In silico and in vitro assessment of drugs potentially causing adverse effects by inhibiting CYP17A1.

Cytochrome P450 enzymes (CYPs) play a crucial role in the metabolism and synthesis of various compound classes. While drug-metabolizing CYP enzymes are frequently investigated as anti-targets, the inhibition of CYP enzymes involved in adrenal steroidogenesis is not well studied. The steroidogenic enzyme CYP17A1 is a dual-function enzyme catalyzing hydroxylase and lyase reactions relevant for the biosynthesis of adrenal glucocorticoids and androgens. Inhibition of CYP17A1-hydroxylase leads to pseudohyperaldosteronism with subsequent excessive mineralocorticoid receptor activation, hypertension and hypokalemia. In contrast, specific inhibition of the lyase function might be beneficial for the treatment of prostate cancer by decreasing adrenal androgen levels. This study combined in silico and in vitro methods to identify drugs inhibiting CYP17A1. The most potent CYP17A1 inhibitors identified are serdemetan, mocetinostat, nolatrexed, liarozole, and talarozole. While some of these drugs are currently under investigation for the treatment of various cancers, their potential for the treatment of prostate cancer is yet to be explored. The DrugBank database was screened for CYP17A1 inhibitors, to increase the awareness for the risk of drug-induced pseudohyperaldosteronism and to highlight drugs so far unknown for their potential to cause side effects resulting from CYP17A1 inhibition.

Shark fish oil prevents scopolamine-induced memory impairment in an experimental model.

Fish oil has been known for its antioxidant, cardioprotective, anti-inflammatory, and neuroprotective characteristics due to the presence of polyunsaturated fatty acids (PUFAs) that are essential for optimal brain function and mental health. The present study investigated the effect of Carcharhinus Bleekeri (Shark Fish) oil on learning and memory functions in scopolamine-induced amnesia in rats. Locomotor and memory-enhancing activity in scopolamine-induced amnesic rats was investigated by assessing the open field and passive avoidance paradigm. Forty male Albino mice were divided into 4 equal groups (n = 10) as bellow: 1 - control (received 0.9% saline), 2 - SCOP (received scopolamine 2 mg/kg for 21 days), 3 - SCOP + SFO (received scopolamine and fish oil 5 mg/kg/ day for 21 days), 4 - SCOP + Donepezil groups (received 3 mg/kg/day for 21 days). SFO produced significant (P < 0.01) locomotor and memory-enhancing activities in open-field and passive avoidance paradigm models. Additionally, SFO restored the Acetylcholine (ACh) concentration in the hippocampus (p < 0.05) and remarkably prevented the degradation of monoamines. Histology of brain tissue showed marked cellular distortion in the scopolamine-treated group, while the SFO treatment restored distortion in the brain's hippocampus region. These results suggest that the SFO significantly ameliorates scopolamine-induced spatial memory impairment by attenuating the ACh and monoamine concentrations in the rat's hippocampus.

Phylogenetic Characterization of HIV-1 Sub-Subtype A1 in Karachi, Pakistan.

(1) Background: HIV-1 sub-subtype A1 is common in parts of Africa, Russia, former Soviet Union countries, and Eastern Europe. In Pakistan, sub-subtype A1 is the predominant HIV-1 subtype. Preliminary evidence suggests that distinct strains of HIV-1 sub-subtype A1 are circulating in Pakistan; however, an in-depth molecular phylogenetic characterization of HIV-1 sub-subtype A1 strains in Pakistan have not been presented. We performed a detailed characterization of the HIV-1 sub-subtype A1 epidemic in Pakistan using state-of-the-art molecular epidemiology and phylodynamics. (2) Methods: A total of 143 HIV-1 sub-subtype A1 gag sequences, including 61 sequences generated specifically for this study from PLHIVs part of our cohort, representing all sub-subtype A1 gag sequences from Pakistan, were analyzed. Maximum-likelihood phylogenetic cluster analysis was used to determine the relationship between Pakistani sub-subtype A1 strains and pandemic sub-subtype A1 strains. Furthermore, we used signature variation, charge distribution, selection pressures, and epitope prediction analyses to characterize variations unique to Pakistani HIV-1 strains and establish the association between signature variations and Gag epitope profile. (3) Results: The HIV-1 sub-subtype A1 sequences from Pakistan formed three main clusters: two that clustered with Kenyan sequences (7 and 10 sequences, respectively) and one that formed a Pakistan-specific cluster of 123 sequences that were much less related to other sub-subtype A1 sequences available in the database. The sequences in the Pakistan-specific cluster and the Kenyan reference strains exhibited several signature variations, especially at amino acid positions 312, 319, 331, 372, 373, 383, and 402. Structural protein modeling suggested that amino acid changes in these positions result in alterations of the Gag protein structure as well as in Gag-specific T-cell epitopes. (4) Conclusions: Our results suggest that the majority of the Pakistan HIV-1 sub-subtype A1 strains were unique to Pakistan and with a specific mutation pattern in Gag.

Comparative antioxidant and analgesic effect of sesame oil, fish oil and their combination in experimental animal model.

Natural oils are rich in polyunsaturated fatty acids (PUFs) like omega 3, omega 6 and other nutrients that boost physical and mental health. Traditionally these oils have been used to treat joint pain associated with several inflammatory conditions. In this study, we investigated the antioxidant and analgesic properties of the sesame oil (SO), fish oil (FO) and combination of these two oils (SO+FO). Different concentrations of the SO, FO and SO+FO combination 0.02-4mg/ml were used for assessing the free radical scavenging activity by DPPH method and the IC50 value was calculated. Acetic acid-induced abdominal writhing test, tail immersion and hot plate models were used to determined analgesic effect. Results showed that both oils were well tolerated as no signs of toxicity or death were noticed during the observational study period. SO+FO combination showed the best antioxidant properties as shown by DPPH assay. Similarly in analgesic models, SO and FO significantly reduced the number of abdominal contractions (p<0.05) however, SO+FO (1:1) exhibited highly significant results (p<0.001) in writhing reflex test. Furthermore, SO and FO both increased the reaction time on a hot plate as well as in tail flick test (p<0.05) whereas, SO+FO significantly increased reaction time (p<0.001) in hot plate and in tail flick test as compared to SO and FO single treatments. Conclusively, our results suggest that the combination of both oils (SO+FO) exhibited significant antioxidant and analgesic potential that it could be considered as one of the active combinations for relieving pain in adjunctive treatment for joint pain associated with rheumatoid arthritis.

Phytochemical analysis and biological activities of "Cherchoomoro" (Nepeta adenophyta Hedge).

ETHNOPHARMACOLOGICAL RELEVANCE: Nepeta adenophyta Hedge (Lamiaceae) is an endemic therapeutic herb from Astore, Gilgit (Pakistan). This plant species has been reported among the local communities, especially for treating abdominal pain, kidney pain, menstrual pain, headache, and controlling bleeding disorders. Therefore, the scientific basis is provided for the relief of pain as it is used in various pain management among the natives, especially as ethnogynecological herbal remedy. AIM OF THE STUDY: The present study investigates the analgesic and anti-inflammatory effects of the ethanolic extract of N. adenophyta in animal models. Furthermore, the extract was also studied to determine their valuable phytoconstituents. MATERIAL AND METHODS: The biological effects were determined via tail-flick, hot plate, and acetic-acid-induced abdominal writhing methods. At the same time, anti-inflammatory activity was assesed via oxidative burst and antioxidant DPPH assay. Gas chromatography-mass spectrometry (GC-MS), and liquid chromatography-mass spectrometry (LC-MS) techniques were employed to understand the phytochemicals present in the crude ethanolic extract of Nepeta adenophyta. RESULTS: In the current study, Nepeta adenophyta extract exhibited potent analgesic and anti-inflammatory effects on different pain models and indicated that the analgesic effect of N. adenophyta extract is mediated both in central and peripheral ways. Dose-dependent and significant (P < 0.05) increases were shown in pain threshold, at 45 min post-treatment, with 20 and 40 mg/kg of the extract in the tail-flick model. The effects of the extract were similar to aspirin but lower to those by morphine (2.5 mg/kg) in the same tests. The extract (20-40 mg/kg) showed dose-dependent inhibition of writhing with a significant (P < 0.001) increase protection against thermal stimuli in hot plate test as compared to control and similar to aspirin and morphine. Further, the anti-inflammatory activity of the crude in oxidative burst and DPPH assays showed significant inhibitory activity. The chemical profile analysis showed major phytochemicals, including long chain derivatives of alkane and alcohol, phenolics, naphthalene, naphthopyran, androsten phenanthrenone, nepetalactones, flavonoids etc. CONCLUSIONS: Nepeta adenophyta Hedge is suggested as a natural alternative for mild pain relief. Our findings endorse the folklore use of N. adenophyta in different pain managements which can be attributed to the presence of polyphenolic compounds, naphthalene derivatives, flavanoids and nepetalactones etc.

A comparative neurobehavioral study of sesame oil and fish oil on experimental animals.

Natural oils are enriched with polyunsaturated fatty acids (PUFAs) which are important for our health. Recent experimental data explained that PUFAs might have a beneficial effect on various brain functions such as anxiety, dementia, epileptic seizures, depression or bipolar and other neurobehavioral diseases. The objective of the current research work was to evaluate the effect of sesame oil, fish oil and mixture of both oils (1:1) on neurobehavioral changes and cognition. For this purpose shark fish oil and sesame oil were extracted out and there poly unsaturated and saturated fatty acids were analyzed by using GCFID that exposed the presence of different PUFs in shark fish oil, sesame oil and mixture of both oils. Neurobehavioral changes were seen after 5ml/kg/day sesame oil, 5ml/kg/day shark fish oil and 1:1 combination of both oil 5ml/kg/day administration on open field, cage crossing, light and dark, stationary rod, forced swimming induced depression test and water maze test. Our GCFID results showed sesame and fish oil enriched with higher amount of PUFs and showed significant anxiolytic and antidepressant like effect after 30 days of treatment (P<0.05) however combination of these both oils exhibited greater efficacy (P<0.01) in reducing anxiety and depression as imipramine standard drug. Results showed that combination of both oils (sesame oil and fish oil) could be a better option to treat neurobehavioral problems as compared to alone.

Review: Herbs, Immunity and nCOVID-19: Old performers in new Pandemic.

The novel coronavirus (nCOVID-19) has spread to endless nations and turn out to be a pandemic around the globe. Because of the developing number of affirmed cases and open public hazard owing to its high risk of infection rate, it has expected a lot of consideration from world health organizations and national health regulatory and monitoring agencies. The world is in surge to explore or discover novel treatment options and vaccine that can lead to cure. There is no proven effective treatment for nCOVID-19 however along with available antiviral therapy Chinese researchers recommended herbal treatments as effective and alternative treatments options to treat this pandemic. Herbal products are wealthy in dynamic phytochemicals, such as the terpenoids, various collection of flavonoids, sulfides, lignans constiuents, coumarins concentrates, saponins moities, polyphenolics composite, numerous alkaloids, polyines, furyl mixtures, proteins and related compounds, thiophenes and peptides groups. In this review we discussed pathogeneis, immunity and current herbal treatment strategies of nCOVID-19 to cure this world wide pandemic.

Exploration of phytochemicals for inhibition of monoamine oxidase-A induced cancer using molecular docking studies.

Monoamine oxidase A (MAO-A), an enzyme found on outer mitochondrial membrane, catalyzes the oxidative deamination of biogenic amines. Recently, it has been studied that MAO-A have a role in the cancer progression by elevating the generation of Reactive oxygen species (ROS) and by promoting epithelial to mesenchymal transition (EMT) through activation of Vascular endothelial growth factor (VEGF) and its co-receptor neuropilin-1. In this study, an attempt has been made to identify new lead candidates for inhibiting the MAO-A induced initiation and progression of cancer by using molecular docking method. For this purpose, 967 phyto-chemicals from African medicinal plants (AfroDb) were docked gainst the MAO-A (PDB ID: 2Z5X) using Molegro Virtual Docker (MVD) software. MVD calculates the binding energies of target enzyme and ligands at lowest energy conformations by using the piecewise linear potential (PLP) scoring functions. Evaluation of docking studies suggests that compounds Quercetin (ZINC03869685), Apigenin (ZINC03871576), Luteolin (ZINC18185774), [(2R,3S,4R,5S) 3,4,5 trihydroxytetrahydropyran-2-yl]methyl (ZINC14422042) and Scutellarein (ZINC05842416) are docked with highest MVD score -104.412 kcal/mol, -100.189 kcal/mol, -98.5797 kcal/mol, -98.1878 kcal/mol, -97.5296 kcal/mol respectively, therefore, can effectively inhibit MAO-A enzyme and can serve a role as potential lead compounds for developing new drugs for the suppression of cancer.

Computational study on the geometry optimization and excited - state properties of riboflavin by ArgusLab 4.0.1.

Riboflavin (vitamin B2) belongs to a group of respiratory enzymes that occur widely in animals and plants participating in vital oxidation- reduction processes in the body. A computational study was conducted on riboflavin by ArgusLab 4.0.1 to obtain the most active conformation of riboflavin and to analyze its excited-state properties. The best conformation of riboflavin was found to be -199.2173 kcal/mol which is the minimum potential energy calculated by geometry convergence function by ArgusLab software; performed according to Hartree-Fock calculation method. Electronic transition states (ground and excited), were also calculated and visualized by semi-empirical ZINDO method by ArgusLab from which molecular properties such as energies, wave function and dipole moments were established. All the results obtained from geometry optimization and excited-state properties lead us to delineate the active sites with charged groups of riboflavin to interact with the receptors. Such types of investigations are significant for drug-receptor interactions.