Pyridine-N-Oxide Alkaloids from Allium stipitatum and Their Synthetic Disulfide Analogs as Potential Drug Candidates against Mycobacterium tuberculosis: A Molecular Docking, QSBAR, and ADMET Prediction Approach.

In this study, we consider pyridine-N-oxide alkaloids from Allium stipitatum and their synthetic disulfide analogs (PDAs) as candidates for next-generational antimycobacterial agents, in light of growing resistance to existing conventional therapies. In silico studies involving molecular docking simulations of 12 PDAs were carried out against 7 Mycobacterium tuberculosis target proteins (MTs) to determine their theoretical binding affinities. Compounds A3, A6, and B9 demonstrated stronger binding affinities on similar MTs. Molecular descriptors (MDs) describing structural and physicochemical properties of the compounds were also calculated using ChemDes, explored using Pearson's correlation analysis, and principal component analysis (PCA) in comparison with MDs from conventional antitubercular medicines. The PDAs possessed similar scores as isoniazid and pyrazinamide. The MDs were also used to conduct a quantitative structure-binding affinity relationship (QSBAR) study by building good fit and significant models through principal component regression (PCR) and partial least squares regression (PLSR). Leave-one-out cross-validation was adopted in the PLSR, resulting in good predictive models on all MTs (range of R 2 = 0.7541-0.8992; range of Q 2 = 0.6183-0.8162). Both PCR and PLSR models predicted the significant effects of ndonr, Hy, Mol wt, nhev, nring, ndb, Log P, W, Pol, ISIZ, TIAC, Getov, and UI on the binding of ligands to the MTs. In silico prediction of PDAs' ADMET profiles was conducted with QikProp utility. The ADMET profiles of the compounds were favorable. The outcome of the current study strengthens the significance of these compounds as promising lead candidates for the treatment of multidrug-resistant tuberculosis.

Chronic toxic effects of polystyrene microplastics on reproductive parameters of male rats.

Microplastics have become a significant environmental concern. However, information on toxicity of microplastics in terrestrial organisms is limited. In this study, the chronic toxic effects of polystyrene microplastics (PS-MPs) on the reproductive system and serum antioxidants of male albino Wistar rats fed for 90 days with standard rat feed containing 1-10% granules of crushed polystyrene disposable plates were evaluated. Significant reductions in volume, motility, epididymal sperm count and serum testosterone level were observed. Histological examination of testicular architecture showed distorted testes with vacuolated seminiferous tubules at the highest percentage, together with increased catalase and decreased superoxide dismutase activities. This study showed that ingestion of PS-MPs caused reproductive dysfunction in male rats and contributes to understanding the potential toxicity of microplastics in terrestrial animals.

Hypoglycaemic activity of Oleanonic acid, a 3-oxotriterpenoid isolated from Aidia Genipiflora (DC.) Dandy, involves inhibition of carbohydrate metabolic enzymes and promotion of glucose uptake.

The present study evaluated the antidiabetic activities of the 70% ethanol stem bark extract of Aidia genipiflora (AGB) and one of its constituents, oleanonic acid in streptozotocin (40 mg/kg)-induced diabetic rats. In vitro assays of glucose uptake and inhibition of carbohydrate metabolizing enzymes were then used to investigate their mechanism(s) of hypoglycaemic action. In silico evaluation of the pharmacokinetic and toxicity properties of the compound was also carried out. Administration of AGB (100-400 mg/kg) and oleanonic acid (15 - 60 mg/kg) resulted in significant reductions (p < 0.001) in the blood glucose and considerable decrease (p < 0.05) in the elevated lipid parameters of the diabetic animals. AGB activity at 200 and 400 mg/kg; and oleanonic acid at 60 mg/kg were comparable to glibenclamide (5 mg/kg). The extract and its isolate strongly inhibited α-glucosidase and α-amylase activity with IC50 values of (10.48 ± 1.39 µg/mL and 14.51 ± 1.26 µg/mL) and (36.52 ± 1.95 µM and 105.84 ± 1.08 µM) respectively. The glucose uptake assays showed that AGB and oleanonic acid exerted both insulin-dependent and independent promotional effect of glucose transport into the periphery by upregulating the expression of PI3K and PPARγ transcripts with a concomitant increase in GLUT-4 transcripts. Although oleanonic acid was predicted to be teratogenic, it was found to be generally non-lethal with favourable pharmacokinetics properties making it suitable for further studies. The study has shown that the stem bark of A. genipiflora is a source of new hypoglycaemic agents and that oleanonic acid possesses hypoglycaemic and anti-hyperlipidaemic activities.

Glycine/NMDA Receptor Pathway Mediates the Rapid-onset Antidepressant Effect of Alkaloids From Trichilia Monadelpha.

INTRODUCTION: Major depressive disorder is often associated with suicidal tendencies, and this condition accentuates the need for rapid-acting antidepressants. We previously reported that Alkaloids (ALK) from Trichilia monadelpha possess antidepressant action in acute animal models of depression and that this effect is mediated through the monoamine and L-arginine-NO-cGMP pathways. This study investigated the possible rapid-onset antidepressant effect of ALK from T. monadelpha and its connection with the glycine/NMDA receptor pathway. METHODS: The onset of ALK action from T. monadelpha was evaluated using the Open Space Swim Test (OSST), a chronic model of depression. The modified forced swimming and tail suspension tests were used to assess the effect of the ALK on the glycine/NMDA receptor pathway. The Instutute of Cancer Research (ICR) mice were treated with either ALK (30-300 mg/kg, orally [PO]), imipramine (3-30 mg/kg, PO), fluoxetine (3-30 mg/kg, PO), or saline. To identify the role of glycine/NMDA receptor pathway in the effect of ALK, we pretreated mice with a partial agonist of the glycine/NMDA receptor, D-cycloserine (2.5 mg/kg, intraperitoneally [IP]), and an agonist of glycine/NMDA receptor, D-serine (600 mg/kg, IP), before ALK administration. RESULTS: ALK reversed immobility in mice after the second day of drug treatment in the OSST. In contrast, there was a delay in the effects induced by fluoxetine and imipramine. ALK also increased mean swimming and climbing scores in mice. ALK was more efficacious than imipramine and fluoxetine in reducing immobility and increasing distance traveled. It is noteworthy that ALK was less potent than fluoxetine and imipramine. D-cycloserine potentiated mobility observed in the ALK- and fluoxetine-treated mice. In contrast, D-serine decreased mobility in the ALK-treated mice. CONCLUSION: The study results suggest that ALK from T. monadelpha exhibits rapid antidepressant action in mice, and the glycine/NMDA receptor pathway possibly mediates the observed effect.

Antithrombotic property of an aqueous extract from Pseudocedrela kotschyi and Adenia cissampeloides.

BACKGROUND AND PURPOSE: An aqueous extract from the root bark of Pseudocedrela kotschyi and aerial parts of Adenia cissampeloides has been proven in previous research to elicit significant anticoagulant property in vitro. This, therefore, indicates the potential usefulness of this extract in managing thromboembolic disease, a major global health risk. The aim of the present work was to establish the antithrombotic effect of a product made from extracts of the root bark of P. kotschyi and the aerial parts of A. cissampeloides (PAE). EXPERIMENTAL APPROACH: The effect of PAE at 500-2000 mg/kg in inhibiting tail infarction and inflammation, as well as its effect on the microthrombi count, hematological, and coagulation profiles in a carrageenan-induced thrombosis model in Sprague-Dawley rats, was studied. FINDINGS/RESULTS: PAE significantly (P ≤ 0.01-0.001) reduced length of tail infarction and inflammation (redness, swelling, pain, and temperature). Histopathological studies revealed a significant reduction (P ≤ 0.0001) in microthrombi count in the liver and the lungs with PAE treatment. PAE treatment caused a marginal (P ≤ 0.01) increase in prothrombin time but resulted in a significant (P ≤ 0.01-0.0001) dose-dependent increase in activated partial thromboplastin time, with the hematological profile being normal. CONCLUSION AND IMPLICATIONS: PAE showed anticoagulant and antithrombotic effects in vivo, indicative of its potential benefit as a natural product, and cost-effective therapeutic option, and hence could be helpful in thromboembolic therapies.

Myrianthus libericus: Possible mechanisms of hypoglycaemic action and in silico prediction of pharmacokinetics and toxicity profile of its bioactive metabolite, friedelan-3-one.

The hypoglycaemic and anti-hyperlipidaemic effects of the 70% ethanol stem bark extract of Myrianthus libericus (MLB), used traditionally in the management of diabetes in Ghana, was evaluated in this study using streptozotocin (45 mg/kg)-induced diabetic rats. In vitro hypoglycaemic activities of the extract and one of its principal compounds, friedelan-3-one were then investigated using α-amylase inhibitory and glucose uptake assay in C2C12 myotubes. In silico analysis of the pharmacokinetic and toxicity properties of the compound was also performed. MLB significantly (p < 0.001) reduced the elevated blood glucose levels and corrected considerably (p < 0.01) the altered serum lipid profiles of the diabetic rats which was comparable to glibenclamide (5 mg/kg). Together with friedelan-3-one, the extract markedly inhibited the activity of α-amylase and promoted glucose uptake in C2C12 cells. Whereas MLB significantly (p < 0.001) up-regulated PI3K and PPARγ transcripts with a corresponding increase in GLUT-4 transcripts within the muscle cells, friedelan-3-one only up-regulated PI3K and GLUT-4 transcripts to promote glucose transport. Friedelan-3-one was shown to be non-carcinogenic, non-hepatotoxic, has decent oral bioavailability and a good compound for optimisation into a drug candidate. The study has demonstrated that MLB possess hypoglycaemic and anti-hyperlipidaemic activities and could be used as a therapeutic agent in the management of diabetes mellitus.

Flavanols and triterpenoids from Myrianthus arboreus ameliorate hyperglycaemia in streptozotocin-induced diabetic rats possibly via glucose uptake enhancement and α-amylase inhibition.

Myrianthus arboreus is use traditionally as an antidiabetic agent in Ghana. We reported the in vivo antidiabetic activity of its 70 % ethanol stem bark extract (MAB) which we found to be strongly concentrated in its EtOAc fraction using glucose uptake and enzyme inhibitory assays. The present study sought to investigate the in vivo hypoglycaemic and anti-hyperlipidaemic activity of this ethyl acetate fraction of MAB (MAB-EtOAc, 50 and 100 mg/kg) in streptozotocin (STZ)-induced diabetic rats for 21 days, isolate and evaluate the bioactive constituents responsible for the antidiabetic activity. In silico pharmacokinetic and toxicity properties of the most active compound was also determined. MAB-EtOAc significantly (p < 0.001) reduced the blood glucose levels while normalizing considerably the altered serum lipid parameters of the diabetic rats which was comparable to glibenclamide (5 mg/kg). Chemical investigation of MAB-EtOAc led to the isolation of seven known compounds including three flavanols which are reported for the first time in the plant: epicatechin (1), epigallocatechin (2), dulcisflavan (3), euscaphic acid (4), tormentic acid (5), sitosterol-3-O-ß-d-glucopyranoside (6) and arjunolic acid (7). The compounds markedly inhibited the action of α-amylase and, except for 4 and 6, which stimulated considerably glucose uptake in C2C12 cells. Compounds 2, 3, 5, 6 and 7 which were further evaluated in STZ-induced diabetic rats demonstrated hypoglycaemic and anti-hyperlipidaemic activities which, however, were not comparable with MAB-EtOAc. Compound 3, the most active compound was predicted to be non-toxic, non-mutagenic, has reasonable oral bioavailability and a decent substrate for further drug development. The findings of this study show that the isolated compounds may contribute to the antidiabetic activity of M. arboreus and could serve as marker compounds for the quality control of herbal medicines that would be made from the plant.

Effect of Trichilia monadelpha (Meliaceae) extracts on bone histomorphology in complete Freund's adjuvant-induced arthritis.

AIM: This study aimed to assess the effect of petroleum ether extract (PEE), ethyl acetate extract (EthE), and ethanol extract (EAE) of Trichilia monadelpha stem bark on bone histomorphology in arthritis. METHODS: Percentage inhibition of edema and arthritic scores in complete Freund's adjuvant-induced (0.1 ml of 5 mg/ml1 of heat-killed Mycobacterium tuberculosis in paraffin oil-injected subplantar into the right hind paw) arthritic Sprague-Dawley rats treated with PEE, EthE, or EAE (10,30, and 100 mg/kg1, respectively), dexamethasone (0.3-3.0 mg/kg1), or methotrexate (0.1-1.0 mg/kg1) over a 28-day period were estimated. Rat paws were radiographed and scored. Body weights were taken and paw tissues were harvested for histopathological studies. RESULTS: The extracts significantly (P ≤ 0.01-0.0001) and dose dependently reduced the polyarthritic phase of arthritis. EAE and PEE significantly (P ≤ 0.01-0.0001) minimized edema spread from acute arthritic phase (days 0-10) to polyarthritic phase (days 10-28). EthE improved which deteriorated body weight in arthritis. All extracts significantly (P ≤ 0.05-0.01) improved arthritic score; reducing erythema, swelling and joint rigidity, and also significantly (P ≤ 0.05-0.01) reduced hyperplasia, pannus formation, and exudation of inflammatory cells into synovial spaces. CONCLUSION: The stem bark extracts of T. monadelpha reduce bone tissue damage and resorption associated with adjuvant-induced arthritis, hence could be useful in managing arthritis in humans.

The possible mode of antitussive and expectorant activity of the ethanol seed extracts of Picralima nitida ((Stapf) Th. & H. Durand).

It has been established that Picralima nitida has antitussive effect. This study therefore aimed at determining the possible mode of antitussive and expectorant activity of an ethanolic seed extract of P. nitida (PNE). The muco-suppressant, mast cell stabilization, and the anxiolytic effects of PNE were ascertained using ammonium chloride-induced phenol red secretion in BALB/c mice; compound 48/80-induced mesenteric mast cell degranulation assay; and the open field and the elevated plus maze models respectively. Antibacterial potential was ascertained by the agar plate diffusion method and its antioxidant potential by the 2,2-diphenyl-1-picrylhydrazyl hydrate (DPPH) free radical scavenging, linoleic acid lipid peroxidation, reducing power, and total antioxidant assays. Data obtained was analyzed using One-way analysis of variance (ANOVA) with Dunnett's Multiple Comparison post hoc test. PNE (100-500 mg/kg) reduced (P ≤ 0.05-0.001) tracheal phenol red secretion. The extract (100-500 µg/ml) also dose-dependently (P ≤ 0.05-0.0001) stabilized mast cells. PNE (100-500 mg/kg) increased open arm activities in the elevated plus maze (P ≤ 0.05) as well as central zone exploration (P ≤ 0.05) in the open field test. PNE (10-50 mg/ml) showed activity against Staphylococcus aureus, Streptococcus pneumonia, Escherichia coli, Klebsiella pneumonia, and Salmonella typhi. By the assays, PNE showed significant antioxidant effect. The ethanolic seed extract of P. nitida has demonstrated very significant mast cell stabilizing, mucus suppressant, and antioxidant activity as well as substantial antibacterial and anxiolytic properties; all of which could contribute to its antitussive and expectorant property.

Anti-anaphylactic effects of Trichilia monadelpha (Thonn.) J. J. De Wilde extracts on rodent models of anaphylaxis.

Effects of petroleum ether and ethanolic extracts of Trichilia monadelpha stem bark (PEE and EAE) on compound 48/80-induced systemic and passive anaphylaxis were determined. Survival rate, extravasation, degranulation of mast cells, and secretion of tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were measured after pre-treatment with extracts (10-100 mg/kg) and disodium chromoglycate (2.5-250 µg/kg) and induction of anaphylaxis in C57BL/6 mice or Sprague-Dawley rats with compound 48/80. Histopathological assessments were made from skin biopsies of rats. Data was analyzed by Kaplan-Meier Survival Log-Rank Analysis, or One-way ANOVA and Holm-Sidak's post hoc test. PEE and EAE inhibited (P ≤ 0.0001) tremors in systemic anaphylaxis passive cutaneous anaphylactic reactions and extravasation, stabilized or prevented (P ≤ 0.001-0.0001) mast cell degranulation, and inhibited (P ≤ 0.001-0.0001) TNF-α and IL-6 secretion. Per the findings, PEE and EAE of T. monadelpha have exhibited substantial anti-anaphylactic and anti-inflammatory property (with PEE performing better) which substantiates its use traditionally in management of allergies and other inflammatory disorders.

Antitussive, expectorant and analgesic effects of the ethanol seed extract of Picralima nitida (Stapf) Th. & H. Durand.

Picralima nitida is used traditionally for management of cough. This study, therefore, investigated the antitussive, expectorant, and analgesic properties of the ethanolic seed extract of Picralima nitida (PNE), and ascertained its safety for use. Presence of secondary metabolites, and safety of PNE (10-2000 mg/kg) were evaluated by preliminary phytochemical screening, and by Irwin's test respectively. Percentage reduction in cough count, percentage increase in latency of cough, and percentage protection offered by PNE were established by the citric acid-induced cough, acetylcholine- and Histamine-induced bronchoconstriction models. Dunkin-Hartley guinea pigs were treated with 100-500 mg/kg PNE or reference drugs, dihydrocodiene, atropine, mepyramine. Expectorant property of PNE (100-1000 mg/kg) was determined using the tracheal phenol red secretion; with ammonium chloride as a reference medication. Percentage maximal possible analgesic effect in the tail immersion test and the total nociceptive score in acetic acid-induced abdominal writhes, after treatment of BALB/c mice with PNE (100-500 mg/kg), diclofenac, and morphine were also estimated. Phytochemical screening revealed the presence of tannins, alkaloids, glycosides, saponins, steroids, terpenoids and anthraquinones. PNEdid not cause any extract-related physical, pharmacological and CNS toxicities or mortality; sedation was observed at doses 1000-2000 mg/kg. It showed significant dose-dependent reduction in cough count, and increased cough latency. PNE (1000 mg/kg) enhanced tracheal phenol red secretion. PNE (100-500 mg/kg) significantly and dose dependently increased tail withdrawal latencies, and nociceptive score. PNE has antitussive, expectorant, and analgesic properties, with an LD50>2000 mg/kg.

Assessment of an ethanolic seed extract of Picralima nitida ([Stapf] Th. and H. Durand) on reproductive hormones and its safety for use.

BACKGROUND: Picralima nitida seed extract (PNE) has aphrodisiac and contraceptive effect. AIM: To investigate the effect of PNE on reproductive hormones. MATERIALS AND METHODS: The size and length of the combs of white leghorn day-old chicks treated with testosterone (0.5-1.5 mg/kg), cyproterone (3-30 mg/kg), or PNE (50-500 mg/kg) for 7 days, as well as cyproterone (10, and 30 mg/kg) on PNE-induced, and PNE (50-500 mg/kg) on testosterone-induced comb growth, were measured in the chick comb test. The effect of PNE the percentage change in an oviduct-chick weight ratio of Rhode Island Red layer day-old chicks treated with 17-ß-estradiol (0.1-0.9 µg), PNE (30-300 mg/kg) or vehicle, for 6 days, was determined in the chick uterotrophic assay. Liver and kidney function was well lipid, and hematological profile tests were conducted to assess safety. RESULTS: 7-day treatment with PNE and testosterone increased significantly (P ≤ 0.01-0.001) while cyproterone significantly decreased (P ≤ 0.001) comb growth dose-dependently. Qualitatively, testosterone and PNE treatment resulted in relatively brighter red combs. Cyproterone caused significant inhibition (P ≤ 0.001) of both testosterone and PNE-induced comb growth. Co-administration of testosterone and PNE suppressed comb growth significantly (P ≤ 0.001). Administration of 17-ß estradiol and PNE increased (P ≤ 0.001) oviduct-chick weight ratio dose-dependently. No significant changes were observed in assessing liver and kidney function, lipid profile, and hematological parameters. CONCLUSION: PNE exhibits both androgenic (partial testosterone agonist) and estrogenic activity. It has no detrimental effects on the blood, liver, and kidney tissue with prolonged use.