Long-term administration of aspirin (ASA, acetylsalicylic acid) in oncogenic patients has been related to a reduction in cancer risk incidence, but its precise mechanism of action is unclear. The ...activation of cancer-associated fibroblasts (CAFs) is a key element in tumor progression and can be triggered by cancer-derived extracellular vesicles (EVs). Targeting the communication between cancer cells and the surrounding tumor microenvironment (TME) may control cancer progression. Our aim was to investigate the effect of ASA on breast cancer cells, focusing on EV secretion and their effect on the biological properties of CAFs. As a result, ASA was shown to reduce the amount and alter the size distribution of EVs produced by MDA-MB-231 tumor cells. Fibroblasts stimulated with EVs derived from MDA-MB-231 treated with ASA (EV-ASA) showed a lower expression of alpha-smooth muscle actin (α-SMA), matrix metalloproteinase-2 (MMP2) but not fibroblast activation protein (FAP) in respect to the ones stimulated with EVs from untreated breast cancer cells (EV-CTR). Furthermore, invasion assays using a three-dimensional (3D) fibroblast spheroid model showed reduced MDA-MB-231 invasion towards fibroblast spheroids pretreated with EV-ASA as compared to spheroids prepared with EV-CTR-stimulated fibroblasts. This suggests that ASA partially inhibits the ability of tumor EVs to stimulate CAFs to promote cancer invasion. In conclusion, ASA can interfere with tumor communication by reducing EV secretion by breast tumor cells as well as by interfering with their capacity to stimulate fibroblasts to become CAFs.
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•Geissoschizoline is a potent inhibitor of both humans AChE and BChE.•Geissoschizoline plays a promising anti-inflammatory role.•It reduces the microglial release of NO• and TNF-α.•It ...shows mixed-type inhibition mechanism; interacts with AS and PAS sites of enzyme.•Geissoschizoline behaves as dual-site inhibitor.
Due to the lack of effective pharmacotherapy options to treats Alzheimer’s disease, new strategies have been approached in the search for multi-target molecules as therapeutic options. In this work, four indole alkaloids, geissoschizoline, geissoschizone, geissospermine, and 3′,4′,5′,6′-tetradehydrogeissospermine were isolated from Geissospermum vellosii (Pao pereira) and evaluated for their anticholinesterase activities. While geissospermine inhibited only butyrylcholinesterase (BChE), the other alkaloids behaved as non-selective inhibitors of acetylcholinesterase (AChE) and BChE. In cell viability tests, only geissoschizoline was not cytotoxic. Therefore, geissoschizoline actions were also evaluated in human cholinesterases, where it was twice as potent inhibitor of hBChE (IC50 = 10.21 ± 0.01 µM) than hAChE (IC50 = 20.40 ± 0.93 µM). On enzyme kinetic studies, geissoschizoline presented a mixed-type inhibition mechanism for both enzymes. Molecular docking studies pointed interactions of geissoschizoline with active site and peripheral anionic site of hAChE and hBChE, indicating a dual site inhibitor profile. Moreover, geissoschizoline also played a promising anti-inflammatory role, reducing microglial release of NO and TNF-α at a concentration (1 μM) ten and twenty times lower than the IC50 values of hBChE and hAChE inhibition, respectively. These actions give geissoschizoline a strong neuroprotective character. In addition, the ability to inhibit hAChE and hBChE, with approximate inhibitory potencies, accredits this alkaloid for therapeutic use in the moderate to severe phase of AD. Thus, geissoschizoline emerges as a possible multi-target prototype that can be very useful in preventing neurodegeneration and restore neurotransmission.
The present study reports the identification and the antileishmanial profile of unusual flavonoids from
Kalanchoe pinnata: kaempferol 3-
O-α-
l-arabinopyranosyl (1
→
2) α-
l-rhamnopyranoside (
1), ...quercetin 3-
O-α-
l-arabinopyranosyl (1
→
2) α-
l-rhamnopyranoside (
2) and 4′,5-dihydroxy-3′,8-dimethoxyflavone 7-
O-β-
d-glucopyranoside (
3).
The importance of flavonoids for the antileishmanial activity of
Kalanchoe pinnata was previously demonstrated by the isolation of quercitrin, a potent antileishmanial flavonoid. In the present study, the aqueous leaf extract from the medicinal plant
K. pinnata (Crassulaceae) afforded a kaempferol di-glycoside, named kapinnatoside, identified as kaempferol 3-
O-α-
l-arabinopyranosyl (1
→
2) α-
l-rhamnopyranoside (
1). In addition, two unusual flavonol and flavone glycosides already reported, quercetin 3-
O-α-
l-arabinopyranosyl (1
→
2) α-
l-rhamnopyranoside (
2) and 4′,5-dihydroxy-3′,8-dimethoxyflavone 7-
O-β-
d-glucopyranoside (
3), have been isolated. Their structures were determined via analyses of mono and bi-dimensional
1H and
13C NMR spectroscopic experiments and HR-MALDI mass spectra. Because of its restricted occurrence and its abundance in
K. pinnata, flavonoid (
2) may be a chemical marker for this plant species of high therapeutic potential. The three flavonoids were tested separately against
Leishmania amazonenis amastigotes in comparison with quercitrin, quercetin and afzelin. The quercetin aglycone – type structure, as well as a rhamnosyl unit linked at C-3, seem to be important for antileishmanial activity.
•A straightforward LdNH activity assay was developed.•Moringa oleifera leaves and flowers extracts as natural products library.•Ten ligands identified by high-resolution inhibition profiling and ...ligand fishing.•Seven ligands characterized by LC-HRMS.
In Leishmania donovani, the causative protozoan of visceral leishmaniasis, nucleoside hydrolase enzyme (NH) is fundamental for the biosynthesis of its DNA and RNA. Therefore, LdNH is considered a potential target for the development of new leishmaniasis chemotherapy. Moringa oleifera Lamarck is a medicinal plant native to northeastern India with numerous pharmacological properties, including antileishmanial activity. Thus, this study aimed to explore the inhibitory activity of different extracts from M. oleifera leaves and flowers on LdNH. Using LdNH covalently immobilized on magnetic particles (LdNH-MPs), a novel activity assay was developed based on the direct quantification of the formed product by HPLC-DAD. This study screened 12 extracts from leaves and flowers of M. oleifera using different extraction methods. The hydroethanolic (70% ethanol) extract from flowers, obtained by infusion (FIEH) or ultrasound-assisted extraction (FUEH), exhibited respectively IC50 values of 26.2 ± 4.63 µg/mL and 4.96 ± 0.52 µg/mL. The most promising extract (FUEH) was investigated by high-resolution LdNH inhibition profiling, which showed different regions of inhibition in the biochromatogram. A ligand fishing assay was attempted to pinpoint the bioactive compounds. Experimental conditions employed in the elution step of the ligand fishing assay did not result in ligands isolation. However, the analyses of the crude extract solution and the supernatants after the incubation with the active and inactive LdNH-MPs indicated missing peaks referring to compounds selectively retained in the active LdNH-MPs incubation. The missing peaks eluted in the same region that exhibits inhibition in the high-resolution LdNH inhibition profiling. The ligands were identified by UHPLC-MS/MS as palatinose, adenosine, 3-p-coumaroylquinic acid, 4-p-coumaroylquinic acid, hyperoside, quercetin-3-O-malonyl glycoside, and kaempferol-3-O-galactoside.
Earthworm metabolism is recognized as a useful tool for monitoring environmental insults and measuring ecotoxicity, yet extensive earthworm metabolic profiling using 1H nuclear magnetic resonance ...(NMR) spectroscopy has been limited in scope. This study aims to expand the embedded metabolic material in earthworm coelomic fluid, coelomocytes, and tissue to aid systems toxicology research. Fifty-nine metabolites within Eisenia fetida were identified, with 47 detected in coelomic fluid, 41 in coelomocytes, and 54 in whole-worm samples and tissue extracts. The newly detected but known metabolites 2-aminobutyrate, nicotinurate, Nδ,Nδ,Nδ-trimethylornithine, and trigonelline are reported along with a novel compound, malylglutamate, elucidated using 2D NMR and high-resolution MS/MS. We postulate that malylglutamate acts as a glutamate/malate store, chelator, and anionic osmolyte and helps to provide electrolyte balance.
The chemical investigation of the fresh flowers of Albizia lebbeck (L.) Benth. (Fabaceae, Mimosoideae) led to the isolation of two new echinocystic acid saponins. They were isolated by using ...chromatographic methods and their structures were elucidated by detailed
1
H and
13
C NMR spectral data including 2 D-NMR (COSY, HSQC, HMBC and APT) spectroscopic techniques, high-resolution electrospray ionization mass spectrometry (HRESIMS) and acid hydrolysis. Their structures were established as 16-hydroxy-3-O-β-D-xylopyranosyl-(1→2)-O-α-L-arabinopyranosyl-(1→6)-2-(acetylamino)-2-deoxy-β-D-glucopyranosyloxy-(3β,16α)-olean-12-en-28-oic acid O-6-deoxy-α-L-mannopyranosyl-(1→4)-O-6-deoxy-α-L-mannopyranosyl-(1→2)-β-D-glucopyranosyl ester (1) and 16-hydroxy-3-O-β-D-xylopyranosyl-(1→2)-O-α-L-arabinopyranosyl-(1→6)-2-(acetylamino)-2-deoxy-β-D-glucopyranosyloxy-(3β,16α)-olean-12-en-28-oic acid 6-O-(2S,3R,4R)-tetrahydro-3-hydroxy-4-(hydroxymethyl)-2-furanyl-β-D-glucopyranosyl ester (2). Additionally, the permeability property and the capacity of interaction with biological membranes of compounds 1 and 2 were investigated.
Among the compounds of natural origin, diterpenes have proved useful as drugs for the treatment of cancer. Marine organisms, such as soft corals and algae, are a promising source of diterpenes, being ...a rich and unexplored source of cytotoxic agents. This study evaluated a library of 32 natural and semisynthetic marine diterpenes, including briarane, cembrane, and dolabellane nuclei, with the aim of determining their cytotoxicity against three human cancer cell lines (A549, MCF7, and PC3). The three most active compounds were submitted to a flow cytometry analysis in order to determine induction of apoptosis against the A549 cell line. An NMR analysis was conducted to determine and evaluate the interactions between active diterpenes and tubulin. These interactions were characterized by a computational study using molecular docking and MD simulations. With these results, two cembrane and one chlorinated briarane diterpenes were active against the three human cancer cell lines, induced apoptosis in the A549 cell line, and showed interactions with tubulin preferably at the taxane‐binding site. This study is a starting point for the identification and optimization of the marine diterpenes selected for better antitumor activities. It also highlights the power of integrating NMR studies, computational predictions, and in vitro assays in the search for compounds with antitumor activity.
Three marine diterpenes were active against three human cancer cell lines. NMR study showed that the active compounds interact with tubulin. The active compounds interact with tubulin as stabilizer agents.
The aim of this research was to perform a phytochemical study of the methanol leaves extract of
(MET) guided by vasodilatory and antioxidant activities. The chemical profile of MET and the ethyl ...acetate fraction (EA fraction) was determined by HPLC-UV-MS and EA fraction guided fractionation by reverse-phase chromatography. The vasorelaxant effects of MET, fractions, sub-fractions and constituents were assessed on rat aorta pre-contracted with phenylephrine. Antioxidant activity was evaluated by using a DPPH assay. The results show that MET-induced vasodilation was dependent on NO/cGMP; and that the PI3K/Akt pathway seems to be the main route involved in eNOS activation. The EA fraction showed greater vasodilatory and antioxidant potency and was submitted to further fractionation. This allowed the isolation and characterization of quercetin, quercetin 3-
-(6″-
-galloyl)-β-d-galactopyranoside and 1,4,6-tri-
-galloyl-β-d-glucose. Also, galloyl-HHDP-hexoside and myricetin deoxyhexoside were identified by HPLC-UV-MS. These compounds are being described for the first time for
. 1,4,6-tri-
-galloyl-β-d-glucose and quercetin 3-
-(6″-
-galloyl)-β-d-galactopyranoside showed no vasodilatory activity. Quercetin and myricetin glycoside seems to contribute to the MET activity, since they have been reported as vasodilatory flavonoids. MET-induced vasodilation could contribute to the hypotensive effect of
previously reported.
Conformational stabilization mediated by hydrogen bonds can play an important role in the drug-target recognition process. Non-classical hydrogen bonding is receiving great attention, where C-H Y ...hydrogen bonds are found in some biological systems and are important for molecular recognition, leading to the possibility of exploration of this interaction in drug design projects. Studies that identify and characterize new non-classical interactions in different systems can assist in the rational application of these interactions. In this paper, we describe the serendipitous identification and characterization of a new non-classical hydrogen bond donor moiety found in 3-acyl-substituted furan. We applied a theoretical and experimental approach in the study of several
N
-acylhydrazones containing 3-acyl-substituted furan, where we describe the presence of a hydrogen bond between the C(2)-H bond of 3-acyl-substituted furan with the imine nitrogen in the
syn
conformer of the
N
-acylhydrazone moiety. In addition, we evaluated the strength of this interaction with intermolecular models. Thus, we believe that the 3-acyl-substituted furan moiety can be rationally explored as a hydrogen bond donor moiety in drug design projects.
A serendipitous identification and characterization of a new non-classical hydrogen bond donor moiety found in
N
-acylhydrazones containing 3-acyl-substituted furan subunit is presented.
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•A polysaccharide was isolated from Cyrtopodium andersonii.•Structural characterization was performed.•The antiinflammatory activity and gastroprotective property were investigated.
A ...polysaccharide with an estimated weight-average molar mass of 5.35×105 was obtained from an aqueous extract of pseudobulbs of Cyrtopodium andersonii R. Br. It was composed of d-glucose and d-mannose in 1:3 molar ratio. Chemical and spectroscopic analyses revealed a linear structure of the polymer with a backbone composed of (1→4)-linked β-d-glucopyranosyl and mannopyranosyl units slightly branched at C-2, C-3, and C-6 by side chains, as terminal non reducing residues of d-mannopyranose and d-glucopyranose. It was found to contain 14.6% of acetyl groups substituted at C-2 of (1→4)-linked β-d-mannopyranosyl units. The acetylated glucomannan demonstrated antiinflammatory and antiulcerogenic activities.
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