Phytochemical analysis and anti-infective potential of fungal endophytes isolated from Nigella sativa seeds.

Endophytic fungi, particularly from higher plants have proven to be a rich source of antimicrobial secondary metabolites. The purpose of this study is to examine the antimicrobial potential of three endophytic fungi Aspergillus sp. SA1, Aspergillus sp. SA2, and Aspergillus sp. SA3, cultivated from Nigella sativa seeds against Staphylococcus aureus (ATCC 9144), Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27853), Klebsiella pneumoniae (ATCC 13883), MRSA (ATCC 33591), and human pathogen Candida albicans (ATCC 10231). Furthermore, the most active cultivated endophytic fungi were molecularly identified via internal transcribed spacer (ITS) sequencing. HR-ESIMS guided approach has been used successfully in chemical profiling of 26 known bioactive secondary metabolites (1-26), which belongs to different classes of natural compounds such as polyketides, benzenoids, quinones, alcohols, phenols or alkaloids. Finally, in-silico interactions within active site of fungal Cyp51 and bacterial DNA gyrase revealed possibility of being a hit-target for such metabolites as antimicrobials.

Evaluation of the anti-infective potential of the seed endophytic fungi of Corchorus olitorius through metabolomics and molecular docking approach.

BACKGROUND: Endophytic fungi are very rich sources of natural antibacterial and antifungal compounds. The main aim of this study is to isolate the fungal endophytes from the medicinal plant Corchorus olitorius seeds (F. Malvaceae), followed by antimicrobial screening against various bacterial and fungal strains. RESULTS: Seven endophytic fungal strains belonging to different three genera were isolated, including Penicillium, Fusarium, and Aspergillus. The seven isolated endophytic strains revealed selective noticeable activity against Escherichia coli (ATCC25922) with varied IC50s ranging from 1.19 to 10 µg /mL, in which Aspergillus sp. (Ar 6) exhibited the strongest potency against E. coli (ATCC 25,922) and candida albicans (ATCC 10,231) with IC50s 1.19 and 15 µg /mL, respectively. Therefore, the chemical profiling of Aspergillus sp. (Ar 6) crude extract was performed using LC-HR-ESI-MS and led to the dereplication of sixteen compounds of various classes (1-16). In-silico analysis of the dereplicated metabolites led to highlighting the compounds responsible for the antimicrobial activity of Aspergillus sp. extract. Moreover, molecular docking showed the potential targets of the metabolites; Astellatol (5), Aspergillipeptide A (10), and Emericellamide C (14) against E. coli and C. albicans. CONCLUSION: These results will expand the knowledge of endophytes and provide us with new approaches to face the global antibiotic resistance problem and the future production of undiscovered compounds different from the antibiotics classes.

Network Pharmacological Analysis of the Red Sea Sponge Hyrtios erectus Extract to Reveal Anticancer Efficacy of Corresponding Loaded Niosomes.

In this study, the LC-HRMS-assisted chemical profiling of Hyrtios erectus sponge led to the annotation of eleven major compounds (1-11). H. erectus-derived crude extract (HE) was tested in vitro for its antiproliferative activity against three human cancer cell lines, Hep-G2 (human liver cancer cell line), MCF-7 (breast cancer cell line), and Caco-2 (colon cancer cell line), before and after encapsulation within niosomes. Hyrtios erectus extract showed moderate in vitro antiproliferative activities towards the studied cell lines with IC50 values 18.5 ± 0.08, 15.2 ± 0.11, and 13.4 ± 0.12, respectively. The formulated extract-containing niosomes (size 142.3 ± 10.3 nm, PDI 0.279, and zeta potential 22.8 ± 1.6) increased the in vitro antiproliferative activity of the entrapped extract significantly (IC50 8.5 ± 0.04, 4.1 ± 0.07, and 3.4 ± 0.05, respectively). A subsequent computational chemical study was performed to build a sponge-metabolite-targets-cancer diseases network, by focusing on targets that possess anticancer activity toward the three cancer types: breast, colon, and liver. Pubchem, BindingDB, and DisGenet databases were used to build the network. Shinygo and KEGG databases in addition to FunRich software were used for gene ontology and functional analysis. The computational analysis linked the metabolites to 200 genes among which 147 genes related to cancer and only 64 genes are intersected in the three cancer types. The study proved that the co-occurrence of compounds 1, 2, 3, 7, 8, and 10 are the most probable compounds possessing cytotoxic activity due to large number of connections to the intersected cytotoxic genes with edges range from 9-14. The targets possess the anticancer effect through Pathways in cancer, Endocrine resistance and Proteoglycans in cancer as mentioned by KEGG and ShinyGo 7.1 databases. This study introduces niosomes as a promising strategy to promote the cytotoxic potential of H. erectus extract.

Bioassay-Guided Fractionation with Antimalarial and Antimicrobial Activities of Paeonia officinalis.

Bioassay-guided fractionation technique of roots of Paeonia officinalis led to isolation and structure elucidation of seven known compounds, including four monoterpene glycosides: lactiflorin (1), paeoniflorin (4), galloyl paeoniflorin (5), and (Z)-(1S,5R)-ß-pinen-10-yl ß-vicianoside (7); two phenolics: benzoic acid (2) and methyl gallate (3); and one sterol glycoside: ß-sitosterol 3-O-ß-D-glucopyranoside (6). The different fractions and the isolated compounds were evaluated for their antimicrobial and antimalarial activities. Fraction II and III showed antifungal activity against Candida neoformans with IC50 values of 28.11 and 74.37 µg/mL, respectively, compared with the standard fluconazole (IC50 = 4.68 µg/mL), and antibacterial potential against Pseudomonas aeruginosa (IC50 = 20.27 and 24.82 µg/mL, respectively) and Klebsiella pneumoniae (IC50 = 43.21 and 94.4 µg/mL, respectively), compared with the standard meropenem (IC50 = 28.67 and 43.94 µg/mL, respectively). Compounds 3 and 5 showed antimalarial activity against Plasmodium falciparum D6 with IC50 values of 1.57 and 4.72 µg/mL and P. falciparum W2 with IC50 values of 0.61 and 2.91 µg/mL, respectively, compared with the standard chloroquine (IC50 = 0.026 and 0.14 µg/mL, respectively).

The Potential of Corchorus olitorius Seeds Buccal Films for Treatment of Recurrent Minor Aphthous Ulcerations in Human Volunteers.

Aphthous ulcers are very common disorders among different age groups and are very noxious and painful. The incidence of aphthous ulcer recurrence is very high and it may even last for a maximum of 6 days and usually, patients cannot stand its pain. This study aims to prepare a buccoadhesive fast dissolving film containing Corchorus olitorius seed extract to treat recurrent minor aphthous ulceration (RMAU) in addition to clinical experiments on human volunteers. An excision wound model was used to assess the in vivo wound healing potential of Corchorus olitorius L. seed extract, with a focus on wound healing molecular targets such as TGF-, TNF-, and IL-1. In addition, metabolomic profiling using HR-LCMS for the crude extract of Corchorus olitorius seeds was explored. Moreover, molecular docking experiments were performed to elucidate the binding confirmation of the isolated compounds with three molecular targets (TNF-α, IL-1ß, and GSK3). Additionally, the in vitro antioxidant potential of C. olitorius seed extract using both H2O2 and superoxide radical scavenging activity was examined. Clinical experiments on human volunteers revealed the efficiency of the prepared C. olitorius seeds buccal fast dissolving film (CoBFDF) in relieving pain and wound healing of RMAU. Moreover, the wound healing results revealed that C. olitorius seed extract enhanced wound closure rates (p ≤ 0.001), elevated TGF-ß levels and significantly downregulated TNF-α and IL-1ß in comparison to the Mebo-treated group. The phenotypical results were supported by biochemical and histopathological findings, while metabolomic profiling using HR-LCMS for the crude extract of Corchorus olitorius seeds yielded a total of 21 compounds belonging to diverse chemical classes. Finally, this study highlights the potential of C. olitorius seed extract in wound repair uncovering the most probable mechanisms of action using in silico analysis.

Targeting 3CLpro and SARS-CoV-2 RdRp by Amphimedon sp. Metabolites: A Computational Study.

Since December 2019, novel coronavirus disease 2019 (COVID-19) pandemic has caused tremendous economic loss and serious health problems worldwide. In this study, we investigated 14 natural compounds isolated from Amphimedon sp. via a molecular docking study, to examine their ability to act as anti-COVID-19 agents. Moreover, the pharmacokinetic properties of the most promising compounds were studied. The docking study showed that virtually screened compounds were effective against the new coronavirus via dual inhibition of SARS-CoV-2 RdRp and the 3CL main protease. In particular, nakinadine B (1), 20-hepacosenoic acid (11) and amphimedoside C (12) were the most promising compounds, as they demonstrated good interactions with the pockets of both enzymes. Based on the analysis of the molecular docking results, compounds 1 and 12 were selected for molecular dynamics simulation studies. Our results showed Amphimedon sp. to be a rich source for anti-COVID-19 metabolites.

Natural Product Repertoire of the Genus Amphimedon.

Marine sponges are a very attractive and rich source in the production of novel bioactive compounds. The sponges exhibit a wide range of pharmacological activities. The genus Amphimedon consists of various species, such as viridis, compressa, complanata, and terpenensis, along with a handful of undescribed species. The Amphimedon genus is a rich source of secondary metabolites containing diverse chemical classes, including alkaloids, ceramides, cerebrososides, and terpenes, with various valuable biological activities. This review covers the literature from January 1983 until January 2018 and provides a complete survey of all the compounds isolated from the genus Amphimedon and the associated microbiota, along with their corresponding biological activities, whenever applicable.

Bioactive Natural Products of Marine Sponges from the Genus Hyrtios.

Marine sponges are known as a rich source for novel bioactive compounds with valuable pharmacological potential. One of the most predominant sponge genera is Hyrtios, reported to have various species such as Hyrtios erectus, Hyrtios reticulatus, Hyrtios gumminae, Hyrtios communis, and Hyrtios tubulatus and a number of undescribed species. Members of the genus Hyrtios are a rich source of natural products with diverse and valuable biological activities, represented by different chemical classes including alkaloids, sesterterpenes and sesquiterpenes. This review covers the literature until June 2016, providing a complete survey of all compounds isolated from the genus Hyrtios with their corresponding biological activities whenever applicable.

Capturing the antimicrobial profile of Paeonia officinalis, Jasminum officinale and Rosa damascene against methicillin resistant Staphylococcus aureus with metabolomics analysis and network pharmacology.

In the current study, we evaluated the in vitro antibacterial efficacy of the roots' extracts of Jasminum officinale, Rosa damascene and Paeonia officinalis against MRSA (methicillin-resistant Staphylococcus aureus) by well diffusion technique. The root extract of P. officinalis exerted a potent anti-MRSA with MIC 0.4673 µg/ml, while both J. officinale and R. damascene exhibited very weak activity. Therefore, chemical profiling of the crude extract P. officinalis roots assisted by LC-HR-ESI-MS was performed and led to the dereplication of twenty metabolites of different classes, in which terpenes are the most abundant compounds. On a molecular level, network pharmacology was used to determine the targets of active metabolites to bacterial infections, particularly MRSA. Online databases PubChem, UniProt, STRING, and Swiss Target Prediction were used. In addition to using CYTOSCAPE software to display and analyze the findings, ShinyGO and FunRich tools were used to identify the gene enrichment analysis to the set of recognized genes. The results detected the identified metabolites were annotated by 254 targets. ALB, ACHE, TYMS, PRKCD, PLG, MMP9, MMP2, ERN1, EDNRA, BRD4 were found to be associated with MRSA infection. The top KEGG pathway was the vascular smooth muscle contraction pathway according to enrichment FDR. The present study suggested a possible implication of P. officinalis roots as a potent candidate having a powerful antibacterial activity against MRSA.

In Vitro and Randomized Controlled Clinical Study of Natural Constituents' Anti-HPV Potential for Treatment of Plantar Warts Supported with In Silico Studies and Network Analysis.

The aim of this study is to evaluate the anti-HPV potential of a Moringa olifera Lam seed, Nigella sativa L. seed, and Musa Acuminata peel herbal mixture in the form of polymer film-forming systems. A clinical trial conducted in outpatient clinics showed that the most significant outcome was wart size and quantity. Compared to the placebo group, the intervention group's size and number of warts were considerably better according to the results. Chemical profiling assisted by LC-HRMS led to the dereplication of 49 metabolites. Furthermore, network pharmacology was established for the mixture of three plants; each plant was studied separately to find out the annotated target genes, and then, we combined all annotated genes of all plants and filtered the genes to specify the genes related to human papilloma virus. In a backward step, the 24 configured genes related to HPV were used to specify only 30 compounds involved in HPV infection based on target genes. CA2 and EGFR were the top identified genes with 16 and 12 edges followed by PTGS2, CA9, and MMP9 genes with 11 edges each. A molecular docking study for the top active identified compounds of each species was conducted in the top target HPV genes, CA2 and EGFR, to investigate the mode of interaction between these compounds and the targets' active sites.

The anti-infective potential of the endophytic fungi associated with Allium cepa supported by metabolomics analysis and docking studies.

Endophytic fungi are known to be a rich source of anti-infective drugs. In our study, Allium cepa was investigated for fungal diversity using different media to give 11 isolates which were identified morphologically. Out of the isolated fungal strains, Penicillium sp. (LCEF10) revealed potential anti-infective activity against the tested microbes (Fusarium solani ATTC 25922, Pseudomonas aeruginosa (ATTC 29231), Staphylococcus aureus ATTC 27853, Candida albicans ATTC 10231), besides, their MICs were measured by well diffusion method, therefore, it was subjected to molecular identification in addition to phylogenetic analysis. Moreover, the ITS sequence of strain LCEF10 showed a consistent assignment with the highest sequence similarity (99.81%) to Penicillium oxalicum NRRL 787. The crude ethyl acetate extract of Penicillium sp. LCEF10 was investigated for metabolomic analysis using LC-HR-ESI-MS. The metabolic profiling revealed the presence of polyketides, macrolides, phenolics and terpenoids. Furthermore, in silico molecular docking study was carried out to predict which compounds most likely responsible for the anti-infective activity.

Pro-Apoptotic Activity of Epi-Obtusane against Cervical Cancer: Nano Formulation, In Silico Molecular Docking, and Pharmacological Network Analysis.

Cancer is a major disease that threatens human health all over the world. Intervention and prevention in premalignant processes are successful ways to prevent cancer from striking. On the other hand, the marine ecosystem is a treasure storehouse of promising bioactive metabolites. The use of such marine products can be optimized by selecting a suitable nanocarrier. Therefore, epi-obtusane, previously isolated from Aplysia oculifera, was investigated for its potential anticancer effects toward cervical cancer through a series of in vitro assays in HeLa cells using the MTT assay method. Additionally, the sesquiterpene was encapsulated within a liposomal formulation (size = 130.8 ± 50.3, PDI = 0.462, zeta potential -12.3 ± 2.3), and the antiproliferative potential of epi-obtusane was investigated against the human cervical cancer cell line HeLa before and after encapsulation with liposomes. Epi-obtusane exhibited a potent effect against the HeLa cell line, while the formulated molecule with liposomes increased the in vitro antiproliferative activity. Additionally, cell cycle arrest analysis, as well as the apoptosis assay, performed via FITC-Annexin-V/propidium iodide double staining (flow cytofluorimetry), were carried out. The pharmacological network enabled us to deliver further insights into the mechanism of epi-obtusane, suggesting that STAT3 might be targeted by the compound. Moreover, molecular docking showed a comparable binding score of the isolated compound towards the STAT3 SH2 domain. The targets possess an anticancer effect through the endometrial cancer pathway, regulation of DNA templated transcription, and nitric oxide synthase, as mentioned by the KEGG and ShinyGo 7.1 databases.

New cytotoxic dammarane type saponins from Ziziphus spina-christi.

Cancer is the world's second-leading cause of death. Drug development efforts frequently focus on medicinal plants since they are a valuable source of anticancer medications. A phytochemical investigation of the edible Ziziphus spina-christi (F. Rhamnaceae) leaf extract afforded two new dammarane type saponins identified as christinin E and F (1, 2), along with the known compound christinin A (3). Different cancer cell lines, such as lung cancer (A549), glioblastoma (U87), breast cancer (MDA-MB-231), and colorectal carcinoma (CT-26) cell lines, were used to investigate the extracted compounds' cytotoxic properties. Our findings showed significant effects on all the tested cell lines at varying concentrations (1, 5, 10, and 20 µg/mL). The three compounds exhibited potent activity at low concentrations (< 10 µg/mL), as evidenced by their low IC50 values. To further investigate the complex relationships between these identified cancer-relevant biological targets and to identify critical targets in the pathogenesis of the disease, we turned to network pharmacology and in silico-based investigations. Following this, in silico-based analysis (e.g., inverse docking, ΔG calculation, and molecular dynamics simulation) was performed on the structures of the isolated compounds to identify additional potential targets for these compounds and their likely interactions with various signalling pathways relevant to this disease. Based on our findings, Z. spina-christi's compounds showed promise as potential anti-cancer therapeutic leads in the future.

Wound Healing and Antioxidant Capabilities of Zizyphus mauritiana Fruits: In-Vitro, In-Vivo, and Molecular Modeling Study.

LC-HRMS-assisted chemical profiling of Zizyphus mauritiana fruit extract (ZFE) led to the dereplication of 28 metabolites. Furthermore, wound healing activity of ZFE in 24 adult male New Zealand Dutch strain albino rabbits was investigated in-vivo supported by histopathological investigation. Additionally, the molecular mechanism was studied through different in-vitro investigations as well as, studying both relative gene expression and relative protein expression patterns. Moreover, the antioxidant activity of ZFE extract was examined using two in-vitro assays including hydrogen peroxide and superoxide radical scavenging activities that showed promising antioxidant potential. Topical application of the extract on excision wounds showed a significant increase in the wound healing rate (p < 0.001) in comparison to the untreated and MEBO®-treated groups, enhancing TGF-ß1, VEGF, Type I collagen expression, and suppressing inflammatory markers (TNF-α and IL-1ß). Moreover, an in silico molecular docking against TNFα, TGFBR1, and IL-1ß showed that some of the molecules identified in ZFE can bind to the three wound-healing related protein actives sites. Additionally, PASS computational calculation of antioxidant activity revealed potential activity of three phenolic compounds (Pa score > 0.5). Consequently, ZFE may be a potential alternative medication helping wound healing owing to its antioxidant and anti-inflammatory activities.

Cytotoxic activity of actinomycetes Nocardia sp. and Nocardiopsis sp. associated with marine sponge Amphimedon sp.

Cancer is a hazard life-threatening disease, which affect huge population worldwide. Marine actinomycetes are considered as promising source for potential chemotherapeutic agents. In our study, we carried out metabolic profiling for Nocardia sp. UR 86 and Nocardiopsis sp. UR 92 that were cultivated from the Red Sea sponge Amphimedon sp. to investigate their chemical diversity using different media conditions. The crude culture extracts were subjected to high-resolution mass spectrometry (HRMS) analysis. The chemical profiles of the different extracts of Nocardia sp. UR 86 and Nocardiopsis sp. UR 92 revealed their richness in diverse metabolites and consequently twenty compounds (1-20) were annotated. Moreover, the obtained extracts of the differently cultivated Nocardia sp. UR 86 and Nocardiopsis sp. UR 92 were investigated against three cell lines HepG2, MCF-7 and CACO2 and revealed the targeted cytotoxicity of Nocardia sp. and Nocardiopsis sp. metabolites against the three cell lines.

Antimicrobial potentials of natural products against multidrug resistance pathogens: a comprehensive review.

Antibiotic resistance is one of the critical issues, describing a significant social health complication globally. Hence, the discovery of novel antibiotics has acquired an increased attention particularly against drug-resistant pathogens. Natural products have served as potent therapeutics against pathogenic bacteria since the glorious age of antibiotics of the mid 20th century. This review outlines the various mechanistic candidates for dealing with multi-drug resistant pathogens and explores the terrestrial phytochemicals isolated from plants, lichens, insects, animals, fungi, bacteria, mushrooms, and minerals with reported antimicrobial activity, either alone or in combination with conventional antibiotics. Moreover, newly established tools are presented, including prebiotics, probiotics, synbiotics, bacteriophages, nanoparticles, and bacteriocins, supporting the progress of effective antibiotics to address the emergence of antibiotic-resistant infectious bacteria. Therefore, the current article may uncover promising drug candidates that can be used in drug discovery in the future.

Antiulcer Potential of Psidium guajava Seed Extract Supported by Metabolic Profiling and Molecular Docking.

One of the most severe human health problems is gastric ulceration. The main aim of our study is to explore the gastroprotective effect of the Psidium guajava seeds extract (PGE). Metabolic profiling based on LC-HRMS for the extract led to the dereplication of 23 compounds (1-23). We carried out a gastric ulcer model induced by indomethacin in male albino rats in vivo and the extract of PGE was investigated at a dose of 300 mg/kg in comparison to cimetidine (100 mg/kg). Furthermore, the assessment of gastric mucosal lesions and histopathology investigation of gastric tissue was done. It has been proved that Psidium guajava seeds significantly decreased the ulcer index and protected the mucosa from lesions. The antiulcer effect of Psidium guajava seed extract, which has the power of reducing the ensuing inflammatory reactions, can counteract the inflammation induced by indomethacin by the downregulation of relative genes expression (IL-1ß, IL-6, and TNF-α). Moreover, PGE significantly downregulated the increased COX-2, TGF-ß, and IGF-1 relative genes expression, confirming its beneficial effect in ulcer healing. Moreover, the possible PGE antioxidant potential was determined by in vitro assays using hydrogen peroxide and superoxide radical scavenging and revealed high antioxidant potential. Additionally, on the putatively annotated metabolites, an in silico study was conducted, which emphasized the extract's antiulcer properties might be attributed to several sterols such as stigmasterol and campesterol. The present study provided evidence of Psidium guajava seeds considered as a potential natural gastroprotective agent.

Mechanistic Wound Healing and Antioxidant Potential of Moringa oleifera Seeds Extract Supported by Metabolic Profiling, In Silico Network Design, Molecular Docking, and In Vivo Studies.

Moringa oleifera Lam. (Moringaceae) is an adaptable plant with promising phytoconstituents, interesting medicinal uses, and nutritional importance. Chemical profiling of M. oleifera seeds assisted by LC-HRMS (HPLC system coupled to a high resolution mass detector) led to the dereplication of 19 metabolites. Additionally, the wound healing potential of M. oleifera seed extract was investigated in male New Zealand Dutch strain albino rabbits and supported by histopathological examinations. Moreover, the molecular mechanisms were investigated via different in vitro investigations and through analyzing the relative gene and protein expression patterns. When compared to the untreated and MEBO®-treated groups, topical administration of M. oleifera extract on excision wounds resulted in a substantial increase in wound healing rate (p < 0.001), elevating TGF-ß1, VEGF, Type I collagen relative expression, and reducing inflammatory markers such as IL-1ß and TNF-α. In vitro antioxidant assays showed that the extract displayed strong scavenging effects to peroxides and superoxide free radicals. In silico studies using a molecular docking approach against TNF-α, TGFBR1, and IL-1ß showed that some metabolites in M. oleifera seed extract can bind to the active sites of three wound-healing related proteins. Protein−protein interaction (PPI) and compound−protein interaction (CPI) networks were constructed as well. Quercetin, caffeic acid, and kaempferol showed the highest connectivity with the putative proteins. In silico drug likeness studies revealed that almost all compounds comply with both Lipinski's and Veber's rule. According to the previous findings, an in vitro study was carried out on the pure compounds, including quercetin, kaempferol, and caffeic acid (identified from M. oleifera) to validate the proposed approach and to verify their potential effectiveness. Their inhibitory potential was evaluated against the pro-inflammatory cytokine IL-6 and against the endopeptidase MMPs (matrix metalloproteinases) subtype I and II, with highest activity being observed for kaempferol. Hence, M. oleifera seeds could be a promising source of bioactive compounds with potential antioxidant and wound healing capabilities.

Cytotoxic potential of the Red Sea sponge Amphimedon sp. supported by in silico modelling and dereplication analysis.

The chemical profile of the butanol fraction of the Red Sea sponge Amphimedon sp. was explored using liquid chromatography coupled with high-resolution mass spectrometry and identified compounds (1-11). Moreover, cytotoxic activities of the total extract and other fractions were examined against three cell lines HEPG2, MCF7 and CACO2, revealed the powerful effect of the total extract and the butanol fraction against the three cell lines. Further chromatographic separation of the active butanol fraction yielded the isolation of three known compounds (9-11). Molecular modelling was carried out with the active site of the SET protein. Docking study results revealed that amphiceramides A-B (7-8) and acetamidoglucosyl ceramide (6) showed the highest energy binding affinities and interaction in the binding site of SET protein. Additionally, ADME/Tox calculations were performed for the compounds to predict their pharmacokinetics profile. These results highlighted the valuable chemical entities of Amphimedon sp. as lead source for cytotoxic natural products.

Hyphaene thebaica (doum)-derived extract alleviates hyperglycemia in diabetic rats: a comprehensive in silico, in vitro and in vivo study.

In the present study, we investigated the hypoglycemic effect of different extracts (i.e. organic and aqueous) derived from the fruits of Hyphaene thebaica (doum) on male streptozotocin-induced diabetic rats. Blood glucose levels as well as the relative gene expression of insulin, TNF-α, and TGF-ß were determined in the pancreatic tissue of the experimental animals. Treatment of STZ-induced diabetic rats with aqueous extracts of the plant fruit over 7 weeks significantly reduced the elevated blood glucose and increased the relative expression of insulin, while the relative expression of inflammatory mediators (i.e. TNF-α and TGF-ß) was significantly reduced. Histopathological investigation also revealed that the aqueous extract treatment effectively reversed the ß-cell necrosis induced by STZ and restored its normal morphology. Furthermore, liquid chromatography high resolution mass spectrometry (LC-HRMS) and in silico chemical investigation of the aqueous extract elucidated its major bioactive phytochemicals (i.e. flavonoids) and putatively determined the pancreatic KATP channel as a target for these bioactive components. In vitro insulin secretion assay revealed that myricetin, luteolin, and apigenin were able to induce insulin secretion by human pancreatic cells (insulin production = 20.9 ± 1.3, 13.74 ± 1.8, and 11.33 ± 1.1 ng mL-1, respectively). Using molecular docking and dynamics simulations, we were able to shed the light on the insulin secretagogue's mode of action through these identified bioactive compounds and to determine the main structural elements required for its bioactivity. This comprehensive investigation of this native fruit will encourage future clinical studies to recommend edible and widely available fruits like doum to be a part of DM treatment plans.