Thermal shift assays of marine-derived fungal metabolites from Aspergillus fischeri MMERU 23 against Leishmania major pteridine reductase 1 and molecular dynamics studies.

Marine-derived fungi are a promising source of bioactive molecules, especially species from extreme habitats. Although several secondary metabolites such as meroterpenoids and alkaloids have been isolated from cultures of Aspergillus fischeri, obtained from terrestrial habitats, there is no report on compounds isolated from marine-derived strains. Many metabolites isolated from marine-derived fungi exhibited a myriad of biological activities. Marine natural products have shown to be an important source of bioactive compounds and can assist in the discovery of molecules with affinity against validated targets from exclusive strains of parasites of medical importance such as pteridine reductase 1 (PTR1), from Leishmania major, which is essential for cell growth. Leishmaniasis is responsible for approximately 65,000 annual deaths. Despite the mortality data, drugs available for the treatment of patients are insufficient and have moderate therapeutic efficacy in addition to serious adverse effects, which make the development of new drugs urgent. The previously described aszonalenin (ASL), aszonapyrone A (ASP), acetylaszonalenin (ACZ), and helvolic acid (HAC) were isolated from the ethyl acetate extract of the culture of a marine sponge-associated A. fischeri MMERU 23 and their affinities against PTR1 were determined by ThermoFluor®. Among the tested compounds, only ACZ showed dose-dependent affinity against PTR1. Moreover, complementary molecular dynamics studies (t = 100 000 ps) have showed that this molecule performs hydrogen bonds with key residues at the active site for more than 60% of the productive trajectory time. The results indicate that ACZ could be a promising PTR1 inhibitor and a potential candidate for development of antileishmanial drug.Communicated by Ramaswamy H. Sarma.

Chemical constituents, antioxidant, anti-inflammatory and, antinociceptive activities of Trichilia ramalhoi.

Trichilia ramalhoi Rizz. is a species from Meliaceae family and its chemical composition and biological activities are still unknown. This work describes the chemical composition and biological activities of the organic extracts of this plant. Therefore, methanolic extract of stem barks and leaves were prepared and submitted to chromatographic procedures. Besides, T. ramalhoi extracts biological evaluation showed antioxidant, antinociceptive and, anti-inflammatory activities. Usual chromatographic procedures of the active extracts permitted to isolate methyl 5-O-caffeoylquinate, apocynin C, cinchonains Ia and Ib, besides ß-sitosterol, stigmasterol and lupeol. The identification of the isolates was based on 13C and 1H NMR (1 D and 2 D) spectroscopic data and mass spectrometry. Although the flavalignans cinchonains Ia and Ib were previously isolated from T. catigua, this is the first occurrence of apocynin C in the Meliaceae family.

Bergenin Reduces Experimental Painful Diabetic Neuropathy by Restoring Redox and Immune Homeostasis in the Nervous System.

Diabetic neuropathy is a frequent complication of diabetes. Symptoms include neuropathic pain and sensory alterations-no effective treatments are currently available. This work characterized the therapeutic effect of bergenin in a mouse (C57/BL6) model of streptozotocin-induced painful diabetic neuropathy. Nociceptive thresholds were assessed by the von Frey test. Cytokines, antioxidant genes, and oxidative stress markers were measured in nervous tissues by ELISA, RT-qPCR, and biochemical analyses. Single (3.125-25 mg/kg) or multiple (25 mg/kg; twice a day for 14 days) treatments with bergenin reduced the behavioral signs of diabetic neuropathy in mice. Bergenin reduced both nitric oxide (NO) production in vitro and malondialdehyde (MDA)/nitrite amounts in vivo. These antioxidant properties can be attributed to the modulation of gene expression by the downregulation of inducible nitric oxide synthase (iNOS) and upregulation of glutathione peroxidase and Nrf2 in the nervous system. Bergenin also modulated the pro- and anti-inflammatory cytokines production in neuropathic mice. The long-lasting antinociceptive effect induced by bergenin in neuropathic mice, was associated with a shift of the cytokine balance toward anti-inflammatory predominance and upregulation of antioxidant pathways, favoring the reestablishment of redox and immune homeostasis in the nervous system. These results point to the therapeutic potential of bergenin in the treatment of painful diabetic neuropathy.

Bergenin from Peltophorum dubium: Isolation, Characterization, and Antioxidant Activities in Non-Biological Systems and Erythrocytes.

BACKGROUND: Bergenin, a compound derived from gallic acid, is a secondary metabolite of the plant Peltophorum dubium (Spreng.) Taub. OBJECTIVE: In this study, we aimed to characterize the ability of bergenin to eliminate the radicals in non-biological systems. METHODS: We evaluated bergenin's ability to protect erythrocytes from oxidative damage in a biological system. We have elucidated bergenin structure using nuclear magnetic resonance, X-ray diffraction, Fourier transform infrared spectroscopy, and differential scanning calorimetry. We then evaluated its antioxidant capacity in vitro against DPPH•, ABTS•+, hydroxyl radicals, and nitric oxide, and determined its ability to transfer electrons owing to its reduction potential and ability to chelate iron. We also evaluated its protective capacity against oxidative damage produced by AAPH in erythrocytes, its hemolytic properties, its ability to inhibit hemolysis, and its ability to maintain intracellular reduced glutathione homeostasis. RESULTS: Bergenin concentrations between 0.1 and 3mM significantly (p < 0.05) and dose dependently decreased formation of ABTS•+, DPPH•, nitrite ions, OH•, reduced formation ferricyanide, ferrozine-Fe2+complex, inhibited AAPH-induced oxidative hemolysis of erythrocytes, raised GSH levels in the presence of AAPH, inhibited AAPH-induced lipid peroxidation in erythrocytes. CONCLUSION: Bergenin may represent a novel alternative antioxidant, with potential applications in various industries, including drugs, cosmetics, and foods.

Poligalen, a new coumarin from Polygala boliviensis, reduces the release of TNF and IL-6 independent of NF-kB downregulation.

An unusually substituted coumarin, named poligalen, was isolated from a chloroform extract of the aerial parts of Polygala boliviensis. This coumarin was identified by one- and two-dimensional NMR techniques, and the structure of the compound was confirmed by X-ray diffraction. Poligalen exhibits immunomodulatory effects, reducing the levels of IL-6 and TNF after LPS stimulation in peritoneal macrophages. However, poligalen potentiates NF-kB activation.

In vitro effects of arylhydrocoumarin on free radicals and oxidative stress in erythrocytes and Saccharomyces cerevisiae.

Neoflavonoids comprise a group of natural compounds with varied chemical structures and promising pharmacological properties, including antioxidant capacity. This work describes an evaluation of the in vitro antioxidant capacity of a new coumarin derivative, i.e., 7-acetoxy-4-aryl-3,4-dihydrocoumarin, in terms of its ability to quench the 2,2- diphenyl-1-picrylhydrazyl (DPPH•), 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS•+), hydroxyl (OH•) and superoxide anion (O2(•-)) radicals, as well as its capacity to initiate electron transfer by reducing potential and inhibit lipid peroxidation by TBARS (thiobarbituric acid reactive substances) method. In addition, the antioxidant capacity of 7-acetoxy-4-aryl-3,4-dihydrocoumarin was evaluated against oxidative damage induced by hydrogen peroxide in erythrocyte suspensions and S. cerevisiae strains. In all methodologies investigated, high antioxidant capacities above 65% were demonstrated by 7-acetoxy-4-aryl-3,4-dihydrocoumarin against the DPPH(•), ABTS(•+), OH(•) and O2(•-) radicals. The ability of 7-acetoxy-4-aryl-3,4-dihydrocoumarin to inhibit oxidative damage induced by hydrogen peroxide in erythrocytes and S. cerevisiae strains demonstrates the importance of this compound in the protection against oxidative stress at the cellular level. Thus, the results obtained in this study suggest that 7-acetoxy-4-aryl-3,4-dihydrocoumarin can assist the development of new antioxidant products for possible use in the prevention or reduction of diseases related to oxidative stress.

Mikania glomerata: Phytochemical, Pharmacological, and Neurochemical Study.

The present study primarily aims to identify the relative density and the fatty acids (methyl esters) content present in the standardized ethanol extract of leaves of M. glomerata (EPMG). Meanwhile, in a second moment, this study evaluated the effects of the EPMG on the levels of amino acids in the hippocampus, and the mechanism of sedative and anxiolytic action. Adult mice were treated with doses of 200, 300, and 400 mg/kg and evaluated in open field, elevated plus-maze, light dark, and rotarod tests. Moreover, in the behavioral tests diazepam (GABAergic anxiolytic, 2 mg/kg) as positive control and flumazenil (GABA antagonist, 2.5 mg/kg) were used to identify mechanism of sedative and anxiolytic action produced by EPMG. The EPMG is constituted by the following compounds: methyl cinnamate, 2H-1-benzopyran-2-one, (2-hydroxyphenyl)methyl propionate, (Z)-methyl-hexadec-7-enoate, methyl hexadecanoate, hexadecanoic acid, (Z)-methyl-octadec-9-enoate, octadecanoic acid, and squalene. This extract demonstrated anxiolytic effects, which may be mediated by GABAergic system, and was able to increase GABA levels and reduce of glutamate and aspartate concentrations in mice hippocampus, which can directly and/or indirectly assist in their anxiolytic effect. Although more studies are needed, the EPMG could represent an interesting therapeutical strategy in the treatment of anxiety.

In vitro acetylcholinesterase activity of peptide derivatives isolated from two species of Leguminosae.

CONTEXT: Cratylia mollis Martius ex Benth. and Cenostigma macrophyllum Tul. (Leguminosae) are both endemic Brazilian plants and they are used by the natives as medicinal plants, and the leaves of C. mollis are also employed as forage for cattle during the dry season of region. OBJECTIVE: Isolation of the compounds responsible for the acetylcholinesterase (AChE) inhibition from the CHCl3 active extract. MATERIALS AND METHODS: Two peptidic compounds were isolated by chromatographic techniques from the CHCl3 extract of the leaves of C. mollis and C. macrophyllum. They were identified by spectrometric data analysis (MS and NMR) and they were subjected to AChE inhibition employing Ellman's test. RESULTS: The peptides were identified as N-benzoylphenylalaninoyl-phenlyalaninolacetate (aurentiamide acetate) (1) and N-benzoylphenylalaninyl-N-benzoylphenylalaninate (2). Both peptides 1 and 2 exhibit AChE inhibition, with IC50 values equal to 111.34 µM and 137.6 µM, respectively. DISCUSSION AND CONCLUSION: Compound 1 (aurentiamide acetate) has rarely been isolated from the Leguminosae family, and N-benzoylphenylalaninyl-N-benzoylphenylalaninate (2) is a compound that has never previously been isolated from this family. Compound 1 is shown to be a potent inhibitor of AChE, with IC50 values similar to the physostigmine control (141.51 µM).