This study aimed to identify potential inhibitors and investigate the mechanism of action on SARS-CoV-2 ACE2 receptors using a molecular modeling study and theoretical determination of biological ...activity. Hydroxychloroquine was used as a pivot structure and antimalarial analogues of 1,2,4,5 tetraoxanes were used for the construction and evaluation of pharmacophoric models. The pharmacophore-based virtual screening was performed on the Molport
database (~7.9 million compounds) and obtained 313 structures. Additionally, a pharmacokinetic study was developed, obtaining 174 structures with 99% confidence for human intestinal absorption and penetration into the blood-brain barrier (BBB); posteriorly, a study of toxicological properties was realized. Toxicological predictions showed that the selected molecules do not present a risk of hepatotoxicity, carcinogenicity, mutagenicity, and skin irritation. Only 54 structures were selected for molecular docking studies, and five structures showed binding affinity (ΔG) values satisfactory for ACE2 receptors (PDB 6M0J), in which the molecule MolPort-007-913-111 had the best ΔG value of -8.540 Kcal/mol, followed by MolPort-002-693-933 with ΔG = -8.440 Kcal/mol. Theoretical determination of biological activity was realized for 54 structures, and five molecules showed potential protease inhibitors. Additionally, we investigated the Mpro receptor (6M0K) for the five structures via molecular docking, and we confirmed the possible interaction with the target. In parallel, we selected the TopsHits 9 with antiviral potential that evaluated synthetic accessibility for future synthesis studies and in vivo and in vitro tests.
This study investigated the potential of selected compounds as inhibitors of SARS-CoV-2 Mpro through pharmacokinetic and toxicological analyses, molecular docking, and molecular dynamics simulations. ...In silico molecular docking simulations revealed promising ligands with favorable binding affinities for Mpro, ranging from −6.2 to −9.5 kcal/mol. Moreover, molecular dynamics simulations demonstrated the stability of protein–ligand complexes over 200 ns, maintaining protein secondary structures. MM-PBSA analysis revealed favorable interactions between ligands and Mpro, with negative binding energy values. Hydrogen bond formation capacity during molecular dynamics was confirmed, indicating consistent interactions with Mpro catalytic residues. Based on these findings, selected ligands show promise for future studies in developing COVID-19 treatments.
We encapsulated MSZ in zein nanoparticles (NP-ZN) using a desolvation method followed by drying in a mini spray dryer. These nanoparticles exhibited a size of 266.6 ± 52 nm, IPD of 0.14 ± 1.1 and ...zeta potential of -36.4 ± 1.5 mV, suggesting colloidal stability. Quantification using HPLC showed a drug-loaded of 43.8 µg/mg. SEM demonstrated a spherical morphology with a size variation from 220 to 400 nm. A FTIR analysis did not show drug spectra in the NPs in relation to the physical mixture, which suggests drug encapsulation without changing its chemical structure. A TGA analysis showed thermal stability up to 300 °C. In vitro release studies demonstrated gastroresistance and a sustained drug release at pH 7.4 (97.67 ± 0.32%) in 120 h. The kinetic model used for the release of MSZ from the NP-ZN in a pH 1.2 medium was the Fickian diffusion, in a pH 6.8 medium it was the Peppas-Sahlin model with the polymeric relaxation mechanism and in a pH 7.4 medium it was the Korsmeyer-Peppas model with the Fickian release mechanism, or "Case I". An in vitro cytotoxicity study in the CT26.WT cell line showed no basal cytotoxicity up to 500 μg/mL. The NP-ZN showed to be a promising vector for the sustained release of MSZ in the colon by oral route.
Tul. var.
Teles Freire (Leguminosae-Caesalpinioideae) is a medicinal plant traditionally used for treatment of gastric ulcer. This study evaluated the ulcer-healing activity of the hydroalcoholic ...fraction of
Tul. var.
Teles Freire leaves (
-FHA) and the tea of the leaves of
(
-tea), as well as the possible action of
-FHA, through
models. Leaves of
were dried and powdered to obtain the
-FHA. Subsequently, the
-FHA was characterized phytochemically and biologically. Besides,
-tea was prepared. The gastric healing effects of
-tea and
-FHA were analyzed using the model of acetic acid-induced gastric ulcer in rats. The human gastric adenocarcinoma (AGS) cell line was employed as an
model.
-tea promoted a protective effect against gastric ulcers induced by absolute ethanol.
-FHA or
-tea (100 mg/kg/7 days) exhibited a significant healing effect on ulcers induced by acetic acid. In the histological analysis, gastric mucosa treated with
-FHA or
-tea advanced restoration of the mucosal epithelium.
, lower concentrations of
-FHA stimulated cell proliferation in the BrdU assay and cell migration.
-tea and
-FHA present a significant gastric healing effect in
and
models.
Bufadienolides are the main active compounds in the Bufonidae family of frogs. Recent studies have demonstrated cytotoxic and/or antitumor activity in these molecules. A HPLC-DAD method was developed ...and validated to quantify three bufadienolides (telocinobufagin, marinobufagin and bufalin) in ethyl acetate extracts of the cane toad poison frogs and smooth-sided toad. The chromatographic analysis was performed on Phenomenex Luna C18 (250.0 × 4.6 mm, 5 μm), using gradient elution with acetonitrile and water, at a flow rate of 1.0 mL min−1 and detection at 296 nm. The method showed linearity (r > 0.999) and adequate recovery values (86%–111%). The limits of quantification of bufadienolides were 7.4 μg mL−1 for telocinobufagin, 4.2 μg mL−1 for marinobufagin and 4.0 μg mL−1 for bufalin. Intraday and interday values of the method were evaluated and presented standard deviation values lower than 5%. The method was successfully applied to quantify the bufadienolides in the venom extract of the cane toad, which showed a content of 60% of marinobufagin. The same method was not selective for the venom extract of the Rhaebo guttatus, despite being linear, accurate and precise, requiring the development of a technique that presents a greater selectivity.
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•A method by HPLC-UV was validated to quantify three bufadienolides in toad venom.•The venom from Rhinella marina presented high percentage of marinobufagin (60%).•The same method was not selective for the venom extract of the Rhaebo guttatus, despite being linear, accurate and precise.
In the search of hepatoprotective agents from natural sources, α- and β-amyrin, a triterpene mixture isolated from the trunk wood resin of folk medicinal plant,
Protium heptaphyllum was tested ...against acetaminophen-induced liver injury in mice. Liver injury was analysed by quantifying the serum enzyme activities and by histopathological observations. In mice, acetaminophen (500
mg/kg, p.o.) caused fulminant liver damage characterized by centrilobular necrosis with inflammatory cell infiltration, an increase in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, a decrease in hepatic glutathione (GSH) and 50% mortality. Pretreatment with α- and β-amyrin (50 and 100
mg/kg, i.p. at 48, 24, and 2
h before acetaminophen) attenuated the acetaminophen-induced acute increase in serum ALT and AST activities, replenished the depleted hepatic GSH, and considerably reduced the histopathological alterations in a manner similar to
N-acetylcysteine, a sulfhydryls donor. Also, the acetaminophen-associated mortality was completely suppressed by terpenoid pretreatment. Further, α- and β-amyrin could potentiate the pentobarbital (50
mg/kg, i.p.) sleeping time, suggesting the possible suppression of liver cytochrome-P450. These findings indicate the hepatoprotective potential of α- and β-amyrin against toxic liver injury and suggest that the diminution in oxidative stress and toxic metabolite formation as likely mechanisms involved in its hepatoprotection. In conclusion, this study supports the traditional use of
Protium heptaphyllum resin as a medicinal agent and suggests the feasibility of developing herbal drugs for treatment of liver disorders.
The present work reports the anti-inflammatory and antinociceptive activities of the ethanol extract obtained from the stem bark of Sterculia striata A. St.-Hil. & Naudin (Ss-EtOH) in the ...experimental models of edema induced by carrageenan, dextran, or histamin and nociception induced by chemical stimuli, such as acetic acid, formalin, capsaicin, or glutamate. The Ss-EtOH (50 mg/kg) promoted a marked inhibition on the hind paw edema induced by carrageenan or dextran (30% and 73%, respectively). Besides, Ss-EtOH (25 mg/kg) exhibited a slight activity (30%) on the hind paw edema induced by histamin. The Ss-EtOH (12.5 and 25 mg/kg) showed the antinociceptive activity on chemical stimuli induced by acetic acid (65.59% and 38.37%, respectively), formalin, in the initial (35.08% and 31.5%, respectively) and late phases (44.09% and 83.57%, respectively), capsaicin (43.77% and 51.31%, respectively), or glutamate (36.6% and 52.12%, respectively). Regarding the possible mechanism involved in the antinociceptive effect, Ss-EtOH (12.5 mg/kg) showed a decrease in the antinociceptive effect (65.8%) in the acetic acid model after pretreatment with naloxone. Thus, opioid mechanisms might be underlying this response.
Objective
To evaluate the anti-inflammatory effect of α,β-amyrin, a pentacyclic triterpenoid from
Protium heptaphyllum
, on cerulein-induced acute pancreatitis in mice.
Methods
Acute pancreatitis was ...induced in Swiss mice by five intraperitoneal injections of cerulein (50 μg/kg), at 1 h intervals. Mice received α,β-amyrin (10, 30 and 100 mg/kg), thalidomide (200 mg/kg), or vehicle (3% Tween 80) orally 1 h before and 12 h after the cerulein challenge. The severity of pancreatitis was evaluated 24 h after cerulein by assessing serum pro-inflammatory cytokines and amylase activity, pancreatic myeloperoxidase (MPO), and thiobarbituric acid-reactive substances (TBARS), as well as by histology.
Results
α,β-Amyrin and thalidomide significantly attenuated the cerulein-induced increase in tumor necrosis factor (TNF)-α, interleukin-6, lipase, amylase, MPO, and TBARS. Moreover, α,β-amyrin greatly suppressed the pancreatic edema, inflammatory cell infiltration, acinar cell necrosis, and expressions of TNFα and inducible nitric oxide synthase.
Conclusions
α,β-Amyrin ameliorates cerulein-induced acute pancreatitis by acting as an anti-inflammatory and antioxidant agent.
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