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J Biol Chem ; 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32414842


Cyclotides are plant-derived peptides characterized by a ~30-amino-acid-long cyclic backbone and a cystine knot motif. Cyclotides have diverse bioactivities, and their cytotoxicity has attracted significant attention for its potential anticancer applications. Hybanthus enneaspermus (Linn) F. Muell is a medicinal herb widely used in India as a libido enhancer, and a previous study has reported that it may contain cyclotides. In the current study, we isolated 11 novel cyclotides and one known cyclotide (cycloviolacin O2) from H. enneaspermus and used tandem MS to determine their amino acid sequences. We found that among these cyclotides, hyen C comprises a unique sequence in loops 1, 2, 3, 4, and 6 compared with known cyclotides. The most abundant cyclotide in this plant, hyen D, had anticancer activity comparable to that of cycloviolacin O2, one of the most cytotoxic known cyclotides. We also provide mechanistic insights into how these novel cyclotides interact with and permeabilize cell membranes. Results from surface plasmon resonance experiments revealed that hyen D, E, L, M, and cycloviolacin O2 preferentially interact with model lipid membranes that contain phospholipids with phosphatidyl-ethanolamine headgroups. The results of a lactate dehydrogenase assay indicated that exposure to these cyclotides compromises cell membrane integrity. Using live-cell imaging, we show that hyen D induces rapid membrane blebbing and cell necrosis. Cyclotide-membrane interactions correlated with the observed cytotoxicity, suggesting that membrane permeabilization and disintegration underpin cyclotide cytotoxicity. These findings broaden our knowledge on the indigenous Indian herb H. enneaspermus and have uncovered cyclotides with potential anticancer activity.

Toxicon ; 172: 33-44, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31682883


Cyclotides are a plant-derived family of peptides that comprise approximately 30 amino acid residues, a cyclic backbone and a cystine knot. Due to their unique structure, cyclotides are exceptionally stable to heat or proteolytic degradation and are tolerant to amino acid substitutions in their backbone loops between conserved cysteine residues. Their toxicity to insect pests and their make-up of natural amino acids has led to their applications in eco-friendly crop protection. Furthermore, their stability and cell penetrating properties make cyclotides ideal scaffolds for bioactive epitope grafting. This article gives a brief overview of cyclotide discovery, characterization, distribution, synthesis and mode of action mechanisms. We focus on their toxicities to insect pests and their medical and agricultural applications.

Curr Protein Pept Sci ; 19(3): 302-310, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28059041


Isosteroidal alkaloids are a category of promising bioactive compounds which mostly exist in plants of genus Veratrum and Fritillaria. The pharmacological activities of isosteroidal alkaloids include antihypertensive, antitussive, anti-inflammatory, antithrombosis, among others. Recently, some studies show that this kind of alkaloids exhibited significant antitumor activity. To the best of our knowledge, there is no review focusing on their antitumor activity and mechanism of their antitumor activity. To fill the gap, in this review, we summarized antitumor effects of the isosteroidal alkaloids from genus Veratrum and Fritillaria on different tumors and the mechanisms of their antitumor activity. In conclusion, this kind of alkaloids has extensive antitumor activity, and there are several main mechanisms of their antitumor activity, including the Hedgehog signaling pathway, caspase-3 dependent apoptosis, cell cycle, and autophagy.

Alcaloides/química , Alcaloides/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Fritillaria/química , Neoplasias/tratamento farmacológico , Veratrum/química , Alcaloides/uso terapêutico , Animais , Antineoplásicos Fitogênicos/uso terapêutico , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proteínas Hedgehog/metabolismo , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Transdução de Sinais/efeitos dos fármacos , Alcaloides de Veratrum/química , Alcaloides de Veratrum/farmacologia , Alcaloides de Veratrum/uso terapêutico
Mediators Inflamm ; 2016: 4192483, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27524867


Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the world. Present therapies for COPD have limited effect on reducing the progression of COPD and suppressing the inflammatory response in the lung. Bulbs of Fritillaria cirrhosa D. Don (BFC) have been used in many Asian countries for a long time to treat pulmonary diseases, such as cough, expectoration, and asthma. Steroidal alkaloids are the major biological active constituents in BFC, whereby imperialine is one of the important steroidal alkaloids. So far, there are no studies reporting the effect of imperialine on COPD. In this study, we investigated the effect of imperialine on pulmonary function and structure and inflammation in a COPD-like rat model which was induced by the combination of exposure to CS and intratracheal administration of LPS. Our data show that imperialine mitigates pulmonary functional and structural impairment and suppressed inflammatory response in a COPD-like rat model by mediating expression of related cytokines in lung tissues of the COPD-like rats, such as IL-1ß, IL-6, IL-8, TNF-α, NF-κB, TGF-ß1, MMP-9, and TIMP-1.

Alcaloides/farmacologia , Fritillaria/química , Inflamação/tratamento farmacológico , Pulmão/efeitos dos fármacos , Extratos Vegetais/farmacologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Animais , Anti-Inflamatórios/farmacologia , Peso Corporal , Cevanas/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Imuno-Histoquímica , Pulmão/metabolismo , Masculino , Raízes de Plantas/química , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Ratos , Ratos Wistar , Testes de Função Respiratória , Esteroides/metabolismo
J Ethnopharmacol ; 193: 150-158, 2016 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-27497638


ETHNOPHARMACOLOGICAL RELEVANCE: Bulb of Fritillaria cirrhosa D.Don (BFC) has been wildly used in China for a long time for folk medicine since its significant therapeutic effects on respiratory diseases, such as cough, expectoration, pneumonia and bronchial inflammation, which are related to respiratory inflammatory response. However, there is a lack of investigation on the in vivo anti-inflammatory properties of BFC. AIM OF THE STUDY: The aim of this study was to evaluate the in vivo anti-inflammatory activity of the purified total alkaloid fraction of BFC (TAF) by using different animal models of inflammation to provide scientific evidence for its traditional use. MATERIALS AND METHODS: The total alkaloid fraction from BFC was prepared by using H-103 resin column. Anti-inflammatory effect of TAF was evaluated by models of acetic acid-induced capillary permeability accentuation, carrageenan-induced rat paw edema, cotton pellet-induced granuloma formation and LPS-induced acute lung injury (ALI). The level of cytokines (TNF, IL-6, IL-4 and IL-10) was measured by ELISA. Histopathological analyses were performed by using hematoxylin and eosin staining. RESULTS: TAF can inhibit acetic acid-induced capillary permeability accentuation, carrageenan-induced paw edema, cotton pellet-induced granuloma formation, suppress inflammatory cells recruitment and cytokine production in the bronchoalveolar lavage fluid from LPS-induced ALI mice, and attenuate pathological changes in the lung tissues of ALI mice. CONCLUSION: This study provides scientific evidence for bulb of F. cirrhosa to treat respiratory inflammation.

Lesão Pulmonar Aguda/prevenção & controle , Alcaloides/farmacologia , Anti-Inflamatórios/farmacologia , Fritillaria/química , Extratos Vegetais/farmacologia , Animais , Líquido da Lavagem Broncoalveolar , Citocinas/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Sprague-Dawley
Biomed Res Int ; 2014: 258402, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24804207


The bulbs of cultivated Fritillaria cirrhosa (BCFC) are used in China both for food and folk medicine due to its powerful biological activities. The aim of this study is to optimize the extraction and enrichment conditions of alkaloids from BCFC. Firstly, the orthogonal experimental design was used to optimize and evaluate four variables (ethanol concentration, solid-liquid ratio, extraction time, and temperature). Thereafter, resin adsorption was as a means to enrich alkaloids. Among 16 tested resins, H-103 resin presented higher adsorption capacity and desorption ratio. The equilibrium experimental data of the adsorption of total alkaloids, imperialine, and peimisine were well-fitted to the pseudo-first-order kinetics model, Langmuir and Freundlich isotherms models. Finally, in order to optimize the parameters for purifying alkaloids, dynamic adsorption and desorption tests were carried out. After one run treatment with H-103 resin, the contents of total alkaloids, imperialine, and peimisine in the product were 21.40-, 18.31-, and 22.88-fold increased with recovery yields of 94.43%, 90.57%, and 96.16%, respectively.

Alcaloides/química , Alcaloides/isolamento & purificação , Fritillaria/química , Esteroides/química , Esteroides/isolamento & purificação