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1.
Fitoterapia ; 153: 105001, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34329727

RESUMO

Four new limonoids, named as trichiconlide G (1), 2-hydroxyltrijugin F (2), 23-oxo-21-hydroxyltrijugin F (3), 21-oxo-23-hydroxyltrijugin F (4), along with sixteen known analogues (5-20) were isolated from the leaves and twigs of Trichilia connaroides. Their structures and absolute configurations were determined by spectroscopic analyses, X-ray diffraction analysis, and TD-DFT-ECD calculations. Trichiconlide G (1) is one rare naturally occurring 1,2-seco phragmalin-type limonoid bearing a C-7/28 δ-lactone ring. Additionally, 2-hydroxyltrijugin F (2), 23-oxo-21-hydroxyltrijugin F (3), and 21-oxo-23-hydroxyltrijugin F (4) are three naturally occurring limonoids with a rare C-16/8 δ-lactone ring. All isolates were evaluated for their cytotoxic and anti-inflammatory activities. None of compounds exhibited cytotoxicity against five human cancer cell lines A-549, HepG2, 5-8F, Siha, and SCC-4 at the concentration of 40 µM. Compounds 16 and 17 showed moderate anti-inflammatory activity with IC50 values of 28.45 ± 2.51 and 22.66 ± 2.01 µM, respectively.


Assuntos
Anti-Inflamatórios/farmacologia , Limoninas/farmacologia , Meliaceae/química , Animais , Anti-Inflamatórios/isolamento & purificação , Linhagem Celular Tumoral , China , Humanos , Limoninas/isolamento & purificação , Camundongos , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Folhas de Planta/química , Células RAW 264.7
2.
Gene ; 801: 145856, 2021 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-34293449

RESUMO

Epidemiological studies have established that untreated hypertension (HTN) is a major independent risk factor for developing cardiovascular diseases (CVD), stroke, renal failure, and other conditions. Several important studies have been published to prevent and manage HTN; however, antihypertensive agents' optimal choice remains controversial. Therefore, the present study is undertaken to update our knowledge in the primary treatment of HTN, specifically in the setting of other three important diseases. MicroRNAs (miRNAs) are remarkably stable short endogenous conserved non-coding RNAs that bind to the mRNA at its (3' UTR) to regulate its gene expression by causing translational repression or mRNA degradation. Through their coordinated activities on different pathways and networks, individual miRNAs control normal and pathological cellular processes. Therefore, to identify the critical miRNA-mRNA-TF interactions, we performed systematic bioinformatics analysis. We have also employed the molecular modelling and docking approach to identify the therapeutic target that delivers novel empathies into Food and Drug Administration approved and herbal drug response physiology. Gene Expression Omnibus (GEO) was employed to identify the differentially expressed genes (DEGs) and hub genes- KNG1, HLA-DPB1, CXCL8, IL1B, and BCL2. The HTN associated feed-forward loop (FFL) network included miR-9-5p, KNG1 and AR. We employed high throughput screening to get the best interacting compounds, telmisartan and limonin, that provided a significant docking score (-13.3 and -12.0 kcal/mol) and a potential protective effect that may help to combat the impact of HTN. The present study provides novel insight into HTN etiology through the identification of mRNAs and miRNAs and associated pathways.


Assuntos
Anti-Hipertensivos/farmacologia , Redes Reguladoras de Genes , Hipertensão/genética , Mapas de Interação de Proteínas/genética , Desenvolvimento de Medicamentos/métodos , Perfilação da Expressão Gênica , Ensaios de Triagem em Larga Escala/métodos , Humanos , Hipertensão/tratamento farmacológico , Cininogênios/química , Cininogênios/genética , Limoninas/química , Limoninas/farmacologia , MicroRNAs/genética , Modelos Moleculares , Simulação de Acoplamento Molecular , Telmisartan/química , Telmisartan/farmacologia , Fatores de Transcrição/genética
3.
Biomed Pharmacother ; 138: 111543, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34311538

RESUMO

Acute lung injury (ALI) is a severe lung disease with limited therapeutic strategies. Munronoid I, a limonoid, which is extracted and purified from Munronia sinica, exhibits effective anti-neoplastic activities. In this study, we attempted to determine the anti-inflammatory effects of Munronoid I using both the lipopolysaccharide (LPS)-induced in vivo murine ALI models and in vitro assays. Our results demonstrated that Munronoid I treatment ameliorated LPS-induced ALI and inflammation in mice. Moreover, it also significantly inhibited LPS-induced pathological injuries, infiltration of inflammatory cells, and production of IL-1ß and IL-6. Furthermore, the in vitro assay showed that Munronoid I could inhibit the LPS-induced expression of inflammatory mediators such as iNOS, COX2, and production of pro-inflammatory cytokines by suppressing the activation of NF-κB signaling pathway in mouse peritoneal macrophages. Munronoid I reduced the LPS-, tumor necrosis factor alpha (TNF-α)- or interleukin 1 beta (IL-1ß)-induced transforming growth factor beta-activated kinase 1 (TAK1) phosphorylation and protein expression. Furthermore, the Munronoid I also promoted K48-linked ubiquitination and proteasomal degradation of TAK1. Taken together, these results demonstrated that Munronoid I exhibited anti-inflammatory activities both in vitro and in vivo, which might be a potential therapeutic candidate for the treatment of ALI and pulmonary inflammation.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Anti-Inflamatórios/farmacologia , Limoninas/farmacologia , Pulmão/efeitos dos fármacos , MAP Quinase Quinase Quinases/metabolismo , Macrófagos Peritoneais/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/enzimologia , Lesão Pulmonar Aguda/patologia , Animais , Anti-Inflamatórios/isolamento & purificação , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Células HEK293 , Humanos , Mediadores da Inflamação/metabolismo , Limoninas/isolamento & purificação , Lipopolissacarídeos , Pulmão/enzimologia , Pulmão/patologia , Macrófagos Peritoneais/enzimologia , Macrófagos Peritoneais/patologia , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo II/metabolismo , Fosforilação , Proteólise , Ubiquitinação
4.
J Chem Ecol ; 47(7): 642-652, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34331170

RESUMO

Finding plant cultivars that are resistant or tolerant against lepidopteran pests, takes time, effort and is costly. We present here a high throughput leaf-disk consumption assay system, to screen plants for resistance or chemicals for their deterrence. A webcam capturing images at regular intervals can follow the feeding activities of 150 larvae placed into individual cages. We developed a computer program running under an open source image analysis program to analyze and measure the surface of each leaf disk over time. We further developed new statistical procedures to analyze the time course of the feeding activities of the larvae and to compare them between treatments. As a test case, we compared how European corn borer larvae respond to a commercial antifeedant containing azadirachtin, and to quinine, which is a bitter alkaloid for many organisms. As expected, increasing doses of azadirachtin reduced and delayed feeding. However, quinine was poorly effective at the range of concentrations tested (10-5 M to 10-2 M). The model cage, the camera holder, the plugins, and the R scripts are freely available, and can be modified according to the users' needs.


Assuntos
Bioensaio/métodos , Comportamento Alimentar , Lepidópteros/fisiologia , Animais , Análise por Conglomerados , Comportamento Alimentar/efeitos dos fármacos , Processamento de Imagem Assistida por Computador , Larva/crescimento & desenvolvimento , Larva/fisiologia , Lepidópteros/crescimento & desenvolvimento , Limoninas/farmacologia , Folhas de Planta/química , Folhas de Planta/metabolismo , Quinina/farmacologia , Zea mays/química , Zea mays/metabolismo
5.
Molecules ; 26(11)2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34063814

RESUMO

In addition to the trichilianones A-D recently reported from Trichilia adolfi, a continuing investigation of the chemical constituents of the ethanol extract of the bark of this medicinal plant yielded the five new limonoids 1-5. They are characterized by having four fused rings and are new examples of prieurianin-type limonoids, having a ε-lactone which in 4 and 5 is α, ß- unsaturated. The structures of the isolated metabolites were determined by high field NMR spectroscopy and HR mass spectrometry. The new metabolites were shown to have the ε-lactone fused with a tetrahydrofuran ring which is connected to an oxidized hexane ring joined with a cyclo-pentanone having a 3-furanyl substituent. As the crude extract possesses antileishmanial activity, the compounds were assayed for cytotoxic and antiparasitic activities in vitro in murine macrophage cells (raw 264.7 cells) and in Leishmania amazoniensis as well as L. braziliensis promastigotes. Metabolites 1-3 and 5 showed moderate cytotoxicity (between 30-94 µg/mL) but are not responsible for the antileishmanial effect of the extract.


Assuntos
Limoninas/isolamento & purificação , Meliaceae/química , Pregnanos/isolamento & purificação , Animais , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13/métodos , Sobrevivência Celular/efeitos dos fármacos , Leishmania/efeitos dos fármacos , Limoninas/química , Limoninas/farmacologia , Espectrometria de Massas/métodos , Camundongos , Estrutura Molecular , Pregnanos/química , Pregnanos/farmacologia , Espectroscopia de Prótons por Ressonância Magnética/métodos , Células RAW 264.7
6.
Int J Mol Sci ; 22(5)2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33801166

RESUMO

Root bark of Dictamnus dasycarpus Turcz. has been widely used as a traditional medicine and is a well-known anti-inflammatory agent. We isolated limonoid triterpene, obacunone (Obac) from the dried root bark of D. dasycarpus. Obac has been reported to exhibit varieties of biological activities including anti-inflammatory, anti-cancer, and anti-oxidant effects. This study aimed to investigate the beneficial effects and biological mechanisms of Obac in osteoblast differentiation and bone matrix mineralization. In the present study, Obac at concentrations ranging from 1 to 100 µM showed no proliferation effects in MC3T3-E1. The treatment of Obac (1 and 10 µM) increased wound healing and migration rates in a dose-dependent manner. Alkaline phosphatase (ALP) staining and activity showed that Obac (1 and 10 µM) enhanced early osteoblast differentiation in a dose-dependent manner. Obac also increased late osteoblast differentiation in a dose-dependent manner, as indicated by the mineralized nodule formation of ARS staining. The effects of Obac on osteoblast differentiation was validated by the levels of mRNAs encoding the bone differentiation markers, including Alp, bone sialoprotein (Bsp), osteopontin (Opn), and osteocalcin (Ocn). Obac increased the expression of bone morphogenetic protein (BMP), and the phosphorylation of smad1/5/8, and the expression of runt-related transcription factor 2 (RUNX2); Obac also inhibited GSK3ß and upregulated the protein level of ß-catenin in a dose-dependent manner during osteoblast differentiation. Obac-mediated osteoblast differentiation was attenuated by a BMP2 inhibitor, Noggin and a Wnt/ß-catenin inhibitor, Dickkopf-1 (Dkk1) with the abolishment of RUNX2 expression and nuclear accumulation by Obac. Taken together, the findings of this study demonstrate that Obac has pharmacological and biological activates to promote osteoblast differentiation and bone mineralization through BMP2, ß-catenin, and RUNX2 pathways, and suggest that Obac might be a therapeutic effect for the treatment and prevention of bone diseases such as osteoporosis and periodontitis.


Assuntos
Benzoxepinas/farmacologia , Diferenciação Celular , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Limoninas/farmacologia , Osteoblastos/citologia , Osteoblastos/fisiologia , Osteogênese , Animais , Proteína Morfogenética Óssea 2/genética , Proteína Morfogenética Óssea 2/metabolismo , Células Cultivadas , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Camundongos , Osteoblastos/efeitos dos fármacos , Via de Sinalização Wnt , beta Catenina/genética , beta Catenina/metabolismo
7.
J Pharm Biomed Anal ; 200: 114079, 2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-33901755

RESUMO

A total of 49 limonoids derivatives were rapidly identified by UNIFI software and three new limonoids derivatives, named dasycarinone (1, DAS), isodictamdiol C (2) and dasycarinone A (3), along with nineteen known compounds, were isolated from the root bark of Dictamnus dasycarpus, named as "Baixianpi" in Chinese. Their structures were elucidated on the basis of spectroscopic data (UV, IR, HR-ESI-MS, NMR, CD spectra and OR). All the compounds were tested for anti-inflammatory activities by suppressing the nitric oxide (NO) production in lipopolysaccharide (LPS) induced BV-2 cells. DAS exhibited a strong anti-inflammatory activity with IC50 value of 1.8 µM. Nuclear Factor kappa B (NF-κB) luciferase assay and enzyme-linked immune sorbent assay indicated that DAS can suppress the release of inflammatory cytokines such as Tumor Necrosis Factor α (TNF-α), interleukin 6 (IL-6) via inactivating NF-κB signaling pathways. Moreover, we found that anti-inflammatory activities of obacunone-class are better than those of limonin-class by analyzing structure-activity relationship. Our results suggested that obacunone derivatives play an important role on anti-inflammation of Baixianpi. As a representative among them, DAS showed a strong anti-inflammatory activity via suppressing NF-κB signaling pathways.


Assuntos
Dictamnus , Limoninas , Anti-Inflamatórios/farmacologia , Limoninas/farmacologia , Lipopolissacarídeos , Casca de Planta , Extratos Vegetais/farmacologia
8.
Biomed Pharmacother ; 139: 111576, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33862494

RESUMO

Diabetes mellitus or type-2 diabetes, commonly referred as diabetes, is a metabolic disorder that results in high blood sugar level. Despite the availability of several antidiabetic drugs in the market, they still do not adequately regulate blood sugar levels. Thus, in general people prefer to use herbal supplements/medicines along with antidiabetic drugs to control blood sugar levels. One of such herbal medicine is Swietenia macrophylla seeds. It is widely used in Asia for controlling blood sugar levels. One of the major bioactive compounds, Swietenine, is reported to be responsible for controlling blood glucose levels. However, there were no studies on its efficacy in controlling the blood glucose in diabetic rats. In this study, we evaluated the antihyperglycemic activity of Swietenine and its pharmacodynamic interaction with Metformin in Streptozotocin induced diabetes in rats. The activity of Swietenine was investigated at three different doses: 10, 20 and 40 mg/kg body weight (bw). Metformin (50 mg/kg bw) was used as a standard drug. Swietenine (20 and 40 mg/kg bw) and Metformin (50 mg/kg bw) showed significant effect in reducing the glucose, cholesterol, triglycerides, low-density lipoprotein, urea, creatinine, alanine transaminase, alkaline phosphatase, aspartate transaminase, alanine transaminase, and malondialdehyde level in serum while it had increased the high-density lipoprotein, glutathione, and total antioxidant capacity level. In addition, Swietenine (20 and 40 mg/kg) had shown significant synergistic effect with Metformin. Administration of Swietenine at 10 mg/kg bw neither showed activity nor influenced Metformin's activity. The results from this study confirmed the beneficial effects of Swietenine and its synergistic action with Metformin in controlling the dysregulated serum parameters in Streptozotocin induced diabetes in rats.


Assuntos
Antioxidantes/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/farmacologia , Limoninas/farmacologia , Metformina/farmacologia , Animais , Antioxidantes/uso terapêutico , Glicemia/metabolismo , Colesterol/sangue , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Feminino , Hiperglicemia/sangue , Hipoglicemiantes/uso terapêutico , Limoninas/uso terapêutico , Lipídeos/sangue , Masculino , Meliaceae/química , Metformina/uso terapêutico , Ratos , Ratos Wistar , Sementes/química
9.
Fitoterapia ; 151: 104900, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33781859

RESUMO

A phytochemical investigation of a medicinal plant Artemisia atrovirens was carried out, resulting in the characterization of a novel bis-nor seco-guaianolide, seco-atrovirenolide A (1), a new 1,10-seco-guaianolide derivative, seco-atrovirenoic acid A (2), and a new artifact 10-methanoyloxy-seco-atrovirenoic acid A (3), together with eight known guaianolide and seco-guaianolide derivatives (4-11). The structures of new compounds were fully established by extensive analysis of MS, 1D and 2D NMR spectroscopic data. The absolute configurations of the isolated compounds were confirmed by TDDFT ECD calculation, Mosher's method, and X-ray crystal diffraction experiment. All the compounds were tested in vitro for their cytotoxicity against HL-60 and A549 cell lines. Some of them showed moderate inhibitory activity against HL-60 cell lines with IC50 values ranging from 5.99 to 11.74 µM.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Artemisia/química , Limoninas/farmacologia , Células A549 , Antineoplásicos Fitogênicos/isolamento & purificação , China , Células HL-60 , Humanos , Limoninas/isolamento & purificação , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Plantas Medicinais/química
10.
Fitoterapia ; 152: 104875, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33675886

RESUMO

One new limonoid, named 19-hydroxy methyl isoobacunoate diosphenol (1); one new degraded limonoid, named 9α-methoxyl dictamdiol (9); two new quinolone alkaloids, 1-methyl-3-[(7E,9E,12Z)-7,9,12-pentadecadienyl]-4(1H)-quinolone (11) and 1-methyl-3-[(7E,9E,11E)-7,9,11-pentadecadienyl]-4(1H)-quinolone (12), along with eight known compounds, evodol (2), 7ß-acetoxy-5-epilimonin (3), rutaevine (4), 6ß-acetoxy-5-epilimonin (5), limonin (6), obacunone (7), clauemargine L (8), hiiranlactone E (10) were isolated from the fruits of Evodia rutaecarpa (Juss.) Benth.. Structures of the four new compounds were elucidated on the basis of extensive spectroscopic techniques, including 1D and 2D NMR techniques. Compounds 3, 5, 9, 11 and 12 showed obviously cytotoxic activity against six human tumor lines, while compounds 11, 12 displayed anti-platelet aggregation induced by ADP at 50 µM and 100 µM.


Assuntos
Alcaloides/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Evodia/química , Limoninas/farmacologia , Quinolonas/farmacologia , Alcaloides/isolamento & purificação , Antineoplásicos Fitogênicos/isolamento & purificação , Plaquetas/efeitos dos fármacos , Linhagem Celular Tumoral , China , Frutas/química , Humanos , Limoninas/isolamento & purificação , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Quinolonas/isolamento & purificação
11.
Fitoterapia ; 151: 104873, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33662446

RESUMO

Five new ring-intact limonoids with isomerized furan ring, chisosiamens A-E (1-5), along with four known compounds (6-9) were isolated from the fruit of Chisocheton siamensis Craib. Their structures were elucidated based on 1D and 2D NMR spectroscopic data, HRESIMS, circular dichroism, and exciton chirality method. The biological activities screening showed that new limonoid 5 exhibited significant NO inhibitory activity in LPS-activated RAW 264.7 macrophages (IC50: 10.13 ± 1.40 µM) and 1, 2, 5, and 9 effectively reversed the resistance in MCF-7/DOX cells with the range IC50 values of 10.20-15.06 µM (RI: 4.05-5.98).


Assuntos
Furanos/farmacologia , Limoninas/farmacologia , Meliaceae/química , Animais , China , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Frutas/química , Furanos/isolamento & purificação , Humanos , Isomerismo , Limoninas/isolamento & purificação , Células MCF-7 , Camundongos , Estrutura Molecular , Óxido Nítrico/metabolismo , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Células RAW 264.7
12.
J Biochem Mol Toxicol ; 35(6): 1-17, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33684251

RESUMO

Triple-negative breast cancer (TNBC) is one of the most aggressive forms of its kind, which accounts for 15-20% of all breast cancers. As this cancer form lacks hormone receptors, targeted chemotherapy remains the best treatment option. Apoptosis and anoikis (detachment-induced cell death) induction by small molecules can prevent TNBC metastasis to a greater extent. Epoxyazadiradione (EAD) is a limonoid from the neem plant with an anticancer property. Here, we demonstrate that EAD induced mitochondria-mediated apoptosis and anoikis in TNBC cells (MDA-MB-231). Apart from this, it promotes antimigration, inhibition of colony formation, downregulation of MMP-9 and fibronectin, induction of G2/M phase arrest with downregulation of cyclin A2/cdk2, interference in cellular metabolism, and inhibition of nuclear factor kappa-B (NF-kB) nuclear translocation. Moreover, a significant reduction is observed in the expression of EGFR on the plasma membrane and nucleus upon treatment with EAD. Among the diverse cellular effects, anoikis induction, metabolic interference, and downregulation of membrane/nuclear EGFR expression by EAD are reported here for the first time. To summarize, EAD targets multiple cellular events to induce growth arrest in TNBC, and hence can be developed into the best antineoplastic agent in the future.


Assuntos
Anoikis/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Limoninas/farmacologia , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Proteínas de Neoplasias/biossíntese , Neoplasias de Mama Triplo Negativas/metabolismo , Feminino , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia
13.
J Med Chem ; 64(7): 3560-3577, 2021 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-33739088

RESUMO

Nimbolide, a major limonoid constituent of Azadirachta indica, commonly known as neem, has attracted increasing research attention owing to its wide spectrum of pharmacological properties, predominantly anticancer activity. Nimbolide is reported to exert potent antiproliferative effects on a myriad cancer cell lines and chemotherapeutic efficacy in preclinical animal tumor models. The potentiality of nimbolide to circumvent multidrug resistance and aid in targeted protein degradation broaden its utility in enhancing therapeutic modalities and outcome. Accumulating evidence indicates that nimbolide prevents the acquisition of cancer hallmarks such as sustained proliferation, apoptosis evasion, invasion, angiogenesis, metastasis, and inflammation by modulating kinase-driven oncogenic signaling networks. Nimbolide has been demonstrated to abrogate aberrant activation of cellular signaling by influencing the subcellular localization of transcription factors and phosphorylation of kinases in addition to influencing the epigenome. Nimbolide, with its ever-expanding repertoire of molecular targets, is a valuable addition to the anticancer drug arsenal.


Assuntos
Antineoplásicos/uso terapêutico , Limoninas/uso terapêutico , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Limoninas/farmacocinética , Limoninas/farmacologia , Transdução de Sinais/efeitos dos fármacos
14.
Molecules ; 26(4)2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33671969

RESUMO

The fractionation of an ethanol extract of the bark of Trichilia adolfi yielded four novel limonoids (trichilinones A-D, 1-4), with five fused rings and related to the hortiolide-type limonoids. Starting with an ε-lactone, which is α,ß-unsaturated in trichilinones A and D (1 and 4), attached to a tetrahydrofuran ring that is connected to an unusual bicyclo [5.1.0] hexane system, joined with a cyclopentanone with a 3-furanyl substituent [(2-oxo)-furan-(5H)-3-yl in trichilinone D (4)], the four compounds isolated display a new 7/5/3/5/5 limonoid ring system. Their structures were established based on extensive analysis of NMR spectroscopic data. As the crude extract possessed anti-leishmanial properties, the compounds were assayed for cytotoxic and anti-parasitic activities in vitro in murine macrophages cells (Raw 264.7) and leishmania promastigotes (L. amazoniensis and L. braziliensis), respectively. The compounds showed moderate cytotoxicity (approximately 70 µg/mL), but are not responsible for the leishmanicidal effect of the extract.


Assuntos
Ciclopropanos/análise , Limoninas/análise , Meliaceae/química , Animais , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Ciclopropanos/química , Ciclopropanos/farmacologia , Leishmania/efeitos dos fármacos , Limoninas/química , Limoninas/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/parasitologia , Camundongos , Espectroscopia de Prótons por Ressonância Magnética , Células RAW 264.7
15.
Fitoterapia ; 150: 104835, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33524516

RESUMO

Seven new limonoids, named krishnolides E-K (1-7), including three khayanolides, two mexicanolides, a derivative of trangmolin A, and an andirobin, were isolated from seeds of the Indian Krishna mangrove, Xylocarpus moluccensis. The structures of these limonoids were established by HRESIMS, extensive NMR investigations, and X-ray crystallography. Most notably, the absolute configurations of 1, 5, 6, and 7 were unequivocally determined by single-crystal X-ray diffraction analyses (Cu Kα). Krishnolide F (2) exhibited significant agonistic effects on human pregnane-X-receptor (hPXR) at the concentration of 10.0 µM. Molecular docking revealed that 2 could bind a helix near the region of the Helix 12 of hPXR. Polar contribution could be electrostatic effects from the formation of two stable protein-ligand hydrogen bonds between Gln285/1-OH and His407/1-OH, respectively. This is the first report of agonistic effects of a khayanolide-type limonoid on hPXR.


Assuntos
Limoninas/farmacologia , Meliaceae/química , Receptor de Pregnano X/agonistas , Humanos , Índia , Limoninas/isolamento & purificação , Simulação de Acoplamento Molecular , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Sementes/química
16.
Fitoterapia ; 150: 104846, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33588006

RESUMO

Four new compounds (1-4) were isolated from the stem bark of Entandrophragma angolense along with eleven known structures (5-15). The chemical structures were elucidated on the basis of spectroscopic and HRMS data, and the absolute configuration was established with the aid of electronic circular dichroism. Compound 5 displayed moderate cytotoxicity against MDA-MB-231, OVCAR3, MDA-MB-435, and HT29 cell lines, with IC50 values ranging from 2.0-5.9 µM.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Limoninas/farmacologia , Meliaceae/química , Triterpenos/farmacologia , Antineoplásicos Fitogênicos/isolamento & purificação , Linhagem Celular Tumoral , Humanos , Limoninas/isolamento & purificação , Estrutura Molecular , Nigéria , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Casca de Planta/química , Plantas Medicinais/química , Triterpenos/isolamento & purificação
17.
J Food Biochem ; 45(4): e13668, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33605461

RESUMO

The fruits of Swietenia macrophylla King have been processed commercially to a variety of health foods and healthcare products and exhibited antidiabetic, anti-inflammatory, antimutagenicity, antitumor activity, and so on. This study was aimed to examine the glucose consumption in human hepatoma HepG2 cells and the expression of PPARγ of limonoids isolated from the fruits of S. macrophylla. The phytochemical investigation of the fruits led to the isolation of ten limonoids which structures were elucidated by spectroscopic analysis as swietenine (1), khayasin T (2), 6-deoxyswietenine (3), 3-O-tigloylswietenolide (4), swietenolide (5), 3,6-O,O-diacetylswietenolide (6), 7-deacetoxy-7-oxogedunin (7), fissinolide (8), proceranolide (9), 7-deacetoxy-7α-hydroxygedunin (10), and compound 10 was isolated from this plant for the first time. The glucose consumption assay revealed that compounds 1, 2, 3, 5, and 9 could promote glucose consumption significantly in normal hyperglycemia-induced HepG2 cells, furthermore, compounds 1, 5, and 9 had a better effect on promoting glucose consumption in insulin-resistant HepG2 cells. In addition, compounds 1 and 5 could dramatically enhance the expression of PPARγ protein in insulin-resistant HepG2 cells according to the western blotting analysis result. PRACTICAL APPLICATIONS: Swietenia macrophylla King belongs to the family Meliaceae and the fruits have been exhibited a wide range of biological activities, such as antidiabetic, anti-inflammatory, antimutagenicity, antitumor activity, and so on. Phytochemical investigations of S. macrophylla have revealed that limonoids and triterpenoids were effective antidiabetic agents. However, the mechanism of these limonoids to antidiabetic activity is unclear. In this study, limonoids were isolated from the fruit of S. macrophylla and their effects on the glucose consumption of insulin-resistant HepG2 cells were studied. The results showed that compounds 1 and 5 could dramatically enhance the expression of PPARγ protein in insulin-resistant HepG2 cells, which will give aid to explore the mechanism of these limonoids in the treatment of type 2 diabetes. Therefore, this research might facilitate further research and development of S. macrophylla.


Assuntos
Diabetes Mellitus Tipo 2 , Limoninas , Meliaceae , Frutas , Glucose , Células Hep G2 , Humanos , Insulina , Limoninas/farmacologia , PPAR gama/genética
18.
J Food Biochem ; 45(4): e13674, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33634871

RESUMO

Curcuma longa and Azadirachta indica are traditionally used in Indian cuisine and Ayurvedic medicine as nutraceuticals against diabetes. The crude C. longa isopropanol extract, bisdemethoxycurcumin (BDMC), the purified bioactive component from C. longa, and limonoids azadiradione, gedunin from A. indica, are able to inhibit in vitro the antidiabetic target human pancreatic α-amylase independently. However, no reports on their in vivo efficacy in animal models exist. Thus, the antidiabetic effect of these orally administered human pancreatic α-amylase inhibitors was performed on streptozotocin-induced Sprague-Dawley rats. Initially, the normal rats were treated with test compounds (10-100 mg/kg of body weight) in corn oil (5 ml/kg), and as no lethality was observed in these doses, further studies were carried out with lowest concentration of 10 mg/kg of body weight. A reduction in area under curve (AUC) suggested glucose-lowering effect of these compounds in starch fed diabetic rats. The efficacy study showed a significant improvement in body weight, blood glucose levels, serum amylase, and fructosamine levels as well in other serum parameters associated with diabetes with respect to liver and renal functions. Hence, under in vivo conditions, inhibition of α-amylase activity by BDMC and limonoids affirms it as one of the mechanisms of action resulting in reduction of blood glucose levels. PRACTICAL APPLICATIONS: Bisdemethoxycurcumin from C. longa and limonoids, namely, azadiradione and gedunin, from A. indica are potent inhibitors of the antidiabetic target human pancreatic α-amylase. Oral Starch Tolerance Test (OSTT) and 28-day efficacy study to check the effect of these orally administered inhibitors in diabetic rat models showed significant improvements in serum blood glucose and amylase levels as well as in other diabetes related serum parameters, namely, bilirubin, lipids, lactate dehydrogenase, alkaline phosphatase, and urea. The study contributes to understanding the action and efficacy of these pancreatic α-amylase inhibitors and suggests a potential role for them as nutraceuticals/therapeutics in management of post-prandial hyperglycemia.


Assuntos
Azadirachta , Diabetes Mellitus Experimental , Limoninas , Administração Oral , Amilases/uso terapêutico , Animais , Glicemia , Curcuma , Diabetes Mellitus Experimental/tratamento farmacológico , Diarileptanoides , Limoninas/farmacologia , Limoninas/uso terapêutico , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Ratos , Ratos Sprague-Dawley
19.
Aging (Albany NY) ; 13(8): 11010-11025, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33535179

RESUMO

Ultra-violet (UV) radiation (UVR) causes significant oxidative injury to retinal pigment epithelium (RPE) cells. Obacunone is a highly oxygenated triterpenoid limonoid compound with various pharmacological properties. Its potential effect in RPE cells has not been studied thus far. Here in ARPE-19 cells and primary murine RPE cells, obacunone potently inhibited UVR-induced reactive oxygen species accumulation, mitochondrial depolarization, lipid peroxidation and single strand DNA accumulation. UVR-induced RPE cell death and apoptosis were largely alleviated by obacunone. Obacunone activated Nrf2 signaling cascade in RPE cells, causing Keap1-Nrf2 disassociation, Nrf2 protein stabilization and nuclear translocation. It promoted transcription and expression of antioxidant responsive element-dependent genes. Nrf2 silencing or CRISPR/Cas9-induced Nrf2 knockout almost reversed obacunone-induced RPE cytoprotection against UVR. Forced activation of Nrf2 cascade, by Keap1 knockout, similarly protected RPE cells from UVR. Importantly, obacunone failed to offer further RPE cytoprotection against UVR in Keap1-knockout cells. In vivo, intravitreal injection of obacunone largely inhibited light-induced retinal damage. Collectively, obacunone protects RPE cells from UVR-induced oxidative injury through activation of Nrf2 signaling cascade.


Assuntos
Benzoxepinas/farmacologia , Limoninas/farmacologia , Degeneração Macular/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Epitélio Pigmentado da Retina/efeitos dos fármacos , Raios Ultravioleta/efeitos adversos , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Benzoxepinas/uso terapêutico , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , DNA de Cadeia Simples/efeitos dos fármacos , DNA de Cadeia Simples/efeitos da radiação , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas de Inativação de Genes , Humanos , Injeções Intravítreas , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Limoninas/uso terapêutico , Peroxidação de Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos da radiação , Degeneração Macular/etiologia , Degeneração Macular/patologia , Camundongos , Membranas Mitocondriais/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/genética , Estresse Oxidativo/efeitos da radiação , Cultura Primária de Células , Espécies Reativas de Oxigênio/metabolismo , Epitélio Pigmentado da Retina/citologia , Epitélio Pigmentado da Retina/patologia , Epitélio Pigmentado da Retina/efeitos da radiação , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/efeitos da radiação
20.
Molecules ; 26(2)2021 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-33435504

RESUMO

Obacunone, a limonin triterpenoid extracted from Phellodendronchinense Schneid or Dictamnus dasycarpusb Turcz plant, elicits a variety of pharmacological effects such as anti-inflammatory, anti-neoplastic, anti-oxidation, and anti-lung-fibrosis ones. However, the anti-fibrotic effect of obacunone and the detailed underlying mechanism in liver fibrosis remain unclear. Liver fibrosis is a debilitating disease threatening human health. Transforming growth factor (TGF)-ß/P-Smad is a major pathway of fibrosis featured with epithelia mesenchymal transformations (EMT) and collagen depositions, accompanying with excessive oxygen-free radicals. Nrf-2 acts as a key anti-oxidative regulator driving the expressions of various antioxidant-related genes. Glutathionperoxidase-4 (GPx-4) is a member of the glutathione peroxidase family that directly inhibits phospholipid oxidation to alleviate oxidative stress. In the present study, we aimed to explore the role of obacunone in mouse liver fibrosis model induced by carbon tetrachloride (CCl4) and in hepatic stellate cells (LX2 cell line) challenging with TGF-ß. Obacunone demonstrated potent ameliorative effects on liver fibrosis both in activated LX2 and in mice liver tissues with reduced levels of α-SMA, collagen1, and vimentin. Obacunone also remarkably suppressed the TGF-ß/P-Smad signals and EMT process. Meanwhile, obacunone exerted a potent anti-oxidation effect by reducing the levels of reactive oxygen species (ROS) in both models. The antioxidant effect of obacunone was attributed to the activation of GPx-4 and Nrf-2. In addition, the therapeutic effect of obacunone on LX2 cells was significantly removed in vitro plus with GPx-4 antagonist RSL3, in parallel with the re-elevated levels of ROS. Thus, we demonstrate that obacunone is able to attenuate liver fibrosis via enhancing GPx-4 signal and inhibition of the TGF-ß/P-Smad pathway and EMT process.


Assuntos
Antioxidantes/farmacologia , Benzoxepinas/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Limoninas/farmacologia , Cirrose Hepática/tratamento farmacológico , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/antagonistas & inibidores , Animais , Antioxidantes/química , Benzoxepinas/química , Células Cultivadas , Humanos , Limoninas/química , Cirrose Hepática/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL
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