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1.
Ecotoxicol Environ Saf ; 189: 110020, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31809954

RESUMO

Azadirachtin, as the most promising and effective botanical insecticide, exhibits significant growth inhibition activity against agricultural and forestry pests. However, its biochemical effects at the metabolic level compared with those of other insect growth regulators have not been studied. Therefore, in this study, a GC-MS based untargeted metabolomics approach was applied to compare azadirachtin with pyriproxyfen (a juvenile hormone analog) and tebufenozide (a molting hormone analog) in terms of their metabolic effects on Bactrocera dorsalis larvae. The bioactivity of azadirachtin against B. dorsalis larvae was significantly different than those of pyriproxyfen and tebufenozide. A total of 693 mass features were recognized, and 112 metabolites were identified in this study. The results showed that a total of 16, 13 and 10 differentially regulated metabolites corresponding to 12, 5 and 8 pathways occur in Aza versus CK, Pyr versus CK and Teb versus CK group, respectively. Further analysis showed that 6 differentially regulated metabolites corresponding to 5 key pathways could be the primary differential metabolic response of B. dorsalis larvae to the three insect growth regulators. The pathways were myo-inositol corresponding to ascorbate and aldarate metabolism as the specific response of B. dorsalis larvae to azadirachtin; xylitol, xylulose and 3-aminopropionitrile corresponding to pentose and glucuronate interconversions, and cyanoamino acid metabolism as the common responses to azadirachtin and pyriproxyfen; and 3-hydroxypropionic acid and beta-alanine corresponding to propanoate metabolism and beta-alanine metabolism as the specific responses to tebufenozide. The results showed that the metabolic response of B. dorsalis larvae to azadirachitin is closer to that of pyriproxyfen than tebufenozide. The differentially regulated metabolites and pathways responsible for this difference are discussed.


Assuntos
Hidrazinas/farmacologia , Hormônios de Inseto/farmacologia , Inseticidas/farmacologia , Limoninas/farmacologia , Piridinas/farmacologia , Tephritidae/metabolismo , Animais , Larva/efeitos dos fármacos , Larva/metabolismo , Metaboloma/efeitos dos fármacos , Metabolômica , Tephritidae/efeitos dos fármacos
2.
Chem Biol Interact ; 316: 108920, 2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31857088

RESUMO

Cedrelone is a limonoid isolated from the plant Trichilia catigua (Meliaceae). Previous studies have demonstrated that cedrelone (1) has several damaging effects on triple negative breast tumor (TNBC) cell line MDA-MB-231. In this work we investigated two new derivatives of cedrelone, the acetate (1a) and the mesylate (1b), to examine whether their effects are improved in comparison to the lead molecule. Cedrelone acetate (1a) was the most cytotoxic compound on TNBC cells and was chosen for additional analyses in traditional two-dimensional (2D) monolayer cultures and three-dimensional (3D) assays. In 2D, 1a induced cell cycle arrest, apoptosis and inhibited essential steps of the metastasis process of the MDA-MB-231 cells, in vitro. Moreover, 1a was able to revert the malignant phenotype of the T4-2 cells in 3D. These effects were concomitant with the downregulation of EGFR, ß1-integrin and phospho-Akt, which could have resulted in a decrease of NFκB levels and MMP9 activity. These results suggest that 1a could be used as an important model for the design of a new drug to be applied in cancer treatment and be further studied in vivo for its antitumor and antimetastatic effects.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Limoninas/química , Acetilação , Antineoplásicos/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Técnicas de Cultura de Células , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Humanos , Integrina beta1/genética , Integrina beta1/metabolismo , Limoninas/farmacologia , Meliaceae/química , Meliaceae/metabolismo , Fenótipo
3.
Am J Physiol Endocrinol Metab ; 317(6): E957-E972, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31593505

RESUMO

Skeletal muscle handles ~80-90% of the insulin-induced glucose uptake. In skeletal muscle, insulin binding to its cell surface receptor triggers redistribution of intracellular glucose transporter GLUT4 protein to the cell surface, enabling facilitated glucose uptake. In adipocytes, the eight-protein exocyst complex is an indispensable constituent in insulin-induced glucose uptake, as it is responsible for the targeted trafficking and plasma membrane-delivery of GLUT4. However, the role of the exocyst in skeletal muscle glucose uptake has never been investigated. Here we demonstrate that the exocyst is a necessary factor in insulin-induced glucose uptake in skeletal muscle cells as well. The exocyst complex colocalizes with GLUT4 storage vesicles in L6-GLUT4myc myoblasts at a basal state and associates with these vesicles during their translocation to the plasma membrane after insulin signaling. Moreover, we show that the exocyst inhibitor endosidin-2 and a heterozygous knockout of Exoc5 in skeletal myoblast cells both lead to impaired GLUT4 trafficking to the plasma membrane and hinder glucose uptake in response to an insulin stimulus. Our research is the first to establish that the exocyst complex regulates insulin-induced GLUT4 exocytosis and glucose metabolism in muscle cells. A deeper knowledge of the role of the exocyst complex in skeletal muscle tissue may help our understanding of insulin resistance in type 2 diabetes.


Assuntos
Exocitose/genética , Transportador de Glucose Tipo 4/metabolismo , Glucose/metabolismo , Insulina/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Vesículas Transportadoras/metabolismo , Animais , Linhagem Celular , Membrana Celular/metabolismo , Exocitose/efeitos dos fármacos , Técnicas de Inativação de Genes , Resistência à Insulina , Limoninas/farmacologia , Mioblastos Esqueléticos , Transporte Proteico/genética , Ratos , Proteínas de Transporte Vesicular/genética
4.
Anticancer Res ; 39(10): 5473-5481, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570441

RESUMO

BACKGROUND/AIM: Aerial parts and seeds of the neem tree (Azadirachta indica) have long been used in traditional medicine such as Ayurveda for health-related purposes. Our interest in neem bioactives lies in their potential use as standalone anticancer agents, or as adjuvants to standard therapy. The aim of the present study was to explore a supercritical CO2 extract (SCNE) of neem leaf and a prominent liminoid in neem leaf, nimbolide, for epigenetic activity. MATERIALS AND METHODS: Human colorectal cancer cell lines (HCT116 and HT29) were cultured for 48 h in the presence of neem extract or nimbolide and evaluated for growth inhibition and evidence of suppression of histone deacetylation and DNA methylation. RESULTS: Both SCNE and nimbolide suppressed the proliferation of colon cancer cells by inducing epigenetic modifications. CONCLUSION: Neem leaf contains bioactive constituents which modify epigenetic activity.


Assuntos
Azadirachta/química , Neoplasias Colorretais/tratamento farmacológico , Epigênese Genética/efeitos dos fármacos , Extratos Vegetais/farmacologia , Folhas de Planta/química , Dióxido de Carbono/química , Dióxido de Carbono/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Células HCT116 , Células HT29 , Humanos , Limoninas/farmacologia
5.
Biomed Pharmacother ; 118: 109366, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31545261

RESUMO

The inhibitory effects of limonin have been disclosed in various tumors, however, its roles in nasopharyngeal carcinoma (NPC) progression are never been revealed. In the current work, we collected NPC cells with a higher stemness compared with bulk cells through isolating the side population (SP) cells. It was found that limonin exhibited a stronger inhibitory effect on SP cells than that in bulk cells, which was evident by a lower IC50 value. Additionally, limonin attenuated the stemness and migration ability of SP cells with the higher stemness, characterized as decreasing the spheroid formation ability, expression of stemness markers and migration ability. Moreover, the proportion of SP cells in G0 phase was remarkably higher than that in bulk cells. Notably, upon limonin treatment, the proportion of SP cells in G0 was decreased and S/G2/M increased. Furthermore, limonin enhanced the radiosensitivity of NPC cells. The mechanistic studies based on RNA-sequencing analysis revealed that limonin inhibited the gene transcription driven by Stat3 (signal transducer and activator of transcription 3) and an activator of Stat3 (Colivelin or IL-6) rescued the inhibitory effects of limonin. Therefore, these results demonstrate that limonin could reduce the stemness of NPC cells and thus the radiosensitivity through suppressing Stat3 transcriptional activity.


Assuntos
Limoninas/farmacologia , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Tolerância a Radiação/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células da Side Population/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
6.
J BUON ; 24(3): 1204-1209, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31424680

RESUMO

PURPOSE: Glioma is one of the most aggressive types of human cancers and responsible for considerable mortality across the globe. Moreover, the development of drug resistance and lack of efficient drug options form the major hurdle in the treatment of gliomas. Herein, the anticancer potential of Cedrelone was examined against temozolomide-resistant glioma cells. METHODS: The proliferation rate of malignant glioma cells was assessed by CCK-8 cell counting assay. Autophagy was detected by electron microscopy. Apoptotic cell death was revealed by propidium iodide (PI) staining. Cell cycle analysis was performed by flow cytometry. Protein expression was determined by immuno blotting. RESULTS: The results showed that Cedrelone could considerably inhibit the proliferation of glioma cells. The anticancer activity of Cedrelone against the U87 malignant glioma cells was found to be due to induction of apoptosis. The Cedrelone-triggered apoptosis was also linked with alteration in the apoptosis-related protein expression. It also caused increase of reactive oxygen species (ROS) and decline of mitochondrial membrane potential (MMP). Additionally, Cedrelone could also trigger G2/M cell cycle arrest of U87 cells. Furthermore, it was found that Cedrelone could inhibit the ERK/MAPK signalling pathway in the temozolomide-resistant malignant glioma cells. CONCLUSIONS: These results indicate that Cedrelone could inhibit the growth of temozolomide-resistant malignant glioma in vitro and may be used for the development of chemotherapy against this disease.


Assuntos
Ciclo Celular/efeitos dos fármacos , Glioma/tratamento farmacológico , Limoninas/uso terapêutico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neovascularização Patológica/tratamento farmacológico , Apoptose , Glioma/genética , Glioma/patologia , Humanos , Limoninas/farmacologia , Transdução de Sinais
7.
Artif Cells Nanomed Biotechnol ; 47(1): 3391-3398, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31394949

RESUMO

Nimbolide, a triterpenoid isolated from flower of neem tree possess various therapeutic properties. The objective of the study was to assess the anti-arthritic activity of nimbolide in arthritis induced rats. Nimbolide (20 mg/kg per day) was given orally to arthritic rats induced with Complete Freund's Adjuvant and changes in paw volume, body weight, organ indices (thymus and spleen), arthritic score, biochemical parameters and proinflammatory cytokines levels were determined. Histopathological analysis was also performed. Western blot analysis was also performed. Rats treated with nimbolide displayed marked reduction in arthritic score, organ indices, volume of paw, edema formation, along with substantial enhancement in body weight. Histopathological findings showed significant reduction in destruction of joints and inflammation following nimbolide treatment. The protective action of arthritic rats treated with nimbolide was also substantiated by molecular and biochemical studies. The results of the study show that nimbolide treatment has markedly enhanced health and reduced inflammation via lessening the proinflammatory cytokines expression in arthritic rats. Hence, nimbolide may be used as a potent therapeutic drug in treating rheumatoid arthritis.


Assuntos
Anti-Inflamatórios/farmacologia , Artrite Experimental/tratamento farmacológico , Adjuvante de Freund/efeitos adversos , Limoninas/farmacologia , Animais , Anti-Inflamatórios/uso terapêutico , Antioxidantes/metabolismo , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Peso Corporal/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Quinase I-kappa B/metabolismo , Articulações/efeitos dos fármacos , Articulações/metabolismo , Articulações/patologia , Limoninas/uso terapêutico , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Ratos
8.
Int Immunopharmacol ; 75: 105768, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31382166

RESUMO

Ulcerative colitis (UC) is a major inflammatory bowel disease (IBD) which has become a global public health problem. Limonin is a triterpenoid extracted from citrus which possesses the capacities to against inflammations and cell apoptosis. However, the efficacy and the underlying mechanisms of limonin in the treatment of UC remain unclear. In this study, we first investigated the therapeutic effects of limonin on dextran sodiumsulfate (DSS)-induced UC in vivo by examining the changes of disease activity index (DAI), the colon length, the colon histology, and cyto/chemokine levels. We found that limonin markedly reduced DAI, intestinal damages, and the levels of pro-inflammatory cytokines, such as TNF-α and IL-6. In vitro, limonin significantly repressed the productions of pro-inflammatory cytokines in cultured normal colonic epithelial cells. Mechanistically, we demonstrated that limonin improved the prognosis of UC mainly through downregulating p-STAT3/miR-214 levels. Collectively, our results suggested that limonin was a novel therapeutic agent and it was expected to be translated into the clinic to improve the prognosis of UC.


Assuntos
Anti-Inflamatórios/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Limoninas/uso terapêutico , MicroRNAs/imunologia , Fator de Transcrição STAT3/imunologia , Animais , Anti-Inflamatórios/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/imunologia , Colite Ulcerativa/patologia , Colo/efeitos dos fármacos , Colo/imunologia , Colo/patologia , Sulfato de Dextrana , Células Epiteliais/efeitos dos fármacos , Interleucina-10/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Limoninas/farmacologia , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Fator de Transcrição STAT3/genética , Transdução de Sinais/efeitos dos fármacos
9.
Int Immunopharmacol ; 75: 105755, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31377591

RESUMO

Pulmonary fibrosis is an irreversible lung disorder with predictable decline in lung function leading to respiratory insufficiency. Incidence of pulmonary fibrosis has been apparently increasing worldwide. Though aetiology of this disease remains unclear, potential roles of infection, disordered cell biology, genetic influence etc. have been proposed. Pirfenidone and nintedanib are the only two US FDA approved drugs to treat pulmonary fibrosis. Autophagy is a catabolic intracellular pathway that plays a crucial role in maintaining cellular homeostasis, which is involved in many disorders including fibrotic diseases. The present study investigated the role of Nimbolide, an important active constituent of Neem in TGF-ß1 induced in vitro and bleomycin induced in vivo model of pulmonary fibrosis, with a slight emphasis on regulation of fibrosis related autophagy. Protein expression studies showed significant reduction in mesenchymal, fibrotic markers and a substantial up regulation of epithelial markers upon treatment with Nimbolide. Nimbolide regulated autophagy signaling by dampening LC-3 and p-62 expression and increasing Beclin 1 expression as evidenced by immunohistochemistry and confocal microscopy. Our study demonstrates Nimbolide as a potent anti-fibrotic agent and its ability to regulate fibrosis associated autophagy.


Assuntos
Limoninas/uso terapêutico , Fibrose Pulmonar/tratamento farmacológico , Animais , Autofagia/efeitos dos fármacos , Bleomicina , Líquido da Lavagem Broncoalveolar/química , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Hidroxiprolina/metabolismo , L-Lactato Desidrogenase/metabolismo , Limoninas/farmacologia , Masculino , Camundongos , Óxido Nítrico/metabolismo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Fator de Crescimento Transformador beta1
10.
BMC Cancer ; 19(1): 764, 2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31375085

RESUMO

BACKGROUND: MAPK/ERK kinases transmit signals from many growth factors/kinase receptors during normal cell growth/differentiation, and their dysregulation is a hallmark of diverse types of cancers. A plethora of drugs were developed to block this kinase pathway for clinical application. With the exception of a recently identified agent, EQW, most of these inhibitors target upstream factors but not ERK1/2; no activator of ERK1/2 is currently available. METHOD: A library of compounds isolated from medicinal plants of China was screened for anti-cancer activities. Three limonoid compounds, termed A1541-43, originally isolated from the plant Melia azedarach, exhibiting strong anti-leukemic activity. The anti-neoplastic activity and the biological target of these compounds were explored using various methods, including western blotting, flow cytometry, molecular docking and animal model for leukemia. RESULTS: Compounds A1541-43, exhibiting potent anti-leukemic activity, was shown to induce ERK1/2 phosphorylation. In contrast, the natural product Cedrelone, which shares structural similarities with A1541-43, functions as a potent inhibitor of ERK1/2. We provided evidence that A1541-43 and Cedrelone specifically target ERK1/2, but not the upstream MAPK/ERK pathway. Computational docking analysis predicts that compounds A1541-43 bind a region in ERK1/2 that is distinct from that to which Cedrelone and EQW bind. Interestingly, both A1541-43, which act as ERK1/2 agonists, and Cedrelone, which inhibit these kinases, exerted strong anti-proliferative activity against multiple leukemic cell lines, and induced robust apoptosis as well as erythroid and megakaryocytic differentiation in erythroleukemic cell lines. These compounds also suppressed tumor progression in a mouse model of erythroleukemia. CONCLUSIONS: This study identifies for the first time activators of ERK1/2 with therapeutic potential for the treatment of cancers driven by dysregulation of the MAPK/ERK pathway and possibly for other disorders.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Leucemia Eritroblástica Aguda/tratamento farmacológico , Limoninas/farmacologia , Limoninas/uso terapêutico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Melia azedarach/química , Animais , Apoptose/efeitos dos fármacos , Sítios de Ligação , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Modelos Animais de Doenças , Progressão da Doença , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Células K562 , Leucemia Eritroblástica Aguda/mortalidade , Leucemia Eritroblástica Aguda/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Simulação de Acoplamento Molecular , Folhas de Planta/química , Transdução de Sinais/efeitos dos fármacos , Taxa de Sobrevida
11.
Biomed Pharmacother ; 117: 109051, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31177062

RESUMO

The inhibitory roles of limonin have been revealed in various tumors. However, the roles and related mechanism of limonin in hepatocellular carcinoma (HCC) progression are still confused. Here, we collected non-adherent spheroids formed by HCC cells and found that the proportion of spheroids in G0 phase was remarkably higher than that in HCC cells. Additionally, limonin increased EdU incorporation without affecting apoptosis in spheroids. Notably, upon limonin treatment, the proportion of spheroids in G0 was decreased and S/G2/M increased. Furthermore, we found that limonin attenuated the stemness of HCC cells, characterized as the decreased ALDH1 activity, stemness marker expression and spheroid formation ability. Moreover, an integrated transcriptional analysis based on RNA-sequencing data was employed to gain mechanistic insight into limonin functioning, and we found that the most significant pathways identified centered on PI3K/Akt signaling. qRT-PCR and western blot obtained the consistent results. Overall, these data suggest that limonin attenuates the stemness of HCC cells by reducing cellular quiescence through activating PI3K/Akt signaling.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Ciclo Celular , Limoninas/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Células-Tronco Neoplásicas/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/patologia , Ciclo Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Células Hep G2 , Humanos , Limoninas/farmacologia , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia
12.
Nat Chem Biol ; 15(7): 747-755, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31209351

RESUMO

Nimbolide, a terpenoid natural product derived from the Neem tree, impairs cancer pathogenicity; however, the direct targets and mechanisms by which nimbolide exerts its effects are poorly understood. Here, we used activity-based protein profiling (ABPP) chemoproteomic platforms to discover that nimbolide reacts with a novel functional cysteine crucial for substrate recognition in the E3 ubiquitin ligase RNF114. Nimbolide impairs breast cancer cell proliferation in-part by disrupting RNF114-substrate recognition, leading to inhibition of ubiquitination and degradation of tumor suppressors such as p21, resulting in their rapid stabilization. We further demonstrate that nimbolide can be harnessed to recruit RNF114 as an E3 ligase in targeted protein degradation applications and show that synthetically simpler scaffolds are also capable of accessing this unique reactive site. Our study highlights the use of ABPP platforms in uncovering unique druggable modalities accessed by natural products for cancer therapy and targeted protein degradation applications.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Produtos Biológicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Proteínas de Transporte/metabolismo , Limoninas/farmacologia , Proteólise/efeitos dos fármacos , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Limoninas/química , Limoninas/isolamento & purificação
13.
Mol Immunol ; 112: 247-255, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31202101

RESUMO

Chronic kidney disease (CKD) involves interstitial fibrosis as an underlying pathological process associated with compromised renal function irrespective of etiological cause of the injury. The transforming growth factor-ß (TGF-ß) plays a pivotal role in progression of renal fibrosis. TGF-ß transduces its downstream signalling by phosphorylation of smad2/3 and also regulates epithelial-mesenchymal-transition (EMT), a program centrally involved in activation of fibroblasts. Renal fibrosis was induced in Swiss albino mice by unilateral ureteral obstruction of animals. Kidney tissues were evaluated for fibrotic protein expression by western blot and immunohistochemistry. The administration of nimbolide (NB) to UUO animals reduced the oxidative stress, expression of ECM proteins, TGF-ß, p-smad and EMT program. Further, NB administration also improved histoarchitecture of obstructed kidney and reduced the collagen deposition in kidney. Our results provided compelling evidence to support antifibrotic activity of NB by reduction in oxidative stress, TGF-ß, and EMT program in fibrotic kidney. The administration of NB in animals blunted the UUO-induced renal injury, inflammation and reduced fibrogenesis in obstructed kidney.


Assuntos
Fibrose/tratamento farmacológico , Limoninas/farmacologia , Insuficiência Renal Crônica/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição da Família Snail/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Obstrução Ureteral/fisiopatologia , Animais , Transição Epitelial-Mesenquimal , Fibrose/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Insuficiência Renal Crônica/metabolismo , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Obstrução Ureteral/metabolismo
14.
Phytomedicine ; 62: 152947, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31102887

RESUMO

BACKGROUND: Multidrug resistance (MDR) refers to the phenotype of tumor cells that are resistant to various chemotherapeutic drugs with different structures and functions, which is clearly disadvantageous for patients. Finding a natural product that can effectively reverse the MDR of tumor cells is important for the treatment of patients. PURPOSE: To prove that tooniliatone A (TA), a novel typical limonoid, can effectively reverse the MDR of tumor cells and to explore its mechanism of action. METHODS: The MTT, CCK-8 and monoclonal formation assays, as well as flow cytometry, were used to evaluate the role of TA in reversing tumor multidrug resistance; then the mechanism of action for TA was explored by western blotting and real-time fluorescent quantitative PCR. RESULTS: TA significantly reversed the MDR of the K562/MDR and MCF-7/MDR cell lines. TA can inhibit the anti-apoptotic protein Bcl-xL to make cells sensitive to common chemotherapeutic drugs and activate the SAPK/JNK pathway to promote phosphorylation of JNK and its downstream cJun protein. Small interfering RNA-mediated knockdown of JNK and cJun could antagonize the MDR reversal effect of TA and the inhibition of Bcl-xL by TA. Therefore, we hypothesized that TA activates the JNK pathway to increase the transcription of the proapoptotic protein Bim, thereby inhibiting Bcl-xL and reversing MDR in tumor cells. CONCLUSION: Our study suggests that TA reverses tumor MDR by activating the SAPK/JNK pathway to inhibit the action of Bcl-xL. TA may be an effective tumor MDR reversal agent.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Limoninas/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteína bcl-X/metabolismo , Apoptose/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Regulação Neoplásica da Expressão Gênica , Humanos , Células K562 , Sistema de Sinalização das MAP Quinases/genética , Células MCF-7 , Magnoliopsida/química , Proteínas Proto-Oncogênicas c-jun/metabolismo , RNA Interferente Pequeno , Proteína bcl-X/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
15.
Molecules ; 24(9)2019 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-31035366

RESUMO

Limonoids are phytochemicals with a variety of biological properties. In the present study, we elucidated the molecular mechanism of suppression of adipogenesis in adipocytes by a limonoid, 7-deacetoxy-7-oxogedunin (CG-1) from Carapa guianensis (Meliaceae), known as andiroba. CG-1 reduced the accumulation of intracellular triglycerides in a concentration-dependent manner. The expression levels of the adipogenic, lipogenic, and lipolytic genes were decreased by CG-1 treatment, whereas the glycerol release level was not affected. When CG-1 was added into the medium during days 0-2 of 6-days-adipogenesis, the accumulation of intracellular lipids and the mRNA levels of the adipogenesis-related genes were decreased. In addition, the phosphorylation level of insulin receptor substrate-1 (IRS-1) and Akt in the early phase of adipocyte differentiation (within 1 day after initiating adipocyte differentiation) was reduced by CG-1. Furthermore, insulin-activated translocation of glucose transporter 4 to the plasma membranes in adipocytes was suppressed by CG-1, followed by decreased glucose uptake into the cells. These results indicate that an andiroba limonoid CG-1 suppressed the accumulation of intracellular lipids in the early phase of adipocyte differentiation through repression of IRS-1/Akt-mediated glucose uptake in adipocytes.


Assuntos
Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Transportador de Glucose Tipo 4/genética , Glucose/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Limoninas/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células 3T3-L1 , Adipogenia/efeitos dos fármacos , Animais , Transportador de Glucose Tipo 4/metabolismo , Limoninas/química , Meliaceae/química , Camundongos , Estrutura Molecular
16.
Mol Neurobiol ; 56(11): 7851-7862, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31127528

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disorder and the leading cause of dementia in aged populations worldwide. The deposition of toxic protein aggregates such as amyloid beta (Aß) is a hallmark of AD, and there is growing awareness that a key driver of AD pathogenesis is the neuroinflammatory cascade triggered and sustained by these proteins. Consequently, interventions that suppress prolonged neuroinflammation represent viable therapeutic approaches for AD. In this context, we tested the natural product gedunin which is an anti-inflammatory molecule, found in the seeds of the neem tree (Azadirachta indica), whose mechanism of action remains to be fully elucidated. Using a mouse microglia cell line (IMG), we show that gedunin suppresses neuroinflammation arising from Aß1-42 oligomer exposure. Our results demonstrate that gedunin suppresses Aß1-42-induced NF-κB activation and its targets, including nitric oxide (NO) and IL-1ß, known proinflammatory molecules. Further, we show that gedunin inhibits neuroinflammation by activating nuclear factor 2 erythroid-related factor 2 (Nrf2) and its downstream targets γ-glutamylcysteine synthetase, heme oxygenase 1, and NADPH quinone dehydrogenase 1, which are involved in quenching reactive oxygen and nitrogen species (NO) generated by NF-κB activation. Nrf2 activation appears essential for the anti-inflammatory effect because when silenced, the proinflammatory effects of Aß1-42 are enhanced and the protective effect of gedunin against NO production is reduced. Additionally, using human neuronal cells (SH-SY5Y), we show that gedunin prevents neurotoxicity secondary to Aß-induced microglial activation. In conclusion, our findings highlight a potential therapeutic role of gedunin in neurodegenerative diseases.


Assuntos
Peptídeos beta-Amiloides/toxicidade , Limoninas/farmacologia , Microglia/patologia , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Fragmentos de Peptídeos/toxicidade , Transdução de Sinais , Animais , Linhagem Celular , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Humanos , Interleucina-1beta/metabolismo , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Neurotoxinas/toxicidade , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Fosforilação/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteínas tau/metabolismo
17.
J Nat Med ; 73(3): 641-647, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30972689

RESUMO

Three andirobin- and one trijugin-class limonoids, named koetjapins A-D (1-4), have been isolated from the seed extracts of Sandoricum koetjape. The structures of these compounds were determined by extensive NMR and mass spectral data, and the chemotaxonomic significance of these limonoids in the family Meliaceae is highlighted. Preliminary biological activity showed that only compound 4 has significant inhibitory activity against P-388 cells, while antibacterial tests showed that none of these compounds were active.


Assuntos
Frutas/química , Limoninas/uso terapêutico , Sementes/química , Limoninas/farmacologia , Estrutura Molecular
18.
Biochem Biophys Res Commun ; 513(1): 226-233, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-30954216

RESUMO

Hyperglycemia-induced proximal tubule injury plays a critical role in the pathogenesis of diabetic nephropathy (DN). Attenuating high glucose (HG)-induced oxidative damage in renal tubular epithelial cells has been documented to ameliorate DN. Obacunone (OB), a natural bioactive compound isolated from the Rutaceae family, has been demonstrated to possess various pharmacological effects with low toxicity. However, the role of OB in DN has not yet been investigated. To explore the influence of OB on oxidative damage that is induced by HG and its potential mechanisms of action, we set up a high glucose model and induced oxidative damage in NRK-52E cells. OB could protect the NRK-52E cells from the HG-induced decrease of cell viability and the accumulation of ROS. The protective effects of OB were associated with its ability to increase the levels of antioxidants (SOD, GSH and CAT), inhibit the production of ROS, and stabilize the mitochondrial membrane potential. In addition, OB significantly downregulated the activity of GSK-3ß, enhanced the nuclear translocation of Nrf2 and increased the mRNA expression of the Nrf2-driven genes NQO-1 and HO-1 in HG-treated cells. OB also decreased the release of cytochrome c from the mitochondria to the cytosol and inhibited the activation of caspase-3 in HG-treated cells. Pretreatment with a GSK-3ß activator blocked the protective effects of OB, while pretreatment with a GSK-3ß inhibitor yielded opposite results. These findings indicate that the renoprotective effects of OB against HG-induced oxidative damage in NRK-52E cells may be mediated by its ability to inhibit oxidative stress and mitochondrial dysfunction through the GSK-3ß signaling pathway.


Assuntos
Antioxidantes/farmacologia , Benzoxepinas/farmacologia , Glucose/metabolismo , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Limoninas/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Linhagem Celular , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Rim/citologia , Rim/efeitos dos fármacos , Rim/metabolismo , Ratos
19.
Biomed Pharmacother ; 112: 108699, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30970511

RESUMO

Limonin has been shown to exert anti-inflammatory effects, however, its roles in tumor progression remain unclear. This work aims to investigate the roles and related mechanism of limonin in the stemness of breast cancer cells. Here, we found that limonin attenuated the stemness of breast cancer cells in a concentration-dependent manner, evident by the decreasing the capacity of cell spheroid formation, expression of stemness markers and ALDH1 activity, whereas had no toxicity on non-tumorigenic cells. Additionally, limonin enhanced adriamycin sensitivity of breast cancer cells and attenuated adriamycin resistance in adriamycin-resistant breast cancer cells. Mechanistically, limonin decreased MIR216A methylation level and thus increased miR-216a-3p expression. Furthermore, miR-216a-3p could directly bind to WNT3A and thus inactivated Wnt/ß-catenin pathway. Therefore, our results indicate that limonin could attenuate the stemness and chemoresistance via inhibiting MIR216A methylation and subsequently suppressing Wnt/ß-catenin pathway.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/patologia , Limoninas/farmacologia , MicroRNAs/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , Aldeído Desidrogenase 1 , Apoptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Isoenzimas/metabolismo , Células MCF-7 , MicroRNAs/genética , Células-Tronco Neoplásicas/metabolismo , Retinal Desidrogenase/metabolismo
20.
Fitoterapia ; 135: 73-78, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30999025

RESUMO

Four new limonoids, 7,12-dihydroxyvilasinone (1), vilasindione (2), 4-dehydroxynimbandiol (3) and azadiramide B (4), were isolated from extracts of Bacillus subtilis-fermented neem seeds. Their planar structures and relative configurations were elucidated by spectroscopic methods including UV, IR, MS and NMR, and the absolute stereochemistry was determined by comparing their experimental and calculated CD spectra. 4 is a rare salannin-class limonoid alkaloid. In cytotoxic assays, 3 showed inhibitory activity against MDA-MB-231, A375 and Hela cell lines with IC50 values of 21.45 ±â€¯5.41, 17.67 ±â€¯3.96 and 28.13 ±â€¯9.12 µM, respectively, while 4 selectively inhibited growth of MDA-MB-231 cell line with an IC50 value of 15.73 ±â€¯6.07 µM.


Assuntos
Azadirachta/química , Bacillus subtilis/fisiologia , Limoninas/farmacologia , Extratos Vegetais/química , Alcaloides/química , Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Azadirachta/microbiologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Fermentação , Humanos , Limoninas/química , Limoninas/isolamento & purificação , Estrutura Molecular , Sementes/química , Triterpenos/química , Triterpenos/isolamento & purificação , Triterpenos/farmacologia
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