RESUMO
Mycobacterium avium complex (MAC) is a serious disease that is mainly caused by infection with the non-tuberculous mycobacteria (NTM), Mycobacterium avium and Mycobacterium intracellulare. Seven new compounds, designated mavintramycins A-G (1-7), were isolated along with structurally related compounds, including amicetin (9) and plicacetin (10), from the culture broth of Streptomyces sp. OPMA40551 as anti-MAC compounds that were active against M. avium and M. intracellulare. Among them, mavintramycin A showed the most potent and selective inhibition of M. avium and M. intracellulare. Furthermore, mavintramycin A was active against more than 40 clinically isolated M. avium, including multidrug-resistant strains, and inhibited the growth of M. avium in a persistent infection cell model using THP-1 macrophages. Mavintramycin A also exhibited in vivo efficacy in silkworm and mouse infection assays with NTM. An experiment to elucidate its mechanism of action revealed that mavintramycin A inhibits protein synthesis by binding to 23S ribosomal RNA in NTM. Mavintramycin A, with a different chemical structure from those of clinically used agents, is a promising drug candidate for the treatment of MAC infectious disease.
Assuntos
Doenças Transmissíveis , Infecção por Mycobacterium avium-intracellulare , Animais , Camundongos , Complexo Mycobacterium avium , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Infecção por Mycobacterium avium-intracellulare/tratamento farmacológico , Infecção por Mycobacterium avium-intracellulare/microbiologia , Mycobacterium aviumRESUMO
BACKGROUND: Postmenopausal estrogen decline increases the risk of developing nonalcoholic steatohepatitis (NASH), and it might accelerate progression to cirrhosis and hepatocellular carcinoma. AIMS: This study aimed to investigate a novel therapy for postmenopausal women who are diagnosed with NASH. METHODS: Seven-week-old female C57BL/6 J mice were divided into three experimental groups as follows: (1) sham operation (SHAM group), (2) ovariectomy (OVX group), and (3) ovariectomy + 0.02% astaxanthin (OVX + ASTX group). These three groups of mice were fed a choline-deficient high-fat (CDHF) diet for 8 weeks. Blood serum and liver tissues were collected to examine liver injury, histological changes, and hepatic genes associated with NASH. An in vitro study was performed with the hepatic stellate cell line LX-2. RESULTS: The administration of ASTX significantly improved pathological NASH with suppressed steatosis, inflammation, and fibrosis, in comparison with those in the OVX-induced estrogen deficiency group. As a result, liver injury was also attenuated with reduced levels of alanine aminotransferase and aspartate transaminase. In addition, our study found that ASTX supplementation decreased hepatic osteoprotegerin (OPG) in vivo, a possible factor that contributes to NASH development. In vitro, this study further confirmed that ASTX has an inhibitory effect on the secretion of OPG in LX-2 human hepatic stellate cells. CONCLUSIONS: Our findings suggest that ASTX alleviates CDHF-OVX-induced pathohistological NASH with downregulated OPG, possibly via suppression of the transforming growth factor beta pathway. ASTX could has promise for use in postmenopausal women diagnosed with NASH.
Assuntos
Hepatopatia Gordurosa não Alcoólica , Feminino , Humanos , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Colina , Dieta Hiperlipídica/efeitos adversos , Regulação para Baixo , Osteoprotegerina/genética , Osteoprotegerina/metabolismo , Osteoprotegerina/farmacologia , Camundongos Endogâmicos C57BL , Fígado/patologia , Cirrose Hepática/patologia , Fibrose , Estrogênios/farmacologia , DietaRESUMO
Using activity guided purification, four known compounds, sesquiterpene atractylenolide III (1), and the polyacetylenes 14-acetoxy-12-senecioyloxytetradeca-2E,8E,10E-trien-4,6-diyn-1-ol (2), 14-acetoxy-12-α-methylbutyl-2E,8E,10E-trien-4,6-diyn-1-ol (3), and 14-acetoxy-12-ß -methylbutyl-2E,8E,10E-trien-4,6-diyn-1-ol (4), were isolated from a traditional herbal medicine, Atractylodes rhizome. Structurally similar 3 and 4 (3/4 mixture) were obtained as a mixture. In intact Chinese hamster ovary (CHO) K1 cell assays, 1, 2, and a 3/4 mixture selectively inhibited cholesterol [14C]oleate synthesis from [14C]oleate with IC50 values of 73.5 µM, 35.4 µM, and 10.2 µM, respectively, without any effects on cytotoxicity. As a potential target of these inhibitors involved in cholesteryl ester (CE) synthesis, effects on sterol O-acyltransferase (SOAT) activity were investigated using microsomes prepared from CHO-K1 cells as an enzyme source. Hence, these compounds inhibit SOAT activity with IC50 values (211 µM for 1, 29.0 µM for 2, and 11.8 µM for 3/4 mixture) that correlate well with those measured from intact cell assays. Our results strongly suggest that these compounds inhibit CE synthesis by blocking SOAT activity in CHO-K1 cells.
Assuntos
Atractylodes/química , Ésteres do Colesterol/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Poli-Inos/farmacologia , Rizoma/química , Animais , Células CHO , Cricetulus , Ensaios Enzimáticos , Inibidores Enzimáticos/isolamento & purificação , Lactonas/isolamento & purificação , Lactonas/farmacologia , Microssomos/efeitos dos fármacos , Poli-Inos/isolamento & purificação , Sesquiterpenos/isolamento & purificação , Sesquiterpenos/farmacologia , Esterol O-Aciltransferase/antagonistas & inibidoresRESUMO
The fungal 13-membered cyclodepsipeptides, beauveriolides I and III, were previously reported to be atheroprotective activity in mouse models via inhibiting sterol O-acyltransferase (SOAT) activity. A total of 149 beauveriolide derivatives (BVDs) synthesized combinatorially were evaluated in in silico absorption, distribution, metabolism and excretion (ADME) analysis and inhibitory activity toward the two SOAT isozymes, SOAT1 and SOAT2. Hence, only 11 BVDs exhibited SOAT2-selective inhibition. Among these, we chose BVD327, which had the highest ADME score, for further evaluation. BVD327 administration (50 mg/kg/d, per os (p.o.)) significantly decreased atherosclerotic lesions in the aorta and heart (25.4 ± 6.9 and 20.6 ± 2.9%, respectively) in apolipoprotein E knockout (Apoe-/-) mice fed a cholesterol-enriched diet (0.2% cholesterol and 21% fat) for 12 weeks. These findings indicate that beauveriolide derivatives can be used as anti-atherosclerotic agents.
Assuntos
Aterosclerose/tratamento farmacológico , Esterol O-Aciltransferase/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Aorta/efeitos dos fármacos , Aorta/patologia , Aterosclerose/metabolismo , Aterosclerose/patologia , Proteínas Sanguíneas/metabolismo , Barreira Hematoencefálica/metabolismo , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP2D6/metabolismo , Canal de Potássio ERG1/genética , Valvas Cardíacas/efeitos dos fármacos , Valvas Cardíacas/patologia , Humanos , Absorção Intestinal , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos Knockout para ApoE , Esterol O-Aciltransferase/metabolismo , Esterol O-Aciltransferase 2RESUMO
New terpendoles N-P (1-3) were isolated along with 8 structurally related known compounds including terpendoles and voluhemins from a culture broth of the fungus Volutella citrinella BF-0440. The structures of 1-3 were elucidated using various spectroscopic experiments including 1D- and 2D-NMR. All compounds 1-3 contained a common indole-diterpene backbone. Compounds 2 and 3 had 7 and 6 consecutive ring systems with an indole ring, respectively, whereas 1 had a unique indolinone plus 4 consecutive ring system. Compounds 2 and 3 inhibited both sterol O-acyltransferase 1 and 2 isozymes, but 1 lost the inhibitory activity. Structure-activity relationships of fungal indole-diterpene compounds are discussed.
Assuntos
Diterpenos/química , Hypocreales/química , Esterol O-Aciltransferase/antagonistas & inibidores , Animais , Células CHO , Cricetulus , Diterpenos/isolamento & purificação , Hypocreales/metabolismo , Indóis/química , Isoenzimas/antagonistas & inibidores , Espectroscopia de Ressonância Magnética , Relação Estrutura-AtividadeRESUMO
The effects of 14 sesquiterpene hydroquinones, including 8 marine sponge-derived avarols (1-8) and 6 semisynthetic derivatives (9-14), on lipid droplet accumulation and neutral lipid synthesis in Chinese hamster ovary (CHO) K1 cells were investigated. In intact CHO-K1 cell assays, avarol (1) markedly decreased the number and size of lipid droplets in CHO-K1 cells and exhibited the most potent inhibitory activity on the synthesis of cholesteryl ester (CE) and triglyceride (TG) with IC50 values of 5.74 and 6.80⯵M, respectively. In enzyme assays, sterol O-acyltransferase (SOAT), the final enzyme involved in CE biosynthesis, and diacylglycerol acyltransferase (DGAT), the final enzyme involved in TG biosynthesis, were inhibited by 1 with IC50 values of 7.31 and 20.0⯵M, respectively, which correlated well with those obtained in the intact cell assay. These results strongly suggest that 1 inhibited SOAT and DGAT activities in CHO-K1 cells, leading to a reduction in the accumulation of CE and TG in lipid droplets.
Assuntos
Lipídeos/antagonistas & inibidores , Sesquiterpenos/farmacologia , Animais , Células CHO , Cricetulus , Relação Dose-Resposta a Droga , Gotículas Lipídicas/efeitos dos fármacos , Lipídeos/síntese química , Lipídeos/química , Estrutura Molecular , Tamanho da Partícula , Poríferos , Sesquiterpenos/síntese química , Sesquiterpenos/química , Relação Estrutura-Atividade , Propriedades de SuperfícieRESUMO
Callyspongiamides A (1) and B (2), two new sterol O-acyltransferase (SOAT) inhibitors, were isolated from the Indonesian marine sponge Callyspongia sp. together with a known congener, dysamide A (3). The structures of 1 and 2 were elucidated to be polychlorine-containing modified dipeptides based on their spectroscopic data. Compounds 1-3 inhibited both of the SOAT isozymes, SOAT1 and SOAT2, in cell-based and enzyme-based assays.
Assuntos
Callyspongia/química , Dipeptídeos/farmacologia , Inibidores Enzimáticos/farmacologia , Esterol O-Aciltransferase/antagonistas & inibidores , Animais , Callyspongia/metabolismo , Dipeptídeos/química , Dipeptídeos/isolamento & purificação , Ensaios Enzimáticos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Indonésia , Concentração Inibidora 50 , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Espectroscopia de Ressonância Magnética , Conformação Molecular , Esterol O-Aciltransferase/metabolismoRESUMO
Atropisomeric dinapinonesâ A1 and A2 (DPA1 and DPA2) were isolated from a culture of Talaromyces pinophilus FKI-3864. Monapinone coupling enzyme (MCE), which dimerizes naphthopyranone monapinoneâ A (MPA), was purified from a cell-free extract of T.â pinophilus FKI-3864. MCE regioselectively dimerizes MPA at the 8,8'-positions to synthesize the atropisomers DPA1 and DPA2 in a ratio of approximately 1:2.5 without a cofactor. The optimal pHâ value and temperature for MCE were 4.0 and 50 °C, and the apparent Km and Vmax values for MPA were (72.7±23.2)â µm and (1.21±0.170)â µmol min-1 mg-1 protein. The MCE polypeptide is significantly homologous with multicopper oxidases. Heterologous expression of MCE and functional analysis confirmed that MCE catalyzes the regioselective coupling reaction of MPA to produce DPA. No fungal multicopper oxidase has previously been reported to catalyze regioselective intermolecular oxidative phenol coupling to produce naphthopyranone atropisomers.
Assuntos
Cobre/metabolismo , Cumarínicos/metabolismo , Naftalenos/metabolismo , Oxirredutases/metabolismo , Pironas/metabolismo , Talaromyces/enzimologia , Biocatálise , Cobre/química , Cumarínicos/química , Estrutura Molecular , Naftalenos/química , Oxirredutases/química , Pironas/química , EstereoisomerismoRESUMO
Biseokeaniamides A, B, and C (1-3), structurally novel sterol O-acyltransferase (SOAT) inhibitors, were isolated from an Okeania sp. marine cyanobacterium. Their structures were elucidated by spectroscopic analyses and degradation reactions. Biseokeaniamide B (2) exhibited moderate cytotoxicity against human HeLa cancer cells, and compounds 1-3 inhibited both SOAT1 and SOAT2, not only at an enzyme level but also at a cellular level. Biseokeaniamides (1-3) are the first linear lipopeptides that have been shown to exhibit SOAT-inhibitory activity.
Assuntos
Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Cianobactérias/química , Lipopeptídeos/isolamento & purificação , Lipopeptídeos/farmacologia , Esterol O-Aciltransferase/antagonistas & inibidores , Antineoplásicos/química , Caspase 3/metabolismo , Células HeLa , Humanos , Lipopeptídeos/química , Biologia Marinha , Estrutura Molecular , Ressonância Magnética Nuclear BiomolecularRESUMO
Synthesis of new functionalized molecules and identification of biofunctional molecules can lead to the development of therapeutic leads and molecular tools for biomedical research. We have recently reported oxa-hetero-Diels-Alder reactions of enones with isatins to provide functionalized spirooxindole tetrahydropyran derivatives. Twenty-one compounds from the spirooxindole tetrahydropyran derivatives and related molecules were screened for inhibition of sterol O-acyltransferase (SOAT) isozymes SOAT1 and SOAT2. Three racemic derivatives inhibited the SOAT2 isozyme with three-fold or better selectivity for SOAT2 than for SOAT1. The enantiomerically enriched forms of the most efficient racemic inhibitor of SOAT2 were further evaluated; one enantiomer inhibited SOAT2 with an IC50 of 1.5µM and was 10-fold more selective for SOAT2 than SOAT1.
Assuntos
Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Piranos/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Esterol O-Aciltransferase/antagonistas & inibidores , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Piranos/síntese química , Piranos/química , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Esterol O-Aciltransferase/metabolismo , Relação Estrutura-Atividade , Esterol O-Aciltransferase 2RESUMO
Beauveriolides I and III, which are naturally occurring cyclodepsipeptides, have been reported to bind to sterol O-acyltransferase (SOAT), inhibiting its ability to synthesize cholesteryl esters. To facilitate an analysis of the binding site(s) of these compounds, we designed beauveriolide analogues 1a-d wherein the Leu or D-allo-Ile residue was replaced by photoreactive amino acids possessing methyldiazirine or trifluoromethyldiazirine in the side chains. The methyldiazirine moiety was installed by reaction of methyl ketones with liquid ammonia to provide imine intermediates, followed by treatment with hydroxylamine-O-sulfonic acid to provide the diaziridines. Subsequent oxidation gave methyldiazirines. In contrast, trifluoromethyldiazirine derivatives were prepared from trifluoromethyl ketones via the oxime intermediates, which were transformed into diaziridines. Subsequent oxidation afforded trifluoromethyldiazirines. The synthesized photoreactive amino acids 3a-d were coupled with 3-hydroxy-4-methyloctanoic acid 4 and dipeptide 5, followed by macrolactamization to provide beauveriolide analogues 1a-d. The SOAT inhibitory activities of 1a-d were found to be as potent as those of beauveriolides I and III. Moreover, 1a-d inhibited SOAT1 selectively rather than SOAT2, which was also consistent with the behavior of beauveriolides I and III.
Assuntos
Aminoácidos/química , Depsipeptídeos/química , Depsipeptídeos/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Esterol O-Aciltransferase/antagonistas & inibidores , Animais , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Processos Fotoquímicos , Esterol O-Aciltransferase/metabolismo , Relação Estrutura-AtividadeRESUMO
Sterol O-acyltransferase 2 (SOAT2; also known as ACAT2) is considered as a new therapeutic target for the treatment or prevention of hypercholesterolemia and atherosclerosis. Fungal pyripyropene A (PPPA: 1,7,11-triacyl type), the first SOAT2-selective inhibitor, proved orally active in vivo using atherogenic mouse models. The purpose of the present study was to demonstrate that the PPPA derivatives (PRDs) prove more effective in the mouse models than PPPA. Among 196 semisynthetic PPPA derivatives, potent, SOAT2-selective, and stable PRDs were selected. In vivo antiatherosclerotic activity of selected PRDs was tested in apolipoprotein E knockout (Apoe(-/-)) mice or low-density lipoprotein receptor knockout (Ldlr(-/-)) mice fed a cholesterol-enriched diet (0.2% cholesterol and 21% fat) for 12 weeks. During the PRD treatments, no detrimental side effects were observed. Among three PRDs, Apoe(-/-) mice treated with PRD125 (1-,11-O-benzylidene type) at 1 mg/kg/day had significantly lower total plasma cholesterol concentration by 57.9 ± 9.3%; further, the ratio of cholesteryl oleate to cholesteryl linoleate in low-density lipoprotein was lower by 55.6 ± 7.5%, respectively. The hepatic cholesteryl ester levels and SOAT2 activity in the small intestines and livers of the PRD-treated mice were selectively lowered. The atherosclerotic lesion areas in the aortae of PRD125-treated mice were significantly lower at 62.2 ± 13.1%, respectively. Furthermore, both PRDs were also orally active in atherogenic Ldlr(-/-) mice. Among the PRDs tested, PRD125 was the most potent in both mouse models. These results suggest that SOAT2-selective inhibitors such as PRD125 have a high potential as poststatin agents for treatment and/or prevention in patients with atherosclerosis and hypercholesterolemia.
Assuntos
Anticolesterolemiantes/química , Aterosclerose/tratamento farmacológico , Hipercolesterolemia/tratamento farmacológico , Piridinas/química , Sesquiterpenos/química , Esterol O-Aciltransferase/antagonistas & inibidores , Animais , Anticolesterolemiantes/síntese química , Anticolesterolemiantes/farmacologia , Aorta/patologia , Apolipoproteínas E/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Células CHO , Colesterol/sangue , Ésteres do Colesterol/sangue , Cricetulus , Hipercolesterolemia/metabolismo , Hipercolesterolemia/patologia , Gotículas Lipídicas/metabolismo , Lipoproteínas/sangue , Fígado/metabolismo , Masculino , Camundongos Knockout , Piridinas/síntese química , Piridinas/farmacologia , Receptores de LDL/genética , Sesquiterpenos/síntese química , Sesquiterpenos/farmacologia , Esterol O-Aciltransferase/metabolismo , Relação Estrutura-Atividade , Esterol O-Aciltransferase 2RESUMO
In most organs, the bulk of cholesterol is unesterified, although nearly all possess a varying capability of esterifying cholesterol through the action of either sterol O-acyltransferase (SOAT) 1 or, in the case of hepatocytes and enterocytes, SOAT2. Esterified cholesterol (EC) carried in plasma lipoproteins is hydrolyzed by lysosomal acid lipase (LAL) when they are cleared from the circulation. Loss-of-function mutations in LIPA, the gene that encodes LAL, result in Wolman disease or cholesteryl ester storage disease (CESD). Hepatomegaly and a massive increase in tissue EC levels are hallmark features of both disorders. While these conditions can be corrected with enzyme replacement therapy, the question arose as to whether pharmacological inhibition of SOAT2 might reduce tissue EC accretion in CESD. When weaned at 21 days, Lal(-/-) mice, of either gender, had a whole liver cholesterol content that was 12- to 13-fold more than that of matching Lal(+/+) littermates (23 versus 1.8 mg, respectively). In Lal(-/-) males given the selective SOAT2 inhibitor PRD125 1,11-O-o-methylbenzylidene-7-O-p-cyanobenzoyl-1,7,11-trideacetylpyripyropene A in their diet (â¼10 mg/day per kg body weight) from 21 to 53 days, whole liver cholesterol content was 48.6 versus 153.7 mg in untreated 53-day-old Lal(-/-) mice. This difference reflected a 59% reduction in hepatic EC concentration (mg/g), combined with a 28% fall in liver mass. The treated mice also showed a 63% reduction in plasma alanine aminotransferase activity, in parallel with decisive falls in hepatic mRNA expression levels for multiple proteins that reflect macrophage presence and inflammation. These data implicate SOAT2 as a potential target in CESD management.
Assuntos
Ésteres do Colesterol/biossíntese , Fígado/efeitos dos fármacos , Piridinas/farmacologia , Sesquiterpenos/farmacologia , Esterol Esterase/genética , Esterol O-Aciltransferase/antagonistas & inibidores , Animais , Feminino , Hepatite/tratamento farmacológico , Hepatite/imunologia , Hepatite/metabolismo , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/metabolismo , Fígado/fisiologia , Masculino , Camundongos , Camundongos Knockout , Tamanho do Órgão , Transaminases/sangue , Esterol O-Aciltransferase 2RESUMO
Hydrolysis of intracellular cholesteryl ester (CE) is the rate-limiting step in the efflux of cholesterol from macrophage foam cells. In mouse peritoneal macrophages (MPMs), this process is thought to involve several enzymes: hormone-sensitive lipase (Lipe), carboxylesterase 3 (Ces3), neutral CE hydrolase 1 (Nceh1). However, there is some disagreement over the relative contributions of these enzymes. To solve this problem, we first compared the abilities of several compounds to inhibit the hydrolysis of CE in cells overexpressing Lipe, Ces3, or Nceh1. Cells overexpressing Ces3 had negligible neutral CE hydrolase activity. We next examined the effects of these inhibitors on the hydrolysis of CE and subsequent cholesterol trafficking in MPMs. CE accumulation was increased by a selective inhibitor of Nceh1, paraoxon, and two nonselective inhibitors of Nceh1, (+)-AS115 and (-)-AS115, but not by two Lipe-selective inhibitors, orlistat and 76-0079. Paraoxon inhibited cholesterol efflux to apoA-I or HDL, while 76-0079 did not. These results suggest that Nceh1 plays a dominant role over Lipe in the hydrolysis of CE and subsequent cholesterol efflux in MPMs.
Assuntos
Ésteres do Colesterol/metabolismo , Macrófagos Peritoneais/enzimologia , Esterol Esterase/metabolismo , Animais , Transporte Biológico Ativo/efeitos dos fármacos , Transporte Biológico Ativo/genética , Carboxilesterase/genética , Carboxilesterase/metabolismo , Ésteres do Colesterol/genética , Inibidores Enzimáticos/farmacologia , Células HEK293 , Humanos , Hidrólise , Camundongos , Camundongos Knockout , Esterol Esterase/antagonistas & inibidores , Esterol Esterase/genéticaRESUMO
An excess of cholesterol and/or oxysterols induces apoptosis in macrophages, contributing to the development of advanced atherosclerotic lesions. In foam cells, these sterols are stored in esterified forms, which are hydrolyzed by two enzymes: neutral cholesterol ester hydrolase 1 (Nceh1) and hormone-sensitive lipase (Lipe). A deficiency in either enzyme leads to accelerated growth of atherosclerotic lesions in mice. However, it is poorly understood how the esterification and hydrolysis of sterols are linked to apoptosis. Remarkably, Nceh1-deficient thioglycollate-elicited peritoneal macrophages (TGEMs), but not Lipe-deficient TGEMs, were more susceptible to apoptosis induced by oxysterols, particularly 25-hydroxycholesterol (25-HC), and incubation with 25-HC caused massive accumulation of 25-HC ester in the endoplasmic reticulum (ER) due to its defective hydrolysis, thereby activating ER stress signaling such as induction of CCAAT/enhancer-binding protein-homologous protein (CHOP). These changes were nearly reversed by inhibition of ACAT1. In conclusion, deficiency of Nceh1 augments 25-HC-induced ER stress and subsequent apoptosis in TGEMs. In addition to reducing the cholesteryl ester content of foam cells, Nceh1 may protect against the pro-apoptotic effect of oxysterols and modulate the development of atherosclerosis.
Assuntos
Apoptose , Estresse do Retículo Endoplasmático , Hidroxicolesteróis/metabolismo , Macrófagos Peritoneais/enzimologia , Transdução de Sinais , Esterol Esterase/metabolismo , Acetil-CoA C-Acetiltransferase/genética , Acetil-CoA C-Acetiltransferase/metabolismo , Animais , Aterosclerose/enzimologia , Aterosclerose/genética , Aterosclerose/patologia , Retículo Endoplasmático/enzimologia , Retículo Endoplasmático/patologia , Macrófagos Peritoneais/patologia , Camundongos , Camundongos Knockout , Esterol Esterase/genética , Fator de Transcrição CHOP/genética , Fator de Transcrição CHOP/metabolismoRESUMO
Nectriatide 1a, a naturally occurring cyclic tetrapeptide, has been reported to a potentiator of amphotericin B (AmB) activity. In order to elucidate its structure-activity relationships, we synthesized nectriatide derivatives with different amino acids in solution-phase synthesis and evaluated AmB-potentiating activity against Candida albicans. Among them, C-and N-terminal protected linear peptides were found to show the most potent AmB-potentiating activity.
Assuntos
Anfotericina B , Antifúngicos , Anfotericina B/química , Antifúngicos/química , Candida albicans , Peptídeos , Testes de Sensibilidade MicrobianaRESUMO
Seriniquinone was isolated as a melanoma-selective anti-cancer agent from a culture broth of the marine-derived bacterium Serinicoccus marinus CNJ927 in 2014. It targets the unique small protein, dermcidin, which affects the drug resistance of cancer cells. Due to its significant activity against cancer cells, particularly melanoma, and its unique target, seriniquinone has been developed as a new pharmacophore. However, it has the disadvantage of poor solubility in drug discovery research, which needs to be resolved. A new seriniquinone glycoside (1) was synthesized by the biological transformation of seriniquinone using the deep sea-derived bacterium Bacillus licheniformis KDM612. Compound 1 exhibited selective anti-cancer activity against melanoma, similar to seriniquinone, and was 50-fold more soluble in DMSO than seriniquinone.
Assuntos
Antineoplásicos , Bacillus licheniformis , Glicosídeos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Glicosídeos/farmacologia , Glicosídeos/química , Glicosídeos/isolamento & purificação , Bacillus licheniformis/metabolismo , Humanos , Biotransformação , Solubilidade , QuinonasRESUMO
Two new cyclic dipeptides, paranazzamides A (1) and B (2) containing a C7-prenylated tryptophan, were isolated from a culture broth of snake fungal disease-isolate Paranannizziopsis sp. UH-21. This is the first report on the new secondary metabolites from Paranannizziopsis sp. The planar structures of 1 and 2 were elucidated using various spectroscopic techniques including MS and 1D/2D NMR. The absolute configuration of 1 was assigned by comparison with the synthesized compound. Compounds 1 and 2 exhibited no antifungal activity, no antibacterial activity, and no cytotoxic activity even at a concentration of 128 µg ml-1, whereas 1 and 2 exhibited amphotericin B potentiating activity against Candida auris in combination treatment.
Assuntos
Dipeptídeos , Peptídeos Cíclicos , Triptofano , Triptofano/química , Triptofano/metabolismo , Dipeptídeos/química , Dipeptídeos/isolamento & purificação , Dipeptídeos/farmacologia , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Peptídeos Cíclicos/isolamento & purificação , Animais , Antifúngicos/farmacologia , Antifúngicos/química , Antifúngicos/isolamento & purificação , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/isolamento & purificação , Candida/efeitos dos fármacos , Prenilação , Anfotericina B/farmacologia , Estrutura Molecular , HumanosRESUMO
During our screening for anti-mycobacterial agents against Mycobacterium avium complex (MAC), two new polycyclic tetramate macrolactams (PTMs), named hydroxycapsimycin (1) and brokamycin (2), were isolated along with the known PTM, ikarugamycin (3), from the culture broth of marine-derived Streptomyces sp. KKMA-0239. The relative structures of 1 and 2 were elucidated by spectroscopic data analyses, including 1D and 2D NMR. Furthermore, the absolute configuration of 1 was confirmed by a single-crystal X-ray diffraction analysis. Compounds 2 and 3 exhibited moderate antimycobacterial activities against MAC, including clinically isolated drug-resistant M. avium.
Assuntos
Antibacterianos , Lactamas , Testes de Sensibilidade Microbiana , Streptomyces , Streptomyces/metabolismo , Streptomyces/química , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/isolamento & purificação , Complexo Mycobacterium avium/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Lactamas Macrocíclicas/farmacologia , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/isolamento & purificação , Cristalografia por Raios X , Antituberculosos/farmacologia , Antituberculosos/química , Antituberculosos/isolamento & purificação , Compostos Policíclicos/farmacologia , Compostos Policíclicos/isolamento & purificação , Compostos Policíclicos/química , Estrutura MolecularRESUMO
The role of macrophage lipoprotein lipase (LpL) in the development of atherosclerosis and adiposity was examined in macrophage LpL knockout (MLpLKO) mice. MLpLKO mice were generated using cre-loxP gene targeting. Loss of LpL in macrophages did not alter plasma LpL activity or lipoprotein levels. Incubation of apolipoprotein E (ApoE)-deficient ß-VLDL with peritoneal macrophages from ApoE knockout mice lacking macrophage LpL (MLpLKO/ApoEKO) led to less cholesteryl ester formation than that found with ApoEKO macrophages. MLpLKO/ApoEKO macrophages had reduced intracellular triglyceride levels, with decreased CD36 and carnitine palmitoyltransferase-1 mRNA levels compared with ApoEKO macrophages, when incubated with VLDL. Although both MLpLKO/ApoEKO and ApoEKO mice developed comparable hypercholesterolemia in response to feeding with a Western-type diet for 12 weeks, atherosclerosis was less in MLpLKO/ApoEKO mice. Epididymal fat mass and gene expression levels associated with inflammation did not differ between the two groups. In conclusion, macrophage LpL plays an important role in the development of atherosclerosis but not adiposity.