of compounds as sources of the terpenoid moiety. The production of terpenoid alkaloids containing various types of terpenoid moiety may provide useful, chemically diverse compound libraries for drug discovery. Herein, we report the construction of a library of terpenoid alkaloid-like compounds based on Lewis-acid-catalyzed transannulation of humulene diepoxide and subsequent sequential olefin metathesis. Cheminformatic analysis quantitatively showed that the synthesized terpenoid alkaloid-like compound library has a high level of three-dimensional-shape diversity. Extensive pharmacological screening of the library has led to the identification of promising compounds for the development of antihypolipidemic drugs. Therefore, the synthesis of terpenoid alkaloid-like compound libraries based on humulene is well suited to drug discovery. Synthesis of terpenoid alkaloid-like compounds based on several natural terpenoids is an effective strategy for producing chemically diverse libraries.


Asunto(s)
Alcaloides/química , Terpenos/química , Descubrimiento de Drogas , Estructura Molecular , Sesquiterpenos Monocíclicos , Extractos Vegetales , Sesquiterpenos , Bibliotecas de Moléculas Pequeñas
7.
Front Med (Lausanne) ; 11: 1396783, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38887673

RESUMEN

Background: L-ergothioneine (EGT), an antioxidative and anti-inflammatory amino acid, is abundant in various mushroom fruiting bodies. Meanwhile, the effects of EGT-containing mushrooms on human skin are unknown. This study investigated the effects of oral ingestion of a novel EGT-rich strain of Pleurotus species (hiratake) on skin conditions in humans. Methods: We conducted a 12-week, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate skin moisturizing functions and facial conditions in 80 healthy women who were randomly assigned to either a group that was supplemented with hiratake tablets containing 25 mg of EGT/day or a placebo group. Skin moisture content, transepidermal water loss (TEWL), and facial scores (VISIA scores) were measured at baseline, 8 weeks, and 12 weeks of supplementation. Results: At 8 weeks, the skin moisture content was significantly higher on the temple in the hiratake group than in the placebo group. The hiratake group also exhibited a significant increase in skin moisture content on the arm at 8 and 12 weeks compared with baseline. At 12 weeks, wrinkle and texture scores were significantly better in the hiratake group than in the placebo group, and plasma EGT concentrations in the hiratake group were 4.7-fold higher than baseline (from 3.4 to 15.9 µM). Furthermore, EGT concentrations in plasma were significantly correlated with improvements in skin moisture content and TEWL on the arm, implying that these skin moisturizing benefits could be partly attributed to EGT. A stratified analysis of participants with a low baseline plasma EGT concentration (< 3.3 µM) revealed that skin moisture content on the temple was significantly higher at 8 and 12 weeks, and skin moisture content on the arm at 12 weeks tended to be higher (p = 0.074), in the hiratake group than in the placebo group. These findings suggested that oral ingestion of EGT-rich hiratake can improve skin moisturizing functions. Conclusion: EGT-rich hiratake may help maintain skin conditions in healthy women, and EGT may play a role in these beneficial effects.

8.
ACS Med Chem Lett ; 15(7): 1010-1016, 2024 Jul 11.
Artículo en Inglés | MEDLINE | ID: mdl-39015278

RESUMEN

Previously, we reported the new pyrido-pyridazinone template as a feline sarcoma-related (FER) tyrosine kinase inhibitor. Representative compound 1 (DS21360717) showed strong enzyme inhibitory activity (IC50 = 0.5 nM), however, its antitumor effect was insufficient, probably due to poor solubility and resultant low bioavailability (BA). In addition, the kinase selectivity was inadequate, which may result in certain safety risks. Here, we focused on derivatization of the unoptimized C-5 position to obtain promising FER inhibitors possessing strong antitumor effects and improved selectivity, referring to their X-ray crystal structure and the docking model with FES proto-oncogene tyrosine kinase as an FER surrogate. While establishing the synthetic route of the pyrido-pyridazinone scaffold, we obtained a desired compound via our derivatization. Our optimized compound 17c (DS08701581) showed the highest class cell-free and cell activities in this template, good oral BA, and improved kinase selectivity, resulting in significant tumor growth inhibition in the Ba/F3-FER tumor model without body weight loss.

9.
Chemistry ; 19(36): 11904-15, 2013 Sep 02.
Artículo en Inglés | MEDLINE | ID: mdl-23922181

RESUMEN

The tri-tert-butylphenalenyl (TBPLY) radical exists as a π dimer in the crystal form with perfect overlapping of the singly occupied molecular orbitals (SOMOs) causing strong antiferromagnetic exchange interactions. 2,5-Di-tert-butyl-6-oxophenalenoxyl (6OPO) is a phenalenyl-based air-stable neutral π radical with extensive spin delocalization and is a counter analogue of phenalenyl in terms of the topological symmetry of the spin density distribution. X-ray crystal structure analyses showed that 8-tert-butyl- and 8-(p-XC6H4)-6OPOs (X=I, Br) also form π dimers in the crystalline state. The π-dimeric structure of 8-tert-butyl-6OPO is seemingly similar to that of TBPLY even though its SOMO-SOMO overlap is small compared with that of TBPLY. The 8-(p-XC6H4) derivatives form slipped stacking π dimers in which the SOMO-SOMO overlaps are greater than in 8-tert-butyl-6OPO, but still smaller than in TBPLY. The solid-state electronic spectra of the 6OPO derivatives show much weaker intradimer charge-transfer bands, and SQUID measurements for 8-(p-BrC6H4)-6OPO show a weak antiferromagnetic exchange interaction in the π dimer. These results demonstrate that the control of the spin distribution patterns of the phenalenyl skeleton switches the mode of exchange interaction within the phenalenyl-based π dimer. The formation of the relevant multicenter-two-electron bonds is discussed.

10.
Front Nutr ; 9: 1078060, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36698463

RESUMEN

Background: Mushrooms are rich in dietary fiber, and fiber intake has been reported to increase the levels of short-chain fatty acids (SCFAs). It has also been reported that SCFAs promote immunoglobulin A (IgA) production, indicating involvement in systemic immunity. Objectives: The objective of this study was to evaluate the effects of mushroom consumption on the amount of intestinal IgA. We also aimed to comprehensively evaluate the gut microbiota and intestinal metabolome and to conduct an exploratory analysis of their relationship with IgA. Methods: Healthy adults (n = 80) were enrolled in a parallel group trial. Participants consumed a diet with mushrooms or a placebo diet once daily for 4 weeks. Gut microbiota profiles were assessed by sequencing the bacterial 16S ribosomal RNA-encoding gene. Intestinal metabolome profiles were analyzed using capillary electrophoresis-time of flight mass spectrometry (CE-TOFMS). Results: Mushroom consumption tended to increase IgA levels at 4 weeks of consumption compared to those in the control group (p = 0.0807; Hedges' g = 0.480). The mushroom group had significantly higher levels of intestinal SCFAs, such as butyrate and propionate, than the control group (p = 0.001 and 0.020; Hedges' g = 0.824 and 0.474, respectively). Correlation analysis between the changes in the amount of intestinal IgA and the baseline features of the intestinal environment showed that the increasing amount of intestinal IgA was positively correlated with the baseline levels of SCFAs (Spearman's R = 0.559 and 0.419 for butyrate and propionate, respectively). Conclusion: Consumption of mushrooms significantly increased the intestinal SCFAs and IgA in some subjects. The increase in intestinal IgA levels was more prominent in subjects with higher SCFA levels at baseline. This finding provides evidence that mushroom alters the intestinal environment, but the intensity of the effect still depends on the baseline intestinal environment. This trial was registered at www.umin.ac.jp as UMIN000043979.

11.
Org Lett ; 24(4): 1033-1037, 2022 Feb 04.
Artículo en Inglés | MEDLINE | ID: mdl-35050630

RESUMEN

Tri-tert-butylated 4,7-dihydroxyphenalenone was designed and synthesized from a corresponding 4,9-dimethoxyphenalenone derivative by regioselective deoxygenation/oxygenation. The 4,7-dihydroxyphenalenone derivative showed a chromic behavior accompanied by protonation and deprotonation, giving monocation and dianion species, respectively, and their C3 symmetric electronic structures were elucidated by experimental and theoretical methods.

12.
Artículo en Inglés | MEDLINE | ID: mdl-32544819

RESUMEN

ATP-binding cassette transporter C4 (ABCC4) is associated with multidrug resistance and the regulation of cell signalling. Some prostaglandins (PGs), including: PGE2, PGF2α, PGE3, and PGF3α are known substrates of ABCC4, and are released from some types of cells to exert their biological effects. In the present study, we demonstrate that PGD2 is a novel substrate of ABCC4 using a transport assay based on inside-out membrane vesicles prepared from ABCC4-overexpressing cells. Then, we used two types of cell lines with confirmed ABCC4 mRNA and PGD2 release capacity (human mast cell lines HMC-1 cells and human rhabdomyosarcoma cell lines TE671 cells) to evaluate the contribution of ABCC4. The extracellular levels of PGD2 were unchanged following addition of a selective ABCC4 inhibitor in TE671 cells. Pharmacological inhibition and knockdown of ABCC4 significantly reduced the extracellular levels of PGD2 by at least 53% in HMC-1 cells. Moreover, the extracellular levels of PGD2 decreased by at least 20% using the selective ABCC4 inhibitor in the other mast cell line RBL-2H3 cells. Therefore, our results suggest that ABCC4 functions as a PGD2 exporter in HMC-1 cells.


Asunto(s)
Mastocitos/metabolismo , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Prostaglandina D2/metabolismo , Transporte Biológico Activo , Línea Celular Tumoral , Humanos
13.
Food Sci Nutr ; 8(2): 1030-1037, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32148811

RESUMEN

Maltobionic acid is known to have an inhibitory effect on the differentiation of osteoclasts, and it has also been reported in an intervention trial that ingestion of corn syrup solids containing maltobionic acid maintained and increased the bone density of postmenopausal women. However, there is no information on whether maltobionic acid improves bone metabolism in humans. Therefore, we evaluated the influence of corn syrup solids containing maltobionic acid (maltobionic acid calcium salt) on bone resorption markers in healthy Japanese women. Forty-one individuals were selected from 68 participants and assigned to two groups: 21 individuals in the test food antecedent group and 20 individuals in the placebo food antecedent group; individuals in the first group ingested 4 g of corn syrup solids containing maltobionic acid, and subjects in the second group ingested 4 g of placebo (hydrous crystalline maltose and calcium carbonate) for 4 weeks. Bone resorption marker levels (DPD and u-NTx) were evaluated by urinalysis. Forty subjects completed the study, and no adverse events related to the test food were observed. Fourteen subjects were excluded prior to the efficacy analysis because of conflict with the control criteria; the remaining 33 subjects were analyzed. Consumption of corn syrup solids containing maltobionic acid was maintained; DPD and u-NTx values were improved (p < .05). These results indicate that corn syrup solids containing maltobionic acid might contribute to suppress bone resorption and improve bone metabolism in postmenstrual women. (UMIN-CTR ID: UMIN000034257; Foundation: San-ei Sucrochemical Co., Ltd.).

14.
J Vet Med Sci ; 71(6): 713-7, 2009 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-19578278

RESUMEN

The purpose of this study was to investigate the pathology of zymosan-induced arthritis in the SKG mouse model of rheumatoid arthritis in humans, and to validate this model as a reliable drug screening system. To achieve this purpose, methotrexate (1 or 10 mg/kg, once daily) or vehicle only was administered intraperitoneally to SKG mice with zymosan-induced arthritis. Histologically, this arthritis was characterized by the presence of granulation tissue rich in granulocytes. Methotrexate suppressed the development of arthritis in ankle and wrist joints in both clinical and histological studies. These results indicated that methotrexate has not only prophylactic, but also therapeutic effects on zymosan-induced arthritis developed in SKG mice and may thus be a promising control agent for drug research in the SKG mouse model of rheumatoid arthritis.


Asunto(s)
Antirreumáticos/farmacología , Artritis Experimental/prevención & control , Artritis Reumatoide/prevención & control , Metotrexato/farmacología , Animales , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/patología , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/patología , Modelos Animales de Enfermedad , Femenino , Inmunohistoquímica , Ratones , Ratones Endogámicos BALB C , Distribución Aleatoria
15.
ACS Med Chem Lett ; 10(6): 893-898, 2019 Jun 13.
Artículo en Inglés | MEDLINE | ID: mdl-31223444

RESUMEN

Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) plays a key role in one-carbon (1C) metabolism in human mitochondria, and its high expression correlates with poor survival of patients with various types of cancer. An isozyme-selective MTHFD2 inhibitor is highly attractive for potential use in cancer treatment. Herein, we disclose a novel isozyme-selective MTHFD2 inhibitor DS44960156, with a tricyclic coumarin scaffold, which was initially discovered via high-throughput screening (HTS) and improved using structure-based drug design (SBDD). DS44960156 would offer a good starting point for further optimization based on the following features: (1) unprecedented selectivity (>18-fold) for MTHFD2 over MTHFD1, (2) a molecular weight of less than 400, and (3) good ligand efficiency (LE).

16.
J Med Chem ; 62(22): 10204-10220, 2019 11 27.
Artículo en Inglés | MEDLINE | ID: mdl-31638799

RESUMEN

We report the discovery of a potent and isozyme-selective MTHFD2 inhibitor, DS18561882 (2). Through investigation of the substituents on our tricyclic coumarin scaffold (1,2,3,4-tetrahydrochromeno[3,4-c]pyridin-5-one), MTHFD2 inhibitory activity was shown to be elevated by incorporating an amine moiety at the 8-position and a methyl group at the 7-position of the initial lead 1. X-ray structure analysis revealed that a key interaction for enhanced potency was salt bridge formation between the amine moiety and the diphosphate linker of an NAD+ cofactor. Furthermore, ortho-substituted sulfonamide in place of benzoic acid of 1 significantly improved cell permeability and cell-based growth inhibition against a human breast cancer cell line. The thus-optimized DS18561882 showed the strongest cell-based activity (GI50 = 140 nM) in the class, a good oral pharmacokinetic profile, and thereby tumor growth inhibition in a mouse xenograft model upon oral administration.


Asunto(s)
Aminohidrolasas/antagonistas & inhibidores , Antineoplásicos/química , Antineoplásicos/farmacología , Metilenotetrahidrofolato Deshidrogenasa (NADP)/antagonistas & inhibidores , Enzimas Multifuncionales/antagonistas & inhibidores , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Línea Celular Tumoral , Permeabilidad de la Membrana Celular/efectos de los fármacos , Cristalografía por Rayos X , Femenino , Humanos , Masculino , Ratones Endogámicos BALB C , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto
18.
Org Lett ; 20(22): 7317-7320, 2018 11 16.
Artículo en Inglés | MEDLINE | ID: mdl-30395476

RESUMEN

An unnatural terpenoid scaffold containing a bicyclo[5.4.0]undecane moiety, as well as a salvialane skeleton based on an intramolecular C-C bond formation strategy were synthesized. Such a strategy was made possible by the removal of strained E-olefin conformations of the humulene skeleton. Some compounds were identified to show PPARα antagonist activity.

19.
Int J Oncol ; 48(4): 1670-8, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26893131

RESUMEN

Agaricus blazei (A. blazei) is a mushroom with many biological effects and active ingredients. We purified a tumoricidal substance from A. blazei, an ergosterol derivative, and named it 'Agarol'. Cytotoxic effects of Agarol were determined by the MTT assay using A549, MKN45, HSC-3, and HSC-4 human carcinoma cell lines treated with Agarol. Apoptosis was detected by flow cytometry analysis. Reactive oxygen species (ROS) levels and mitochondria membrane potential (∆ψm) were also determined by flow cytometry. Western blot analysis was used to quantify the expression of apoptosis-related proteins. Agarol predominantly induced apoptosis in two p53-wild cell lines (A549 and MKN45) compared to the other p53-mutant cell lines (HSC-3 and HSC-4). Further mechanistic studies revealed that induction of apoptosis is associated with increased generation of ROS, reduced ∆ψm, release of apoptosis-inducing factor (AIF) from the mitochondria to the cytosol, upregulation of Bax, and downregulation of Bcl-2. Caspase-3 activities did not increase, and z-VAD-fmk, a caspase inhibitor, did not inhibit the Agarol-induced apoptosis. These findings indicate that Agarol induces caspase-independent apoptosis in human carcinoma cells through a mitochondrial pathway. The in vivo anticancer activity of Agarol was confirmed in a xenograft murine model. This study suggests a molecular mechanism by which Agarol induces apoptosis in human carcinoma cells and indicates the potential use of Agarol as an anticancer agent.


Asunto(s)
Agaricus/química , Antineoplásicos/administración & dosificación , Ergosterol/administración & dosificación , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Especies Reactivas de Oxígeno/metabolismo , Animales , Antineoplásicos/farmacología , Apoptosis , Caspasas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ergosterol/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Ratones , Neoplasias/metabolismo , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
20.
Org Lett ; 5(18): 3289-91, 2003 Sep 04.
Artículo en Inglés | MEDLINE | ID: mdl-12943409

RESUMEN

[structure: see text] Topological symmetry-based extensions of a pi-conjugation network in an odd alternant phenalenyl radical have enabled us to control the spin density distribution systematically. ESR/ENDOR and NICS studies on the topological isomers of oxophenalenoxyl have revealed that the unpaired electron tends to localize in the antiaromatic ring systems.

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