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1.
J Ethnopharmacol ; 305: 116145, 2023 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-36623753

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Tylophora yunnanensis Schltr (TYS) is widely distributed in Yunnan, Guizhou, and other places in China. It is commonly used by folks to treat hepatitis and other liver-related diseases; however, its mechanism of action is still unclear. AIM OF THE STUDY: This study aimed to determine the effects of TYS on regulating gut microbiota and its metabolites in non-alcoholic steatohepatitis (NASH) rats by inhibiting the activation of NOD-like receptor protein3 (NLRP3). MATERIAL AND METHODS: An HFD-induced rat model was established to investigate if the intragastric administration of TYS could mediate gut microbiota and their metabolites to ultimately improve the symptoms of NASH. The improving effects of TYS on NASH rats were assessed by measuring their body weight, lipid levels, histopathology, and inflammatory factor levels in the rat models. The regulatory effects of TYS on NLRP3 in the NASH rats were analyzed using real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA), which determined the levels of NLRP3-related factors. The changes in the composition of the gut microbiota of NASH rats were analyzed using 16S rRNA gene sequencing technology. Meanwhile, the Ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used for the non-targeted analysis of metabolites in the cecum contents. RESULTS: The results showed that TYS could improve NASH by decreasing the body weight and levels of lipid, AST, ALT, LPS, FFA, VLDL, IL-1ß, IL-6, TNF-α, TGF-ß, NLRP3, ASC, and Caspase-1 in the NASH rats. The analysis of gut microbiota showed that TYS could improve the diversity and abundance of gut microbiota and alter their composition by decreasing the Firmicutes/Bacteroidetes (F/B) ratio and relative abundances of Lachnospiraceae, Christensenellaceae, Blautia, etc. while increasing those of Muribaculaceae, Rumiaococcus, Ruminococcaceae, etc. The analysis of metabolites in the cecum contents suggested that the arachidonic acid metabolism, bile secretion, serotonergic synapse, Fc epsilon RI signaling pathway, etc. were regulated by TYS. The metabolites enriched in these pathways mainly included chenodeoxycholic acid, prostaglandin D2, TXB2, 9-OxoODE, and 13(S)-HOTrE. CONCLUSIONS: These findings suggested that TYS could alleviate the NASH symptoms by decreasing the body weight, regulating the lipid levels, reducing the inflammatory response, and inhibiting the expression levels of NLRP3, ASC, and Caspase-1 in the NASH rats. The changes in the composition of gut microbiota and their metabolic disorder were closely related to the activation of NLRP3. TYS could significantly inhibit the activation of NLRP3 and regulate the composition of gut microbiota and the disorder of metabolites during NASH modeling.


Assuntos
Microbioma Gastrointestinal , Hepatopatia Gordurosa não Alcoólica , Animais , Ratos , Peso Corporal , Caspase 1/metabolismo , China , Cromatografia Líquida , Lipídeos/farmacologia , Fígado/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas NLR/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , RNA Ribossômico 16S/metabolismo , Espectrometria de Massas em Tandem , Tylophora/genética
2.
Int J Mol Sci ; 23(18)2022 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-36142230

RESUMO

Triple-negative breast cancer (TNBC), representing the most aggressive form of breast cancer with currently no targeted therapy available, is characterized by an inflammatory and hypoxic tumor microenvironment. To date, a broad spectrum of anti-tumor activities has been reported for phenanthroindolizidine alkaloids (PAs), however, their mode of action in TNBC remains elusive. Thus, we investigated six naturally occurring PAs extracted from the plant Tylophora ovata: O-methyltylophorinidine (1) and its five derivatives tylophorinidine (2), tylophoridicine E (3), 2-demethoxytylophorine (4), tylophoridicine D (5), and anhydrodehydrotylophorinidine (6). In comparison to natural (1) and for more-in depth studies, we also utilized a sample of synthetic O-methyltylophorinidine (1s). Our results indicate a remarkably effective blockade of nuclear factor kappa B (NFκB) within 2 h for compounds (1) and (1s) (IC50 = 17.1 ± 2.0 nM and 3.3 ± 0.2 nM) that is different from its effect on cell viability within 24 h (IC50 = 13.6 ± 0.4 nM and 4.2 ± 1 nM). Furthermore, NFκB inhibition data for the additional five analogues indicate a structure-activity relationship (SAR). Mechanistically, NFκB is significantly blocked through the stabilization of its inhibitor protein kappa B alpha (IκBα) under normoxic as well as hypoxic conditions. To better mimic the TNBC microenvironment in vitro, we established a 3D co-culture by combining the human TNBC cell line MDA-MB-231 with primary murine cancer-associated fibroblasts (CAF) and type I collagen. Compound (1) demonstrates superiority against the therapeutic gold standard paclitaxel by diminishing spheroid growth by 40% at 100 nM. The anti-proliferative effect of (1s) is distinct from paclitaxel in that it arrests the cell cycle at the G0/G1 state, thereby mediating a time-dependent delay in cell cycle progression. Furthermore, (1s) inhibited invasion of TNBC monoculture spheroids into a matrigel®-based environment at 10 nM. In conclusion, PAs serve as promising agents with presumably multiple target sites to combat inflammatory and hypoxia-driven cancer, such as TNBC, with a different mode of action than the currently applied chemotherapeutic drugs.


Assuntos
Alcaloides , Neoplasias de Mama Triplo Negativas , Alcaloides/farmacologia , Alcaloides/uso terapêutico , Animais , Linhagem Celular Tumoral , Proliferação de Células , Colágeno Tipo I , Humanos , Alcaloides Indólicos , Indolizinas , Inflamação , Camundongos , Inibidor de NF-kappaB alfa , NF-kappa B/farmacologia , Paclitaxel/farmacologia , Fenantrenos , Fenantrolinas , Neoplasias de Mama Triplo Negativas/patologia , Microambiente Tumoral , Tylophora
3.
J Asian Nat Prod Res ; 24(5): 468-482, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35118925

RESUMO

Six new secondary metabolites, including two new nor-triterpenes (1 and 2), one new sesquiterpene (4), two new α-pyrone derivatives (6 and 7), and one new natural product (5) along with two known compounds (3 and 8) were isolated from an endophytic fungus Colletotrichum gloeosporioides obtained from a toxic medicinal plant Tylophora ovata. Their structures were elucidated by spectroscopic data analyses, while their absolute configurations were determined by CD and X-ray diffraction analyses. The in vitro anti-inflammatory activities of these compounds were evaluated.


Assuntos
Colletotrichum , Plantas Medicinais , Colletotrichum/química , Colletotrichum/metabolismo , Endófitos/química , Estrutura Molecular , Tylophora
4.
Artigo em Inglês | MEDLINE | ID: mdl-32955006

RESUMO

BACKGROUND: Tylophora hirsuta (Wall) has long been used as traditional medicine for the treatment of diabetes. The current study is designed to evaluate the anti-diabetic and anti-inflammatory activity of different extracts of aerial parts of Tylophora hirsuta. METHODS: Sequential maceration was conducted to obtain extracts. Total phenolic contents were determined by the Folin-Ciocalteau method. The anti-oxidant activity was assessed by DPPH free radical scavenging assay. The extracts were tested for its inhibitory activity against α-amylase in-vitro. In-vivo anti-diabetic assay was conducted using alloxan-induced diabetic model and OGTT was conducted on normal rats. ELISA was used to determine the pro-inflammatory cytokines (TNF-α and IL-6). The polyphenolic composition of the extract was analyzed using an HPLC system. RESULTS: Aqueous extract exhibited highest total phenolic contents (985.24± 3.82 mg GAE/100 g DW), antioxidant activity (IC50 = 786.70 ± 5.23 µg/mL), and alpha-amylase inhibition (IC50 =352.8 µg/mL). The aqueous extract of Tylophora hirsuta showed remarkable in-vivo anti-diabetic activity. Results were compared with standard drug glibenclamide. Alloxan induced diabetic mediated alterations in liver function enzymes, renal function determinants, and lipid parameters were significantly restored in aqueous extract treated diabetic rats. A significant reduction in pro-inflammatory cytokines (p<0.001) was observed when compared to the control group. HPLC analysis confirms the presence of quercetin, gallic acid, cinnamic acid, and p-coumaric acid. CONCLUSION: These results showed that Tylophora hirsuta possesses strong anti-diabetic and anti-inflammatory potentials and justify its folklore use for the management of diabetes.


Assuntos
Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Sequestradores de Radicais Livres/uso terapêutico , Hipoglicemiantes/uso terapêutico , Extratos Vegetais/uso terapêutico , Tylophora , Aloxano , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Relação Dose-Resposta a Droga , Feminino , Sequestradores de Radicais Livres/isolamento & purificação , Sequestradores de Radicais Livres/farmacologia , Hipoglicemiantes/isolamento & purificação , Hipoglicemiantes/farmacologia , Masculino , Componentes Aéreos da Planta , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Ratos , Ratos Wistar
5.
J Ethnopharmacol ; 262: 113122, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32730871

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Tylophora indica (Burm. f.) Merr. commonly known as ananthamool is a climbing perennial plant which is widely used in Indian traditional medicine. T. indica exhibits diverse range of pharmacological activities viz. antiasthmatic, antidiarrheal, anticancer, antiarthritic, antiepileptic, anti-inflammatory etc. AIM OF THE STUDY: Present review aims to grant an up-to-date insight into the botany, ethnopharmacology, phytochemistry, pharmacology and toxicology of T. indica, exploring its future research and opportunities. MATERIAL AND METHODS: Comprehensive information regarding T. indica was collected using the keywords Tylophora indica or Indian ipecac or ananthamool in various electronic databases ACS, Google Scholar, Pubmed, Science Direct, SciFinder, Web of Science, Springer Link and Wiley. In addition, some books and book chapters were also consulted. RESULTS: T. indica has been traditionally used in India, Bangladesh and Sri Lanka in the form of various preparations like powder, decoction, pulp, paste and extract alone or in combination with other herbs against various ailments like skin disorders, inflammation, cough, asthma, diarrhea, cancer, microbial infections etc. In vitro and in vivo pharmacological studies on T. indica revealed its potential as antiasthmatic, antiallergic, anti-inflammatory, anticancer, antimicrobial, antioxidant, antidiarrheal agent etc. A diverse range of phytochemical constituents have been isolated and identified from T. indica namely alkaloids (Tylophorine, Tylophorinine, Tylophorinidine), flavonoids (Kaempferol & Quercetin) terpenoids (α-Amyrin & ß-Amyrin) and sterols (ß-sitosetrol). Amongst which phenanthroindolizidine alkaloids isolated from roots and leaves are largely explored and considered to be the most active constituent of plant. CONCLUSION: Present review provides an insight into botany, ethnopharmacology, phytochemistry, pharmacology and toxicology of T. indica. As an important traditional Indian medicine, few ethnobotanicals use of T. indica have been supported by modern pharmacological studies, especially in asthma, cancer and inflammation. Among compounds from various phytochemical classes, phenanthoindolizidine alkaloids namely tylophorine and tylophorinidine alkaloids have been considered as bioactive components of the plant and widely investigated. However, further identification, isolation and quantification employing some advanced hyphenated techniques viz. LC-MS/MS, LC-NMR to discover new pharmacologically active phytoconstituents in the management of different diseases. Several investigators have highlighted possible therapeutic roles of T. indica extracts and isolated compounds. Moreover, information about various aspects of T. indica pertaining to phytochemistry, toxicology and quality control are still unresolved. Further in-depth studies are required to discover key features viz. structure activity relationships, mode of action, safety and toxicity and therapeutic potentials T. indica in clinical settings.


Assuntos
Etnofarmacologia/métodos , Medicina Tradicional/métodos , Compostos Fitoquímicos/uso terapêutico , Extratos Vegetais/uso terapêutico , Tylophora , Animais , Etnofarmacologia/tendências , Fármacos Gastrointestinais/isolamento & purificação , Fármacos Gastrointestinais/uso terapêutico , Humanos , Medicina Tradicional/tendências , Compostos Fitoquímicos/isolamento & purificação , Extratos Vegetais/isolamento & purificação
6.
Chem Biodivers ; 17(9): e2000066, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32567792

RESUMO

Structural simplification and modification of natural products are always very important resources to antitumor drugs. By introducing various aminomethyl groups and amide groups into the phenanthrene ring of tylophorine, a novel series of tylophorine derivatives have been designed and synthesized, and their antiproliferative activities against MCF-7, A549 and HepG-2 cells have been evaluated, too. The results indicated that most of the prepared compounds exhibited good antitumor activities. Especially, one compound with an {ethyl[2-(morpholin-4-yl)ethyl]amino}methyl group at the side chain exhibited the most significant cytotoxic effects.


Assuntos
Alcaloides/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Desenho de Fármacos , Indolizinas/farmacologia , Fenantrenos/farmacologia , Alcaloides/síntese química , Alcaloides/química , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indolizinas/síntese química , Indolizinas/química , Estrutura Molecular , Fenantrenos/síntese química , Fenantrenos/química , Relação Estrutura-Atividade , Tylophora/química
7.
Zhongguo Zhong Yao Za Zhi ; 45(6): 1368-1373, 2020 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-32281350

RESUMO

Eight compounds,(R)-2-[5-(methoxycarbonyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]acetic acid(1),(3S,4R)-3,4-dihydro-3,4-epoxy-5-hydroxynaphthalen-1(2H)-one(2),(-)-mitorubrinol(3),(-)-mitorubrin(4),(±)-asperlone A(5), terreusinone(6), verrucisidinol(7) and cerebroside C(8) were isolated from the endophytic fungus Talaromyces purpurogenus by using various column chromatographic techniques. Their structures were identified by NMR, MS, CD and optical rotation. Compounds 1 and 2 were new compounds. Their anti-diabetic activities in vitro were evaluated, and compound 1 showed moderate inhibitory activity toward XOD at 10 µmol·L~(-1) with the inhibition rate of 69.9%.


Assuntos
Talaromyces/química , Tylophora/microbiologia , Endófitos/química , Hipoglicemiantes/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Metabolismo Secundário , Xantina Oxidase/antagonistas & inibidores
8.
PLoS One ; 15(3): e0230142, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32210464

RESUMO

Neuroinflammation is a major risk factor associated with the pathogenesis of neurodegenerative diseases. Conventional non-steroidal anti-inflammatory drugs are prescribed but their long term use is associated with adverse effects. Thus, herbal based medicines are attracting major attraction worldwide as potential therapeutic candidates. Tylophora indica (Burm. f) Merrill is a valuable medicinal plant well known in Ayurvedic practices for its immunomodulatory, anti-oxidant, anti-asthmatic and antirheumatic activities. The present study aimed to elucidate the anti-neuroinflammatory potential of water and hydroalcoholic leaf extracts of micropropagated plants of T. indica using BV-2 microglia activated with lipopolysaccharide as an in vitro model system and development of an efficient reproducible protocol for its in vitro cloning. Non cytotoxic doses of the water and hydroalcoholic extracts (0.2µg/ml and 20µg/ml, respectively) were selected using MTT assay. α-Tubulin, Iba-1 and inflammatory cascade proteins like NFκB, AP1 expression was studied using immunostaining to ascertain the anti-neuroinflammatory potential of these extracts. Further, anti-migratory activity was also analyzed by Wound Scratch Assay. Both extracts effectively attenuated lipopolysaccharide induced microglial activation, migration and the production of nitrite via regulation of the expression of NFκB and AP1 as the possible underlying target molecules. An efficient and reproducible protocol for in vitro cloning of T. indica through multiple shoot proliferation from nodal segments was established on both solid and liquid Murashige and Skoog's (MS) media supplemented with 15µM and 10µM of Benzyl Amino Purine respectively. Regenerated shoots were rooted on both solid and liquid MS media supplemented with Indole-3-butyric acid (5-15µM) and the rooted plantlets were successfully acclimatized and transferred to open field conditions showing 90% survivability. The present study suggests that T. indica may prove to be a potential anti-neuroinflammatory agent and may be further explored as a potential therapeutic candidate for the management of neurodegenerative diseases. Further, the current study will expedite the conservation of T. indica ensuring ample supply of this threatened medicinal plant to fulfill its increasing demand in herbal industry.


Assuntos
Microglia/efeitos dos fármacos , Extratos Vegetais/uso terapêutico , Plantas Medicinais/crescimento & desenvolvimento , Tylophora/crescimento & desenvolvimento , Complexo 1 de Proteínas Adaptadoras/efeitos dos fármacos , Complexo 1 de Proteínas Adaptadoras/metabolismo , Linhagem Celular , Humanos , Técnicas In Vitro , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipopolissacarídeos/imunologia , Microglia/imunologia , NF-kappa B/efeitos dos fármacos , NF-kappa B/metabolismo , Doenças Neurodegenerativas/tratamento farmacológico
9.
J Nat Prod ; 82(11): 2953-2962, 2019 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-31710490

RESUMO

Six new nonadride derivatives (1-6) and three new spirocyclic anhydride derivatives (7-9) were isolated from the endophytic fungus Talaromyces purpurogenus obtained from fresh leaves of the toxic medicinal plant Tylophora ovata. The structures of these compounds were determined by spectroscopic analyses including 1D and 2D NMR, HRESIMS, and ECD techniques. Maleic anhydride derivatives 1-9 were evaluated for their in vitro anti-inflammatory activities. Compound 1 showed significant inhibitory activity against NO production in LPS-induced RAW264.7 cells with an IC50 value of 1.9 µM. Compounds 2 and 6 showed moderate inhibitory activities toward XOD and PTP1b, respectively, at 10 µM with inhibition rates of 67% and 76%.


Assuntos
Anidridos/química , Endófitos/química , Furanos/química , Talaromyces/química , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Fermentação , Hipoglicemiantes/farmacologia , Anidridos Maleicos/química , Camundongos , Estrutura Molecular , Folhas de Planta/microbiologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Células RAW 264.7 , Tylophora/microbiologia , Xantina Oxidase/antagonistas & inibidores
10.
Sci Rep ; 9(1): 7288, 2019 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-31086268

RESUMO

Hepatitis C virus (HCV) is the major causative agent of chronic liver diseases, including liver cirrhosis and hepatocellular carcinoma. The recent development of highly effective direct-acting antivirals (DAAs) has revolutionized the treatment of HCV patients. However, these DAAs are exorbitantly expensive for the majority of HCV patients worldwide. Moreover, these drugs still show genotypic difference in cure rate and have some resistant-associated variants. Tylophorine, a natural compound derived from Tylophora indica plants, is known to have anti-inflammatory and anti-cancerous growth activities. In the present study, we showed that two tylophorine intermediates, 5-Oxo-1-[(2,3,6,7-tetramethoxy-9-phenanthrenyl) methyl]-L-proline (O859585) and 2,3,6,7-tetramethoxy-9-phenanthrenecarboxylic acid (T298875), displayed anti-HCV activity with an EC50 of 38.25 µM for T298875 and 29.11~35.3 µM for O859585 in various HCV genotypes. We demonstrated that O859585 efficiently blocked HCV attachment by neutralizing free viral particles without affecting other stages of the HCV life cycle and interferon stimulation. O859585 interrupted binding between HCV E2 and CD81. Of note, co-treatment of O859585 with either interferon alpha (IFNα) or sofosbuvir exerted either an additive or synergistic antiviral activity in HCV-infected cells with no measurable effect on cell viability. Most importantly, O859585 in combination with IFNα and sofosbuvir exhibited synergistic effects on anti-HCV activity in primary human hepatocytes. Collectively, these data suggest that O859585 may be a novel antiviral agent for HCV therapy.


Assuntos
Alcaloides/farmacologia , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Indolizinas/farmacologia , Fenantrenos/farmacologia , Prolina/farmacologia , Internalização do Vírus/efeitos dos fármacos , Alcaloides/química , Alcaloides/uso terapêutico , Antivirais/química , Antivirais/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Quimioterapia Combinada , Células HEK293 , Hepacivirus/metabolismo , Hepatite C Crônica/virologia , Hepatócitos/metabolismo , Hepatócitos/virologia , Humanos , Indolizinas/química , Indolizinas/uso terapêutico , Interferon-alfa/farmacologia , Interferon-alfa/uso terapêutico , Fenantrenos/química , Fenantrenos/uso terapêutico , Cultura Primária de Células , Prolina/uso terapêutico , Sofosbuvir/farmacologia , Sofosbuvir/uso terapêutico , Tetraspanina 28/metabolismo , Tylophora/química , Proteínas do Envelope Viral/metabolismo
11.
Curr Med Chem ; 26(25): 4709-4725, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30047325

RESUMO

Cancer chemotherapies or antitumor agents mainly remain the backbone of current treatment based on killing the rapidly dividing cancer cell such as tylophora alkaloids and their analogues which have also demonstrated anticancer potential through diverse biological pathways including regulation of the immune system. The introduction of durable clinically effective monoclonal antibodies, however, unmasked a new era of cancer immunotherapies. Therefore, the understanding of cancer pathogenesis will provide new possible treatment options, including cancer immunotherapy and targeted agents. Combining cytotoxic agents and immunotherapies may offer several unique advantages that are complementary to and potentially synergistic with biologic modalities. Herein, we highlight the dynamic mechanism of action of immune modulation in cancer and the immunological aspects of the orally active antitumor agents tylophora alkaloids and their analogues. We also suggest that future cancer treatments will rely on the development of combining tumor-targeted agents and biologic immunotherapies.


Assuntos
Alcaloides/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Antineoplásicos/uso terapêutico , Antivirais/uso terapêutico , Neoplasias/dietoterapia , Tylophora/química , Alcaloides/química , Alcaloides/isolamento & purificação , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/isolamento & purificação , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antivirais/química , Antivirais/isolamento & purificação , Humanos , Inflamação/tratamento farmacológico , Neoplasias/diagnóstico por imagem , Viroses/tratamento farmacológico
12.
Zhongguo Zhong Yao Za Zhi ; 43(14): 2944-2949, 2018 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-30111053

RESUMO

One new compound (2S, 3S)-2,3-dihydroxybutyl 2-hydroxy-3,5,6-trimethylbenzoate (1) and six known compounds xylariphthalide A (2), convolvulol (3), cis-4-hydroxy-6-deoxytalone (4), phomoxydienes B (5), 5,6-dihydroxy-2,3,6-trimethylcyclohex-2-enone (6), trans-cyclo-(D-tryptophanyl-L-tyrosyl) (7) were isolated from Diaporthe sp., an endophytic fungus hosted in the leaves of the toxic Chinese folk medicine Tylophora ouata, using the combination methods of silica gel column chromatography, medium-pressure ODS column chromatography and RP-preparative HPLC. The structure of compound 1 was elucidated by NMR and MS data analyses. The absolute configurations were established according to the ¹H-NMR data and exciton chirality method. Compound 1 inhibited the activation of human lung fibroblasts MRC-5 cells by 64.0% at 10 µmol·L⁻¹. The MTT assay showed that compounds 2 and 4 displayed cytotoxic activity against human tumor cell lines BGC-823 cells with IC50 values of 1.5 and 8.6 µmol·L⁻¹, respectively.


Assuntos
Tylophora , Linhagem Celular Tumoral , Endófitos , Humanos , Estrutura Molecular , Folhas de Planta
13.
Fitoterapia ; 127: 7-14, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29660469

RESUMO

Nine new compounds (1-6 and 16-18) and nine known compounds (7-15) were isolated from Diaporthe pseudomangiferaea, an endophytic fungus obtained from the leaves of the toxic Chinese folk medicine Tylophora ouata. Their structures were elucidated by NMR spectroscopy and MS spectrometry analyses. The absolute configurations were established according to the specific rotation or electron circular dichroism method. Compounds 1, 4, 9, 11, 14 and 15 inhibited the TFG-ß induced activation of human lung fibroblasts MRC-5 cells by 17.4%, 59.2%, 62.9%, 41.1%, 32.9% and 52.1% at 10 µM, respectively, while positive control pirfenidone showed 53.2% inhibition rate at 1 mM. The MTT assay showed that compounds 13 and 14 displayed cytotoxicity against BGC-823 cells, with IC50 values of 8.1 and 4.4 µM, respectively.


Assuntos
Ascomicetos/química , Ciclopentanos/farmacologia , Endófitos/química , Fibroblastos/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Ciclopentanos/isolamento & purificação , Humanos , Estrutura Molecular , Tylophora/microbiologia
14.
Chemistry ; 23(50): 12149-12152, 2017 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-28603842

RESUMO

Herein, we report a Cp*CoIII -catalyzed C-H activation approach as the key step to create highly valuable isoquinolones and pyridones as building blocks that can readily be applied in the total syntheses of a variety of aromathecin, protoberberine, and tylophora alkaloids. This particular C-H activation/annulation reaction was achieved with several terminal as well as internal alkyne coupling partners delivering a broad scope with excellent functional group tolerance. The synthetic applicability of this protocol reported herein was demonstrated in the total syntheses of two Topo-I-Inhibitors and two 8-oxyprotoberberine cores that can be further elaborated into the tetrahydroprotoberberine and the protoberberine alkaloid core. Moreover these building blocks were also transformed to six different tylophora alkaloids in expedient fashion.


Assuntos
Alcaloides/síntese química , Alcaloides de Berberina/síntese química , Cobalto/química , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Alcaloides/química , Alcaloides de Berberina/química , Carbono/química , Catálise , Compostos Heterocíclicos de 4 ou mais Anéis/química , Hidrogênio/química , Piridonas/química , Quinolonas/química , Tylophora/química , Tylophora/metabolismo
15.
Plant Cell Rep ; 35(11): 2207-2225, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27553812

RESUMO

KEY MESSAGE: This review provides an in-depth and comprehensive overview of the in vitro culture of Tylophora species, which have medicinal properties. Tylophora indica (Burm. f.) Merr. is a climbing perennial vine with medicinal properties. The tissue culture and genetic transformation of T. indica, which has been extensively studied, is reviewed. Micropropagation using nodal explants has been reported in 25 % of all publications. Leaf explants from field-grown plants has been the explant of choice of independent research groups, which reported direct and callus-mediated organogenesis as well as callus-mediated somatic embryogenesis. Protoplast-mediated regeneration and callus-mediated shoot organogenesis has also been reported from stem explants, and to a lesser degree from root explants of micropropagated plants in vitro. Recent studies that used HPLC confirmed the potential of micropropagated plants to synthesize the major T. indica alkaloid tylophorine prior to and after transfer to field conditions. The genetic integrity of callus-regenerated plants was confirmed by RAPD in a few reports. Tissue culture is an essential base for genetic transformation studies. Hairy roots and transgenic T. indica plants have been shown to accumulate tylophorine suggesting that in vitro biology and transgenic methods are viable ways of clonally producing valuable germplasm and mass producing compounds of commercial value. Further studies that investigate the factors affecting the biosynthesis of Tylophora alkaloids and other secondary metabolites need to be conducted using non-transformed as well as transformed cell and organ cultures.


Assuntos
Técnicas de Cultura de Tecidos/métodos , Transformação Genética , Tylophora/crescimento & desenvolvimento , Tylophora/genética , Reatores Biológicos , Protoplastos/metabolismo , Metabolismo Secundário
16.
J Nat Med ; 69(3): 397-401, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25840916

RESUMO

Adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature peripheral T lymphocytes caused by human T-cell lymphotropic virus type 1 (HTLV-1). There are an estimated 5 million to 20 million HTLV-1-infected individuals worldwide; their lifetime risk of developing ATL is 3-5 %, and high HTLV-1 proviral loads have been shown to be an independent risk factor. Although conventional chemotherapeutic regimens used against other malignant lymphomas have been administered to ATL patients, the prognosis is often poor. In previous studies, we screened 459 extracts from 344 plants to isolate components exhibiting antiproliferative activity against HTLV-1-infected T-cell lines (MT-1 and MT-2). In our continuing search for potential anti-HTLV-1 natural products, 15 extracts of Asclepiadaceae plants were further tested against MT-1 and MT-2 cells. The MeOH extract of aerial parts of Tylophora tanakae showed antiproliferative activity. Activity-guided fractionation resulted in the isolation of 6 phenanthroindolizidine alkaloids (including a new compound), and we examined their antiproliferative activity against MT-1 and MT-2 cells. The EC50 value of some of the alkaloids was in the low nanomolar range, comparable to that of the clinically used antineoplastic drug doxorubicin. Structure-activity relationship analyses suggested that a 14ß-hydroxy moiety is essential for activity against HTLV-1-infected T cells. In contrast, the presence of a 2-methoxy moiety, a 7-methoxy moiety, or an N-oxide moiety appears to reduce the potency of the antiproliferative activity against HTLV-1-infected T cells.


Assuntos
Alcaloides/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Leucemia-Linfoma de Células T do Adulto/tratamento farmacológico , Tylophora/química , Alcaloides/isolamento & purificação , Antineoplásicos Fitogênicos/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Infecções por HTLV-I/tratamento farmacológico , Humanos , Indolizinas/isolamento & purificação , Indolizinas/farmacologia , Leucemia-Linfoma de Células T do Adulto/virologia , Fenantrolinas/isolamento & purificação , Fenantrolinas/farmacologia , Folhas de Planta/química , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacos
17.
Mol Cancer ; 12: 82, 2013 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-23895055

RESUMO

BACKGROUND: Anti-angiogenesis targeting VEGFR2 has been considered as an important strategy for cancer therapy. Tylophorine is known to possess anti-inflammatory and antitumor activity, but its roles in tumor angiogenesis, the key step involved in tumor growth and metastasis, and the involved molecular mechanism is still unknown. Therefore, we examined its anti-angiogenic effects and mechanisms in vitro and in vivo. METHODS: We used tylophorine and analyzed its inhibitory effects on human umbilical vein endothelial cells (HUVEC) in vitro and Ehrlich ascites carcinoma (EAC) tumor in vivo. RESULTS: Tylophorine significantly inhibited a series of VEGF-induced angiogenesis processes including proliferation, migration, and tube formation of endothelial cells. Besides, it directly inhibited VEGFR2 tyrosine kinase activity and its downstream signaling pathways including Akt, Erk and ROS in endothelial cells. Using HUVECs we demonstrated that tylophorine inhibited VEGF-stimulated inflammatory responses including IL-6, IL-8, TNF-α, IFN-γ, MMP-2 and NO secretion. Tylophorine significantly inhibited neovascularization in sponge implant angiogenesis assay and also inhibited tumor angiogenesis and tumor growth in vivo. Molecular docking simulation indicated that tylophorine could form hydrogen bonds and aromatic interactions within the ATP-binding region of the VEGFR2 kinase unit. CONCLUSION: Tylophorine exerts anti-angiogenesis effects via VEGFR2 signaling pathway thus, may be a viable drug candidate in anti-angiogenesis and anti-cancer therapies.


Assuntos
Alcaloides/farmacologia , Inibidores da Angiogênese/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Indolizinas/farmacologia , Neovascularização Fisiológica/efeitos dos fármacos , Fenantrenos/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Alcaloides/administração & dosagem , Alcaloides/química , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/química , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Indolizinas/administração & dosagem , Indolizinas/química , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Conformação Molecular , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/mortalidade , Neoplasias/patologia , Óxido Nítrico/metabolismo , Fenantrenos/administração & dosagem , Fenantrenos/química , Ligação Proteica/efeitos dos fármacos , Domínios e Motivos de Interação entre Proteínas , Transdução de Sinais/efeitos dos fármacos , Carga Tumoral/efeitos dos fármacos , Tylophora/química , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
18.
BMC Complement Altern Med ; 13: 135, 2013 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-23773697

RESUMO

BACKGROUND: We have previously reported that aerial parts of Tylophora hirsuta have antispasmodic profile. The current work is an attempt for isolation of pharmacologically active compound(s) that contribute for its antispasmodic activity. METHODS: Preliminary phytochemical screening for crude methanol extract of Tylophora hirsuta (Th.Cr) is performed. Brine shrimp cytotoxicity of crude methanol extract is performed. Column chromatography was used for isolation of compounds. Mass spectroscopy, H(1) NMR and C(13) NMR were used for structural determination of compounds. α-amyrin acetate was tried for possible spasmolytic activity in rabbit's jejunal preparations and KCl-induced contractions. RESULTS: Th.Cr tested positive for saponins, alkaloids, flavonoids and terpenoids. Compound 1 was isolated as α-amyrin acetate. Compound 2 was heptaeicosanol. Crude methanol extract tested positive for brine shrimp cytotoxicity with LC(50) 492.33± 8.08 mg/ml. Compound 1 tested positive for antispasmodic activity on spontaneous rabbits' jejunum preparations with EC(50) (60 ± 2) × 10(-5)M. The compound also tested positive on KCl induced contractions with EC(50) (72 ± 3) × 10(-5)M. CONCLUSIONS: The present work confirms that α-amyrin acetate is has antispasmodic profile and the relaxant effect may be attributed to α-amyrin acetate which is a major compound.


Assuntos
Artemia/efeitos dos fármacos , Ácido Oleanólico/análogos & derivados , Parassimpatolíticos/toxicidade , Extratos Vegetais/toxicidade , Tylophora/química , Animais , Bioensaio , Dose Letal Mediana , Estrutura Molecular , Ácido Oleanólico/química , Ácido Oleanólico/isolamento & purificação , Ácido Oleanólico/farmacologia , Parassimpatolíticos/química , Parassimpatolíticos/isolamento & purificação , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação
19.
Carcinogenesis ; 34(6): 1304-14, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23385061

RESUMO

Tylophorine, a phenanthroindolizidine alkaloid, is the major medicinal constituent of herb Tylophora indica. Tylophorine treatment increased the accumulation of c-Jun protein, a component of activator protein 1 (AP1), in carcinoma cells. An in vitro kinase assay revealed that the resultant c-Jun phosphorylation was primarily mediated via activated c-Jun N-terminal protein kinase (JNK). Moreover, flow cytometry indicated that ectopically overexpressed c-Jun in conjunction with tylophorine significantly increased the number of carcinoma cells that were arrested at the G1 phase. The tylophorine-mediated downregulation of cyclin A2 protein levels is known to be involved in the primary G1 arrest. Chromatin immunoprecipitation and reporter assays revealed that tylophorine enhanced the c-Jun downregulation of the cyclin A2 promoter activity upon increased binding of c-Jun to the deregulation AP1 site and decreased binding to the upregulation activating transcription factor (ATF) site in the cyclin A2 promoter, thereby reducing cyclin A2 expression. Further, biochemical studies using pharmacological inhibitors and RNA silencing approaches demonstrated that tylophorine-mediated elevation of the c-Jun protein level occurs primarily via two discrete prolonged signaling pathways: (i) the NF-κB/PKCδ_(MKK4)_JNK cascade, which phosphorylates c-Jun and increases its stability by slowing its ubiquitination, and (ii) the PI3K_PDK1_PP2A_eEF2 cascade, which sustains eukaryotic elongation factor 2 (eEF2) activity and thus c-Jun protein translation. To the best of our knowledge, this report is the first to demonstrate the involvement of c-Jun in the anticancer activity of tylophorine and the release of c-Jun translation from a global translational blockade via the PI3K_PDK1_eEF2 signaling cascade.


Assuntos
Alcaloides/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Carcinoma/tratamento farmacológico , Indolizinas/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Fenantrenos/farmacologia , Proteínas Proto-Oncogênicas c-jun/metabolismo , Fator 1 Ativador da Transcrição/metabolismo , Linhagem Celular Tumoral , Ciclina A2/biossíntese , Ciclina A2/genética , Regulação para Baixo , Quinase do Fator 2 de Elongação/genética , Quinase do Fator 2 de Elongação/metabolismo , Fatores de Iniciação em Eucariotos/genética , Fatores de Iniciação em Eucariotos/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular , Células Hep G2 , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/biossíntese , Sistema de Sinalização das MAP Quinases , NF-kappa B/metabolismo , Fenantrolinas , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Regiões Promotoras Genéticas/efeitos dos fármacos , Proteína Quinase C-delta/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-jun/genética , Piruvato Desidrogenase Quinase de Transferência de Acetil , Interferência de RNA , RNA Interferente Pequeno , Fator de Transcrição AP-1/metabolismo , Tylophora
20.
J Nat Prod ; 76(2): 275-8, 2013 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-23369033

RESUMO

The alkaloid (-)-tylophorine was isolated from a sample of Tylophora indica, and the crude extract was analyzed by HPLC/MS(n) and chiral HPLC/MS. While the literature states that the naturally occurring form of this alkaloid is the R-enantiomer and that its S-antipode is usually not found in nature, we confirmed the hypothesis of Govindachari and Nagarajan that natural levorotatory tylophorine is indeed a nearly racemic mixture with a slight excess of the R-enantiomer.


Assuntos
Alcaloides/química , Indolizinas/química , Fenantrolinas/química , Tylophora/química , Estrutura Molecular , Fenantrenos
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