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1.
J Mol Cell Cardiol ; 193: 11-24, 2024 May 24.
Artículo en Inglés | MEDLINE | ID: mdl-38797242

RESUMEN

Atrial fibrillation (AF) is the most common cardiac rhythm disorder, often occurring in the setting of atrial distension and elevated myocardialstretch. While various mechano-electrochemical signal transduction pathways have been linked to AF development and progression, the underlying molecular mechanisms remain poorly understood, hampering AF therapies. In this review, we describe different aspects of stretch-induced electro-anatomical remodeling as seen in animal models and in patients with AF. Specifically, we focus on cellular and molecular mechanisms that are responsible for mechano-electrochemical signal transduction and the development of ectopic beats triggering AF from pulmonary veins, the most common source of paroxysmal AF. Furthermore, we describe structural changes caused by stretch occurring before and shortly after the onset of AF as well as during AF progression, contributing to longstanding forms of AF. We also propose mechanical stretch as a new dimension to the concept "AF begets AF", in addition to underlying diseases. Finally, we discuss the mechanisms of these electro-anatomical alterations in a search for potential therapeutic strategies and the development of novel antiarrhythmic drugs targeted at the components of mechano-electrochemical signal transduction not only in cardiac myocytes, but also in cardiac non-myocyte cells.

2.
Lipids Health Dis ; 22(1): 107, 2023 Jul 26.
Artículo en Inglés | MEDLINE | ID: mdl-37495992

RESUMEN

BACKGROUND: Thermoxidation of edible oil through deep fat frying results in the generation of several oxidized products that promote lipid peroxidation and ROS production when eaten. Consumption of thermoxidized oil in post-menopausal conditions where the estrogen level is low contributes to cardiovascular disease. This study evaluates the role of estradiol and antihyperlipidemic agents (AHD) in restoring the vascular health of ovariectomized (OVX) rats fed with thermoxidized palm oil (TPO) and thermoxidized soya oil (TSO) diets. METHOD: A total of 10 groups of rats (n = 6) were set up for the experiment. Group I (normal control) rats were sham handled while other groups were OVX to bring about estrogen deficient post-menopausal state. Group II (OVX only) was not treated and received normal rat chow. Groups III-X were fed with either TPO or TSO diet for 12 weeks and treated with estradiol (ETD) 0.2 mg/kg/day, atorvastatin (ATV) 10 mg/kg/day, and a fixed-dose combination of ezetimibe and ATV (EZE 3 mg/kg/day + ATV 10 mg/kg/day). RESULTS: Pro-atherogenic lipids levels were significantly elevated in untreated TSO and TPO groups compared to OVX and sham, resulting in increased atherogenic and Coronary-risk indices. Treatment with Estradiol and AHDs significantly reduced the total cholesterol, triglycerides, low-density lipoprotein cholesterol as well as AI and CRI compared to untreated TSO and TPO groups, whereas TSO and TPO groups showed significant elevation in these parameters compared to Group I values. Moreover, aortic TNF-α levels were extremely elevated in the untreated TSO and TPO compared to Group I. TNF-α levels were significantly reduced in rats treated with AHDs and ETD. Localized oxidative stress was indicated in the aortic tissues of TSO and TPO-fed OVX rats by increased malondialdehyde and decreased glutathione, catalase, and superoxide dismutase levels. This contributed to a depletion in aortic nitric oxide. AHDs and ETD replenished the nitric oxide levels significantly. Histological evaluation of the aorta of TSO and TPO rats revealed increased peri-adventitia fat, aortic medial hypertrophy, and aortic recanalization. These pathologic changes were less seen in AHDs and ETD rats. CONCLUSION: This study suggests that ETD and AHDs profoundly attenuate oxidized lipid-induced vascular inflammation and atherogenesis through oxidative-stress reduction and inhibition of TNF-α signaling.


Asunto(s)
Aterosclerosis , Estradiol , Ratas , Animales , Femenino , Humanos , Estradiol/farmacología , Óxido Nítrico , Posmenopausia , Factor de Necrosis Tumoral alfa , Lípidos , Hipolipemiantes/farmacología , Hipolipemiantes/uso terapéutico , Dieta , Atorvastatina , Colesterol , Estrógenos , Aterosclerosis/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Ovariectomía
3.
Mol Divers ; 2023 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-37338673

RESUMEN

Neurodegenerative disorders (NDDs) are associated with increased activities of the brain acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and ß-secretase enzyme (BACE1). Inhibition of these enzymes affords therapeutic option for managing NDDs such as Alzheimer's disease (AD) and Parkinson's disease (PD). Although, Gongronema latifolium Benth (GL) has been widely documented in ethnopharmacological and scientific reports for the management of NDDs, there is paucity of information on its underlying mechanism and neurotherapeutic constituents. Herein, 152 previously reported Gongronema latifolium derived-phytochemicals (GLDP) were screened against hAChE, hBChE and hBACE-1 using molecular docking, molecular dynamics (MD) simulations, free energy of binding calculations and cluster analysis. The result of the computational analysis identified silymarin, alpha-amyrin and teraxeron with the highest binding energies (-12.3, -11.2, -10.5 Kcal/mol) for hAChE, hBChE and hBACE-1 respectively as compared with those of the reference inhibitors (-12.3, -9.8 and - 9.4 for donepezil, propidium and aminoquinoline compound respectively). These best docked phytochemicals were found to be orientated in the hydrophobic gorge where they interacted with the choline-binding pocket in the A-site and P-site of the cholinesterase and subsites S1, S3, S3' and flip (67-75) residues of the pocket of the BACE-1. The best docked phytochemicals complexed with the target proteins were stable in a 100 ns molecular dynamic simulation. The interactions with the catalytic residues were preserved during the simulation as observed from the MMGBSA decomposition and cluster analyses. The presence of these phytocompounds most notably silymarin, which demonstrated dual high binding tendencies to both cholinesterases, were identified as potential neurotherapeutics subject to further investigation.

4.
J Biomol Struct Dyn ; 41(11): 5022-5044, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-35635123

RESUMEN

The inhibition of capping enzymes such as guanine-N7-methyltransferase (GMT) is an attractive target for regulating viral replication, transcription, virulence, and pathogenesis. Thus, compounds that target the Severe Acute Respiratory Syndrome Corona Virus 2 GMT (S2GMT) will enhance drug development against COVID-19. In this study, an in-house library of 249 phytochemicals from African medicinal plants was screened using computational approaches including homology modeling, molecular docking, molecular dynamic simulations, binding free energy calculations based on molecular mechanics/Poisson-Boltzmann surface area (MMPBSA) and Absorption-Distribution-Metabolism-Excretion-Toxicity (ADMET) analysis for inhibitors of S2GMT. The top-ten ranked phytochemicals (TTRP) obtained from the docking analysis to S2GMT were further docked to SARS-COV N7-MTase. Among the TTRP, the top-four ranked phytocompounds (TFRP) viz: 3 alkaloids (Isocryptolepine, 10'-Hydroxyusambarensine and Isostrychnopentamine) and a flavonoid (Mulberrofuran F) interacted strongly with critical catalytic residues whose interference either reduce or completely abolish N7-MTase activity, indicating their potential as capping machinery disruptors. The interactions of TFRP with the catalytic residues of S2GMT were preserved in a 100 ns simulated dynamic environment, thereby, demonstrating high degree of structural stability. The MMPBSA binding free energy calculations corroborated the docking scores with biscryptolepine having the highest binding free energy to S2GMT. The TFRP showed favourable drug-likeness and ADMET properties over a wide range of molecular descriptors. Therefore, the TFRP can be further explored as potential S2GMT inhibitors in in vitro and in vivo experiments.Communicated by Ramaswamy H. Sarma.


Asunto(s)
Antimaláricos , COVID-19 , Antagonistas del Ácido Fólico , Humanos , SARS-CoV-2 , Metiltransferasas , Simulación del Acoplamiento Molecular , Fitoquímicos
5.
Niger J Physiol Sci ; 38(1): 37-46, 2023 Jun 30.
Artículo en Inglés | MEDLINE | ID: mdl-38243349

RESUMEN

Glucocorticoids have therapeutic benefits in the management of several inflammatory and immunological disorders. Despite these medicinal effects, they have the drawback of causing metabolic disorders such as hyperglycemia, insulin resistance etc., which is known to be a key indicator of metabolic syndrome. Metabolic syndrome is a major predisposing factor to type 2 diabetes mellitus and cardiomyopathy. This study was designed to compare and evaluate the effects of saxagliptin, metformin and intranasal insulin (when used singly or in combination) on dexamethasone induced insulin resistance. Fifty-six female rats were randomly assigned into eight groups. Group 1 represented the control; Group 2 was administered with dexamethasone (1mg/kg) (untreated); Group 3 received dexamethasone + intranasal insulin (2IU); Group 4 received dexamethasone + intranasal insulin + metformin (40mg/kg); Group 5; received dexamethasone + intranasal + saxagliptin (8mg/kg); Group 6 received dexamethasone + metformin (40mg/kg); Group 7 received dexamethasone + saxagliptin (8mg/kg); Group 8 received dexamethasone + saxagliptin(8mg/kg) + metformin(40mg/kg). Treatments were given for one week. At the end of the study, blood samples were collected for biochemical assays and pancreas excised for histological examination. Dexamethasone (1mg/kg) induced hyperglycemia, hyperinsulinemia, dyslipidemia, impaired glucose tolerance and disrupted the structural integrity of the pancreas. Treatment with saxagliptin, metformin and their combination significantly decreased blood glucose level, decreased LDL Level and improved glucose tolerance. The selected hypoglycemic agents used in present study ameliorate the dexamethasone induced hyperglycemia and insulin resistance of which the combination of metformin with saxagliptin showed greater efficacy.


Asunto(s)
Adamantano/análogos & derivados , Diabetes Mellitus Tipo 2 , Dipéptidos , Hiperglucemia , Resistencia a la Insulina , Síndrome Metabólico , Metformina , Femenino , Ratas , Animales , Metformina/farmacología , Insulina , Ratas Wistar , Glucemia/metabolismo , Hipoglucemiantes/farmacología , Hiperglucemia/tratamiento farmacológico , Dexametasona , Quimioterapia Combinada
6.
J Mol Struct ; 1262: 133019, 2022 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-35431328

RESUMEN

Despite the ongoing vaccination against the life-threatening COVID-19, there is need for viable therapeutic interventions. The S-adenosyl-l-Methionine (SAM) dependent 2-O'-ribose methyltransferase (2'-O-MTase) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents a therapeutic target against COVID-19 infection. In a bid to profile bioactive principles from natural sources, a custom-made library of 226 phytochemicals from African medicinal plants with especially anti-malarial activity was screened for direct interactions with SARS-CoV-2 2'-O-MTase (S2RMT) using molecular docking and molecular dynamics (MD) simulations as well as binding free energies methods. Based on minimal binding energy lower than sinefungin (a reference methyl-transferase inhibitor) and binding mode analysis at the catalytic site of S2RMT, a list of 26 hit phytocompounds was defined. The interaction of these phytocompounds was compared with the 2'-O-MTase of SARS-CoV and MERS-CoV. Among these compounds, the lead phytocompounds (LPs) viz: mulberrofuran F, 24-methylene cycloartenol, ferulate, 3-benzoylhosloppone and 10-hydroxyusambarensine interacted strongly with the conserved KDKE tetrad within the substrate binding pocket of the 2'-O-MTase of the coronavirus strains which is critical for substrate binding. The thermodynamic parameters analyzed from the MD simulation trajectories of the LPs-S2RMT complexes presented an eminent structural stability and compactness. These LPs demonstrated favorable druggability and in silico ADMET properties over a diverse array of molecular computing descriptors. The LPs show promising prospects in the disruption of S2RMT capping machinery in silico. However, these LPs should be validated via in vitro and in vivo experimental models.

7.
J Biomol Struct Dyn ; 40(5): 2121-2145, 2022 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33089728

RESUMEN

COVID-19 is a respiratory disease caused by SARS-CoV-2, an enveloped positive sense RNA virus. The SARS-CoV-2 spike glycoprotein, human angiotensin-converting enzyme 2 (ACE2) and human transmembrane protease serine 2 (TMPRSS2) are essential for the host cell-mediated viral entry. Targeting these proteins represent viable options to stop the first stage of infection and transmission. Hence, 97 alkaloids from African medicinal plants with reported antiviral activity were evaluated for this purpose via in silico studies. These alkaloids were docked for their interactions with SARS-CoV-2 spike glycoprotein, ACE2, and TMPRSS2. Top 20 alkaloids with highest binding affinities were further screened for their interactions with spike glycoprotein of SARS-CoV and MERS-CoV, and with ACE2-SARS-CoV-2 receptor-binding domain complex (ACE2-RBD). The energy profiling, molecular dynamics simulation (MDS), binding free energy base on Molecular Mechanics/Generalized Born Surface Area (MMGBSA), clustering of MDS trajectories, and virtual physicochemical and pharmacokinetic screening of the best docked alkaloids were performed. Results revealed that more than 15 alkaloids interacted better than the reference compounds. 10-Hydroxyusambarensine and Cryptospirolepine were docked in a similar binding pattern to the S1-specificy pocket of TMPRSS2 as camostat (reference inhibitor). The strong binding affinities, stability of the alkaloid-protein complexes and amino acid interactions displayed by cryptospirolepine, 10-hydroxyusambarensine, and cryptoquindoline with important binding hotspots of the proteins suggest these alkaloids have the potential of altering the capacity of SARS-CoV-2 membrane mediated host cell entry. Further in vitro and in vivo evaluation of these "drug-like" alkaloids as potential inhibitors of coronavirus cell entry is proposed.Communicated by Ramaswamy H. Sarma.


Asunto(s)
Alcaloides , Tratamiento Farmacológico de COVID-19 , Preparaciones Farmacéuticas , Alcaloides/farmacología , Enzima Convertidora de Angiotensina 2 , Glicoproteínas/metabolismo , Humanos , Unión Proteica , SARS-CoV-2 , Serina Endopeptidasas/metabolismo , Internalización del Virus
8.
Int J Reprod Med ; 2021: 9693171, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34938803

RESUMEN

OBJECTIVE: To evaluate the effect of the chronic use of combined oral contraceptives (COCs: ethinyl estradiol and levonorgestrel) on the indices of metabolic syndrome in adult female Wistar rats and possible therapeutic management. MATERIALS AND METHODS: 64 female Wistar rats received either distilled water, norethindrone (NOR), COC, intranasal insulin (INI), metformin (MET), saxagliptin (SAX), INI+MET, and INI+SAX. After 8 weeks of exposure to COC, the animals were sorted into the therapeutic groups. Several parameters were assayed for, such as body weight changes, fasting blood glucose (FBG) level, insulin levels, inflammatory cytokines, and glycated hemoglobin (Hb1Ac). RESULTS: The levels of FBG, insulin, and Hb1Ac were increased consequent upon COC treatment. Treatment with INI+SAX and INI+MET reduced significantly the levels of FBG and Hb1Ac; in addition, the level of insulin was significantly increased in the INI+MET groups (p ≤ 0.05). Serum lipid profile analysis showed a statistical reduction in high-density lipoprotein (HDL) level; this reduction was also significantly reversed in the INI+SAX group. Reduced catalase activity observed in the COC group was reversed in the INI+MET group (p ≤ 0.05). A nonsignificant increase in the level of TNF-α as a result of COC treatment was reversed by INI and INI+MET treatment. Liver GLUT4 and G-6-phosphate levels were significantly increased by COC treatment, and this effect was reversed by INI+SAX in both assays, respectively (p ≤ 0.01). CONCLUSIONS: The use of MET and SAX in combination with INI has been shown to reverse some indices of MetS. This study proposes a clinical phase to backup and ascertain these preclinical findings.

9.
J Genet Eng Biotechnol ; 19(1): 113, 2021 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-34351542

RESUMEN

BACKGROUND: Targeting viral cell entry proteins is an emerging therapeutic strategy for inhibiting the first stage of SARS-CoV-2 infection. In this study, 106 bioactive terpenoids from African medicinal plants were screened through molecular docking analysis against human angiotensin-converting enzyme 2 (hACE2), human transmembrane protease serine 2 (TMPRSS2), and the spike (S) proteins of SARS-CoV-2, SARS-CoV, and MERS-CoV. In silico absorption-distribution-metabolism-excretion-toxicity (ADMET) and drug-likeness prediction, molecular dynamics (MD) simulation, binding free energy calculations, and clustering analysis of MD simulation trajectories were performed on the top docked terpenoids to respective protein targets. RESULTS: The results revealed eight terpenoids with high binding tendencies to the catalytic residues of different targets. Two pentacyclic terpenoids (24-methylene cycloartenol and isoiguesteri) interacted with the hACE2 binding hotspots for the SARS-CoV-2 spike protein, while the abietane diterpenes were found accommodated within the S1-specificity pocket, interacting strongly with the active site residues TMPRSS2. 3-benzoylhosloppone and cucurbitacin interacted with the RBD and S2 subunit of SARS-CoV-2 spike protein respectively. These interactions were preserved in a simulated dynamic environment, thereby, demonstrating high structural stability. The MM-GBSA binding free energy calculations corroborated the docking interactions. The top docked terpenoids showed favorable drug-likeness and ADMET properties over a wide range of molecular descriptors. CONCLUSION: The identified terpenoids from this study provides core structure that can be exploited for further lead optimization to design drugs against SARS-CoV-2 cell-mediated entry proteins. They are therefore recommended for further in vitro and in vivo studies towards developing entry inhibitors against the ongoing COVID-19 pandemic.

10.
Heliyon ; 7(6): e07363, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-34222697

RESUMEN

BACKGROUND: Parquetina nigrescens is among the evergreen plants native to West Africa. It is used in the management of various ailments including anemia, fever, asthma and diabetes. This study evaluated the antidiabetic and antihyperlipidemic effect of Parquetina nigrescens in streptozotocin-nicotinamide-induced type 2 diabetic rats. METHODS: Type 2 diabetes mellitus was induced in overnight fasted rats with a single intraperitoneal injection of streptozotocin (60 mg/kg), followed by the administration of nicotinamide (120 mg/kg) after an interval of 15 min. Diabetic rats were orally administered with; 200, 400 and 800 mg/kg of aqueous extract of Parquetina nigrescens (AEPN), metformin (180 mg/kg) and glibenclamide (1 mg/kg) for two weeks. The effect of treatments on fasting blood glucose, serum insulin, leptin, adiponectin, homa-ir, lipid profile, body weight, pancreatic antioxidants parameters, hepatic glycogen content, glucose-6-phosphate activity, α-amylase inhibition, α-glucosidase inhibition, lipase inhibition and histology of the organs were evaluated. RESULTS: Data from this study showed that treatment with AEPN produced a significant reduction (p < 0.05) in fasting blood glucose, glucose-6-phosphatase activity, serum lipase, total triglyceride, total cholesterol, low-density lipoproteins, very low-density lipoprotein, atherogenic index, coronary risk index, pancreatic α-amylase, α-glucosidase and lipase activities. Treatment with AEPN also produced a significant (p < 0.05) increase in; glucose tolerance, glycogen content, leptin, adiponectin and pancreatic antioxidants (glutathione, superoxide dismutase, catalase and high-density lipoproteins). The histology of the organ showed regeneration of the pancreatic tissue after treatment with AEPN. CONCLUSIONS: This study showed that AEPN exhibited antidiabetic and antihyperlipidemic activity in streptozotocin-nicotinamide-induced type 2 diabetic rats.

11.
Comput Biol Med ; 134: 104406, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33915479

RESUMEN

The high morbidity and mortality rate of Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) infection arises majorly from the Acute Respiratory Distress Syndrome and "cytokine storm" syndrome, which is sustained by an aberrant systemic inflammatory response and elevated pro-inflammatory cytokines. Thus, phytocompounds with broad-spectrum anti-inflammatory activity that target multiple SARS-CoV-2 proteins will enhance the development of effective drugs against the disease. In this study, an in-house library of 117 steroidal plant-derived pregnanes (PDPs) was docked in the active regions of human glucocorticoid receptors (hGRs) in a comparative molecular docking analysis. Based on the minimal binding energy and a comparative dexamethasone binding mode analysis, a list of top twenty ranked PDPs docked in the agonist conformation of hGR, with binding energies ranging between -9.8 and -11.2 kcal/mol, was obtained and analyzed for possible interactions with the human Janus kinases 1 and Interleukins-6 and SARS-CoV-2 3-chymotrypsin-like protease, Papain-like protease and RNA-dependent RNA polymerase. For each target protein, the top three ranked PDPs were selected. Eight PDPs (bregenin, hirundigenin, anhydroholantogenin, atratogenin A, atratogenin B, glaucogenin A, glaucogenin C and glaucogenin D) with high binding tendencies to the catalytic residues of multiple targets were identified. A high degree of structural stability was observed from the 100 ns molecular dynamics simulation analyses of glaucogenin C and hirundigenin complexes of hGR. The selected top-eight ranked PDPs demonstrated high druggable potentials and favourable in silico ADMET properties. Thus, the therapeutic potentials of glaucogenin C and hirundigenin can be explored for further in vitro and in vivo studies.


Asunto(s)
COVID-19 , Fitosteroles , Síndrome de Liberación de Citoquinas , Humanos , Simulación del Acoplamiento Molecular , Pregnanos , SARS-CoV-2 , Replicación Viral
12.
J Biomol Struct Dyn ; 39(9): 3396-3408, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32367767

RESUMEN

The novel coronavirus disease 2019 (COVID-19) caused by SARS-COV-2 has raised myriad of global concerns. There is currently no FDA approved antiviral strategy to alleviate the disease burden. The conserved 3-chymotrypsin-like protease (3CLpro), which controls coronavirus replication is a promising drug target for combating the coronavirus infection. This study screens some African plants derived alkaloids and terpenoids as potential inhibitors of coronavirus 3CLpro using in silico approach. Bioactive alkaloids (62) and terpenoids (100) of plants native to Africa were docked to the 3CLpro of the novel SARS-CoV-2. The top twenty alkaloids and terpenoids with high binding affinities to the SARS-CoV-2 3CLpro were further docked to the 3CLpro of SARS-CoV and MERS-CoV. The docking scores were compared with 3CLpro-referenced inhibitors (Lopinavir and Ritonavir). The top docked compounds were further subjected to ADEM/Tox and Lipinski filtering analyses for drug-likeness prediction analysis. This ligand-protein interaction study revealed that more than half of the top twenty alkaloids and terpenoids interacted favourably with the coronaviruses 3CLpro, and had binding affinities that surpassed that of lopinavir and ritonavir. Also, a highly defined hit-list of seven compounds (10-Hydroxyusambarensine, Cryptoquindoline, 6-Oxoisoiguesterin, 22-Hydroxyhopan-3-one, Cryptospirolepine, Isoiguesterin and 20-Epibryonolic acid) were identified. Furthermore, four non-toxic, druggable plant derived alkaloids (10-Hydroxyusambarensine, and Cryptoquindoline) and terpenoids (6-Oxoisoiguesterin and 22-Hydroxyhopan-3-one), that bind to the receptor-binding site and catalytic dyad of SARS-CoV-2 3CLpro were identified from the predictive ADME/tox and Lipinski filter analysis. However, further experimental analyses are required for developing these possible leads into natural anti-COVID-19 therapeutic agents for combating the pandemic.Communicated by Ramaswamy H. Sarma.


Asunto(s)
Alcaloides , COVID-19 , Plantas Medicinales , Alcaloides/farmacología , Quimasas , Simulación por Computador , Humanos , Inhibidores de Proteasas , SARS-CoV-2 , Terpenos
13.
Antivir Chem Chemother ; 28: 2040206620984076, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33372806

RESUMEN

Corona Virus Disease 2019 (COVID-19) is a pandemic caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Exploiting the potentials of phytocompounds is an integral component of the international response to this pandemic. In this study, a virtual screening through molecular docking analysis was used to screen a total of 226 bioactive compounds from African herbs and medicinal plants for direct interactions with SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). From these, 36 phytocompounds with binding affinities higher than the approved reference drugs (remdesivir and sobosivir), were further docked targeting the active sites of SARS-CoV-2, as well as SARS-CoV and HCV RdRp. A hit list of 7 compounds alongside two positive controls (remdesivir and sofosbuvir) and two negative controls (cinnamaldehyde and Thymoquinone) were further docked into the active site of 8 different conformations of SARS-CoV-2 RdRp gotten from molecular dynamics simulation (MDS) system equilibration. The top docked compounds were further subjected to predictive druglikeness and ADME/tox filtering analyses. Drugable alkaloids (10'-hydroxyusambarensine, cryptospirolepine, strychnopentamine) and flavonoids (usararotenoid A, and 12α-epi-millettosin), were reported to exhibit strong affinity binding and interactions with key amino acid residues in the catalytic site, the divalent-cation-binding site, and the NTP entry channel in the active region of the RdRp enzyme as the positive controls. These phytochemicals, in addition to other promising antivirals such as remdesivir and sofosbuvir, may be exploited towards the development of a cocktail of anti-coronavirus treatments in COVID-19. Experimental studies are recommended to validate these study.


Asunto(s)
Alcaloides/farmacología , Antivirales/farmacología , Flavonoides/farmacología , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , SARS-CoV-2/efectos de los fármacos , África , Alcaloides/farmacocinética , Evaluación Preclínica de Medicamentos , Flavonoides/farmacocinética , Humanos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Fitoquímicos/farmacología , SARS-CoV-2/enzimología
14.
Heliyon ; 6(3): e03514, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32190756

RESUMEN

BACKGROUND: Kafura pelebe (camphor) {C10H16O} is a chemical substance used mostly amongst the Yoruba ethnic group in Western Nigeria to treat infantile colic during early childhood. This study assess the neurotoxic potentials of Kafura following sub-chronic exposure in female albino Wistar rats. METHODS: Twenty-eight female rats (mean weight of 130 g) were randomly selected and assigned into four (4) groups. Control, received 1ml coconut oil while the treatment groups received 79, 158 and 237. mg/kg b.wt (d ose p.o) of Kafura for the period of 14 days. On day fifteen, animals were dissected and the brain organ excised for the homogenate and histopathologic assay, blood samples were also collected for haematological analysis. Morris Water Maze experiment for reference memory was also carried out to ascertain effect of Kafura in the Central Nervous system (CNS). RESULTS: A trend toward decreased body-weight gain and increase brain weight was observed in Kafura-treated rats but was statistically not significant, compared to control. The biochemical assessment of the antioxidant status of brains of Kafura-treated rats showed significant (p ≤ 0.05) increase in activities of some anti-oxidant enzymes (Superoxide dismutase (SOD), Glutathione peroxide (GPx), and Catalase (CAT)). There was increase in acetylcholinesterase (AChE), Malondialdehyde (MDA), and Total protein activities in the brain of treated rats compared to control. Alterations of the haematological parameters were observed, with the plasma granulocytes, lymphocytes, and haemoglobin (HGB), showing significant decrease in the treated rats compared to control. The water maze test showed a marked increase in spatial learning and memory time (seconds) in kafura-treated rats, compared to control and across treated groups. CONCLUSIONS: The present study provides indication that kafura Pelebe shows apparent neurotoxicity in experimental animals. Incessant exposure in humans though may lead to development of some central nervous system defects.

15.
Oxid Med Cell Longev ; 2019: 6726312, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31827691

RESUMEN

Plant-based therapies are being explored to prevent or treat several cancer types. The antioxidant properties of Polyalthia longifolia plant are well established. In our previous work, we demonstrated the presence of cytotoxic compounds in the methanol extract of Polyalthia longifolia (MEP) with potent activity against human leukemia cells. In the present study, we evaluated the efficacy of MEP against prostate cancer (PCa) and established the molecular basis of its effect in in vitro and in vivo models. We observed that MEP treatment resulted in a significant decrease in the growth and viability of PCa cells, associated with arrest in the G1/S phase of the cell cycle. Apoptosis was confirmed as the primary mode of MEP-induced cell death through activation of the intrinsic apoptotic machinery. Proteomic and biochemical studies identified BiP as an important target of MEP with the activation of the ER stress pathway, as a potential mechanism driving MEP-induced apoptosis. The extract exhibited strong efficacy in the PCa xenograft mouse model with significant inhibition of tumor growth and reduced tumor burden. Taken together, our findings indicate that MEP-induced apoptosis in PCa cells concomitant with the activation of the ER stress pathways results in the inhibition of tumor growth, in vitro and in vivo. Our studies provide initial evidence of the efficacy of MEP against PCa and advocate for in-depth studies in other preclinical models for its possible use in clinical settings.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Fitoterapia , Extractos Vegetales/farmacología , Polyalthia/química , Neoplasias de la Próstata/tratamiento farmacológico , Animales , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Humanos , Técnicas In Vitro , Masculino , Ratones , Ratones Desnudos , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
16.
Toxicol Rep ; 6: 496-504, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31205861

RESUMEN

This study evaluates the reproductive toxicity of ethyl acetate and butanolic fractions from crude methanolic leaf extract of Ocimum gratissimum in male Wistar rats. Acute toxicity was assessed to determine the safety dose, Sub-chronic reproductive toxicity studies were carried out by administering daily 25, 100 and 400 mg/kg body weight doses of the fractions to respective group of animals and 1 ml of normal saline daily for the control group for 28 days. Blood, epididymis and testes were harvested for reproductive hormones, sperm parameters, and histopathologic analysis respectively. There was significant (P < 0.05) increase in serum levels of testosterone, body-weight gain, sperm count. There was also apparent increase in mean-testicular weight and preservation of testicular histology with increase spermatogenesis in both the ethyl acetate and butanolic fraction treated groups compared with control. Serum levels of luteinising hormone was however significantly (P < 0.05) decrease across the groups compared to control. These effects were more pronounced in the butanolic fraction group compared to the ethyl acetate treated group. Sperm motility was also significantly (P < 0.05) higher in the ethyl acetate treated group compared to control. Findings from this studies demonstrate that these fractions were non-toxic at the tested doses with regards to male reproduction but, rather, exhibited fertility enhancing effects which was better with the butanolic fraction. Our findings also shows that the ethyl acetate fraction may be safer than the butanolic fraction.

17.
Sci Rep ; 8(1): 15726, 2018 10 24.
Artículo en Inglés | MEDLINE | ID: mdl-30356079

RESUMEN

The anti-proliferative activity of dietary flavonoid fisetin has been validated in various cancer models. Establishing its precise mechanism of action has proved somewhat challenging given the multiplicity of its targets. We demonstrated that YB-1 promotes epithelial-to-mesenchymal transition and its inhibition suppressed tumor cell proliferation and invasion. The p90 ribosomal S6 kinase (RSK), an important ERK effector, activates YB-1 to drive melanoma growth. We found that fisetin treatment of monolayer/3-D melanoma cultures resulted in YB-1 dephosphorylation and reduced transcript levels. In parallel, fisetin suppressed mesenchymal markers and matrix-metalloproteinases in melanoma cells. Data from cell-free/cell-based systems indicated that fisetin inhibited RSK activity through binding to the kinase. Affinity studies for RSK isoforms evaluated stronger interaction for RSK2 than RSK1. Competition assays performed to monitor binding responses revealed that YB-1 and RSK2 do not compete, rather binding of fisetin to RSK2 promotes its binding to YB-1. Fisetin suppressed YB-1/RSK signaling independent of its effect on ERK, and reduced MDR1 levels. Comparable efficacy of fisetin and vemurafenib for inhibiting melanoma growth was noted albeit through divergent modulation of ERK. Our studies provide insight into additional modes of regulation through which fisetin interferes with melanoma growth underscoring its potential therapeutic efficacy in disease progression.


Asunto(s)
Flavonoides/farmacología , Melanoma/tratamiento farmacológico , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , Proteína 1 de Unión a la Caja Y/antagonistas & inhibidores , Antineoplásicos/farmacología , Técnicas de Cultivo de Célula/métodos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Flavonoles , Humanos , Sistema de Señalización de MAP Quinasas , Melanoma/patología , Fosforilación , Transducción de Señal , Transcripción Genética/efectos de los fármacos , Proteína 1 de Unión a la Caja Y/metabolismo
18.
J Oleo Sci ; 66(10): 1169-1174, 2017 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-28924081

RESUMEN

The discovery of potent cytotoxic isolates from botanicals provides an opportunity to explore this viable tool for cancer chemoprevention. The antileukemic potential of clerodane diterpene from Polyalthia longifolia leaves has already been established. However, in this present study, utilizing chromatographic techniques we report for the first time, the isolation of a rare tetranorditerpene (compound 1) from P. longifolia. The structure of compound 1 was elucidated and confirmed by spectrophotometric data. UPLC-MS analysis was conducted on the methanolic extract, ethyl acetate fraction, and isolated tetranorditerpene showed that the tetranorditerpene is one of the major constituents of the plant with a retention time of 30.78 min. In addition, a methyl ester derivative (compound 2) of the isolated tetranorditerpene was synthesized. Using the CCK-8 assay, we compared the cytotoxic potential of isolated tetranorditerpene (1) and methyl ester derivative (2) with the previously isolated clerodane diterpenes. Our results showed that the methyl ester derivative (2) displayed the highest inhibitory activity against human leukemia HL-60 cells. The isolated tetranorditerpene (1) did not exhibit significant inhibitory effect against HL-60 cells. Morphological examination indicated chromatin condensation and nuclear fragmentation suggesting induction of apoptosis in compound 2 treated HL-60 cells. The methyl esterification of the isolated tetranorditerpene (1) conferred on it a significant level of antileukemic activity suggesting the possibility of a synergistic relationship between pure compound isolation and synthetic reaction in the discovery of new chemopreventive agents.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Diterpenos de Tipo Clerodano/aislamiento & purificación , Diterpenos de Tipo Clerodano/farmacología , Leucemia/patología , Polyalthia/química , Apoptosis , Diterpenos de Tipo Clerodano/síntesis química , Diterpenos de Tipo Clerodano/química , Esterificación , Ésteres/síntesis química , Ésteres/farmacología , Células HL-60 , Humanos , Leucemia/prevención & control , Hojas de la Planta/química
19.
BMC Complement Altern Med ; 12: 79, 2012 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-22892317

RESUMEN

BACKGROUND: The herbal preparation DAS-77, used for the treatment of various ailments in Nigeria, contains the milled bark of Mangifera indica L. and root of Carica papaya L. Toxicological assessment of the preparation was carried out in this study. METHODS: In the acute toxicity study, DAS-77 was administered to mice p.o. up to 20 g/kg in divided doses and i.p. at 250-3000 mg/kg. Mortality within 24 h was recorded. In the chronic toxicity study, rats were treated p.o. for 90 days at doses of 80, 400 (therapeutic dose, TD) and 2000 mg/kg. By 90 days, animals were sacrificed and blood samples collected for hematological and biochemical analysis. Organs were harvested for weight determination, antioxidants and histopathological assessments. RESULTS: DAS-77 did not produce any lethality administered p.o. up to 20 g/kg in divided doses but the i.p. LD50 was 1122.0 mg/kg. At TD, DAS-77 produced significant (p < 0.05) reductions in body weight, food intake and K+, and increases in ovary weight, neutrophils and HDL, which were reversible. Histopathological presentations were generally normal. Effects at the other doses were comparable to those at TD except for reversible increases in antioxidants in the liver, kidney and testes, and sperm abnormality, and reductions in liver enzymes, sperm motility and count. CONCLUSIONS: Findings in this study revealed that DAS-77 is relatively safe with the potential for enhancing in vivo antioxidant activity. However, possibly reversible side-effects include electrolyte imbalance and sterility in males.


Asunto(s)
Carica/efectos adversos , Infertilidad Masculina/etiología , Mangifera/efectos adversos , Fitoterapia/efectos adversos , Extractos Vegetales/efectos adversos , Desequilibrio Hidroelectrolítico/etiología , Animales , HDL-Colesterol/sangre , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Energía/efectos de los fármacos , Femenino , Riñón/efectos de los fármacos , Riñón/metabolismo , Dosificación Letal Mediana , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Medicinas Tradicionales Africanas , Ratones , Ratones Endogámicos , Neutrófilos/metabolismo , Tamaño de los Órganos , Ovario/efectos de los fármacos , Extractos Vegetales/farmacología , Potasio/sangre , Ratas , Ratas Wistar , Espermatozoides/efectos de los fármacos , Espermatozoides/patología , Testículo/efectos de los fármacos , Testículo/metabolismo , Pérdida de Peso/efectos de los fármacos
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