Mateus Feitosa Alves

Anxiolytic-like activity and GC–MS analysis of (R)-(+)-limonene fragrance, a natural compound found in foods and plants

The traditional use of essential oils in aromatherapy has offered numerous health benefits. However, few scientific studies have been conducted with these oils to confirm their therapeutic efficacy. (+)-Limonene is a chemical constituent of various bioactive essential oils. The present study reports on the anxiolytic-like effects of (+)-limonene in an elevated maze model of anxiety in mice. At concentrations of 0.5% and 1.0%, (+)-limonene, administered to mice by inhalation, significantly modified all the parameters evaluated in the elevated plus maze test. The pharmacological effect of inhaled (+)-limonene (1%) was not blocked by flumazenil. Analysis of (+)-limonene using gas chromatography-mass spectrometry (GC-MS) showed its volatility to be high. These data suggest possible connections between the volatility of (+)-limonene and its anxiolytic-like effect on the parameters evaluated in the elevated plus maze test. The data indicate that (+)-limonene could be used in aromatherapy as an antianxiety agent.

Computer-Aided Drug Design Using Sesquiterpene Lactones as Sources of New Structures with Potential Activity against Infectious Neglected Diseases

This review presents an survey to the biological importance of sesquiterpene lactones (SLs) in the fight against four infectious neglected tropical diseases (NTDs)—leishmaniasis, schistosomiasis, Chagas disease, and sleeping sickness—as alternatives to the current chemotherapies that display several problems such as low effectiveness, resistance, and high toxicity. Several studies have demonstrated the great potential of some SLs as therapeutic agents for these NTDs and the relationship between the protozoal activities with their chemical structure. Recently, Computer-Aided Drug Design (CADD) studies have helped increase the knowledge of SLs regarding their mechanisms, the discovery of new lead molecules, the identification of pharmacophore groups and increase the biological activity by employing in silico tools such as molecular docking, virtual screening and Quantitative-Structure Activity Relationship (QSAR) studies.

Anxiolytic Effect of Citrus aurantium L. on Patients with Chronic Myeloid Leukemia.

The bone marrow aspiration procedure is used in hematological diseases and consists of a painful, invasive procedure causing anxiety‐associated symptoms. The present study assessed the effect of Citrus aurantium L. essential oil on the treatment of anxiety, in the moment that precedes the collection of medullary material in patients with chronic myeloid leukemia (CML). Volunteers from both sexes were divided into groups receiving either the C. aurantium essential oil through inhalation, diazepam (10 mg), or the placebo. The evaluation was performed through psychometric scales [State‐Trait Anxiety Inventory (STAI)] and physiological measurements (blood pressure and cardiac and respiratory frequency). Inhalation of C. aurantium was associated with a decrease in the STAI‐S scores, suggesting an anxiolytic effect. In support of these results, a change in all the physiological measurements was observed in the group exposed to C. aurantium. In the diazepam group, only the diastolic pressure decreased, and no effect was observed in the placebo group. Therefore, the results showed that C. aurantium exhibits an anxiolytic effect and reduces the signs and symptoms associated with anxiety in patients with CML. Copyright

Histopathological and biochemical assessment of d-limonene-induced liver injury in rats

The aim of the present work was to develop a biochemical, histologic and immunohistochemical study about the potential hepatotoxic effect of d-limonene – a component of volatile oils extracted from citrus plants. Blood alkaline phosphatase (ALP), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) from d-limonene-treated animals were determined and compared to morphologic hepatic lesions in order to investigate the possible physiopathologic mechanisms involved in the liver toxicity, in experimental animals treated with d-limonene. Wistar rats were randomly divided into seven groups: two control groups (untreated or receiving only vehicle, tween-80); one positive control (vehicle); two experimental groups treated with d-limonene at doses of 25 mg/kg/day and 75 mg/kg/day for 45 days, and two other groups treated with the same doses for 30 days and kept under observation during 30 more days. Biochemical data showed significant reduction in ALT levels in the animals treated with 75 mg/kg of d-limonene. Histological analysis revealed some hepatocyte morphological lesions, including hydropic degeneration, microvesicular steatosis and necrosis, Kupffer cell hyperplasia and incipient fibrosis. By immunohistochemistry, influx of T (CD3+) and cytotoxic (CD8+) lymphocytes was observed in the rats treated with d-limonene at both dose levels. In conclusion, it is possible that d-limonene has been directly responsible for hepatic parenchymal and matrix damage following subchronic treatment with d-limonene.

Predictive ecotoxicity of MoA 1 of organic chemicals using in silico approaches

Persistent organic products are compounds used for various purposes, such as personal care products, surfactants, colorants, industrial additives, food, pesticides and pharmaceuticals. These substances are constantly introduced into the environment and many of these pollutants are difficult to degrade. Toxic compounds classified as MoA 1 (Mode of Action 1) are low toxicity compounds that comprise nonreactive chemicals. In silico methods such as Quantitative Structure-Activity Relationships (QSARs) have been used to develop important models for prediction in several areas of science, as well as aquatic toxicity studies. The aim of the present study was to build a QSAR model-based set of theoretical Volsurf molecular descriptors using the fish acute toxicity values of compounds defined as MoA 1 to identify the molecular properties related to this mechanism. The selected Partial Least Squares (PLS) results based on the values of cross-validation coefficients of determination (Qcv2) show the following values: Qcv2 = 0.793, coefficient of determination (R2) = 0.823, explained variance in external prediction (Qext2) = 0.87. From the selected descriptors, not only the hydrophobicity is related to the toxicity as already mentioned in previously published studies but other physicochemical properties combined contribute to the activity of these compounds. The symmetric distribution of the hydrophobic moieties in the structure of the compounds as well as the shape, as branched chains, are important features that are related to the toxicity. This information from the model can be useful in predicting so as to minimize the toxicity of organic compounds.

Chemotaxonomic Study of Sesquiterpene Lactones of Asteraceae: Classical and Modern Methods

Chemotaxonomy is a classification method based on the comparison of similarities of natural compounds among the organisms to be classified. However, it presents some difficulties because the chemical compounds present large variability. Currently, different classification methods are available in chemotaxonomy involving classical and modern taxonomy. Asteraceae is one of the largest families of angiosperms, and its sesquiterpene lactones are considered important taxonomic markers. They have been studied as promising new drug sources as a consequence of their enormous pharmacological potential. With regard to modern methods to study taxonomy, in the last two decades, linear approaches such as principal component analysis and partial least squares as well as other machine learning methods like artificial neural networks, k-nearest neighbors, and self-organizing maps have been used as pattern recognition methods to study the distribution of sesquiterpene lactones among the tribes and genera of Asteraceae. For this purpose, thousands of chemical structures and molecular descriptors that encode different physicochemical features of compounds have been used. Such studies are empowered by computational methods and databases of secondary metabolites. In this sense, systems that are able to manage large databases of sesquiterpene lactones are crucial for more robust chemotaxonomic studies of Asteraceae. The web tool AsterDB (www.asterbiochem.org/asterdb) is an interesting database with a friendly interface that contains thousands of chemical structures of secondary metabolites from this family and comprises more than 1000 chemical structures of sesquiterpene lactones. The great evolution in the study of natural products based on computational methods shows that modern and integrated platforms will be available soon for several purposes.

Virtual screening studies for discovery of novel inhibitors of inflammatory process targets

Inflammation has been very evident in infectious diseases, but in recent times research has increasingly shown that a range of non-infectious diseases may present with inflammatory conditions. This fact becomes important as new anti-inflammatory drugs emerge with different targets for treatment of diseases. Virtual screening (VS) involves applying computational methods to discover new ligands for biological structures from the formation of large libraries composed of a large number of compounds. This review aims to report several studies employing a variety of VS: ligand-based and structure-based VS are being used more frequently in combination to decrease the probability of choosing false positive candidates. There are also studies that use only one approach. Docking is widely employed as structure-based VS methodology, however pharmacophore models based on the structure are becoming more prevalent. Molecular dynamics simulations, despite their computational cost, are still utilized to validate docking scores and analyze the stability of the complex ligand-structure. It is important to note that several studies employed several drug-like rules to screen structures, as well, decoys and PAINS to validate the models. Natural product databases, despite the lower number of the compounds compared to other databases that are available, are commonly referred to as a source of drug-like molecules. There is a literal explosion of software being released for a variety of purposes and several of them are free tools and/or web tools. Overall, VS studies are nowadays a normal part of medicinal chemistry to determine novel potential inhibitors for targets of inflammatory diseases.

Toxicological evaluation in silico and in vivo of secondary metabolites of Cissampelos sympodialis in Mus musculus mice following inhalation

Abstract The ethanolic extract of the leaves of Cissampelos sympodialis showed great pharmacological potential, with inflammatory and immunomodulatory activities, however, it showed some toxicological effects. Therefore, this study aims to verify the toxicological potential of alkaloids of the genus Cissampelos through in silico methodologies, to develop a method in LC-MS/MS verifying the presence of alkaloids in the infusion and to evaluate the toxicity of the infusion of the leaves of C. sympodialis when inhaled by Swiss mice. Results in silico showed that alkaloid 93 presented high toxicological potential along with the products of its metabolism. LC-MS/MS results showed that the infusion of the leaves of this plant contained the alkaloids warifteine and methylwarifteine. Finally, the in vivo toxicological analysis of the C. sympodialis infusion showed results, both in biochemistry, organ weights and histological analysis, that the infusion of C. sympodialis leaves presents a low toxicity.

Alkaloids From the Family Menispermaceae: A New Source of Compounds Selective for β-Adrenergic Receptors

Abstract Pharmacological receptors are important because they produce an interaction with drugs leading to a biological response. The β1- and β2-adrenergic receptors are found in cardiac muscle and bronchial tissue. The family Menispermaceae is composed of over 70 genera with a wide global distribution, many of them having different pharmacological activities. Several secondary metabolites, particularly alkaloids, have been isolated from this family. The aim of this study was to evaluate a number of alkaloids and their affinity to β1- and β2-adrenergic receptors. Therefore, a combination of ligand- and structure-based virtual screening methods was applied to the study of a small data set formed by 786 secondary metabolites of the Menispermaceae family that were extracted from an in-house database. The multitarget selectivity of the alkaloid dauricine (482) was observed through the inhibition of β1-adrenergic receptors and activation of β2-adrenergic receptors. These compounds can be used as starting points for studies of proposed structures for cardioprotective and/or antiasthmatic activity.

New Therapeutic Targets and Drugs for the Treatment of Asthma

Asthma is an inflammatory disease which affects millions of people worldwide. Therefore, it is necessary to search for new sources of therapies for the treatment of these patients in order to improve their quality of life. From content analysis of literature of new therapeutic targets, there are various targets and drugs reported to be promising for the treatment of asthma. Interleukins involved in inflammatory processes are often presented as candidate targets for new drugs. The action of such therapeutics would not only affect interleukins, but also their receptors. Small molecules (e.g. ligustrazine and SP600125) and large molecule antibodies (e.g. lebrikizumab, benralizumab, dupilumab) are being considered as novel agents for the pharmacotherapy of asthma. Therefore, through this research, we can see advances in the search for new targets and promising drugs to treat asthma. It is expected that these new drug candidates will eventually be approved and marketed so that asthma patients can use them to enhance their quality of life.