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1.
J Biol Regul Homeost Agents ; 34(3): 785-794, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32723437

RESUMO

Previous reports indicated that specific cyclooxygenase-2 (COX-2) inhibitor suppresses osteoarthritis (OA). This study aimed to further explore the possible mechanism of Rofecoxib as a COX-2 inhibitor on the inhibition of chondrocyte (CH) hypertrophic development and tested the optimal treatment of Rofecoxib on CH. Basically, IL-1ß was used as a stimulus to establish a degenerated CH model. Immunofluorescence, Western blot, and RT-PCR were performed to determine the gene expression of Axin2, ß-catenin, GSK3ß, collagen X, collagen II, COX-2, PGE-2, SOX-9, Runx-2, and MMP- 13 expression. Cell Counting Kit (CCK-8) assay was used to analyze the viability of CHs. The data indicated that Rofecoxib significantly inhibited COX-2 expression and had less harmful effects on CH viability. Rofecoxib reversed the IL-1ß-induced upregulation of collagen X, COX-2, PGE-2, Runx-2, and MMP-13 expression, and promoted the viability of collagen II, SOX-9 expression of CHs. Furthermore, Rofecoxib suppressed Axin2, ß-catenin, and GSK3ß expression of the Wnt pathway, which was activated by IL-1ß or human recombinant Wnt-1 protein treatment. Therefore, Rofecoxib is an effective COX-2 inhibitor that protects CHs from hypertrophy by suppression of the Wnt/ß-catenin pathway.


Assuntos
Condrócitos/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase 2/farmacologia , Lactonas/farmacologia , Sulfonas/farmacologia , Via de Sinalização Wnt , Células Cultivadas , Condrócitos/citologia , Humanos , Hipertrofia , beta Catenina
2.
Life Sci ; 257: 118111, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32682918

RESUMO

BACKGROUND AND AIMS: Bacterial translocation (BT) is strongly associated with disease progression and poor outcome in cirrhotic patients. The role of Pregnane X receptor (PXR) in regulating bacterial translocation in cirrhosis is unknown. We previously showed that Ginkgolide-A (GA), a natural PXR ligand, attenuated BT in cirrhotic mice by abrogating inflammation along the gut-liver-axis, and by protecting small intestinal tight junctions (TJ). Here, we aimed to investigate the effect of GA in activating PXR and associated antimicrobial peptides (AMPs) in regulating BT in experimental cirrhosis. METHODS: Male Swiss albino mice were administered CCl4 (0.5 mL/kg body-weight, i.p twice a week) for 12 consecutive weeks. After the 12th week, mice were randomized and administered with GA (100-mg/kg body-weight, oral) every-day for 2 weeks. At termination, blood, gut and liver tissues were collected for molecular studies. RESULTS: GA treatment to cirrhotic mice significantly increased the expression of small intestinal PXR and Regenerating family member 3 alpha (Reg3A), which were otherwise reduced in CCl4 cirrhotic mice. Moreover, compared to naive mice a significantly reduced Lactobacillus, and increased Bacteroides and Enterococcus 16s rRNA levels were observed in the small intestine and liver of cirrhotic mice. Treatment with GA to cirrhotic mice significantly reduced intestinal overgrowth and translocation of Enterococcus and Bacteroides to the liver. Furthermore, GA treatment significantly attenuated intestinal permeability and BT marker soluble-CD14 (sCD14), which were increased in CCl4 cirrhotic mice. CONCLUSION: The study showed for the first time that, GA treatment to cirrhotic rodents attenuates BT, by improving PXR and Reg3A expression.


Assuntos
Translocação Bacteriana/efeitos dos fármacos , Ginkgolídeos/farmacologia , Lactonas/farmacologia , Cirrose Hepática Experimental/metabolismo , Proteínas Associadas a Pancreatite/metabolismo , Receptor de Pregnano X/metabolismo , Animais , Peptídeos Catiônicos Antimicrobianos/metabolismo , Western Blotting , Células Hep G2 , Humanos , Cirrose Hepática Experimental/complicações , Masculino , Camundongos , Simulação de Acoplamento Molecular , Receptor de Pregnano X/efeitos dos fármacos
3.
Mol Pharmacol ; 98(2): 156-167, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32591477

RESUMO

The natural product (+)-discodermolide (DDM) is a microtubule stabilizing agent and potent inducer of senescence. We refined the structure of DDM and evaluated the activity of novel congeners in triple negative breast and ovarian cancers, malignancies that typically succumb to taxane resistance. Previous structure-activity analyses identified the lactone and diene as moieties conferring anticancer activity, thus identifying priorities for the structural refinement studies described herein. Congeners possessing the monodiene with a simplified lactone had superior anticancer efficacy relative to taxol, particularly in resistant models. Specifically, one of these congeners, B2, demonstrated 1) improved pharmacologic properties, specifically increased maximum response achievable and area under the curve, and decreased EC50; 2) a uniform dose-response profile across genetically heterogeneous cancer cell lines relative to taxol or DDM; 3) reduced propensity for senescence induction relative to DDM; 4) superior long-term activity in cancer cells versus taxol or DDM; and 5) attenuation of metastatic characteristics in treated cancer cells. To contrast the binding of B2 versus DDM in tubulin, X-ray crystallography studies revealed a shift in the position of the lactone ring associated with removal of the C2-methyl and C3-hydroxyl. Thus, B2 may be more adaptable to changes in the taxane site relative to DDM that could account for its favorable properties. In conclusion, we have identified a DDM congener with broad range anticancer efficacy that also has decreased risk of inducing chemotherapy-mediated senescence. SIGNIFICANCE STATEMENT: Here, we describe the anticancer activity of novel congeners of the tubulin-polymerizing molecule (+)-discodermolide. A lead molecule is identified that exhibits an improved dose-response profile in taxane-sensitive and taxane-resistant cancer cell models, diminished risk of chemotherapy-mediated senescence, and suppression of tumor cell invasion endpoints. X-ray crystallography studies identify subtle changes in the pose of binding to ß-tubulin that could account for the improved anticancer activity. These findings support continued preclinical development of discodermolide, particularly in the chemorefractory setting.


Assuntos
Alcanos/química , Carbamatos/química , Lactonas/síntese química , Neoplasias Ovarianas/metabolismo , Pironas/química , Neoplasias de Mama Triplo Negativas/metabolismo , Moduladores de Tubulina/síntese química , Células A549 , Área Sob a Curva , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Lactonas/química , Lactonas/farmacologia , Estrutura Molecular , Neoplasias Ovarianas/tratamento farmacológico , Taxoides/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia
4.
Phytomedicine ; 71: 153239, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32447245

RESUMO

BACKGROUND AND PURPOSE: Multidrug resistance (MDR) remains the main obstacle in cancer treatment and overexpression of P-glycoprotein (P-gp) is one of the most common causes of chemoresistance. The development of novel P-gp inhibitors from natural products is a prospective strategy to combat MDR cancers. Among the natural sesquiterpene compounds, sesquiterpene pyridine alkaloids exhibit various biological properties. Therefore, in the present study, we evaluated the modulatory effects of wilforine on P-gp expression and function. The molecular mechanisms and kinetic models of wilforine-mediated P-gp inhibition were further investigated. METHODS: The human P-gp stable expression cells (ABCB1/Flp-InTM-293) and human cervical cancer cells (sensitive: HeLaS3; MDR: KBvin) were used. The cell viability was assessed by SRB assay. The inhibitory effect of wilforine on P-gp efflux and the underlying mechanism were evaluated by assays for calcein-AM uptake, rhodamine123 and doxorubicin efflux, ATPase activity, real-time quantitative RT-PCR, apoptosis, and cell cycle analysis. Molecular docking was performed by the docking software CDOCKER with BIOVIA Discovery Studio 4.5 (D.S. 4.5). RESULTS: We found that wilforine significantly inhibited the efflux activity of P-gp in a concentration-dependent manner. Further kinetic analysis demonstrated that wilforine significantly inhibited P-gp efflux function by competitive inhibition and stimulated the basal P-gp ATPase activity. In addition, wilforine re-sensitized MDR cancer cells to chemotherapeutic drugs. The docking model indicated that wilforine was bound to residues of P-gp such as LEU884, LYS887, THR176 and ASN172. CONCLUSION: These results suggest a novel future therapeutic strategy for MDR cancer using wilforine as an adjuvant treatment with chemotherapy.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Lactonas/farmacologia , Piridinas/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/química , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/fisiologia , Células HeLa , Humanos , Cinética , Lactonas/química , Simulação de Acoplamento Molecular , Estudos Prospectivos , Piridinas/química
5.
Toxicol Appl Pharmacol ; 401: 115071, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32454055

RESUMO

Prostate Cancer (PCa) is the second most common cancer among men in United States after skin cancer. Conventional chemotherapeutic drugs available for PCa treatment are limited due to toxicity and resistance issues. Therefore, there is an urgent need to develop more effective treatment for advanced PCa. In this current study, we focused on evaluating the anti-cancer efficacy of Eprinomectin (EP), a novel avermectin analog against PC3 metastatic PCa cells. EP displayed robust inhibition of cell viability of PC3 cells in addition to suppressing the colony formation and wound healing capabilities. Our study showed that EP targets PC3 cells via inducing ROS and apoptosis activation. EP treatment enforces cell cycle arrest at G0/G1 phase via targeting cyclin-dependent kinase 4 (CDK4) and subsequent induction of apoptosis in PC3 cells. At the molecular level, EP effectively inhibited the expression of various cancer stem cell markers such as ALDH1, Sox-2, Nanog, Oct3/4 and CD44. Interestingly, EP also inhibited the activity of alkaline phosphatase, a maker of pluripotent stem cells. Of note, EP treatment resulted in the translocation of ß-catenin from the nucleus to the cytoplasm indicating that EP antagonizes Wnt/ß-catenin signaling pathway. Western blotting analysis revealed that EP downregulated the expression of key cell cycle markers such as cyclin D1, cyclin D3, CDK4, and c-Myc. In addition, EP inhibited the anti-apoptotic markers such as Mcl-1, XIAP, c-IAP1 and survivin in PC3 cells. On the other hand, EP treatment resulted in the activation of pH2A.X, Bad, caspase-9, caspase-3 and cleavage of PARP1. Taken together, our data suggests that EP is a potential agent to treat advanced PCa cells via modulating apoptosis signaling.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ivermectina/análogos & derivados , Lactonas/farmacologia , Compostos Macrocíclicos/farmacologia , Neoplasias da Próstata/metabolismo , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Apoptose/fisiologia , Citotoxinas/química , Citotoxinas/farmacologia , Citotoxinas/uso terapêutico , Relação Dose-Resposta a Droga , Humanos , Ivermectina/química , Ivermectina/farmacologia , Ivermectina/uso terapêutico , Lactonas/uso terapêutico , Compostos Macrocíclicos/química , Compostos Macrocíclicos/uso terapêutico , Masculino , Células PC-3 , Neoplasias da Próstata/tratamento farmacológico , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo
6.
J Nat Med ; 74(3): 584-590, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32207026

RESUMO

Three new 5,6-dihydro-α-pyrones derivatives, named (S)-rugulactone (1) pulchrinervialactone A (2), and pulchrinervialactone B (4), along with one known pyrone, cryptobrachytone C (3), and three known amide derivatives (5-7) have been isolated from the leaves of Cryptocarya pulchrinervia. The structures of 1-7 were elucidated based on extensive spectroscopic data and comparison with literatures. The configurations of compounds 3 and 4 were established by single crystal X-ray diffraction analysis. This is also the first report in finding (S)-rugulactone (1) as a natural product. In addition, the preliminary cytotoxic activity of the isolated compounds was evaluated against P-388 cells using the [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. All the pyrones, except compound 4, were active significantly inhibiting the growth of P-388 cells, while the amides derivatives (5-7) showed moderate to weak activities. Therefore, compounds 1-3 could be potentially examined further for anticancer agents.


Assuntos
Antineoplásicos/farmacocinética , Proliferação de Células/efeitos dos fármacos , Cryptocarya/química , Lactonas/farmacologia , Pironas/farmacologia , Animais , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Lactonas/isolamento & purificação , Camundongos , Estrutura Molecular , Neoplasias/tratamento farmacológico , Folhas de Planta/química , Pironas/isolamento & purificação
7.
Phytomedicine ; 68: 153191, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32135457

RESUMO

BACKGROUND: Atractylenolide I (ATL-1) is a natural herbal compound used in traditional Chinese medicine that has exhibited anti-cancer properties. The anti-tumorigenic activity of ATL-1 against colorectal cancer (CRC) and the underlying signaling pathways involved in its mechanisms are examined here. HYPOTHESIS: ATL-1 exerts therapeutic effect against CRC by disrupting glucose metabolism and cancer stem cell maintenance via AKT/mTOR pathway regulation. STUDY DESIGN: In vitro studies were performed in COLO205 and HCT116 CRC cell lines and in vivo studies were conducted in a mouse xenograft model of CRC tumor. METHODS: CRC cells were treated with ATL-1 at various concentrations, with or without inhibitors of AKT or mTOR. Cell proliferation, apoptosis, invasion, stemness maintenance, glucose metabolism, and AKT/mTOR signaling were evaluated. CRC tumor-xenografted mice were treated with an AKT inhibitor and/or ATL-1, and glucose metabolism and stemness maintenance were examined in tumor tissues. RESULTS: ATL-1 significantly inhibited the invasion of CRC cells by inducing their apoptosis, possibly via the excessive production of reactive oxygen species. Glucose metabolism (Warburg effect) was also altered and stem-like traits were suppressed by ATL-1. In addition, ATL-1 effectively acted as an inhibitor or AKT/mTOR by downregulating the phosphorylation of proteins related to the AKT/mTOR pathway. In vivo studies showed that tumor weight and volume were reduced by ATL-1 and that aerobic glycolysis, stemness maintenance, and AKT/mTOR activation were impaired by ATL-1 in colorectal tumors. CONCLUSIONS: ATL-1 acts as an effective agent to suppress colorectal tumor progression, mainly by inhibiting CRC cell proliferation through altering apoptosis, glucose metabolism, and stem-like behavior. These processes were mediated by the AKT/mTOR signaling pathway both in vitro and in vivo. ATL-1 may be a potential agent to be used in molecular-targeted strategies for cancer treatment.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Lactonas/farmacologia , Sesquiterpenos/farmacologia , Animais , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Regulação para Baixo/efeitos dos fármacos , Células HCT116 , Humanos , Masculino , Camundongos Endogâmicos BALB C , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Parasit Vectors ; 13(1): 127, 2020 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-32169109

RESUMO

BACKGROUND: Psoroptic mange is an important disease in Belgian Blue cattle. Treatment failure of macrocyclic lactones against Psoroptes ovis has been reported, but clear evidence of in vivo resistance is lacking. This study assessed the efficacy of macrocyclic lactone products on 16 beef farms in Belgium and the Netherlands in vivo and in vitro. METHODS: On each farm a group of animals (n = 7-14) with psoroptic mange was treated with two subcutaneous injections of a macrocyclic lactone product with 7-10 days interval (15 farms) or a single injection with a long-acting macrocyclic lactone (1 farm). In vivo efficacy was assessed by the reduction in mite counts, clinical index (proportion of the body surface affected by lesions), the proportion of the animals with negative mite counts after the first treatment round and the number of treatment rounds needed to obtain zero mites counts in all animals. A mite population was categorized as sensitive when the mite count reduction after the first treatment round > 95% and the lower limit of the uncertainty interval > 90%. Resistance was detected when both parameters were below their threshold and suspected when one parameter was too low. In vitro knockdown and mortality were evaluated in a contact test. RESULTS: The proportion of the animals with negative mite counts after the first treatment round varied from 0 to 80%. All farms needed two or more treatments rounds to obtain zero mite counts on all animals. Clinical index only started to reduce after the second treatment round. Mite populations from three farms were categorized as sensitive, one as suspected resistant and 12 as resistant. No correlation was found between in vitro lethal dose 50 and knockdown dose 50 values and in vivo efficacy parameters. CONCLUSIONS: Unambiguous treatment failure was detected on 12 out of 16 farms, confirming the presence of macrocyclic lactone resistance on Belgian Blue beef farms. In vitro parameters could not discriminate the farms based on their in vivo sensitivity. The mean reduction in mite counts and the lower limit of the confidence interval are proposed as parameters to identify acaricide resistance.


Assuntos
Doenças dos Bovinos/parasitologia , Resistência a Medicamentos , Lactonas/farmacologia , Infestações por Ácaros/veterinária , Psoroptidae/efeitos dos fármacos , Acaricidas/farmacologia , Animais , Bélgica , Bovinos , Doenças dos Bovinos/tratamento farmacológico , Fazendas , Feminino , Injeções Subcutâneas , Dose Letal Mediana , Masculino , Infestações por Ácaros/tratamento farmacológico , Países Baixos , Resultado do Tratamento
9.
Cancer Cell ; 37(3): 308-323.e12, 2020 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-32142668

RESUMO

Diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors for which there is currently no effective treatment. Some of these tumors combine gain-of-function mutations in ACVR1, PIK3CA, and histone H3-encoding genes. The oncogenic mechanisms of action of ACVR1 mutations are currently unknown. Using mouse models, we demonstrate that Acvr1G328V arrests the differentiation of oligodendroglial lineage cells, and cooperates with Hist1h3bK27M and Pik3caH1047R to generate high-grade diffuse gliomas. Mechanistically, Acvr1G328V upregulates transcription factors which control differentiation and DIPG cell fitness. Furthermore, we characterize E6201 as a dual inhibitor of ACVR1 and MEK1/2, and demonstrate its efficacy toward tumor cells in vivo. Collectively, our results describe an oncogenic mechanism of action for ACVR1 mutations, and suggest therapeutic strategies for DIPGs.


Assuntos
Receptores de Ativinas Tipo I/química , Receptores de Ativinas Tipo I/genética , Neoplasias Encefálicas/patologia , Glioma/patologia , Mutação , Receptores de Ativinas Tipo I/antagonistas & inibidores , Receptores de Ativinas Tipo I/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Diferenciação Celular/genética , Linhagem Celular Tumoral , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Feminino , Glioma/tratamento farmacológico , Glioma/genética , Histonas/genética , Histonas/metabolismo , Humanos , Lactonas/farmacologia , Masculino , Camundongos Transgênicos , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Neuroglia/metabolismo , Neuroglia/patologia , Oligodendroglia/patologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Fatores de Transcrição SOXC/genética , Fatores de Transcrição SOXC/metabolismo
10.
Cell Immunol ; 349: 104046, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32057354

RESUMO

Uncontrolled activation of NLRP3 inflammasome initiates a series of human inflammatory diseases. Targeting NLRP3 inflammasome has attracted considerable attention in developing potential therapeutic interventions. Here, we reported that dehydrocostus lactone (DCL), a main component of Saussurea lappa from the traditional Chinese medicine, inhibited NLRP3 inflammasome-mediated caspase-1 activation and subsequent interleukin (IL)-1ß production in primary mouse macrophages and human peripheral blood mononuclear cells and exerted an inhibitory effect on NLRP3-driven inflammation. Mechanistically, DCL significantly blocked the ASC oligomerization, which is essential for the assembly of activated inflammasome. Importantly, in vivo experiments showed that DCL reduced IL-1ß secretion and peritoneal neutrophils recruitment in LPS-mediated inflammation mouse model, which is demonstrated to be NLRP3 dependent. These results suggest that DCL is a potent pharmacological inhibitor of NLRP3 inflammasome and may be developed as a therapeutic drug for treating NLRP3-associated diseases.


Assuntos
Quimiotaxia de Leucócito/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Inflamassomos/efeitos dos fármacos , Inflamação/prevenção & controle , Lactonas/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Sesquiterpenos/farmacologia , Adulto , Animais , Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Proteínas Reguladoras de Apoptose/fisiologia , Proteínas Adaptadoras de Sinalização CARD/antagonistas & inibidores , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Proteínas de Ligação ao Cálcio/antagonistas & inibidores , Proteínas de Ligação ao Cálcio/fisiologia , Caspase 1/metabolismo , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/fisiologia , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Interleucina-1beta/biossíntese , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Lipopolissacarídeos/toxicidade , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/efeitos dos fármacos , Nigericina/farmacologia , Poli I-C/farmacologia , Polimerização/efeitos dos fármacos , Organismos Livres de Patógenos Específicos , Ácido Úrico/farmacologia
11.
Phytochemistry ; 171: 112248, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31918304

RESUMO

The phytochemical investigation of the twig and leaf extracts of Goniothalamus tamirensis led to the isolation and identification of 15 compounds including three rare previously undescribed styryllactones, goniotamirenones A-C, together with 12 known compounds. (Z)-6-Styryl-5,6-dihydro-2-pyranone and 5-(1-hydroxy-3-phenyl-allyl)-dihydro-furan-2-one are reported here for the first time as previously undescribed natural products. Their structures were elucidated by spectroscopic methods. Goniotamirenone A was synthesized via a [2 + 2] cycloaddition reaction of 6-styrrylpyran-2-one in quantitative yield. The absolute configurations of goniotamirenones B and C were identified from experimental and calculated ECD data, while the absolute configurations of (-)-5-acetoxygoniothalamin, (-)-isoaltholactone, parvistone E, and 5-(1-hydroxy-3-phenyl-allyl)-dihydro-furan-2-one were identified by single-crystal X-ray diffraction analysis using Cu Kα radiation. The absolute configurations of the other related compounds were determined from comparisons of their ECD spectra with relevant compounds reported in the literature. (-)-5-Acetoxygoniothalamin exhibited potent cytotoxicity against the colon cancer cell line (HCT116) with an IC50 value of 8.6 µM which was better than the standard control (doxorubicin, IC50 = 9.7 µM), while (Z)-6-styryl-5,6-dihydro-2-pyranone was less active with an IC50 value of 22.1 µM.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Goniothalamus/química , Lactonas/farmacologia , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Estirenos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Teoria da Densidade Funcional , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Lactonas/química , Lactonas/isolamento & purificação , Modelos Moleculares , Estrutura Molecular , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Estirenos/química , Estirenos/isolamento & purificação
12.
Mol Med Rep ; 21(2): 675-684, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31974628

RESUMO

Osteosarcoma is the most common type of malignant bone cancer and results in cancer­related deaths among adolescents. Alantolactone (ALT) demonstrates antitumor properties in various diseases; however, its potential role in osteosarcoma is relatively unclear. The aim of the present study was to evaluate the effect of ALT on osteosarcoma. ALT significantly decreased the viability of U2OS and HOS osteosarcoma cell lines. Cells flow cytometry assay and Hoechst 33258 staining assay revealed that ALT significantly increased the proportion of apoptotic U2OS cells. In addition, wound healing and Transwell invasion assays demonstrated that the invasion and migration of osteosarcoma were markedly reduced upon ALT treatment. It was hypothesized that the antitumor functions of ALT are mediated through inhibition of the PI3K/AKT signaling pathway. In conclusion, the results of the present study confirmed the inhibition of ALT on osteosarcoma cells via downregulation of PI3K/AKT signaling pathways, suggesting ALT as a potential therapeutic candidate for osteosarcoma.


Assuntos
Lactonas/farmacologia , Osteossarcoma/enzimologia , Osteossarcoma/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sesquiterpenos de Eudesmano/farmacologia , Transdução de Sinais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Lactonas/química , Invasividade Neoplásica , Sesquiterpenos de Eudesmano/química , Transdução de Sinais/efeitos dos fármacos
13.
Acta Pharm ; 70(2): 215-226, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31955145

RESUMO

Heliangolide is a naturally occurring sesquiterpene lactone and its derivatives are biologically active compounds present in most medicinal plants. This study evaluated the antioxidant and antidiabetic properties of a heliangolide sesquiterpene lactone isolated from Helianthus annuus L. leaves. The heliangolide sesquiterpene lactone was isolated through a combination of solvent-solvent partitioning, column chromatography, thin layer chromatography and high-performance liquid chromatography techniques. The antioxidant activity of the compound was evaluated using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and nitric oxide radical scavenging assays while the antidiabetic effects were investigated in alloxan-induced diabetic rats. The heliangolide derivative at the concentration of 954.2 µmol L-1 showed 23.7 % DPPH and 26 % nitric oxide radical inhibitions compared with 96.6 and 50.9 %, resp., displayed by the controls (2,271.2 µmol L-1). It also reduced the fasting blood glucose (FBG) levels in a time-dependent manner. The highest activity was recorded within 6 h post-treatment at 0.2 mmol kg-1 bm. The heliangolide derivative exhibited significant (p < 0.05) antioxidant and antidiabetic properties and provides a basis for further development of constituents of Helianthus annuus leaves for the management of such diseases.


Assuntos
Antioxidantes/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Helianthus/química , Hipoglicemiantes/farmacologia , Lactonas/farmacologia , Extratos Vegetais/farmacologia , Folhas de Planta/química , Sesquiterpenos/farmacologia , Animais , Compostos de Bifenilo/química , Modelos Animais de Doenças , Flavonoides/farmacologia , Masculino , Picratos/química , Plantas Medicinais/química , Ratos , Ratos Wistar
14.
Fitoterapia ; 140: 104444, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31790768

RESUMO

Alpinia zerumbet (Pers.) B.L.Burtt & R.M.Sm. (Zingiberaceae) is a perennial plant native to the East Indies and is widely distributed in South America, Oceania, and Asia. The mature fruits of the plant have been used in traditional medicine in China. In this study, we compared the chemical constituents in the methanol extracts of the leaves, the placenta, the pericarps, and the seeds obtained from the same plant using LC-MS, and we examined the NO inhibitory activities of the respective extracts and the isolated compounds. As a result of LC-MS analyses, kavalactone derivatives (1-6) were detected in the methanol extracts of the leaves, placenta, and pericarps. Of these, compound 6 was identified as a new asymmetrical cyclobutane dimer of 5,6-dehydrokawain. Quantitative analysis showed that the total amounts of kavalactone derivatives were highest in the methanol extract of the pericarps. Moreover, the results of measurements of the anti-inflammatory activity revealed that the pericarps extract showed the strongest activity. The compounds responsible for the anti-inflammatory activity of the extracts from A. zerumbet were identified. Of these, five were known kavalactone derivatives and one was a new kavalactone derivative (aniba dimer C). The results showed that the pericarps of A. zerumbet are a rich source of kavalactone derivatives, and that the pericarps of A. zerumbet can be utilized as an important medicinal resource.


Assuntos
Alpinia/química , Anti-Inflamatórios/farmacologia , Lactonas/farmacologia , Animais , Anti-Inflamatórios/isolamento & purificação , Células Cultivadas , Hepatócitos/efeitos dos fármacos , Japão , Lactonas/isolamento & purificação , Estrutura Molecular , Óxido Nítrico/metabolismo , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química , Folhas de Planta/química , Ratos
15.
Chem Biol Interact ; 315: 108891, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31697926

RESUMO

BACKGROUND AND AIMS: Pregnane X receptor (PXR) is a ligand-activated transcription factor and nuclear receptor expressed ubiquitously along gut-liver-axis. Inflammatory bowel disorders have been reported to implicate PXR in maintaining tight junction (TJ) integrity and countering inflammation. However, the hepatoprotective role of PXR activation in soothing bacterial translocation in liver cirrhosis has not been explored. Ginkgolide A (GA), a terpene trilactone from Ginkgo Biloba extract, is a natural ligand of rodent and human PXR. This study aims to investigate the effect of GA in activating PXR and improving associated tight junction integrity and reducing bacterial translocation in gut-liver axis of CCl4 induced cirrhosis model. METHODS: Swiss albino mice were administered with CCl4 (0.5 ml/kg body weight, i.p) in corn oil for 12 weeks at an interval of two times a week. Following ascites induction, mice were randomized & administered 100 mg/kg body weight of GA through oral gavage for 2 weeks. At termination, blood, gut and liver tissues were collected for biochemical and molecular studies. RESULTS: When compared to naïve mice, protein expression of hepatic and small intestinal PXR, CYP3A, ZO-1 and occludin were found to be significantly (p < 0.01) decreased in CCl4 induced cirrhotic mice. Treatment with GA to cirrhotic mice significantly (p < 0.05) induced the expression of both hepatic and small intestinal PXR, CYP3A, ZO-1 and Occludin. Furthermore, increased (p < 0.01) hepatic and small intestinal NFκB was observed in CCl4 induced cirrhotic mice that was significantly (p < 0.05) lowered following GA treatment. Over expression of TLR4/MyD88/NFκB axis and its downstream pro-inflammatory mediators TNF-α, IL6 and IFN-γ were observed in CCl4 induced mice, and these indices were abrogated significantly after GA treatment. Furthermore, significantly increased plasma levels of bacterial translocation markers LBP and procalcitonin were found in CCl4 mice, which were reduced significantly (p < 0.05 & p < 0.0001) after GA treatment. CONCLUSION: In conclusion, our data supports the hypothesis that, GA treatment to CCl4 induced cirrhotic mice, activated hepatic and small intestinal PXR and diminished inflammation, thereby improving tight junction integrity and attenuating bacterial translocation.


Assuntos
Translocação Bacteriana/efeitos dos fármacos , Ginkgolídeos/farmacologia , Lactonas/farmacologia , Cirrose Hepática/metabolismo , Receptor de Pregnano X/metabolismo , Proteínas de Junções Íntimas/metabolismo , Animais , Citocromo P-450 CYP3A/metabolismo , Inflamação/metabolismo , Interferon gama/metabolismo , Interleucina-6/metabolismo , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/metabolismo , Ligantes , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , NF-kappa B/metabolismo , Extratos Vegetais/farmacologia , Proteína da Zônula de Oclusão-1/metabolismo
16.
Phytochemistry ; 170: 112196, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31731238

RESUMO

Seven previously undescribed sesquiterpene lactones, three known sesquiterpene lactones (ixerin D, 15-p-hydroxyphenylacetyllactucin, and 15-p-hydroxyphenylacetyllactucin-8-sulfate), and two known quinic acid derivatives (3-O-feruloylquinic acid and 3,5-di-O-caffeoylquinic acid) were isolated from Sonchus palustris L. roots. Four formerly undescribed compounds were elucidated to be 3ß,14-dihydroxycostunolide-3-O-ß-D-glucopyranosyl-(2-O-p-hydroxyphenylacetyl)-14-O-p-hydroxyphenylacetate, 15-p-methoxyphenylacetyllactucin, 15-p-methoxyphenylacetyllactucin-8-sulfate, and 8-p-hydroxyphenylacetyllactucin-15-sulfate. Additionally, three undescribed conjugates of lactucin and a eudesmanolide type sesquiterpenic acid, sonchpalustrin, 4″-O-methylsonchpalustrin, and isosonchpalustrin, were characterized. The structures of the newly discovered natural products were elucidated using 1D and 2D NMR spectroscopy and UHPLC-HRMS. 15-p-Hydroxyphenylacetyllactucin and 15-p-methoxyphenylacetyllactucin showed significant in vitro cytotoxicity against CEM and BJ cells with IC50 values ranging from 3.9 to 9.8 µM. Compounds 3 and 4 showed also strong anti-inflammatory activity in vitro.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Asteraceae/química , Lactonas/farmacologia , Compostos Fitoquímicos/farmacologia , Sesquiterpenos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Lactonas/química , Lactonas/isolamento & purificação , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação , Sesquiterpenos/química , Sesquiterpenos/isolamento & purificação
17.
J Chem Ecol ; 46(1): 63-75, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31832894

RESUMO

Plants experience seasonal fluctuations in abiotic and biotic factors such as herbivore attack rates. If and how root defense expression co-varies with seasonal fluctuations in abiotic factors and root herbivore attack rates is not well understood. Here, we evaluated seasonal changes in defensive root latex chemistry of Taraxacum officinale plants in the field and correlated the changes with seasonal fluctuations in abiotic factors and damage potential by Melolontha melolontha, a major natural enemy of T. officinale. We then explored the causality and consequences of these relationships under controlled conditions. The concentration of the defensive sesquiterpene lactone taraxinic acid ß-D glucopyranosyl ester (TA-G) varied substantially over the year and was most strongly correlated to mean monthly temperature. Both temperature and TA-G levels were correlated with annual fluctuations in potential M. melolontha damage. Under controlled conditions, plants grown under high temperature produced more TA-G and were less attractive for M. melolontha. However, temperature-dependent M. melolontha feeding preferences were not significantly altered in TA-G deficient transgenic lines. Our results suggest that fluctuations in temperature leads to variation in the production of a root defensive metabolites that co-varies with expected attack of a major root herbivore. Temperature-dependent herbivore preference, however, is likely to be modulated by other phenotypic alterations.


Assuntos
Besouros/fisiologia , Glucosídeos/metabolismo , Lactonas/metabolismo , Sesquiterpenos/metabolismo , Taraxacum/química , Animais , Biomassa , Besouros/crescimento & desenvolvimento , Glucosídeos/química , Glucosídeos/farmacologia , Herbivoria/efeitos dos fármacos , Lactonas/química , Lactonas/farmacologia , Larva/efeitos dos fármacos , Larva/fisiologia , Raízes de Plantas/química , Raízes de Plantas/metabolismo , Raízes de Plantas/parasitologia , Plantas Geneticamente Modificadas/metabolismo , Plantas Geneticamente Modificadas/parasitologia , Estações do Ano , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Taraxacum/metabolismo , Taraxacum/parasitologia , Temperatura
18.
Food Chem Toxicol ; 135: 111044, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31830547

RESUMO

Hemistepsin A (HsA), isolated from Hemistepta lyrata (Bunge) Bunge, has the ability to ameliorate hepatitis in mice. However, the effects of H. lyrata and HsA on other types of liver disease have not been explored. In this report, we investigated the effects of H. lyrata and HsA on liver fibrosis and the underlying molecular mechanisms in activated hepatic stellate cells (HSCs). Based on cell viability-guided isolation, we found HsA was the major natural product responsible for H. lyrata-mediated cytotoxicity in LX-2 cells. HsA significantly decreased the viability of LX-2 cells and primary activated HSCs, increased the binding of Annexin V, and altered the expression of apoptosis-related proteins, suggesting that HsA induces apoptosis in activated HSCs. HsA reduced the phosphorylation of IKKε and the transactivation of nuclear factor-κB (NF-κB). Moreover, HsA decreased the phosphorylation of Akt and its downstream signaling molecules. Transfection experiments suggested that inhibition of NF-κB or Akt is essential for HsA-induced apoptosis of HSCs. In a CCl4-induced liver fibrosis model, HsA administration significantly decreased ALT and AST activities. Furthermore, HsA attenuated CCl4-mediated collagen deposits and profibrogenic genes expression in hepatic tissue. Thus, HsA may serve as a natural product for managing liver fibrosis through inhibition of NF-κB/Akt-dependent signaling.


Assuntos
Apoptose/efeitos dos fármacos , Células Estreladas do Fígado/efeitos dos fármacos , Lactonas/farmacologia , Cirrose Hepática/prevenção & controle , Sesquiterpenos/farmacologia , Animais , Linhagem Celular Transformada , Clorofórmio/farmacologia , Células Estreladas do Fígado/metabolismo , Humanos , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Camundongos , NF-kappa B/metabolismo , Extratos Vegetais/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos
19.
Planta Med ; 86(1): 26-31, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31711251

RESUMO

Kava, the extract of the roots of Piper methysticum, has been traditionally consumed in the South Pacific islands for its natural relaxing property. Epidemiological data suggests that kava consumption may reduce human cancer risk, and in vitro and in vivo models suggest chemopreventive potential against carcinogen-induced tumorigenesis. Therefore, knowledge about its molecular mechanisms and responsible ingredient(s) for these beneficial properties will better guide kava's use for the management of these disorders. Psychological stress typically results in increased production of stress hormones, such as norepinephrine (NE), which activate adrenergic receptors (ARs). Psychological stress has also been associated with increased cancer incidence and poor clinical outcomes in cancer patients. Mechanistically, binding of NE to ARs induces intracellular calcium influx, which activates downstream signaling pathways involved in both stress and cancer development. In this study, we characterized the effect of kava and its components, 3 fractions and 6 major kavalactones, on NE-induced intracellular calcium influx in H1299, a human non-small cell lung carcinoma cell line. Results show that kava extract effectively inhibits NE-mediated intracellular calcium influx in H1299 cells, potentially through antagonizing ß-AR signaling. This inhibitory activity is recapitulated by the major kavalactones in kava. Among the 6 major kavalactones, DHK demonstrated the best potency. Taken together, our study suggests a novel mechanism through which kava and its ingredients potentially offer the anxiolytic and cancer-preventive activity.


Assuntos
Ansiolíticos/isolamento & purificação , Antineoplásicos Fitogênicos/isolamento & purificação , Cálcio/metabolismo , Kava/química , Lactonas/farmacologia , Neoplasias Pulmonares/prevenção & controle , Extratos Vegetais/farmacologia , Ansiolíticos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Humanos , Lactonas/isolamento & purificação , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/psicologia , Norepinefrina/antagonistas & inibidores , Estresse Psicológico/complicações , Estresse Psicológico/tratamento farmacológico
20.
Eur J Med Chem ; 185: 111807, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31675512

RESUMO

An efficient four-step synthesis of tetracyclic lactones from 1,4-benzodioxine-2-carboxylic acid was developed. Ellipticine derivatives exhibit antitumor activity however only a few derivatives without carbazole subunit have been studied to date. Herein, several tetracyclic lactones were synthesized and biologically evaluated. Several compounds (2a, 3a, 4a and 5a) were found to be inhibitors of the Kras-Wnt pathway. The lactone 2a also exerted a potent inhibition of Tau protein translation and was shown to have capacity for CYP1A1-bioactivation. The results obtained are further evidence of the therapeutic potential of tetracyclic lactones related to ellipticine. Molecular modeling studies showed that compound 2a is inserted between helix α3 and α4 of the KRas protein making interactions with the hydrophobic residues Phe90, Glu91, Ile9364, Hie94, Leu133 and Tyr137and a hydrogen bond with residue Arg97.


Assuntos
Antineoplásicos/farmacologia , Citocromo P-450 CYP1A1/metabolismo , Lactonas/farmacologia , Compostos Policíclicos/farmacologia , Proteínas tau/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Lactonas/síntese química , Lactonas/química , Modelos Moleculares , Estrutura Molecular , Compostos Policíclicos/síntese química , Compostos Policíclicos/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Proteínas tau/metabolismo
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