Laherradurin Inhibits Tumor Growth in an Azoxymethane/Dextran Sulfate Sodium Colorectal Cancer Model In Vivo.

Colorectal cancer (CRC) is the third most common neoplasia in the world. Its mortality rate is high due to the lack of specific and effective treatments, metastasis, and resistance to chemotherapy, among other factors. The natural products in cancer are a primary source of bioactive molecules. In this research, we evaluated the antitumor activity of an acetogenin (ACG), laherradurin (LH), isolated from the Mexican medicinal plant Annona macroprophyllata Donn.Sm. in a CRC murine model. The CRC was induced by azoxymethane-dextran sulfate sodium (AOM/DSS) in Balb/c mice and treated for 21 days with LH or cisplatin. This study shows for the first time the antitumor activity of LH in an AOM/DSS CRC model. The acetogenin diminished the number and size of tumors compared with cisplatin; the histologic studies revealed a recovery of the colon tissue, and the blood toxicity data pointed to less damage in animals treated with LH. The TUNEL assay indicated cell death by apoptosis, and the in vitro studies exhibited that LH inhibited cell migration in HCT116 cells. Our study provides strong evidence of a possible anticancer agent for CRC.

Interaction of Bephratelloides cubensis (Hymenoptera: Eurytomidae) with Annona macroprophyllata fruits in orchards of Chiapas, Mexico / Interacción de Bephratelloides cubensis (Hymenoptera: Eurytomidae) con frutos de Annona macroprophyllata en huertos de Chiapas, México

Introduction: Annona macroprophyllata Donn. Smith. (Annonaceae) (syn. Annona diversifolia Saff.) is a valued fruit tree species known as papausa. In Mexico and Central America, this fruit has become an important crop because of its tasty flavor and high pulp content. Its fruits are frequently damaged by the incidence of wasps of the genus Bephratelloides Girault (Hymenoptera: Eurytomidae), which develop inside the seeds. Objective: To report the interaction of Bephratelloides cubensis Ashmead during its life cycle in fruits of A. macroprophyllata. Methods: We periodically collected fruits in different states of growth recording a) oviposition, b) the moment of evident infection, c) the development of the wasps inside the seeds, and d) their emergence as adults. We also determined the proportion of damaged fruits and seeds. Results: The data indicate that wasps preferred to oviposit on fruits with a diameter of less than 8 cm, oviposition was more frequent between 11:00 am and 03:00 pm., and there was 26 % infestation of fruits, and 9 % of seeds. Conclusion: It is an obligatory interaction for the wasp, the highest proportion of attack on fruits was in the early stages of fruit development and control actions should focus on the protection of these early stages.

Introducción: Annona macroprophyllata Donn. Smith. (Annonaceae) es una especie de árbol frutal, conocida como papausa. En México y América Central, esta fruta se ha convertido en un cultivo importante y valorado debido a su delicioso sabor y la cremosa textura de su pulpa. Sus frutos son frecuentemente dañados por la incidencia de avispas del género Bephratelloides Girault (Hymenoptera: Eurytomidae), que se desarrollan dentro de las semillas. Objetivo: Describir la interacción de Bephratelloides cubensis Ashmead durante su ciclo de vida en frutos de A. macroprophyllata. Método: Recolectamos frutos en diferentes estados de crecimiento registrando a) la ovoposición, b) el momento de la infección evidente, c) el desarrollo de las avispas dentro de las semillas, y d) su emergencia como adultos. También determinamos la proporción de frutas y semillas dañadas. Resultados: Los datos indican que las avispas preferían ovipositar en frutas con un diámetro de menos de 8 cm, la oviposición era más frecuente entre las 11:00 a.m. y las 3:00 p.m., y que había un 26 % de la infestación en las frutas y un 9 % en semillas. Conclusión: Es una interacción obligada para la avispa y la mayor proporción de ataque a los frutos fue en las etapas tempranas de desarrollo de frutos y las acciones de control se deberían enfocar a la protección de estas etapas.

Antifungal activity of liriodenine on agents of systemic mycoses, with emphasis on the genus Paracoccidioides

Endemic systemic mycoses remain a health challenge, since these opportunistic diseases are increasingly infecting immunosuppressed patients. The simultaneous use of antifungal compounds and other drugs to treat infectious or non-infectious diseases has led to several interactions and undesirable effects. Thus, new antifungal compounds should be investigated. The present study aimed to evaluate the activity of liriodenine extracted from Annona macroprophyllata on agents of systemic mycoses, with emphasis on the genus Paracoccidioides. Methods: The minimum inhibitory concentration (MIC) and minimum fungicide concentration (MFC) were determined by the microdilution method. The cellular alterations caused by liriodenine on a standard P. brasiliensis (Pb18) strain were evaluated by transmission and scanning electron microscopy. Results: Liriodenine was effective only in 3 of the 8 strains of the genus Paracoccidioides and in the Histoplasma capsulatum strain, in a very low concentration (MIC of 1.95 µg.mL-1); on yeasts of Candida spp. (MIC of 125 to 250 µg.mL-1), including C. krusei (250 µg.mL-1), which has intrinsic resistance to fluconazole; and in Cryptococcus neoformans and Cryptococcus gattii (MIC of 62.5 µg.mL-1). However, liriodenine was not effective against Aspergillus fumigatus at the studied concentrations. Liriodenine exhibited fungicidal activity against all standard strains and clinical isolates that showed to be susceptible by in vitro tests. Electron microscopy revealed cytoplasmic alterations and damage to the cell wall of P. brasiliensis (Pb18). Conclusion: Our results indicate that liriodenine is a promising fungicidal compound that should undergo further investigation with some chemical modifications.(AU)

Selective Acetogenins and Their Potential as Anticancer Agents.

The Kingdom Plantae has provided several successful drugs for the treatment of different diseases, including cancer, and continues to be a source of new possible therapeutic molecules. For example, the annonaceous acetogenins (AAs) are secondary metabolites found in the Annonaceae family, which are plants employed in traditional medicine for the treatment of cancer and various other diseases. These polyketides are inhibitors of Complex I in the respiratory chain of tumor cells, a process that is closely related to tumor metabolism, cell death, apoptosis, and autophagy. The goal of this review is to update readers on the role of the AAs as antitumor agents using in vitro and in vivo studies to demonstrate their importance in the area of oncology drug discovery. For this purpose, we performed a literature search in the PubMed scientific database using a range of keywords, including acetogenins and cancer, acetogenins antitumor activity, acetogenins and cytotoxicity, and acetogenins mechanism of action, among others. As a result, we found that the AAs are cytotoxic compounds that can induce apoptosis, cell cycle arrest, and autophagy in vitro, in addition to exhibiting tumor growth inhibition in vivo. The functional group related to their antineoplastic activity is suggested to be the mono or bis tetrahydrofuran ring accompanied by two or more hydroxy groups. The versatility of the AA bioactivity therefore renders them potential therapeutic agents for cancer treatment. It is therefore apparent that nature is worth further examination to aid in the discovery of more effective, accurate, and less harmful therapies in the fight against cancer.

A Histochemical Technique for the Detection of Annonaceous Acetogenins.

Annonaceous acetogenins (ACGs) are molecules with carbon numbers C35-C37, usually with tetrahydrofuran and tetrahydropyran rings and one terminal γ-lactone (usually α,ß-unsaturated), in a large aliphatic chain that is varyingly hydroxylated, acetoxylated or ketonized. ACGs have ecological functions as insecticides and are pharmacologically promising due to their cytotoxic and antitumoral properties. They are found in the seeds, leaves, roots, flowers and fruits of annonaceous plants and can be detected during isolation via thin-layer chromatography using Kedde's reagent, which reacts with the unsaturated lactone. This chapter describes the location in situ of ACGs in fresh sections of annonaceous seeds using Kedde's reagent.The acetogenins are located in the idioblasts, in the endosperm and in the embryonic axis during differentiation. This method can aid in the detection of ACGs with a terminal unsaturated γ-lactone in organs and tissues.

Biosíntesis de alcaloides bencilisoquinolínicos / Benzylisoquinoline alkaloid biosynthesis / Biossíntese de alcalóides benzilisoquinolinas

Los alcaloides bencilisoquinolínicos (ABI) son metabolitos especializados con una distribución filogenética antigua pero conservadatodavía en clados modernos. Varios de ellos, como la morfina, sanguinerina y berberina tienen importancia en la medicina moderna. Enesta revisión se analizan los aspectos más sobresalientes del estado actual de la biosíntesis de ABI. Se han realizado estudios que hanpermitido conocer la biosíntesis de 22 de estos metabolitos nitrogenados. En su formación participan 43 enzimas agrupadas en oxidoreductasas,transferasas y liasas, que en algunos casos representan ejemplos atípicos de la forma en la que se originó la diversificación delmetabolismo secundario, entre ellos proteínas citocromo P450 (CYP450) con actividades catalíticas para la ruta de los ABI, o la enzimanorcoclaurina sintasa (NCS) que esta emparentada con proteínas alergénicas de defensa. Así mismo, hay avances genéticos en los quese ha podido caracterizar 30 enzimas, permitiendo conocer procesos de regulación. Otro aspecto interesante es la compartimentaciónde los sitios de biosíntesis y acumulación de ABI ya que en varios casos están separados espacialmente y en distintas especies o en lamisma pueden participar varios tipos de células. Ello ha sugerido el transporte intra e intercelular de los alcaloides, los precursores yde las enzimas, se ha documentado el transporte de berberina entre el citoplasma y las vacuolas del almacenamiento. El panorama de labiosíntesis de ABI se ha construido con los estudios de ejemplares de importancia farmacológica...

The benzylisoquinoline alkaloids (BIA) are specialized metabolites with an ancient phylogeneticdistribution, but still preserved in modern clades. Some of them, such as morphine, sanguinerine or berberine, are important for modernmedicine. This review discusses the highlights of the current state of the biosynthesis of BIA. There have been studies that show thebiosynthesis of 22 of these nitrogenous metabolites. In their formation there are 43 enzymes grouped into oxidoreductases, transferasesand lyases, which in some cases represent atypical examples of the manner in which the secondary metabolism diversification wasoriginated. Two of these examples are the cytochrome proteins P450 (P450), with catalytic activities for ABI route, or the norcoclaurinesynthase enzyme (NCS), which share substantial identity with defense allergenic proteins. Likewise, there are genetic advances thathave produced the characterization of 30 enzymes, allowing knowledge of regulatory processes. Another interesting aspect is thecompartmentation of the biosynthesis sites and accumulation of BIA, since in several cases they are spatially separated and in differentspecies, or in the same species several types of cells may be involved. This has suggested intra and intercellular transport of alkaloids,precursors and enzymes, and it has been documented berberine transport between the cytoplasm and the vacuoles of storage. The picturefor the biosynthesis of BIA has been constructed with exemplary studies of alkaloids with pharmacological importance...

Os alcalóides benzilisoquinolinas (ABI) são metabólitos especializados com umadistribuição filogenética antiga, mas ainda preservada em clados modernos. Vários deles, como a morfina, sanguinarina e berberina sãoimportantes na medicina moderna. Neste artigo, se analisam os aspectos mais destacados do estado atual da biossíntese de ABI; há estudosque tem permitido conhecer a biossíntese de 22 desses metabólitos nitrogenados. Na sua síntese participam 43 enzimas agrupadas emoxidoreductases, transferases, liases e, em alguns casos, representam exemplos atípicos da forma pela qual se originou a diversificaçãodo metabolismo secundário, incluindo as proteínas do citocromo P450 (CYP450), com atividades catalíticas para a rota dos ABI, ou aenzima norcoclaurina sintase (NCS), que está relacionada com proteínas alergênicas de defesa. Da mesma forma, há avanços genéticosna caracterização de 30 enzimas, permitindo conhecer processos de regulação. Outro aspecto interessante é a compartimentalização dossítios de biossíntese e acumulação de ABI uma vez que em muitos casos estão separados espacialmente e em diferentes espécies, ou namesma podem participar vários tipos de células. Isto há sugerido o transporte intra e intercelular de alcalóides, precursores das enzimas;tem sido documentado o transporte de berberina entre o citoplasma e os vacúolos de armazenamento. A perspectiva na biossíntese deABI foi construída com os estudos de exemplares de importância farmacológica...

In vitro and in vivo antiproliferative activity of laherradurin and cherimolin-2 of Annona diversifolia Saff.

Acetogenins from Annonaceae (ACG) are potent inhibitors of the mitochondrial complex I, they present cytotoxic activity on neoplasic lines, including those with multiresistance to drugs. In vivo antitumor activities of some ACG have been reported; however, no information is available regarding the relationship between their cytotoxic activity in cell cultures and their antiproliferative action in vivo. Laherradurin and cherimolin-2 acetogenins were isolated from Annona diversifolia seeds, and their inhibitory potential was analysed in vitro on HeLa and SW-480 cells. Doses containing 1, 10, 100 and 500 times the IC50 obtained from the proliferation assays and multiplied by the weight of the animal, were injected once daily into athymic mice bearing these cancer cell lines; their effect upon tumor growth was measured over a period of 20 days. Laherradurin was more active than cherimolin-2, and it showed in in vitro proliferation assays a similar IC50 in both neoplasic lines. In athymic mice, laherradurin administered in 10x, 100x and 500x doses, reduced the size of HeLa tumors, and with 100x and 500x doses, affected the SW-480 tumor development. These doses were similar to results found with the control drug doxorubicin (p < or = 0.05). On the other hand, cherimolin-2 had an effect on HeLa tumors cells at 100x and 500x doses (p < or = 0.05).