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1.
Int J Mol Sci ; 22(11)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34205991

RESUMO

The aim of this study was to determine whether the lactones dehydroleucodine, xanthatin and 3-benzyloxymethyl-5H-furan-2-one, would be effective in an animal model of gastric ulcer induced by mast cell activation. Rats were divided into ten groups. Treatments were repeated for four days. The degree of gastric erosion was assessed with a scoring system and histological preparations. Gastric mast cell morphology was analyzed by histological procedures. Serum serotonin levels were determined as markers of mast cell activation. Statistical analyses were done using ANOVA and Tukey-Kramer test. We demonstrated that the repeated administration of compound 48/80 results in extensive mucosal lesions in the gastric mucosa and that such lesions occurred in association with mast cell degranulation and a significant increase of serum serotonin. We showed that these lesions were prevented by dehydroleucodine, xanthatin, and 3-benzyloxymethyl-5H-furan-2-one and that this effect was similar to that obtained with sodium cromoglycate. In conclusion, the results of the present study indicate that the optimal gastric cytoprotective dose of dehydroleucodine, xanthatin, and 3-benzyloxymethyl-5H-furan-2-one is efficacious in an animal model of gastric ulcer induced by mast cell activation. Our findings suggest that these lactones could be valuable tools for designing novel therapeutic agents for digestive disorders associated with inappropriate mast cell activation.


Assuntos
Proliferação de Células/efeitos dos fármacos , Mucosa Gástrica/efeitos dos fármacos , Mastocitose/tratamento farmacológico , Úlcera Gástrica/tratamento farmacológico , Animais , Modelos Animais de Doenças , Furanos/farmacologia , Mucosa Gástrica/patologia , Humanos , Lactonas/farmacologia , Mastocitose/metabolismo , Mastocitose/patologia , Ratos , Sesquiterpenos/farmacologia , Úlcera Gástrica/metabolismo , Úlcera Gástrica/patologia , p-Metoxi-N-metilfenetilamina/farmacologia
2.
Anticancer Res ; 41(7): 3389-3400, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230134

RESUMO

BACKGROUND/AIM: Cholangiocarcinoma (CCA), a biliary cancer, is a health problem worldwide. The major problem in CCA treatment presents limited options. To date, targeting cancer metabolism is a promising anti-cancer strategy. To elucidate the functional importance of lipid metabolism in CCA, de novo lipogenesis was inhibited using 5-(tetradecyloxy)-2-furoic acid (TOFA), an acetyl CoA carboxylase inhibitor. MATERIALS AND METHODS: Anti-proliferative effects of TOFA were determined both in vitro and in vivo. Its inhibitory effect on cell-cycle and apoptosis was investigated by flow cytometry and western blot analysis of relevant markers. RESULTS: TOFA inhibited CCA cell growth, induced cell-cycle progression accompanied by apoptosis in a dose-dependent manner. Induction of p21, and caspase-3, -8, and -9 cleavages, while down-regulation of cyclin B1 and cyclin D1 were observed in TOFA-treated cells. The therapeutic potential was demonstrated in vivo. CONCLUSION: De novo lipogensis is essential for CCA cell growth and is an alternative target for CCA treatment.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias dos Ductos Biliares/tratamento farmacológico , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Colangiocarcinoma/tratamento farmacológico , Furanos/farmacologia , Acetil-CoA Carboxilase/metabolismo , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Regulação para Baixo/efeitos dos fármacos , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos
3.
Biochem J ; 478(13): 2517-2531, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34198325

RESUMO

The COVID-19 pandemic has emerged as the biggest life-threatening disease of this century. Whilst vaccination should provide a long-term solution, this is pitted against the constant threat of mutations in the virus rendering the current vaccines less effective. Consequently, small molecule antiviral agents would be extremely useful to complement the vaccination program. The causative agent of COVID-19 is a novel coronavirus, SARS-CoV-2, which encodes at least nine enzymatic activities that all have drug targeting potential. The papain-like protease (PLpro) contained in the nsp3 protein generates viral non-structural proteins from a polyprotein precursor, and cleaves ubiquitin and ISG protein conjugates. Here we describe the expression and purification of PLpro. We developed a protease assay that was used to screen a custom compound library from which we identified dihydrotanshinone I and Ro 08-2750 as compounds that inhibit PLpro in protease and isopeptidase assays and also inhibit viral replication in cell culture-based assays.


Assuntos
Antivirais/química , Antivirais/farmacologia , Proteases Semelhantes à Papaína de Coronavírus/antagonistas & inibidores , Avaliação Pré-Clínica de Medicamentos , SARS-CoV-2/enzimologia , Bibliotecas de Moléculas Pequenas/farmacologia , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Alanina/análogos & derivados , Alanina/farmacologia , Compostos de Anilina/farmacologia , Animais , Benzamidas/farmacologia , Chlorocebus aethiops , Proteases Semelhantes à Papaína de Coronavírus/genética , Proteases Semelhantes à Papaína de Coronavírus/isolamento & purificação , Proteases Semelhantes à Papaína de Coronavírus/metabolismo , Sinergismo Farmacológico , Ensaios Enzimáticos , Flavinas/farmacologia , Transferência Ressonante de Energia de Fluorescência , Furanos/farmacologia , Ensaios de Triagem em Larga Escala , Concentração Inibidora 50 , Naftalenos/farmacologia , Fenantrenos/farmacologia , Quinonas/farmacologia , Reprodutibilidade dos Testes , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/crescimento & desenvolvimento , Bibliotecas de Moléculas Pequenas/química , Células Vero , Replicação Viral/efeitos dos fármacos
4.
Nat Commun ; 12(1): 3964, 2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-34172720

RESUMO

The regulation of bone vasculature by chronic diseases, such as heart failure is unknown. Here, we describe the effects of myocardial infarction and post-infarction heart failure on the bone vascular cell composition. We demonstrate an age-independent loss of type H endothelium in heart failure after myocardial infarction in both mice and humans. Using single-cell RNA sequencing, we delineate the transcriptional heterogeneity of human bone marrow endothelium, showing increased expression of inflammatory genes, including IL1B and MYC, in ischemic heart failure. Endothelial-specific overexpression of MYC was sufficient to induce type H bone endothelial cells, whereas inhibition of NLRP3-dependent IL-1ß production partially prevented the post-myocardial infarction loss of type H vasculature in mice. These results provide a rationale for using anti-inflammatory therapies to prevent or reverse the deterioration of bone vascular function in ischemic heart disease.


Assuntos
Osso e Ossos/irrigação sanguínea , Células Endoteliais/patologia , Insuficiência Cardíaca/fisiopatologia , Infarto do Miocárdio/fisiopatologia , Idoso , Animais , Osso e Ossos/fisiopatologia , Estudos de Casos e Controles , Células Endoteliais/metabolismo , Feminino , Furanos/farmacologia , Genes myc , Insuficiência Cardíaca/etiologia , Células-Tronco Hematopoéticas/patologia , Humanos , Indenos/farmacologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Infarto do Miocárdio/complicações , Infarto do Miocárdio/genética , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Sulfonamidas/farmacologia
5.
ACS Chem Biol ; 16(6): 982-990, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34003636

RESUMO

Inhibition of inflammasome and pyroptotic pathways are promising strategies for clinical treatment of autoimmune and inflammatory disorders. MCC950, a potent inhibitor of the NLR-family inflammasome pyrin domain-containing 3 (NLRP3) protein, has shown encouraging results in animal models for a range of conditions; however, until now, no off-targets have been identified. Herein, we report the design, synthesis, and application of a novel photoaffinity alkyne-tagged probe for MCC950 (IMP2070) which shows direct engagement with NLRP3 and inhibition of inflammasome activation in macrophages. Affinity-based chemical proteomics in live macrophages identified several potential off-targets, including carbonic anhydrase 2 (CA2) as a specific target of IMP2070, and independent cellular thermal proteomic profiling revealed stabilization of CA2 by MCC950. MCC950 displayed noncompetitive inhibition of CA2 activity, confirming carbonic anhydrase as an off-target class for this compound. These data highlight potential biological mechanisms through which MCC950 and derivatives may exhibit off-target effects in preclinical or clinical studies.


Assuntos
Anidrase Carbônica II/antagonistas & inibidores , Furanos/farmacologia , Indenos/farmacologia , Inflamassomos/antagonistas & inibidores , Macrófagos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Sulfonamidas/farmacologia , Anidrase Carbônica II/metabolismo , Linhagem Celular , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Furanos/química , Humanos , Indenos/química , Inflamassomos/metabolismo , Macrófagos/metabolismo , Modelos Moleculares , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteômica , Sulfonamidas/química
6.
J Med Chem ; 64(9): 5551-5576, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33934604

RESUMO

N-Methyl-d-aspartate receptors (NMDARs) are glutamate-gated Na+ and Ca2+-permeable ion channels involved in excitatory synaptic transmission and synaptic plasticity. NMDAR hypofunction has long been implicated in the pathophysiology including major depressive disorders (MDDs). Herein, we report a series of furan-2-carboxamide analogues as novel NMDAR-positive allosteric modulators (PAMs). Through structure-based virtual screen and electrophysiological tests, FS2921 was identified as a novel NMDAR PAM with potential antidepressant effects. Further structure-activity relationship studies led to the discovery of novel analogues with increased potentiation. Compound 32h caused a significant increase in NMDAR excitability in vitro and impressive activity in the forced swimming test. Moreover, compound 32h showed no significant inhibition of hERG or cell viability and possessed a favorable PK/PD profile. Our study presented a series of novel NMDAR PAMs and provided potential opportunities for discovering of new antidepressants.


Assuntos
Antidepressivos/química , Transtorno Depressivo Maior/tratamento farmacológico , Receptores de N-Metil-D-Aspartato/metabolismo , Potenciais de Ação/efeitos dos fármacos , Regulação Alostérica/efeitos dos fármacos , Animais , Antidepressivos/metabolismo , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Sítios de Ligação , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Furanos/química , Furanos/metabolismo , Furanos/farmacologia , Furanos/uso terapêutico , Meia-Vida , Humanos , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Receptores de N-Metil-D-Aspartato/química , Receptores de N-Metil-D-Aspartato/genética , Relação Estrutura-Atividade
7.
Anticancer Res ; 41(4): 1779-1784, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33813382

RESUMO

BACKGROUND/AIM: Osteosarcoma is a rare type of bone cancer that affects mostly children and adolescents. First-line chemotherapy for osteosarcoma has not been improved for many decades. Eribulin has been used to treat breast cancer and liposarcoma in the clinic. MATERIALS AND METHODS: A patient-derived orthotopic xenograft (PDOX) mouse model of osteosarcoma was established by tumor insertion within the tibia. This model more closely mimics osteosarcoma in clinical settings and was used to test the efficacy of eribulin. Tibia-insertion osteosarcoma PDOX mouse models were randomized into two groups: a control group (n=4) and an eribulin-treatment group (n=5). Mice were treated for fourteen days, four weeks after initial implantation. Tumor size and body weight were measured, and tumor histology was examined. RESULTS: Significant tumor growth inhibition (p=0.044) was observed in mice treated with eribulin compared to the control group. Histology demonstrated necrosis in the eribulin-treated tumors. There was no body-weight loss in the treated mice. CONCLUSION: Eribulin may be a clinically-effective, off-label chemotherapy for recalcitrant osteosarcoma that has failed first- and second-line therapy.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Furanos/farmacologia , Cetonas/farmacologia , Osteossarcoma/tratamento farmacológico , Tíbia/efeitos dos fármacos , Adolescente , Animais , Neoplasias Ósseas/patologia , Humanos , Masculino , Camundongos Nus , Necrose , Osteossarcoma/patologia , Tíbia/patologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Molecules ; 26(7)2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33916300

RESUMO

Cholinesterase (ChE) inhibition is an important treatment strategy for Alzheimer's disease (AD) as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are involved in the pathology of AD. In the current work, ChE inhibitory potential of twenty-four natural products from different chemical classes (i.e., diosgenin, hecogenin, rockogenin, smilagenin, tigogenin, astrasieversianins II and X, astragalosides I, IV, and VI, cyclocanthosides E and G, macrophyllosaponins A-D, kokusaginin, lamiide, forsythoside B, verbascoside, alyssonoside, ipolamide, methyl rosmarinate, and luteolin-7-O-glucuronide) was examined using ELISA microtiter assay. Among them, only smilagenin and kokusaginine displayed inhibitory action against AChE (IC50 = 43.29 ± 1.38 and 70.24 ± 2.87 µg/mL, respectively). BChE was inhibited by only methyl rosmarinate and kokusaginine (IC50 = 41.46 ± 2.83 and 61.40 ± 3.67 µg/mL, respectively). IC50 values for galantamine as the reference drug were 1.33 ± 0.11 µg/mL for AChE and 52.31 ± 3.04 µg/mL for BChE. Molecular docking experiments showed that the orientation of smilagenin and kokusaginine was mainly driven by the interactions with the peripheral anionic site (PAS) comprising residues of hAChE, while kokusaginine and methyl rosmarinate were able to access deeper into the active gorge in hBChE. Our data indicate that similagenin, kokusaginine, and methyl rosmarinate could be hit compounds for designing novel anti-Alzheimer agents.


Assuntos
Produtos Biológicos/química , Produtos Biológicos/farmacologia , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Sítios de Ligação , Produtos Biológicos/isolamento & purificação , Inibidores da Colinesterase/isolamento & purificação , Furanos/química , Furanos/farmacologia , Concentração Inibidora 50 , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Ligação Proteica , Quinolinas/química , Quinolinas/farmacologia , Espirostanos/química , Espirostanos/farmacologia , Relação Estrutura-Atividade
9.
Molecules ; 26(8)2021 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-33920352

RESUMO

The pathological finding of amyloid-ß (Aß) aggregates is thought to be a leading cause of untreated Alzheimer's disease (AD). In this study, we isolated 2-butoxytetrahydrofuran (2-BTHF), a small cyclic ether, from Holothuria scabra and demonstrated its therapeutic potential against AD through the attenuation of Aß aggregation in a transgenic Caenorhabditis elegans model. Our results revealed that amongst the five H. scabra isolated compounds, 2-BTHF was shown to be the most effective in suppressing worm paralysis caused by Aß toxicity and in expressing strong neuroprotection in CL4176 and CL2355 strains, respectively. An immunoblot analysis showed that CL4176 and CL2006 treated with 2-BTHF showed no effect on the level of Aß monomers but significantly reduced the toxic oligomeric form and the amount of 1,4-bis(3-carboxy-hydroxy-phenylethenyl)-benzene (X-34)-positive fibril deposits. This concurrently occurred with a reduction of reactive oxygen species (ROS) in the treated CL4176 worms. Mechanistically, heat shock factor 1 (HSF-1) (at residues histidine 63 (HIS63) and glutamine 72 (GLN72)) was shown to be 2-BTHF's potential target that might contribute to an increased expression of autophagy-related genes required for the breakdown of the Aß aggregate, thus attenuating its toxicity. In conclusion, 2-BTHF from H. scabra could protect C. elegans from Aß toxicity by suppressing its aggregation via an HSF-1-regulated autophagic pathway and has been implicated as a potential drug for AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Furanos/farmacologia , Holothuria/química , Fármacos Neuroprotetores/farmacologia , Paralisia/prevenção & controle , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Animais Geneticamente Modificados , Proteínas Relacionadas à Autofagia/genética , Proteínas Relacionadas à Autofagia/metabolismo , Sítios de Ligação , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/antagonistas & inibidores , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Modelos Animais de Doenças , Furanos/química , Furanos/isolamento & purificação , Regulação da Expressão Gênica , Humanos , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Paralisia/genética , Paralisia/metabolismo , Paralisia/patologia , Agregados Proteicos/efeitos dos fármacos , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
10.
Int J Mol Sci ; 22(7)2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33807167

RESUMO

Atractylodin (ATR) is a bioactive component found in dried rhizomes of Atractylodes lancea (AL) De Candolle. Although AL has accumulated empirical evidence for the treatment of pain, the molecular mechanism underlying the anti-pain effect of ATR remains unclear. In this study, we found that ATR increases transient receptor potential ankyrin-1 (TRPA1) single-channel activity in hTRPA1 expressing HEK293 cells. A bath application of ATR produced a long-lasting calcium response, and the response was completely diminished in the dorsal root ganglion neurons of TRPA1 knockout mice. Intraplantar injection of ATR evoked moderate and prolonged nociceptive behavior compared to the injection of allyl isothiocyanate (AITC). Systemic application of ATR inhibited AITC-induced nociceptive responses in a dose-dependent manner. Co-application of ATR and QX-314 increased the noxious heat threshold compared with AITC in vivo. Collectively, we concluded that ATR is a unique agonist of TRPA1 channels, which produces long-lasting channel activation. Our results indicated ATR-mediated anti-nociceptive effect through the desensitization of TRPA1-expressing nociceptors.


Assuntos
Furanos/metabolismo , Furanos/farmacologia , Canal de Cátion TRPA1/metabolismo , Analgésicos/metabolismo , Analgésicos/farmacologia , Animais , Cálcio/metabolismo , Canais de Cálcio/metabolismo , Gânglios Espinais/metabolismo , Células HEK293 , Humanos , Isotiocianatos/farmacologia , Lidocaína/análogos & derivados , Lidocaína/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/metabolismo , Nociceptividade/efeitos dos fármacos , Nociceptores/metabolismo , Dor/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Canal de Cátion TRPA1/agonistas , Canal de Cátion TRPA1/efeitos dos fármacos , Canais de Cátion TRPC/metabolismo , Canais de Potencial de Receptor Transitório/metabolismo
11.
Molecules ; 26(6)2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33803983

RESUMO

Quorum sensing (QS), a sophisticated system of bacterial communication that depends on population density, is employed by many pathogenic bacteria to regulate virulence. In view of the current reality of antibiotic resistance, it is expected that interfering with QS can address bacterial pathogenicity without stimulating the incidence of resistance. Thus, harnessing QS inhibitors has been considered a promising approach to overriding bacterial infections and combating antibiotic resistance that has become a major threat to public healthcare around the globe. Pseudomonas aeruginosa is one of the most frequent multidrug-resistant bacteria that utilize QS to control virulence. Many natural compounds, including furanones, have demonstrated strong inhibitory effects on several pathogens via blocking or attenuating QS. While the natural furanones show no activity against P. aeruginosa, furanone C-30, a brominated derivative of natural furanone compounds, has been reported to be a potent inhibitor of the QS system of the notorious opportunistic pathogen. In the present study, we assess the molecular targets and mode of action of furanone C-30 on P. aeruginosa QS system. Our results suggest that furanone C-30 binds to LasR at the ligand-binding site but fails to establish interactions with the residues crucial for the protein's productive conformational changes and folding, thus rendering the protein dysfunctional. We also show that furanone C-30 inhibits RhlR, independent of LasR, suggesting a complex mechanism for the agent beyond what is known to date.


Assuntos
Antibacterianos/farmacologia , Furanos/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Percepção de Quorum/efeitos dos fármacos , Proteínas de Bactérias/metabolismo , Biofilmes/efeitos dos fármacos , Resistência Microbiana a Medicamentos/efeitos dos fármacos , Pseudomonas aeruginosa/metabolismo , Virulência/efeitos dos fármacos
12.
FASEB J ; 35(5): e21496, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33904622

RESUMO

Saururus chinensis (S chinensis) has been used as an herb to treat edema, jaundice, and gonorrhea. Manassantin B (MNSB), a dineolignan isolated from S chinensis, was identified as a potent adipogenesis/lipogenesis inhibitor (IC50  = 9.3 nM). To explore the underlying mechanism, both adipogenesis and lipogenesis were measured in differentiated 3T3-L1 preadipocytes, murine primary preadipocytes and adipose tissue explants upon MNSB treatment. Key regulators of adipogenesis/lipogenesis were downregulated by MNSB treatment, mainly resulting from increased phosphorylation of AMPK which was identified as a vital regulator of adipogenesis and lipogenesis. Moreover, MNSB did not increase AMPK phosphorylation in 3T3-L1 cells transfected with Prkaa1 (encoding protein kinase AMP-activated catalytic subunit alpha 1) siRNA or adipose tissue explants isolated from adipose-specific Prkaa1-disrupted mice (Prkaa1Δad ). In diet-induced obese C57BL/6N mice, MNSB displayed preventive and therapeutic effects on obesity accompanied by decreased adipocyte size. MNSB was also found to increase AMPK phosphorylation both in subcutaneous white adipose tissue and brown adipose tissue in vivo. These findings suggest that MNSB can be a new therapeutic agent for the prevention and treatment of obesity and other related metabolic disorders.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Adipócitos/efeitos dos fármacos , Adipogenia , Dieta Hiperlipídica/efeitos adversos , Furanos/farmacologia , Lipogênese , Obesidade/tratamento farmacológico , Células 3T3-L1 , Adipócitos/metabolismo , Animais , Diferenciação Celular , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Obesidade/patologia , Fosforilação
13.
Int J Mol Sci ; 22(4)2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33669867

RESUMO

RIDR-PI-103 is a novel reactive oxygen species (ROS)-induced drug release prodrug with a self-cyclizing moiety linked to a pan-PI3K inhibitor (PI-103). Under high ROS, PI-103 is released in a controlled manner to inhibit PI3K. The efficacy and bioavailability of RIDR-PI-103 in breast cancer remains unexplored. Cell viability of RIDR-PI-103 was assessed on breast cancer cells (MDA-MB-231, MDA-MB-361 and MDA-MB-453), non-tumorigenic MCF10A and fibroblasts. Matrigel colony formation, cell proliferation and migration assays examined the migratory properties of breast cancers upon treatment with RIDR-PI-103 and doxorubicin. Western blots determined the effect of doxorubicin ± RIDR-PI-103 on AKT activation and DNA damage response. Pharmacokinetic (PK) studies using C57BL/6J mice determined systemic exposure (plasma concentrations and overall area under the curve) and T1/2 of RIDR-PI-103. MDA-MB-453, MDA-MB-231 and MDA-MB-361 cells were sensitive to RIDR-PI-103 vs. MCF10A and normal fibroblast. Combination of doxorubicin and RIDR-PI-103 suppressed cancer cell growth and proliferation. Doxorubicin with RIDR-PI-103 inhibited p-AktS473, upregulated p-CHK1/2 and p-P53. PK studies showed that ~200 ng/mL (0.43 µM) RIDR-PI-103 is achievable in mice plasma with an initial dose of 20 mg/kg and a 10 h T1/2. (4) The prodrug RIDR-PI-103 could be a potential therapeutic for treatment of breast cancer patients.


Assuntos
Antraciclinas/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Dano ao DNA , Fosfatidilinositol 3-Quinases/metabolismo , Pró-Fármacos/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Animais , Antraciclinas/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Colágeno , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Combinação de Medicamentos , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Furanos/farmacocinética , Furanos/farmacologia , Furanos/uso terapêutico , Humanos , Laminina , Camundongos Endogâmicos C57BL , Pró-Fármacos/farmacologia , Proteoglicanas , Piridinas/farmacocinética , Piridinas/farmacologia , Piridinas/uso terapêutico , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico
14.
Molecules ; 26(5)2021 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-33673560

RESUMO

BACKGROUND: Khella (Ammi visnaga Lam.) fruits (Apiaceae) are rich in furanochromones, mainly khellin and visnagin, and are thus incorporated in several pharmaceutical products used mainly for treatment of renal stones. METHODS: The objective of this study was to compare the yield of khellin and visnagin obtained using different conventional solvents and supercritical fluid extraction (SCFE) with carbon dioxide (containing 5% methanol as co-solvent). Water, acetone and ethanol (30% and 95%) were selected as conventional solvents. RESULTS: Highest extract yield was obtained from 30% ethanol (15.44%), while SCFE gave the lowest yield (4.50%). However, the percentage of furanochromones were highest in SCFE (30.1%), and lowest in boiling water extract (5.95%). HPLC analysis of conventional solvent extracts showed other coumarins that did not appear in supercritical fluid extraction chromatogram due to non-selectivity of solvent extraction. Ammi visnaga extracts as well as standard khellin and visnagin were tested for their cytotoxic activity using sulforhodamine B assay on breast cancer (MCF-7) and hepatocellular carcinoma (Hep G2) cell lines. Results revealed a strong cytotoxic activity (IC50 < 20 µg/mL) for the SCFE and standard compounds (khellin and visnagin) (IC50 ranging between 12.54 ± 0.57 and 17.53 ± 1.03 µg/mL). However, ethanol and acetone extracts had moderate cytotoxic activity (IC50 20-90 µg/mL) and aqueous extract had a weak activity (IC50 > 90 µg/mL). CONCLUSIONS: Thus, supercritical fluid extraction is an efficient, relatively safe, and cheap technique that yielded a more selective purified extract with better cytotoxic activity.


Assuntos
Ammi/química , Cromatografia com Fluido Supercrítico/métodos , Cromonas/química , Furanos/química , Extratos Vegetais/química , Dióxido de Carbono/química , Cromonas/farmacologia , Cumarínicos/química , Etanol/química , Furanos/farmacologia , Células Hep G2 , Humanos , Quelina/farmacologia , Quelina/normas , Células MCF-7 , Metanol/química , Extratos Vegetais/farmacologia , Solventes/química
15.
Eur J Med Chem ; 216: 113322, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33652353

RESUMO

In this paper, the 2,5-disubstituted furan derivatives containing 1,3,4-thiadiazole were synthesized and screened for their inhibitory activity against α-glucosidase and ß-glucuronidases to obtain potent α-glucosidase inhibitor 9 (IC50 = 0.186 µM) and E. coli ß-glucuronidase inhibitor 26 (IC50 = 0.082 µM), respectively. The mechanisms of the compounds were studied. The kinetic study revealed that compound 9 is a competitive inhibitor against α-glucosidase (Ki = 0.05 ± 0.003 µM) and molecular docking simulation showed several key interactions between 9 and the target including hydrogen bond and p-π stacking interaction. Derivative 26 (Ki = 0.06 ± 0.005 µM) displayed uncompetitive inhibition behavior against EcGUS. Furthermore, the result of docking revealed the furan ring of 26 may be a key moiety in obstructing the active domain of EcGUS. In addition, compound 15 exhibited significant inhibitory activity against these two enzymes, with potential therapeutic effects against diabetes and against CPT-11-induced diarrhea. At the same time, their low toxicity against normal liver tissue LO2 cells lays the foundation for in vivo studies and the development of bifunctional drug.


Assuntos
Escherichia coli/enzimologia , Furanos/química , Glicoproteínas/química , Inibidores de Glicosídeo Hidrolases/química , Tiadiazóis/química , Sítios de Ligação , Domínio Catalítico , Linhagem Celular , Sobrevivência Celular , Proteínas de Escherichia coli/antagonistas & inibidores , Proteínas de Escherichia coli/metabolismo , Furanos/farmacologia , Glucuronidase/antagonistas & inibidores , Glucuronidase/metabolismo , Glicoproteínas/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Humanos , Cinética , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade
16.
Eur J Med Chem ; 216: 113336, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33725657

RESUMO

P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) is a phenomenon in which cells become resistant to structurally and mechanistically unrelated drugs resulting in low intracellular drug concentrations. It is one of the noteworthy problems in malignant tumor clinical therapeutics. So P-gp protein is one of the ideal targets to solve MDR. Based on the lead compound 5m obtained from our previous work, a series of furan derivatives featuring alkyl-substituted phenols and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline were designed and synthesized as reversal agents against P-gp in this paper. Compound 16 containing isopropoxy possessed good potency against P-gp mediated MDR in MCF-7/ADR (IC50 (doxorubicin) = 0.73 µM, RF = 69.6 with 5 µM 16 treated). Western blot results and Rh123 accumulation assays showed that 16 effectively inhibited P-gp efflux function but not its expression. The preliminary structure-activity relationship and docking studies demonstrated that compound 16 would be a potential P-gp inhibitor. Most worthy of mention is that compound 16 has achieved satisfactory results in combination with a variety of anti-tumor drugs, such as doxorubicin, paclitaxel, and vincristine. This study forwards a hopeful P-gp inhibitor for withstanding malignant tumor cell with multidrug resistance setting the basis for further studies.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/farmacologia , Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Furanos/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/farmacologia , Furanos/metabolismo , Furanos/farmacologia , Humanos , Simulação de Acoplamento Molecular , Paclitaxel/farmacologia , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/química , Tetra-Hidroisoquinolinas/metabolismo , Tetra-Hidroisoquinolinas/farmacologia
17.
Nat Commun ; 12(1): 1431, 2021 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-33664266

RESUMO

The structural complexity and bioactivity of natural products often depend on enzymatic redox tailoring steps. This is exemplified by the generation of the bisbenzannulated [5,6]-spiroketal pharmacophore in the bacterial rubromycin family of aromatic polyketides, which exhibit a wide array of bioactivities such as the inhibition of HIV reverse transcriptase or DNA helicase. Here we elucidate the complex flavoenzyme-driven formation of the rubromycin pharmacophore that is markedly distinct from conventional (bio)synthetic strategies for spiroketal formation. Accordingly, a polycyclic aromatic precursor undergoes extensive enzymatic oxidative rearrangement catalyzed by two flavoprotein monooxygenases and a flavoprotein oxidase that ultimately results in a drastic distortion of the carbon skeleton. The one-pot in vitro reconstitution of the key enzymatic steps as well as the comprehensive characterization of reactive intermediates allow to unravel the intricate underlying reactions, during which four carbon-carbon bonds are broken and two CO2 become eliminated. This work provides detailed insight into perplexing redox tailoring enzymology that sets the stage for the (chemo)enzymatic production and bioengineering of bioactive spiroketal-containing polyketides.


Assuntos
Antibacterianos/síntese química , Furanos/síntese química , Oxigenases de Função Mista/metabolismo , Policetídeos/química , Compostos de Espiro/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Produtos Biológicos/farmacologia , DNA Helicases/antagonistas & inibidores , Furanos/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , Oxirredução , Policetídeos/farmacologia , Compostos de Espiro/farmacologia
18.
Phytomedicine ; 85: 153536, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33765552

RESUMO

BACKGROUND: Leishmaniasis is a neglected tropical disease caused by protozoan parasites of the Leishmania genus. Currently, the treatment has limited effectiveness and high toxicity, is expensive, requires long-term treatment, induces significant side effects, and promotes drug resistance. Thus, new therapeutic strategies must be developed to find alternative compounds with high efficiency and low cost. Solidagenone (SOL), one of the main constituents of Solidago chilensis, has shown gastroprotective, anti-inflammatory and immunomodulatory effects. PURPOSE: This study assessed the in vitro effect of SOL on promastigotes and Leishmania amazonensis-infected macrophages, as well its microbicide and immunomodulatory mechanisms. METHODS: SOL was isolated from the roots of S. chilensis, 98% purity, and identified by chromatographic methods, and the effect of SOL on leishmanicidal activity against promastigotes in vitro, SOL-induced cytotoxicity in THP-1, J774 cells, sheep erythrocytes, and L. amazonensis-infected J774 macrophages, and the mechanisms of death involved in this action were evaluated. RESULTS: In silico predictions showed good drug-likeness potential for SOL with high oral bioavailability and intestinal absorption. SOL treatment (10-160 µM) inhibited promastigote proliferation 24, 48, and 72 h after treatment. After 24 h of treatment, SOL at the IC50 (34.5 µM) and 2 × the IC50 (69 µM) induced several morphological and ultrastructural changes in promastigotes, altered the cell cycle and cellular volume, increased phosphatidylserine exposure on the cell surface, induced the loss of plasma membrane integrity, increased the reactive oxygen species (ROS) level, induced loss of mitochondrial integrity (characterized by an apoptosis-like process), and increased the number of lipid droplets and autophagic vacuoles. Additionally, SOL induced low cytotoxicity in J774 murine macrophages (CC50 of 1587 µM), THP-1 human monocytes (CC50 of 1321 µM), and sheep erythrocytes. SOL treatment reduced the percentage of L. amazonensis-infected macrophages and the number of amastigotes per macrophage (IC50 9.5 µM), reduced TNF-α production and increased IL-12p70, ROS and nitric oxide (NO) levels. CONCLUSION: SOL showed in vitro leishmanicidal effects against the promastigotes by apoptosis-like mechanism and amastigotes by reducing TNF-α and increasing IL-12p70, ROS, and NO levels, suggesting their potential as a candidate for use in further studies on the design of antileishmanial drugs.


Assuntos
Apoptose/efeitos dos fármacos , Furanos/farmacologia , Leishmania/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Naftalenos/farmacologia , Animais , Antiprotozoários/farmacologia , Linhagem Celular , Humanos , Macrófagos/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Óxido Nítrico/metabolismo , Fosfatidilserinas/metabolismo , Raízes de Plantas/química , Espécies Reativas de Oxigênio/metabolismo , Ovinos , Solidago/química , Células THP-1
19.
Exp Parasitol ; 224: 108100, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33744229

RESUMO

Chagas disease and leishmaniasis are neglected diseases caused by parasites of the Trypanosomatidae family and together they affect millions of people in the five continents. The treatment of Chagas disease is based on benznidazole, whereas for leishmaniasis few drugs are available, such as amphotericin B and miltefosine. In both cases, the current treatment is not entirely efficient due to toxicity or side effects. Encouraged by the need to discover valid targets and new treatment options, we evaluated 8 furan compounds against Trypanosoma cruzi and Leishmania amazonensis, considering their effects against proliferation, infection, and ultrastructure. Many of them were able to impair T. cruzi and L. amazonensis proliferation, as well as cause ultrastructural alterations, such as Golgi apparatus disorganization, autophagosome formation, and mitochondrial swelling. Taken together, the results obtained so far make these compounds eligible for further steps of chemotherapy study.


Assuntos
Furanos/farmacologia , Leishmania mexicana/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacos , Linhagem Celular , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Cromatografia em Camada Delgada , Doenças Endêmicas , Furanos/química , Humanos , Concentração Inibidora 50 , Leishmania mexicana/crescimento & desenvolvimento , Leishmania mexicana/ultraestrutura , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/parasitologia , Macrófagos , Espectroscopia de Ressonância Magnética , Microscopia Eletrônica de Varredura , Simulação de Acoplamento Molecular , Doenças Negligenciadas/tratamento farmacológico , Doenças Negligenciadas/parasitologia , Trypanosoma cruzi/crescimento & desenvolvimento , Trypanosoma cruzi/ultraestrutura
20.
Free Radic Biol Med ; 167: 335-347, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33722629

RESUMO

Inflammation is a fundamental pathophysiological process which occurs in the course of several diseases. The present work describes the capacity of phytoprostanes (PhytoPs) and phytofurans (PhytoFs) (plant oxylipins), present in plant-based foods, to modulate inflammatory processes mediated by prostaglandins (PGs, human oxylipins) in lipopolysaccharide (LPS)-stimulated THP-1 monocytic cells, through a panel of 21 PGs and PG's metabolites, analyzed by UHPLC-QqQ-ESI-MS/MS. Also, the assessment of the cytotoxicity of PhytoPs and PhytoFs on THP-1 cells evidenced percentages of cell viability higher than 90% when treated with up to 100 µM. Accordingly, 50 µM of the individual PhytoPs and PhytoFs 9-F1t-PhytoP, 9-epi-9-F1t-PhytoP, ent-16-F1t-PhytoP, ent-16-epi-16-F1t-PhytoP, ent-9-D1t-PhytoP, 16-B1-PhytoP, 9-L1-PhytoP, ent-16(RS)-9-epi-ST-Δ14-10-PhytoF, ent-9(RS)-12-epi-ST-Δ10-13-PhytoF, and ent-16(RS)-13-epi-ST-Δ14-9-PhytoF were evaluated on their capacity to modulate the expression of inflammatory markers. The results obtained demonstrated the presence of 7 metabolites (15-keto-PGF2α, PGF2α, 11ß-PGF2α, PGE2, PGD2, PGDM, and PGF1α) in THP-1 monocytic cells, which expression was significantly modulated when exposed to LPS. The evaluation of the capacity of the individual PhytoPs and PhytoFs to revert the modification of the quantitative profile of PGs induced by LPS revealed the anti-inflammatory ability of 9-F1t-PhytoP, ent-9-D1t-PhytoP, 16-B1-PhytoP, 9-L1-PhytoP, and ent-9(RS)-12-epi-ST-Δ10-13-PhytoF, as evidenced by their capacity to prevent the up-regulation of 15-keto-PGF2α, PGF2α, PGE2, PGF1α, PGDM, and PGD2 induced by LPS. These results indicated that specific plant oxylipins can protect against inflammatory events, encouraging further investigations using plant-based foods rich in these oxylipins or enriched extracts, to identify specific bioactivities of the diverse individual molecules, which can be useful for nutrition and health in the frame of well-defined pathophysiological processes.


Assuntos
Lipopolissacarídeos , Espectrometria de Massas em Tandem , Ciclo-Oxigenase 2 , Furanos/farmacologia , Humanos , Inflamação , Lipidômica , Monócitos , Fluxo de Trabalho
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