Antioxidant and Anti-Inflammatory Profiles of Two Mexican Heteropterys Species and Their Relevance for the Treatment of Mental Diseases: H. brachiata (L.) DC. and H. cotinifolia A. Juss. (Malpighiaceae).

Depression and anxiety are recognized as the most common mental diseases worldwide. New approaches have considered different therapeutic targets, such as oxidative stress and the inflammation process, due to their close association with the establishment and progression of mental diseases. In the present study, we evaluated the antioxidant and anti-inflammatory activities of the methanolic extracts of the plant species Heteropterys brachiata and Heteropterys cotinifolia and their main compounds, chlorogenic acid and rutin, as potential complementary therapeutic tools for the treatment of anxiety and depression, since the antidepressant and anxiolytic activities of these methanolic extracts have been shown previously. Additionally, we also evaluated their inhibitory activity on the enzyme acetylcholinesterase (AChE). Our results revealed that both species exhibited potent antioxidant activity (>90%) through the TBARS assay, while by means of the DPPH assay, only H. cotinifolia exerted potent antioxidant activity (>90%); additionally, low metal chelating activity (<40%) was detected for all samples tested in the ferrozine assay. The methanolic extracts of H. brachiata and H. cotinifolia exhibited significant anti-inflammatory activities in the TPA-induced ear edema, while only H. cotinifolia exerted significant anti-inflammatory activities in the MPO assay (>45%) and also exhibited a higher percentage of inhibition on AChE of even twice (>80%) as high as the control in concentrations of 100 and 1000 µg/mL. Thus, the potent antioxidant and inflammatory properties and the inhibition of AChE may be involved in the antidepressant activities of the species H. cotinifolia, which would be positioned as a candidate for study in drug development as an alternative in the treatment of depression.

Chia (Salvia hispanica L.), a Pre-Hispanic Food in the Treatment of Diabetes Mellitus: Hypoglycemic, Antioxidant, Anti-Inflammatory, and Inhibitory Properties of α-Glucosidase and α-Amylase, and in the Prevention of Cardiovascular Disease.

Diabetes mellitus (DM) is considered one of the major health diseases worldwide, one that requires immediate alternatives to allow treatments for DM to be more effective and less costly for patients and also for health-care systems. Recent approaches propose treatments for DM based on that; in addition to focusing on reducing hyperglycemia, they also consider multitargets, as in the case of plants. Among these, we find the plant known as chia to be highlighted, a crop native to Mexico and one cultivated in Mesoamerica from pre-Hispanic times. The present work contributes to the review of the antidiabetic effects of chia for the treatment of DM. The antidiabetic effects of chia are effective in different mechanisms involved in the complex pathogenesis of DM, including hypoglycemic, antioxidant, and anti-inflammatory mechanisms, and the inhibition of the enzymes α-glucosidase and α-amylase, as well as in the prevention of the risk of cardiovascular disease. The tests reviewed included 16 in vivo assays on rodent models, 13 clinical trials, and 4 in vitro tests. Furthermore, chia represents advantages over other natural products due to its availability and its acceptance and, in addition, as a component of the daily diet worldwide, especially due to its omega-3 fatty acids and its high concentration of dietary fiber. Thus, chia in the present work represents a source of antidiabetic agents that would perhaps be useful in novel clinical treatments.

Punica granatum as Anticandidal and Anti-HIV Agent: An HIV Oral Cavity Potential Drug.

The oral cavity is crucial from diagnosis to adherence to HAART therapy in the HIV/AIDS population; consequently, drugs that can maintain healthy conditions in the oral cavity are necessary for patients with HIV/AIDS. Punica granatum (pomegranate) is a tree that has been employed extensively for centuries in the traditional medicine of ancient cultures for the treatment of a wide range of diseases, including oral and dental diseases. In recent decades, its potent anticandidal properties have been shown, especially on Candida albicans, the cause of the most common clinical manifestation in HIV patients. The present work contributes to the review of the anti-HIV and anticandidal properties of the plant species P. granatum as involved with the oral cavity. The literature reviewed revealed that crude extracts of pomegranate and its main isolated compounds possess inhibitory activity on different HIV targets, including binding viral proteins and the three replicative HIV enzymes. In addition, in the literature reviewed, pomegranate exhibited anticandidal effects on 10 different species. Thus, pomegranate appears to be an excellent candidate to explore and incorporate into the treatment of the oral cavity of HIV/AIDS patients, in that, in addition to its pharmacological effects such as antiviral and anticandidal, pomegranate represents an easily available, inexpensive, and safe natural source.

Selected Species of the Cucurbitaceae Family Used in Mexico for the Treatment of Diabetes Mellitus.

In Mexico, Diabetes mellitus (DM) is a serious health problem, and although the current pharmacological treatments for DM such as insulin and oral hypoglycemics are available, the Mexican population continues to use medicinal plants in the treatment of DM. The antidiabetic properties of the plant species that belong to the Cucurbitaceae family has already been recognized worldwide. Since Mexico is one of the most important centers of diversity of Cucurbitaceae, the present work contributes to the review of the most used species of Cucurbitaceae in the treatment of DM in Mexico. The reviewed species (Cucurbita ficifolia, C. maxima, C. moschata, C. pepo, Ibervillea sonorae, Sechium edule, Citrullus lanatus, Cucumis melo, and C. sativus) revealed that the antidiabetic effects exerted are effective in a number of mechanisms involved in the complex pathogenesis of DM: hypoglycemic, antioxidant, anti-inflammatory, anti-obesity, protective effects on diverse organs and cells, as well as in the control of dyslipidemias; furthermore, the select species of the Cucurbitaceae family could also be essential components of diets for the control of DM in patients with the disease. Thus, the Cucurbitaceae species selected in the present work represent a source of antidiabetic agents that perhaps establish the bases for novel clinical treatments.

Contribution of Stemness-Linked Transcription Regulators to the Progression of Breast Cancer.

Although there are currently several factors that allow measuring the risk of having breast cancer or predicting its progression, the underlying causes of this malignancy have remained unknown. Several molecular studies have described some mechanisms involved in the progress of breast cancer. These have helped in identifying new targets with therapeutic potential. However, despite the therapeutic strategies implemented from the advances achieved in breast cancer research, a large percentage of patients with breast cancer die due to the spread of malignant cells to other tissues or organs, such as bones and lungs. Therefore, determining the processes that promote the migration of malignant cells remains one of the greatest challenges for oncological research. Several research groups have reported evidence on how the dedifferentiation of tumor cells leads to the acquisition of stemness characteristics, such as invasion, metastasis, the capability to evade the immunological response, and resistance to several cytotoxic drugs. These phenotypic changes have been associated with a complex reprogramming of gene expression in tumor cells during the Epithelial- Mesenchymal Transition (EMT). Considering the determining role that the transcriptional regulation plays in the expression of the specific characteristics and attributes of breast cancer during ETM, in the present work, we reviewed and analyzed several transcriptional mechanisms that support the mesenchymal phenotype. In the same way, we established the importance of transcription factors with a therapeutic perspective in the progress of breast cancer.

Anti-HIV and Anti-Candidal Effects of Methanolic Extract from Heteropterys brachiata.

Nowadays, the HIV pandemic is far from controlled. HIV+/AIDS patients show a serious risk of developing resistance to HIV antiretroviral drugs and to be orally colonized by albicans and non-albicans Candida strains resistant to antifungals. As a consequence, new drugs that possess anti-candidal and anti-HIV effects would represent an alternative in the comprehensive treatment of HIV+/AIDS patients. The present study evaluates the possible anti-HIV and anti-Candida effects of a methanolic extract from Heteropterys brachiata (Hb MeOH), an American tropical plant. The anti-HIV effect of Hb MeOH was tested using a non-radioactive colorimetric method (Lenti RT® Activity Assay; Cavidi Tech) that uses reverse transcriptase of HIV-1 enzyme as enzymatic target. The anti-candidal effect of HbMeOH extract was evaluated by following a standardized test protocol of microdilution for yeast using the Candida albicans strain ATCC® 90028. The Hb MeOH at 1 mg/mL concentration shows 38.5% RT-HIV inhibition, while Hb MeOH at 10 mg/mL concentration produced 98% C. albicans growth inhibition. Our findings show that the Hb MeOH possesses a strong anti-candidal activity and moderate anti-HIV effect and suggests that the plant extract could be considered as a potential candidate for HIV/AIDS treatment.

Contributions from Mexican Flora for the Treatment of Diabetes Mellitus: Molecules of Psacalium decompositum (A. Gray) H. Rob & Brettell.

Diabetes mellitus (DM) is cited as a serious worldwide health problem that occupies second place in causes of annual mortality in Mexico. Among Mexican flora, nearly 300 plant species have been employed as hypoglycemic in popular use. Thus, their study entertains great relevance In this context, this work contributes a clear and timely review of the plant species utilized in Traditional Mexican Medicine and experimental biological models in which not only have the hypoglycemic properties of the extracts and the isolated compounds been considered, but also the anti-inflammatory and antioxidant properties, taking into account an integral focus based on the complex mechanisms involved in the pathogenesis and physiopathology of DM. Among the species reviewed, we highlight Psacalium decompositum (Asteraceae), due to the potent hypoglycemic, anti-inflammatory, and antioxidant activity of the sesquiterpenes identified as majority compounds isolated from the root, such as cacalol and cacalone that also possess the capacity of increasing insulin levels. In this manner, the present manuscript attempts to contribute necessary information for the future study of bioactive molecules that are useful in the treatment of DM, as well as also being a contribution to the knowledge and diffusion of Mexican Traditional Medicine.

Three­dimensional models to study breast cancer (Review).

Breast cancer (BC) is the most commonly occurring cancer and primary cause of cancer­related mortality in women worldwide. Investigations into BC have been conducted in in vitro and in vivo models. Of these models, the cultivation of tumor cell lines in two­dimensional models is the most widely employed in vitro model to study tumor physiology. However, this approach does not accurately model all aspects observed in tumors. To address these limitations, three­dimensional (3D) in vitro models have been developed. In these, it is possible to reproduce the interaction between tumor cells and the extracellular matrix, as well as the interrelationship between tumor cells and stromal cells, in order to replicate the interactions observed within the 3D environment of in vivo tumors. The present review summarizes the most common 3D in vitro models used to study BC, including spheroid models, organ­on­a­chip models, hydrogel models and bio­printed models, with a discussion of their particular advantages and limitations.

Treatment of Breast Cancer With Gonadotropin-Releasing Hormone Analogs.

Although significant progress has been made in the implementation of new breast cancer treatments over the last three decades, this neoplasm annually continues to show high worldwide rates of morbidity and mortality. In consequence, the search for novel therapies with greater effectiveness and specificity has not come to a stop. Among the alternative therapeutic targets, the human gonadotropin-releasing hormone type I and type II (hGnRH-I and hGnRH-II, respectively) and its receptor, the human gonadotropin-releasing hormone receptor type I (hGnRHR-I), have shown to be powerful therapeutic targets to decrease the adverse effects of this disease. In the present review, we describe how the administration of GnRH analogs is able to reduce circulating concentrations of estrogen in premenopausal women through their action on the hypothalamus-pituitary-ovarian axis, consequently reducing the growth of breast tumors and disease recurrence. Also, it has been mentioned that, regardless of the suppression of synthesis and secretion of ovarian steroids, GnRH agonists exert direct anticancer action, such as the reduction of tumor growth and cell invasion. In addition, we discuss the effects on breast cancer of the hGnRH-I and hGnRH-II agonist and antagonist, non-peptide GnRH antagonists, and cytotoxic analogs of GnRH and their implication as novel adjuvant therapies as antitumor agents for reducing the adverse effects of breast cancer. In conclusion, we suggest that the hGnRH/hGnRHR system is a promising target for pharmaceutical development in the treatment of breast cancer, especially for the treatment of advanced states of this disease.

Cadmium exposure induces interleukin-6 production via ROS-dependent activation of the ERK1/2 but independent of JNK signaling pathway in human placental JEG-3 trophoblast cells.

Maternal exposure to cadmium (Cd) has been associated with preeclampsia (PE), which is a multisystemic disorder characterized by endothelial dysfunction. Elevated interleukin (IL)-6 expression is linked to PE and has been suggested to contribute to maternal endothelial dysfunction. Cd induces IL-6 production in various cell types through different signaling pathways. Thus, this study was designed to investigate the effect of Cd on IL-6 production and the underlying mechanisms in a trophoblast-derived cell line. Cultured JEG-3 trophoblast cells were exposed to non-toxic concentrations of CdCl2 in the presence or absence of various MAPK inhibitors or N-Acetyl-L-cysteine (NAC). IL-6 was measured by ELISA. Phosphorylation of ERK1/2, JNK, and c-Jun was assessed by Western blotting. Cd exposure induced IL-6 production and increased ERK1/2, JNK, and c-Jun phosphorylation. NAC and the inhibition of ERK1/2 significantly reduced Cd-induced IL-6 production. These data indicate that Cd induces IL-6 production in trophoblast cells through a ROS-dependent activation of ERK1/2.

Activation of human gonadotropin-releasing hormone receptor promotes down regulation of ARHGAP18 and regulates the cell invasion of MDA-MB-231 cells.

The Gonadotropin-Releasing Hormone Receptor (GnRHR) is expressed mainly in the gonadotrope membrane of the adenohypophysis and its natural ligand, the Gonadotropin-Releasing Hormone (GnRH), is produced in anterior hypothalamus. Furthermore, both molecules are also present in the membrane of cells derived from other reproductive tissues such as the breast, endometrium, ovary, and prostate, as well as in tumors derived from these tissues. The functions of GnRH receptor and its hormone in malignant cells have been related with the decrease of proliferation and the invasiveness of those tumors however, little is known about the molecules associated with the signaling pathways regulated by both molecules in malignant cells. To further analyze the potential mechanisms employed by the GnRHR/GnRH system to reduce the tumorigenesis of the highly invasive breast cancer cell line MDA-MB-231, we performed microarrays experiments to evaluated changes in genes expression and validate these modifications by functional assays. We show that activation of human GnRHR is able to diminish the expression and therefore functions of the Rho GTPase-Activating Protein 18 (ARHGAP18). Decrease of this GAP following GnRHR activation, correlates to the higher of cell adhesion and also with reduction of tumor cell invasion, supporting the notion that GnRHR triggers intracellular signaling pathways that acts through ARHGAP18. On the contrary, although a decline of cellular proliferation was observed during GnRHR activation in MDA-MB-231, this was independent of ARHGAP18 showing the complex system in which is involved the signaling pathways regulated by the GnRHR/GnRH system.

Anti-inflammatory, antioxidant and anti-acetylcholinesterase activities of Bouvardia ternifolia: potential implications in Alzheimer's disease.

Bouvardia ternifolia has been used medicinally to treat inflammation. In the present study, we investigate the anti-Alzheimer's potential effect of the hydroalcoholic extract of B. ternifolia through evaluation of anti-inflammatory and antioxidant activities, quantification of the percentage inhibition of acetylcholinesterase activity, protection effect against ß-amyloid fibrillar-induce neurotoxicity, and the identification of the main constituents. Our results show that B. ternifolia extract and ethyl acetate fraction induced anti-inflammatory effects by reducing inflammation by >70 %, while antioxidant test revealed significant IC50 values for flavonoid content fraction (30.67 ± 2.09 µg/ml) and ethyl acetate fraction (42.66 ± 0.93 µg/ml). The maximum inhibition of acetylcholinesterase was exhibited by scopoletin content fraction (38.43 ± 3.94 %), while ethyl acetate fraction exerted neuroprotective effect against ß-amyloid peptide (83.97 ± 5.03 %). Phytochemical analysis, showed the presence of 3-O-quercetin glucopyranoside (415 mg/g), rutin (229.9 mg/g), ursolic and oleanolic acid (54 and 20.8 mg/g respectively), 3-O-quercetin rhamnopyranoside (12.8 mg/g), chlorogenic acid (9.5 mg/g), and scopoletin (1.38 mg/g). Our findings support the use of B. ternifolia since the extract induced significant neuroprotection against ß-amyloid peptide, anti-inflammatory, antioxidant and anti-acetylcholinesterase effects that could be attributed to its contents of polyphenols, coumarins, and triterpenes, and encourage further studies for development of this extract as therapeutic agent in treatment of Alzheimer's disease.

Neuropharmacological in vivo effects and phytochemical profile of the extract from the aerial parts of Heteropterys brachiata (L.) DC. (Malpighiaceae).

ETHNOPHARMACOLOGICAL RELEVANCE: Heteropterys brachiata is a plant species that has been used in traditional Mexican medicine for the treatment of nervous disorders. AIM OF THE STUDY: To evaluate the anxiolytic, anticonvulsant, antidepressant and sedative effects produced by the methanolic extract of Heteropterys brachiata (HbMeOH) in ICR mice. Additionally, we determine the acute toxicity profiles of the extract and the presence of its main constituents. MATERIAL AND METHODS: The neuropharmacological effects of the extract were evaluated using a variety of models, such as the elevated plus maze (EPM), the forced swimming test (FST), the pentobarbital potentiation test (PTBt), pentylenetetrazole-induced seizures test (PTZt), and the open field test (OFT). HPLC was employed for obtention of phytochemical profile. RESULTS: HbMeOH produced a significant antidepressant effect in FST at 500 and 750 mg/kg doses, while doses from 500 to 1500 mg/kg exhibited a clear dose-dependent anxiolytic activity in EPM. A dose of 500 mg/kg showed a significant anticonvulsant activity in PTZt and an absence of sedation effects in PTBt. The main compounds of HbMeOH were chlorogenic acid and chlorogenic acid methyl ester, as well as less abundant terpene-type compounds. Furthermore, the extract was either safe with no deaths in mice treated orally with 2000 mg/kg. CONCLUSIONS: HbMeOH extract which contains mainly hydroxycinnamic acids and triterpene-type compounds, possesses antidepressant, anxiolytic and anticonvulsive properties and can be considered safe or of low toxicity when orally administrated. These findings lend pharmacological justification to the traditional use of Heteropterys brachiata in the treatment of nervous disorders.

Heteropterys cotinifolia: a neuropharmacological and phytochemical approach with possible taxonomic implications.

Heteropterys cotinifolia (Malpighiaceae) has been used in traditional Mexican medicine mainly for the treatment of nervous disorders. However, the specific neuropharmacological activities responsible for this use remain to be defined. The present study evaluates the antidepressant and anxiolytic effects produced by the methanolic extract of Heteropterys cotinifolia and the influence of such effects on motor activity in ICR mice. Our results show that the methanolic extract of Heteropterys cotinifolia produces a dose-dependent antidepressant effect in the forced swimming test in mice at doses from 31 to 310 mg/kg, with no reduction of mice locomotion. However, no anxiolytic properties were observed. Our findings suggest that the main extract compounds identified as chlorogenic acid and rutin may be involved in the antidepressant effects. To our knowledge, the present study constitutes the first report of pharmacological and phytochemical data of Heteropterys cotinifolia. The presence of flavonoids in the methanolic extract of Heteropterys cotinifolia may also provide further data to characterize taxonomically this species in order to be distinguished from others species closely related and belonging to the same genus.

Gonadotropin-releasing hormone receptor activates GTPase RhoA and inhibits cell invasion in the breast cancer cell line MDA-MB-231.

BACKGROUND: Gonadotropin-releasing hormone (GnRH) and its receptor (GnRHR) are both expressed by a number of malignant tumors, including those of the breast. In the latter, both behave as potent inhibitors of invasion. Nevertheless, the signaling pathways whereby the activated GnRH/GnRHR system exerts this effect have not been clearly established. In this study, we provide experimental evidence that describes components of the mechanism(s) whereby GnRH inhibits breast cancer cell invasion. METHODS: Actin polymerization and substrate adhesion was measured in the highly invasive cell line, MDA-MB-231 transiently expressing the wild-type or mutant DesK191 GnRHR by fluorometry, flow cytometric analysis, and confocal microscopy, in the absence or presence of GnRH agonist. The effect of RhoA-GTP on stress fiber formation and focal adhesion assembly was measured in MDA-MB-231 cells co-expressing the GnRHRs and the GAP domain of human p190Rho GAP-A or the dominant negative mutant GAP-Y1284D. Cell invasion was determined by the transwell migration assay. RESULTS: Agonist-stimulated activation of the wild-type GnRHR and the highly plasma membrane expressed mutant GnRHR-DesK191 transiently transfected to MDA-MB-231 cells, favored F-actin polymerization and substrate adhesion. Confocal imaging allowed detection of an association between F-actin levels and the increase in stress fibers promoted by exposure to GnRH. Pull-down assays showed that the effects observed on actin cytoskeleton resulted from GnRH-stimulated activation of RhoA GTPase. Activation of this small G protein favored the marked increase in both cell adhesion to Collagen-I and number of focal adhesion complexes leading to inhibition of the invasion capacity of MDA-MB-231 cells as disclosed by assays in Transwell Chambers. CONCLUSIONS: We here show that GnRH inhibits invasion of highly invasive breast cancer-derived MDA-MB-231 cells. This effect is mediated through an increase in substrate adhesion promoted by activation of RhoA GTPase and formation of stress fibers and focal adhesions. These observations offer new insights into the molecular mechanisms whereby activation of overexpressed GnRHRs affects cell invasion potential of this malignant cell line, and provide opportunities for designing mechanism-based adjuvant therapies for breast cancer.

The standardized extract of Loeselia mexicana possesses anxiolytic activity through the γ-amino butyric acid mechanism.

ETHNOPHARMACOLOGICAL RELEVANCE: Loeselia mexicana (Lam.) Brand has been used in Mexican Traditional Medicine to treat "espanto" or "susto" (fear), which is a culturally affiliated syndrome whose symptomatology comprises loss of appetite, difficulty in sleeping, and also nausea and fatigue, with a sensation of fear or risk - real or imagined - to external stimuli. AIM OF THE STUDY: The anxiolytic effect of the standardized methanol extract of Loeselia mexicana, with regard to its content of coumarin daphnoretin, was researched utilizing the elevated plus maze (EPM) in order to demonstrate whether the biological effect produced by the plant is antagonized by drugs that block γ-amino butyric acid (GABA)ergic transmission. MATERIALS AND METHODS: The methanolic extract of Loeselia mexicana (LmMeOH) was tested at different doses on the EPM and then the interaction of this extract was evaluated in the same model with different GABAergic drugs, such as flumazenil (FLU) 10mg/kg, bicuculline (BIC) 5mg/kg, pentylenetetrazole (PTZ) 10mg/kg, and picrotoxin (PTX) 2mg/kg. The effect of all of these treatments was evaluated by means of the open field test (OFT). Coumarin content was measured by the high performance liquid chromatography (HPLC) technique. RESULTS: The 200- and 400-mg/kg doses of methanolic extract containing 3.14 and 6.28 mg of daphnoretin, respectively, induced an anxiolytic effect in the EPM without modification of the spontaneous motor activity. The anxiolytic activity of 200mg/kg of methanolic extract in EPM-exposed mice was antagonized by PTX, BIC, and FLU, but not by PTZ. CONCLUSION: The data presented here indicate that the Loeselia mexicana Brand methanolic extract possesses a significant anxiolytic effect that appears to be mediated in part by activation of the GABAergic system.

Effect on the wound healing process and in vitro cell proliferation by the medicinal Mexican plant Ageratina pichinchensis.

The species Ageratina pichinchensis (Asteraceae) has been used for a long time in Mexican traditional medicine for the treatment of different skin conditions and injuries. In this study, the healing capacity of the plant extracts obtained was evaluated and, in order to understand the mechanism of healing, we also analyzed its effect on cell proliferation IN VITRO, cytotoxicity, and skin irritation. Different extracts obtained from the aerial parts of A. pichinchensis, topically administrated, were evaluated in a healing model by scalpel-blade incision on the rat. The extracts, at 10 % concentrations, were administrated daily during an eight-day period. A control group, to which the vehicle was administered, was used; while fibrinolysin (Fibrase SA®) was administered for positive control purposes. Reduction in wound size and the histological characteristics of the skin at the end of the treatment were evaluated. Cytotoxicity was evaluated in cell lines KB (nasopharyngeal carcinoma), UISO (squamous cell carcinoma of the cervix), OVCAR (ovarian carcinoma), and HCT-15 (colon carcinoma). In addition, the effect on cell proliferation of cell line MRC-5 (normal cells from human fetal lung) was measured, and skin irritation was evaluated. The results showed an important healing capacity of A. pichinchensis extract in noninfected wounds; the aqueous extract was found to be the most efficient. The extracts exhibited no cytotoxic effect; however, there was an effect that promoted cell proliferation in cell line MRC-5. The products tested demonstrated no skin irritant effects.

Human gonadotropin-releasing hormone receptor-activated cellular functions and signaling pathways in extra-pituitary tissues and cancer cells (Review).

Human gonadotropin-releasing hormone receptor (GnRHR) and its natural ligand human gonadotropin-releasing hormone (GnRH) were initially described as signaling complexes that play a key role in reproductive functions. By binding to specific receptors present on pituitary gonadotropes, GnRH regulates the sperm and ovum maturation, as well as steroidogenesis within the context of the hypothalamus-hypophysis axis. The expression of GnRH and its receptor has clearly been established in many extra-pituitary organs. Some of them are tumors from non-reproductive tissues such as liver, larynx, pancreas, colon, lymphoma, kidney, skin, blood and brain as well as tissues from reproductive track, for example ovary, endometrium, prostate and breast or tumors derived from these organs. Expression of GnRH and its receptor in these organs has gained much attention and several research groups have established their role during cell proliferation and cell motility. Although the signaling pathways and their effector proteins in these samples remain unclear, the molecular mechanism employed for GnRH and its receptor in extra-pituitary tissues could be related with non-classical GnRHR-signaling pathways. In the present review, we explore the vast literature reported on GnRH and GnRHR principally in tumors, describing how cross-talk between GnRHR and growth factor receptor, the coupling between GnRHR and many G proteins depending on cell context, and the regulation of several proteins associated with cell proliferation and cell motility are employed by GnRHR/GnRH to regulate their extra-pituitary activities.

Compuestos naturales de plantas de la familia clusiaceae: Inhibidores del virus de inmunodeficiencia humana tipo 1 / Natural compounds from plants of the clusiaceae family: Type 1 human immunodeficiency virus inhibitors / Compostos naturais de plantas da família clusiaceae: Inibidores do virus de imunodeficiência humana tipo 1

El SIDA es un problema de salud pública mundial, por lo que es necesario coordinar los esfuerzos para combatir esta enfermedad. En esta perspectiva, se revisan las investigaciones tendientes al descubrimiento y desarrollo de nuevos fármacos contra el virus de inmunodeficiencia humana (VIH) a partir de metabolitos secundarios de origen vegetal aislados de especies de la familia Clusiaceae. En particular, la revisión se enfoca en las cumarinas tetracíclicas inhibidoras de la transcriptasa reversa del VIH-1, como el (+)-calanólido A. También se presenta una semblanza sobre la biología del VIH y de los estudios llevados a cabo en México referentes a la búsqueda de compuestos antiVIH a partir de la flora local.

AIDS being a worldwide public health problem, it is necessary to coordinate efforts to fight the disease. Under this viewpoint, we review research aiming at the discovery and development of new drugs against the human immunodeficiency virus (HIV) from secondary metabolites of vegetal origin, isolated from species of the clusiaceae family. Particularly, the review centers on tetracyclic cumarines that inhibit the HIV-1 reverse transcriptase, such as the (+)-calanolide A. A summary of HIV biology and the studies carried out in Mexico concerning the search of anti-HIV compounds from the local flora is also presented.

A AIDS é um problema de saúde pública mundial, pelo qual é necessário coordenar os esforços para combater esta enfermidade. Nesta perspectiva, se revisam as investigações tendentes ao descubrimento e desenvolvimento de novos fármacos contra o virus da imunodeficiência humana (HIV) a partir de metabólitos secundários de origem vegetal isolados de espécies da família Clusiaceae. Em particular, a revisão é focada nas cumarinas tetracíclicas inibidoras da transcriptase reversa do HIV-1, como o (+)-calanolide A. Também é apresentado um esboço sobre a biologia do HIV e dos estudos levados a efeifo no México referentes à procura de compostos anti-HIV a partir da flora local.

HIV-1 inhibitory compounds from Calophyllum brasiliense leaves.

The hexane, acetone and methanol extracts of Calophyllum brasiliense leaves were fractionated following a three bioassay guide: high HIV-1 RT inhibition, low cytotoxicity on MT2 cells and high inhibition of HIV-1 IIIb/LAV replication. This led to the isolation of three anti HIV-1 dipyranocoumarins: calanolides A and B and soulattrolide. In contrast, other isolated compounds such as apetalic acid, isoapetalic acid, a structural isomer of isoapetalic acid, friedelin, canophyllol and amentoflavone were devoid of HIV-1 RT inhibitory activity. Calanolide C was also obtained as a natural product and showed moderate inhibitory properties.