Integrating Chemical Profiling, In Vivo Study, and Network Pharmacology to Explore the Anti-inflammatory Effect of Pterocarpus dalbergioides Fruits and Its Correlation with the Major Phytoconstituents.

The purpose of this study is to explore the anti-inflammatory activity of Pterocarpus dalbergioides fruit extract (PFE) and the underlying mechanism. Chemical profiling using ultraperformance liquid chromatography/mass spectrometry identified 28 compounds in PFE (12 flavonoids, 5 fatty acids, 4 phenolic compounds, 3 alkaloids, 2 sesquiterpenes, and 2 xanthophylls). PFE (2 g/kg) significantly inhibited carrageenan-induced rat paw edema after 4 h of administration (42% inhibition). A network-based strategy and molecular docking studies were utilized to uncover the anti-inflammatory mechanism. Out of the identified compounds, 16 compounds with DL ≥ 0.18 and F ≥ 30% were selected using bioavailability (F) and drug-likeness (DL) metrics. The network analysis revealed that 90 genes are considered key targets for the selected compounds and linked to the anti-inflammatory effect. Among all compounds, linoleic acid was found to be the top-most active constituent as it targets maximum genes. Four targets (TNF, IL6, AKT1, and CCL2) among the top 10 genes were found to be the main target genes that may contribute to the anti-inflammatory potential of PFE. Furthermore, KEGG (Kyoto encyclopedia of genes and genomes) pathway analysis revealed that PFE might regulate inflammation through five pathways: neuroactive ligand-receptor interaction, lipid and atherosclerosis, fluid shear stress and atherosclerosis, TNF signaling pathway, and rheumatoid arthritis. The docking study predicted the significant binding affinity between the top four active constituents (linoleic acid, 9-octadecenoic acid, 11,12,13-trihydroxy-9-octadecenoic acid, and rhamnetin-3-O-rhamnoside) and the selected target proteins (TNF and AKT1). The findings highlight PFE as a promising drug lead for controlling inflammation.

Network pharmacology and molecular docking study for biological pathway detection of cytotoxicity of the yellow jasmine flowers.

BACKGROUND: The yellow jasmine flower (Jasminum humile L.) is a fragrant plant belonging to the Oleaceae family with promising phytoconstituents and interesting medicinal uses. The purpose of this study was to characterize the plant metabolome to identify the potential bioactive agents with cytotoxic effects and the underlying mechanism of cytotoxic activity. METHODS: First, HPLC-PDA-MS/MS was used to identify the potential bioactive compounds in the flowers. Furthermore, we assessed the cytotoxic activity of the flower extract against breast cancer (MCF-7) cell line using MTT assay followed by the cell cycle, DNA-flow cytometry, and Annexin V-FITC analyses alongside the effect on reactive oxygen species (ROS). Finally, Network pharmacology followed by a molecular docking study was performed to predict the pathways involved in anti-breast cancer activity. RESULTS: HPLC-PDA-MS/MS tentatively identified 33 compounds, mainly secoiridoids. J. humile extract showed a cytotoxic effect on MCF-7 breast cancer cell line with IC50 value of 9.3 ± 1.2 µg/mL. Studying the apoptotic effect of J. humile extract revealed that it disrupts G2/M phase in the cell cycle, increases the percentage of early and late apoptosis in Annexin V-FTIC, and affects the oxidative stress markers (CAT, SOD, and GSH-R). Network analysis revealed that out of 33 compounds, 24 displayed interaction with 52 human target genes. Relationship between compounds, target genes, and pathways revealed that J. humile exerts its effect on breast cancer by altering, Estrogen signaling pathway, HER2, and EGFR overexpression. To further verify the results of network pharmacology, molecular docking was performed with the five key compounds and the topmost target, EGFR. The results of molecular docking were consistent with those of network pharmacology. CONCLUSION: Our findings suggest that J. humile suppresses breast cancer proliferation and induces cell cycle arrest and apoptosis partly by EGFR signaling pathway, highlighting J. humile as a potential therapeutic candidate against breast cancer.

Revealing the Underlying Mechanism of Acacia Nilotica against Asthma from a Systematic Perspective: A Network Pharmacology and Molecular Docking Study.

Acacia Nilotica (AN) has long been used as a folk cure for asthma, but little is known about how AN could possibly modulate this disease. Thus, an in-silico molecular mechanism for AN's anti-asthmatic action was elucidated utilizing network pharmacology and molecular docking techniques. DPED, PubChem, Binding DB, DisGeNET, DAVID, and STRING were a few databases used to collect network data. MOE 2015.10 software was used for molecular docking. Out of 51 searched compounds of AN, eighteen compounds interacted with human target genes, a total of 189 compounds-related genes, and 2096 asthma-related genes were found in public databases, with 80 overlapping genes between them. AKT1, EGFR, VEGFA, and HSP90AB were the hub genes, whereas quercetin and apigenin were the most active components. p13AKT and MAPK signaling pathways were found to be the primary target of AN. Outcomes of network pharmacology and molecular docking predicted that AN might exert its anti-asthmatic effect probably by altering the p13AKT and MAPK signaling pathway.

Wound Healing and Antioxidant Properties of Launaea procumbens Supported by Metabolomic Profiling and Molecular Docking.

Wounds adversely affect people's quality of life and have psychological, social, and economic impacts. Herbal remedies of Launaea procumbens (LP) are used to treat wounds. In an excision wound model, topical application of LP significantly promoted wound closure (on day 14, LP-treated animals had the highest percentages of wound closure in comparison with the other groups, as the wound was entirely closed with a closure percentage of 100%, p < 0.05). Histological analysis revealed a considerable rise in the number of fibroblasts, the amount of collagen, and its cross-linking in LP-treated wounds. Gene expression patterns showed significant elevation of TGF-ß levels (2.1-fold change after 7 days treatment and 2.7-fold change in 14 days treatment) and downregulation of the inflammatory TNF-α and IL-1ß levels in LP-treated wounds. Regarding in vitro antioxidant activity, LP extract significantly diminished the formation of H2O2 radical (IC50 = 171.6 µg/mL) and scavenged the superoxide radical (IC50 of 286.7 µg/mL), indicating antioxidant potential in a dose-dependent manner. Dereplication of the secondary metabolites using LC-HRMS resulted in the annotation of 16 metabolites. The identified compounds were docked against important wound-healing targets, including vascular endothelial growth factor (VEGF), collagen α-1, tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and transforming growth factor-ß (TGF-ß). Among dereplicated compounds, luteolin 8-C-glucoside (orientin) demonstrated binding potential to four investigated targets (VEGF, interleukin 1ß, TNF-α, and collagen α-1). To conclude, Launaea procumbens extract could be regarded as a promising topical therapy to promote wound healing in excisional wounds, and luteolin 8-C-glucoside (orientin), one of its constituents, is a potential wound-healing drug lead.

A Network Pharmacology Analysis of Cytotoxic Triterpenes Isolated from Euphorbia abyssinica Latex Supported by Drug-likeness and ADMET Studies.

Euphorbia plants have been identified as potential sources of antitumor lead compounds. The current study aimed to isolate and identify the main active constituents of Euphorbia abyssinica latex followed by a cytotoxic evaluation. A network pharmacology approach was employed to predict the underlying mechanism. Finally, drug-likeness and ADMET studies were conducted for active compounds. The phytochemical investigation of the latex of E. abyssinica resulted in the isolation of two triterpenes, 3-acetyloxy-(3α)-urs-12-en-28-oic methyl ester (1) and lup-20(29)-en-3α,23-diol (2). The dichloromethane extract displayed potent cytotoxic activity against the MCF7 cell line with an IC50 value of 4.27 ± 0.12 µg/mL but weak activity against HepG2 and HeLa cell lines (IC50 = 20.47 ± 1.17 and 26.73 ± 2.99 µg/mL, respectively) compared to doxorubicin. Compound 1 showed an encouraging cytotoxic effect against MCF7 with IC50 = 4.20 ± 0.20 µg/mL, followed by compound 2 (IC50 = 5.8 ± 0.35 µg/mL). The network analysis revealed that the two isolated compounds are linked to 68 targets of human nature, among which 51 genes are linked to breast carcinomas and 5 targets (AR, CYP19A1, EGFR, PGR, and PTGS2) might be the top therapeutic targets of isolated compounds on breast cancer. Furthermore, the gene-enrichment analysis revealed that E. abyssinica could play a role in the treatment of breast cancer by striking 51 potential targets via mainly three signaling pathways: P13K-AKT, Wnt, and VEGF. Therefore, isolated triterpenes could be considered effective antitumor agents for breast cancer by elucidating their candidate target to alleviate breast cancer and related signaling pathways of the targets.

Assessment of Ferula hermonis Boiss fertility effects in immature female rats supported by quantification of ferutinin via HPLC and molecular docking.

ETHNOPHARMACOLOGICAL RELEVANCE: Ferula hermonis is a small shrub renowned for its aphrodisiac abilities. Middle East herbalists have utilized Ferula hermonis seed and root as an aphrodisiac folk medicine to treat women's frigidity and male erectile and sexual dysfunction. AIM OF THE STUDY: Assessment of follicle-stimulating hormone-like (FSH), luteinizing hormone-like (LH), and estrogenic activities of the methanolic extract (ME) of the roots of Ferula hermonis on female reproductive function. MATERIALS AND METHODS: The methanolic extract was prepared from the root of F. hermonis and studied at dose level 6 mg/kg in immature female rats for FSH-like, LH-like, and estrogenic activities. These activities were determined by analyzing gross anatomical features, relative organ weight, and serum level of FSH, LH, progesterone and estrogen hormones, and histopathological characteristics. Quantification of the main phytoestrogenic component ferutinin carried out by HPLC. In addition, molecular docking for the binding affinity of ferutinin inside active sites of both estrogen receptor alpha (ERα) and FSH receptor (FSHR) was performed to predict the potential role of ferutinin in regulating the female reproductive process. RESULTS: Ferula hermonis (ME) showed potent FSH-like, LH-like activities and moderate estrogenic effect at the dose of 6 mg/kg. The content of ferutinin in F. hermonis was estimated to be 92 ± 1.33 mg/g of the methanolic extract. Molecular docking of ferutinin with ERα and FSHR displayed strong interaction with target proteins. CONCLUSIONS: Based on results, it can be concluded that Ferula hermonis can be considered as a suitable female fertility improving agent.

Cancer Chemopreventive Potential and Chemical Profiling of Euphorbia abyssinica Endowed with Docking Studies.

Chemical profiling of both fruit and aerial part extracts of Euphorbia abyssinica via ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) showed them to be a rich source of diverse compounds. A total of 39 compounds in both extracts including flavonoids and phenolic compounds were identified as predominant metabolites. The antioxidant activity of both extracts was evaluated using three different in vitro assays (DPPH, ABTS, and FRAP assays). The E. abyssinica fruit extract demonstrated more potent activity compared to the aerial part extract (IC50 of 85.1 ± 1.07 and 562.3 ± 1.01 µg/mL, respectively) in the DPPH assay. Furthermore, using ABTS and FRAP assays, the antioxidant capacities of the fruit extract were 1063.03 ± 37.8 and 1476.5 ± 95.6, respectively, calculated as µM Trolox equivalent/mg extract. One of the existing markers for cancer chemoprevention is the induction of phase II detoxifying enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1), which plays a vital role in cytoprotection against oxidative damage. The extracts were assessed to test their chemopreventive potential via NQO1 enzyme induction. The methanolic extract of fruits demonstrated a concentration-dependent increase in the cancer chemopreventive marker enzyme NQO1 at the protein expression level in a murine hepatoma cell line (Hepa1c1c7). The interaction with Kelch-like ECH-associated protein 1 (KEAP1) is an essential transcription factor that controls the expression of the NQO1 enzyme. The demonstrated induction of NQO1 by the fruit extract is consistent with a molecular docking study of the effect of dereplicated compounds on the KEAP1 target. Among the dereplicated compounds, hesperidin, naringin, and rutin have been established as promising inducer compounds for the chemopreventive marker NQO1. Our results highlight the E. abyssinica fruit extract as a future chemopreventive lead.

Cold-pressed raspberry seeds oil ameliorates high-fat diet triggered non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is considered one of the most serious public health problems affecting liver. The reported beneficial impact of raspberries on obesity and associated metabolic disorder makes it a suitable candidate against NAFLD. In the current study, the chemical profile of raspberry seed oil (RO) was characterized by analysis of fatty acid and tocopherol contents using high-performance liquid chromatography (HPLC) in addition to the determination of total phenolic and flavonoids. High levels of unsaturated fatty acids, linoleic acid (49.9%), α-linolenic acid (25.98%), and oleic acid (17.6%), along with high total tocopherol content (184 mg/100 gm) were detected in oil. The total phenolic and flavonoid contents in RO were estimated to be 22.40 ± 0.25 mg gallic acid equivalent (GAE)/100 mg oil and 1.34 ± 0.15 mg quercetin (QU)/100 mg, respectively. Anti-NAFLD efficacy of RO at different doses (0.4 and 0.8 mL) in a model of a high-fat diet (HFD) fed rats was assessed by estimating lipid profile, liver enzyme activity, glucose and insulin levels as well as adipokines and inflammatory marker. Peroxisome proliferator-activated receptor γ (PPARγ), which is a molecular target for NAFLD was also tested. Liver histopathology was carried out and its homogenate was used to estimate oxidative stress markers. Consumption of RO significantly improved lipid parameters and hepatic enzyme activities, reduced insulin resistance and glucose levels, significantly ameliorated inflammatory and oxidative stress markers. Furthermore, RO treatment significantly modulated adipokines activities and elevated PPARγ levels. Raspberry seed oil administration significantly improved these HFD induced histopathological alterations. Moreover, a molecular docking study was performed on the identified fatty acids and tocopherols. Among the identified compounds, oleic acid, α-linolenic acid and γ-tocopherol exhibited the highest docking score as PPARγ activator posing them as a potential anti-NAFLD drug leads. Study findings suggest RO as an effective therapeutic candidate for ameliorating NAFLD.

Antiulcer Potential of Olea europea L. cv. Arbequina Leaf Extract Supported by Metabolic Profiling and Molecular Docking.

Gastric ulceration is among the most serious humanpublic health problems. Olea europea L. cv. Arbequina is one of the numerous olive varieties which have scarcely been studied. The reported antioxidant and anti-inflammatory potential of the olive plant make it a potential prophylactic natural product against gastric ulcers. Consequently, the main goal of this study is to investigate the gastroprotective effect of Olea europea L. cv. Arbequina leaf extract. LC-HRMS-based metabolic profiling of the alcoholic extract of Olea europea L. cv. Arbequina led to the dereplication of 18 putative compounds (1-18). In vivo indomethacin-induced gastric ulcer in a rat model was established and the Olea europea extract was tested at a dose of 300 mg kg-1 compared to cimetidine (100 mg kg-1). The assessment of gastric mucosal lesions and histopathology of gastric tissue was done. It has been proved that Olea europea significantly decreased the ulcer index and protected the mucosa from lesions. The antioxidant potential of the extract was evaluated using three in vitro assays, H2O2 scavenging, xanthine oxidase inhibitory, and superoxide radical scavenging activities and showed promising activities. Moreover, an in silico based study was performed on the putatively dereplicated compounds, which highlighted that 3-hydroxy tyrosol (4) and oleacein (18) can target the 5-lipoxygenase enzyme (5-LOX) as a protective mechanism against the pathogenesis of ulceration. Upon experimental validation, both compounds 3-hydroxy tyrosol (HT) and oleacein (OC) (4 and 18, respectively) exhibited a significant in vitro 5-LOX inhibitory activity with IC50 values of 8.6 and 5.8 µg/mL, respectively. The present study suggested a possible implication of O. europea leaves as a potential candidate having gastroprotective, antioxidant, and 5-LOX inhibitory activity for the management of gastric ulcers.

Pimenta Oil as A Potential Treatment for Acinetobacter Baumannii Wound Infection: In Vitro and In Vivo Bioassays in Relation to Its Chemical Composition.

Bacterial biofilm contributes to antibiotic resistance. Developing antibiofilm agents, more favored from natural origin, is a potential method for treatment of highly virulent multidrug resistant (MDR) bacterial strains; The potential of Pimenta dioica and Pimenta racemosa essential oils (E.Os) antibacterial and antibiofilm activities in relation to their chemical composition, in addition to their ability to treat Acinetobacter baumannii wound infection in mice model were investigated; P. dioica leaf E.O at 0.05 µg·mL-1 efficiently inhibited and eradicated biofilm formed by A. baumannii by 85% and 34%, respectively. Both P. diocia and P. racemosa leaf E.Os showed a bactericidal action against A. baumanii within 6h at 2.08 µg·mL-1. In addition, a significant reduction of A. baumannii microbial load in mice wound infection model was found. Furthermore, gas chromatography mass spectrometry analysis revealed qualitative and quantitative differences among P. racemosa and P. dioica leaf and berry E.Os. Monoterpene hydrocarbons, oxygenated monoterpenes, and phenolics were the major detected classes. ß-Myrcene, limonene, 1,8-cineole, and eugenol were the most abundant volatiles. While, sesquiterpenes were found as minor components in Pimenta berries E.O; Our finding suggests the potential antimicrobial activity of Pimenta leaf E.O against MDR A. baumannii wound infections and their underlying mechanism and to be further tested clinically as treatment for MDR A. baumannii infections.

In vitro cytotoxic activity of six Syzygium leaf extracts as related to their phenolic profiles: An untargeted UHPLC-QTOF-MS approach.

Untargeted metabolomics was used in this study to discriminate the phenolic fingerprints of six Syzygium species. This approach resulted in the annotation of 441 compounds that belong to different phenolic classes, such as flavonoids, lignans, stilbenes, tyrosols, alkylphenols, and phenolic acids. Multivariate data analysis unraveled the main differences between the studied species. S. paniculatum and S. aqueum were the richest sources in terms of phenolic compounds, cumulatively amounting to 355.3 and 266.4 mg/g dry matter, respectively. Nevertheless, S. jambos showed reduced amounts of phenolics, when compared with other species. The biological activity of Syzygium leaf extracts was assessed on MCF-7 breast adenocarcinoma and MDA-MB-231 breast cancer cell lines. Potent estrogenic activity was detected using the SRB assay on MCF-7. This activity may be ascribable to the presence of phenolic compounds miming phytoestrogens such as lignans, stilbenes, and isoflavonoids in the investigated Syzygium extracts. By examining the biological effect of Syzygium extracts against MDA-MB-231 cell lines, the Syzygium gratum leaf extract exhibited the strongest inhibition, with IC50 = 19.4 µg/mL, followed by S. paniculatum (IC50 = 50.9 µg/mL). However, the Syzygium gratum leaf extract showed a potent cytotoxic effect on normal human skin fibroblasts, HSF (IC50 = 1.24 µg/mL), assuming a nonselective cytotoxic effect. On the other hand, other studied Syzygium leaves proved as safe nutraceuticals (IC50 ≥ 100 µg/mL) on HSF cell lines. Our study suggested a possible implication of Syzygium malaccense and Syzygium aqueum leaves as potential estrogenic candidates in relation to their health-promoting phenolic constituents.