Orally available antivirals against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are necessary because of the continuous circulation of new variants that challenge immunized ...individuals. Because severe COVID-19 is a virus-triggered immune and inflammatory dysfunction, molecules endowed with both antiviral and anti-inflammatory activity are highly desirable. We identified here that kinetin (MB-905) inhibits the in vitro replication of SARS-CoV-2 in human hepatic and pulmonary cell lines. On infected monocytes, MB-905 reduced virus replication, IL-6 and TNFα levels. MB-905 is converted into its triphosphate nucleotide to inhibit viral RNA synthesis and induce error-prone virus replication. Coinhibition of SARS-CoV-2 exonuclease, a proofreading enzyme that corrects erroneously incorporated nucleotides during viral RNA replication, potentiated the inhibitory effect of MB-905. MB-905 shows good oral absorption, its metabolites are stable, achieving long-lasting plasma and lung concentrations, and this drug is not mutagenic nor cardiotoxic in acute and chronic treatments. SARS-CoV-2-infected hACE-mice and hamsters treated with MB-905 show decreased viral replication, lung necrosis, hemorrhage and inflammation. Because kinetin is clinically investigated for a rare genetic disease at regimens beyond the predicted concentrations of antiviral/anti-inflammatory inhibition, our investigation suggests the opportunity for the rapid clinical development of a new antiviral substance for the treatment of COVID-19.
Tabebuia avellanedae Lorentz ex Griseb is a plant employed in tropical America folk medicine for the treatment of several diseases, including depressive disorders.
To investigate the ability of ...Tabebuia avellanedae ethanolic extract (EET) administered chronically to cause an antidepressant-like effect in the tail suspension test (TST), a predictive test of antidepressant activity, and to reverse behavioral (hyperactivity, anhedonic-like behavior and increased immobility time in the TST) and biochemical changes induced by olfactory bulbectomy (OB), a model of depression, in mice.
Mice were submitted to OB to induce depressive-related behaviors, which were evaluated in the open-field test (hyperactivity), splash test (loss of motivational and self-care behavior indicative of an anhedonic-like behavior) and TST (increased immobility time). Phosphorylation levels of Akt, GSK-3β, ERK1/2 and CREB, as well as BDNF immunocontent, were evaluated in the hippocampus of bulbectomized mice or sham-operated mice treated for 14 days by p.o. route with EET or vehicle.
EET (10 and 30mg/kg) given 14 days by p.o route to mice reduced the immobility time in the TST without altering locomotor activity, an indicative of an antidepressant-like effect. EET per se increased both CREB (Ser133) and GSK-3β (Ser9) phosphorylation (at doses of 10–30 and 30mg/kg, respectively) in sham-operated mice. OB caused hyperactivity, loss of motivational and self-care behavior, increased immobility time in the TST and an increase in CREB and ERK1 phosphorylation, as well as BDNF immunocontent. EET abolished all these OB-induced alterations except the increment of CREB phosphorylation. Akt (Ser473) and ERK2 phosphorylation levels were not altered in any group.
EET ability to abolish the behavioral changes induced by OB was accompanied by modulation of ERK1 and BDNF signaling pathways, being a promising target of EET. Results indicate that this plant could constitute an attractive strategy for the management of depressive disorders, once more validating the traditional use of this plant.
Display omitted
The aim of this study was to develop a fast capillary electrophoresis method for the determination of propranolol in pharmaceutical preparations. In the method development the pH and constituents of ...the background electrolyte were selected using the effective mobility
versus pH curves. Benzylamine was used as the internal standard. The background electrolyte was composed of 60
mmol
L
−1 tris(hydroxymethyl)aminomethane and 30
mmol
L
−1 2-hydroxyisobutyric acid, at pH 8.1. Separation was conducted in a fused-silica capillary (32
cm total length and 8.5
cm effective length, 50
μm I.D.) with a short-end injection configuration and direct UV detection at 214
nm. The run time was only 14
s. Three different strategies were studied in order to develop a fast CE method with low total analysis time for propranolol analysis: low flush time (Lflush) 35
runs/h, without flush (Wflush) 52
runs/h, and Invert (switched polarity) 45
runs/h. Since the three strategies developed are statistically equivalent, Wflush was selected due to the higher analytical frequency in comparison with the other methods. A few figures of merit of the proposed method include: good linearity (
R
2
>
0.9999); limit of detection of 0.5
mg
L
−1; inter-day precision better than 1.03% (
n
=
9) and recovery in the range of 95.1–104.5%.
Bark infusion of Tabebuia avellanedae Lorentz ex Griseb is consumed in tropical America folk medicine for the treatment of several diseases, including depressive disorders. It was recently ...demonstrated that the extract from this plant has antidepressant properties. The present study was aimed at investigating the contribution of N-methyl-D-aspartate (NMDA) receptors and the L-arginine–nitric oxide (NO)–cyclic guanosine 3′5′-monophosphate (cGMP) pathway to the antidepressant-like action of the ethanolic extract from T. avellanedae (EET) in the tail suspension test (TST). The anti-immobility effect of the extract (30 mg/kg, orally p.o.) was prevented by pretreatment of mice with NMDA (0.1 pmol/site, intracerebroventicular i.c.v.), L-arginine (750 mg/kg, intraperitoneally i.p.), and sildenafil (5 mg/kg, i.p.). Additionally, the combination of MK-801 (0.01 mg/kg, p.o.), 7-nitroindazole (25 mg/kg, i.p.), and 1H-1,2,4oxadiazole4,3-aquinoxalin-1-one (ODQ) (30 pmol/site, i.c.v.) with a subeffective dose of EET (1 mg/kg, p.o.) produced a synergistic antidepressant-like effect in the TST, without causing significant alterations in the locomotor activity. Moreover, the administration of an effective dose of EET (30 mg/kg, p.o.) produced a reduction in NOx levels in the cerebral cortex. Conversely, a subeffective dose of EET (1 mg/kg, p.o.) caused no changes in the cortical NOx levels. Results suggest that the antidepressant-like effect of EET in the TST is dependent on a blockade of NMDA receptor activation and inhibition of NO-cGMP synthesis, significantly extending literature data about the antidepressant-like action of this plant and reinforcing the notion that this plant may be useful in the management of depressive disorders.
The study systematically investigated the nutritional potential of two different growing populations of Sarcocornia ambigua (salt-tolerant) in terms of nutrients, bioactive compounds, and antioxidant ...activities. The results revealed that the moisture content represented the largest single component (88.15% and 88.57%) in the proximate composition of both samples of S. ambigua. The mineral present in highest amounts in both samples (on a fresh matter basis) was sodium, followed by potassium, magnesium and then calcium. The antioxidant activity for samples measured by DPPH ranged from 34.64 to 135.83μmolTEAC100g−1 and by FRAP from 31.92 to 170.14μmolFe+2100g−1. The fifteen phenolic compounds identified in each extract by HPLC–ESI-MS/MS reveal the presence of one coumarin (scopoletin), one phenolic aldehyde (syringaldehyde), eight phenolic acids (p-coumaric, cinnamic, vanillic, ferulic, caffeic, syringic, sinapic, and chlorogenic acids) and five flavonoids (galangin, quercetin, naringin, kaempferol and isoquercitrin). This information can be useful in determining the possible role of the compounds identified which can participate in the prevention of different health disorders. Further studies are needed to evaluate the bioabsorption and bioavailability of the compounds present in S. ambigua, as well as the interactions between them, after consumption. In summary, the findings of this study highlight the potential of this halophyte as a valuable source of natural antioxidants and nutrients for use in the food and pharmaceutical industries.
•Sodium was the mineral which presented the highest amount in all samples.•HPLC–ESI-MS/MS was employed to detect and quantify phenolic compounds.•22 and 15 phenolic compounds were detected and quantified from extracts of S. ambigua. d) Ferulic and caffeic acids were the major phenolic compounds quantified.•The geographical location of growth, affects the phenolic compounds.
Summary
Cancer treatment is challenging, mainly due to high levels of drug toxicity and the resistance of tumours to chemotherapy. Hydroxamic acid derivatives have recently aroused attention due to ...their potential to treat malignancies. In the present study, we sought to investigate the anticancer effects of a new series of synthetic acetohydroxamates. The in vitro cytotoxic and antiproliferative effects of 11 synthetic acetohydroxamates were evaluated against the melanoma cell line A375. Apoptosis, cell cycle, and autophagy assays were employed to elucidate the cell death pathways induced by the compounds. The in vivo pharmacokinetic profiles of the most promising compounds were determined in CD-1 mice, while the in vivo antitumour efficacies were evaluated using the A375 melanoma xenograft model in nude mice. MTT assays revealed that all compounds presented concentration-dependent cytotoxicity against the A375 cell line. AKS 61 produced the most favourable antiproliferative activity according to the sulphorhodamine B and clonogenic assays. AKS 61 treatment resulted in decreased mitochondrial membrane potential and increased apoptosis and autophagy in the A375 cell line. However, AKS 61 failed to prevent in vivo tumour growth in a melanoma xenograft, whereas compound AKS 7 was able to inhibit tumour growth when administered orally. These in vivo findings may be explained by a more favourable pharmacokinetic profile presented by AKS 7 when compared to AKS 61. Taken together, these results suggest that acetohydroxamates have potential anticancer effects and will guide future optimisation of these molecules to allow for further non-clinical development.
The main objective of the present work was to validate a chromatographic method to determine herbicides commonly applied in the irrigated rice farming. For this, matrix-matched calibration was ...employed along with the extraction and clean-up of the samples by quick, easy, cheap, effective, rugged and safe (QuEChERS) method and determination of the analytes by high performance liquid chromatography tandem mass spectrometry (LC-MS/MS) with electrospray ionization in the positive mode. By this method, it was possible to achieve the ionization and detection of a total of 18 herbicides, with quantification of 12 of them. The method presented adequate precision and accuracy according to the European Commission and the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines for analytes in low concentrations. The limits of quantification ranged from 0.015 μg g-1 for oxadiazon to 0.165 μg g-1 for imazapyr. The method showed good linearity with R2> 0.99 and recovery values from 92 to 103%. The proposed protocol is adequate for monitoring bispyribac-sodium, cyclosulfamuron, cycloxydim, clomazone, ethoxysulfuron, fenoxaprop-p-ethyl, imazapic, imazapyr, imazethapyr, metsulfuron-methyl, oxadiazon and thiobencarb in rice grains in concentrations up to 109 times lower than the maximum residue limits established by the Brazilian Health Surveillance Agency (ANVISA) for these compounds in rice samples.
The present study aimed to develop a methodology using capillary electrophoresis for the determination of sinapaldehyde, syringaldehyde, coniferaldehyde, and vanillin in whiskey samples. The main ...objective was to obtain a screening method to differentiate authentic samples from seized samples suspected of being false using the phenolic aldehydes as chemical markers. The optimized background electrolyte was composed of 20 mmol L–1 sodium tetraborate with 10% MeOH at pH 9.3. The study examined two kinds of sample stacking, using a long-end injection mode: normal sample stacking (NSM) and sample stacking with matrix removal (SWMR). In SWMR, the optimized injection time of the samples was 42 s (SWMR42); at this time, no matrix effects were observed. Values of r were >0.99 for the both methods. The LOD and LOQ were better than 100 and 330 mg mL–1 for NSM and better than 22 and 73 mg L–1 for SWMR. The CE-UV reliability in the aldehyde analysis in the real sample was compared statistically with LC-MS/MS methodology, and no significant differences were found, with a 95% confidence interval between the methodologies.
This article reports a study on the antioxidant activity of juçara (Euterpe edulis M.) (defatted pulp and oil) and the cytoprotective effect in terms of oxidative damage induced by tert-butyl ...hydroperoxide (TBH) in a Vero cell culture. Simultaneously, HPLC–ESI-MS/MS was used to determine the phenolic composition of defatted pulp juçara extracts. The defatted pulp extract exhibited stronger free radical scavenging ability in 1,1-diphenyl-2-picrylhydrazyl (DPPH), ion ferric (FRAP) and β-carotene systems than the lipid extract. The predominance of phenolic acids (benzoic, caffeic, chlorogenic, ferulic, protocatechuic, syringic, vanillic and ρ-coumaric) and flavonols (quercetin and rutin) was observed in the extracts by direct infusion–ESI-MS/MS in negative ion mode. Juçara extracts (1.5, 4.5, 9μgmL−1) had a significant protective effect against TBH-induced oxidative stress in Vero cells compared to the gallic acid control. These results provide novel information on the juçara fruit (E. edulis M.) regarding the relation between the phenolic compound composition and antioxidant and cytoprotective effects.
► The lipid fraction of juçara presented the highest phenolic content. ► Juçara fruit showed in vitro and in vivo antioxidant activity. ► Fruits of juçara are composed of phenolic acids, flavonols and anthocyanins. ► HPLC-ESI-MS/MS identified the chlorogenic, ferulic, rutin and quercetin. ► Juçara have a protective effect against TBH-induced oxidative stress in Vero cells.
A biosensor based on the ionic liquid, 1-
n-butyl-3-methylimidazolium hexafluorophosphate containing dispersed iridium nanoparticles (Ir-BMI.PF
6) and polyphenol oxidase was constructed. This enzyme ...was obtained from the sugar apple (
Annona squamosa), immobilized in chitosan ionically crosslinked with oxalate. The biosensor was used for determination of chlorogenic acid by square wave voltammetry. The polyphenol oxidase catalyzes the oxidation of chlorogenic acid to the corresponding
o-quinone, which is electrochemically reduced back to this substance at +0.25
V
vs. Ag/AgCl. Under optimized operational conditions the chlorogenic acid concentration was linear in the range of 3.48
×
10
−6 to 4.95
×
10
−5
mol
L
−1 with a detection limit of 9.15
×
10
−7
mol
L
−1. The biosensor was applied in the determination of chlorogenic acid in organic and decaffeinated coffee and the results compared with those obtained using the capillary electrophoresis method. The recovery study for chlorogenic acid in these samples gave values of 93.2–105.7%.
PDF
