Improving plant adaptation to soil antimony contamination: the synergistic contribution of arbuscular mycorrhizal fungus and olive mill waste.

BACKGROUND: This study aimed to investigate the alterations in biochemical and physiological responses of oat plants exposed to antimony (Sb) contamination in soil. Specifically, we evaluated the effectiveness of an arbuscular mycorrhizal fungus (AMF) and olive mill waste (OMW) in mitigating the effects of Sb contamination. The soil was treated with a commercial strain of AMF (Rhizophagus irregularis) and OMW (4% w/w) under two different levels of Sb (0 and 1500 mg kg-1 soil). RESULTS: The combined treatment (OMW + AMF) enhanced the photosynthetic rate (+ 40%) and chlorophyll a (+ 91%) and chlorophyll b (+ 50%) content under Sb condition, which in turn induced more biomass production (+ 67-78%) compared to the contaminated control plants. More photosynthesis in OMW + AMF-treated plants gives a route for phenylalanine amino acid synthesis (+ 69%), which is used as a precursor for the biosynthesis of secondary metabolites, including flavonoids (+ 110%), polyphenols (+ 26%), and anthocyanins (+ 63%) compared to control plants. More activation of phenylalanine ammonia-lyase (+ 38%) and chalcone synthase (+ 26%) enzymes in OMW + AMF-treated plants under Sb stress indicated the activation of phenylpropanoid pathways in antioxidant metabolites biosynthesis. There was also improved shifting of antioxidant enzyme activities in the ASC/GSH and catalytic pathways in plants in response to OMW + AMF and Sb contamination, remarkably reducing oxidative damage markers. CONCLUSIONS: While individual applications of OMW and AMF also demonstrated some degree of plant tolerance induction, the combined presence of AMF with OMW supplementation significantly enhanced plant biomass production and adaptability to oxidative stress induced by soil Sb contamination.

In vitro and in silico biopotentials of phytochemical compositions and antistaphylococcal and antipseudomonal activities of volatile compounds of Argania spinosa (L.) seed oil.

Active components in medicinal plants provide unlimited useful and traditional medicines. Antimicrobial activities are found in secondary metabolites in plant extracts such as argan oil. This experimental investigation aims to determine argan oil's volatile compounds and examine their in vitro antimicrobial properties. In silico simulations, molecular docking, pharmacokinetics, and drug-likeness prediction revealed the processes underlying the in vitro biological possessions. Gas chromatography-mass spectrometry (GC/MS) was used to screen argan oil's primary components. In silico molecular docking studies were used to investigate the ability of the selected bioactive constituents of argan oil to act effectively against Pseudomonas aeruginosa and Staphylococcus aureus (S. aureus) isolated from infections. The goal was to study their ability to interact with both bacteria's essential therapeutic target protein. The 21 chemicals in argan oil were identified by GC/MS. Docking results for all compounds with S. aureus and P. aeruginosa protease proteins ranged from -5 to -9.4 kcal/mol and -5.7 to -9.7 kcal/mol, respectively, compared to reference ligands. Our docking result indicates that the 10-octadecenoic acid, methyl ester was the most significant compound with affinity scores of -9.4 and -9.7 kcal/mol for S. aureus and P. aeruginosa proteins, respectively. The minimal bactericidal concentration (MBC) and minimal inhibitory concentration (MIC) of argan oil were 0.7 ± 0.03 and 0.5 ± 0.01 for S. aureus and 0.4 ± 0.01 and 0.3 ± 0.02 for P. aeruginosa, respectively. We confirmed the antimicrobial properties of argan oil that showed significant growth inhibition for S. aureus and P. aeruginosa.

Cytotoxic and Antioxidant Potential of Launaea mucronata Forssk Essential Oil Growing in Northern Saudi Arabia.

Essential oils are naturally occurring multicomponent combinations of isoprenoids with distinctive odors that are produced by aromatic plants from mevalonic acid. They are extensively applied in aromatherapy for the treatment of various ailments. To investigate the potential therapeutic value of the ingredients in Launaea mucronata essential oil (EO), gas chromatography-mass spectrometry (GC-MS) analysis was used for essential oil characterization. Then, 2,2-diphenyl-1-picrylhydrazyl (DPPH), ß-carotene/linoleic acid, and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assays were used to evaluate the antioxidants. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used to estimate the cytotoxicity. Following a thorough analysis of the GC-MS chromatogram, 87 components representing 97.98% of the entire EO mixture were identified. N-eicosane (10.92%), 2E,6Z-farnesol (10.74%), and 2Z,6E-farnesyl acetone (46.35%) were determined to be the major components of the oil. When the produced EO was evaluated for its antioxidant properties, it showed a strong inhibitory effect (%) of 65.34 at a concentration of 80 µg/mL. The results (g/mL) showed a positive response against the tested cell lines for HCT-116, MCF-7, and HepG2 (8.45, 10.24, and 6.78 g/mL, respectively). A high-concentration mixture of deadly components consisting of farnesol, bisabolol, eicosane, and farnesyl acetone may be responsible for this significant cytotoxic action, which was especially noticeable in the HepG2 cell line. Molecular docking occurred between farnesol and farnesyl acetone with the target residues of topoisomerases I and II, CDK4/cyclD1, and Aurora B kinases; these showed binding free energies ranging from -4.5 to -7.4 kcal/mol, thus demonstrating their antiproliferative action. In addition, farnesol and farnesyl acetone fulfilled most of the ADME and drug-likeness properties, indicating their activity.

Introducing of novel class of pyrano[2,3-c]pyrazole-5-carbonitrile analogs with potent antimicrobial activity, DNA gyrase inhibition, and prominent pharmacokinetic and CNS toxicity profiles supported by molecular dynamic simulation.

Microbiological DNA gyrase is recognized as an exceptional microbial target for the innovative development of low-resistant and more effective antimicrobial drugs. Hence, we introduced a one-pot facile synthesis of a novel pyranopyrazole scaffold bearing different functionalities; substituted aryl ring, nitrile, and hydroxyl groups. All new analogs were characterized with full spectroscopic data. The antimicrobial screening for all analogs was assessed against standard strains of Gm + ve and Gm-ve through in vitro considers. The screened compounds displayed very promising MIC/MBC values against some of the bacterial strains with broad or selective antibacterial effects. Of these, 4j biphenyl analog showed 0.5-2/2-8 µg/mL MIC/MBC for suppression and killing of Gm + ve and Gm-ve strains. Moreover, the antimicrobial screening was assessed for the most potent analogs against certain highly resistant microbial strains. Consequently, DNA gyrase supercoiling assay was done for all analogs using ciprofloxacin as reference positive control. Obviously, the results showed a different activity profile with potent analog 4j with IC50 value 6.29 µg/mL better than reference drug 10.2 µg/mL. Additionally, CNS toxicity testing was done using the HiB5 cell line for attenuation of GABA/NMDA expression to both 4j and ciprofloxacin compounds that revealed better neurotransmitter modulation by novel scaffold. Importantly, docking and dynamic simulations were performed for the most active 4j analog to investigate its interaction with DNA binding sites, which supported the in vitro observations and compound stability with binding pocket. Finally, a novel scaffold pyranopyrazole was introduced as a DNA gyrase inhibitor with prominent antibacterial efficacy and low CNS side effect toxicity better than quinolones.Communicated by Ramaswamy H. Sarma.

Phenanthroindolizidine Alkaloids Secondary Metabolites Diversity in Medicinally Viable Plants of the Genus Tylophora.

Plants of the genus Tylophora have commonly been used in traditional medicine in various communities, especially in the tropical and subtropical regions of climatic zones. Of the nearly 300 species reported in the Tylophora genus, eight are primarily used in various forms to treat a variety of bodily disorders based on the symptoms. Certain plants from the genus have found use as anti-inflammatory, anti-tumor, anti-allergic, anti-microbial, hypoglycemic, hypolipidemic, anti-oxidant, smooth muscle relaxant, immunomodulatory, and anti-plasmodium agents, as well as free-radical scavengers. Pharmacologically, a few plant species from the genus have exhibited broad-spectrum anti-microbial and anti-cancer activity, which has been proven through experimental evaluations. Some of the plants in the genus have also helped in alcohol-induced anxiety amelioration and myocardial damage repair. The plants belonging to the genus have also shown diuretic, anti-asthmatic, and hepato-protective activities. Tylophora plants have afforded diverse structural bases for secondary metabolites, mainly belonging to phenanthroindolizidine alkaloids, which have been found to treat several diseases with promising pharmacological activity levels. This review encompasses information on various Tylophora species, their distribution, corresponding plant synonyms, and chemical diversity of the secondary metabolic phytochemicals as reported in the literature, together with their prominent biological activities.

Polymeric Nanoparticles for Delivery of Natural Bioactive Agents: Recent Advances and Challenges.

In the last few decades, several natural bioactive agents have been widely utilized in the treatment and prevention of many diseases owing to their unique and versatile therapeutic effects, including antioxidant, anti-inflammatory, anticancer, and neuroprotective action. However, their poor aqueous solubility, poor bioavailability, low GIT stability, extensive metabolism as well as short duration of action are the most shortfalls hampering their biomedical/pharmaceutical applications. Different drug delivery platforms have developed in this regard, and a captivating tool of this has been the fabrication of nanocarriers. In particular, polymeric nanoparticles were reported to offer proficient delivery of various natural bioactive agents with good entrapment potential and stability, an efficiently controlled release, improved bioavailability, and fascinating therapeutic efficacy. In addition, surface decoration and polymer functionalization have opened the door to improving the characteristics of polymeric nanoparticles and alleviating the reported toxicity. Herein, a review of the state of knowledge on polymeric nanoparticles loaded with natural bioactive agents is presented. The review focuses on frequently used polymeric materials and their corresponding methods of fabrication, the needs of such systems for natural bioactive agents, polymeric nanoparticles loaded with natural bioactive agents in the literature, and the potential role of polymer functionalization, hybrid systems, and stimuli-responsive systems in overcoming most of the system drawbacks. This exploration may offer a thorough idea of viewing the polymeric nanoparticles as a potential candidate for the delivery of natural bioactive agents as well as the challenges and the combating tools used to overcome any hurdles.

LC-MS/MS approach for simultaneous assessment of hyoscine N-butyl bromide and ketoprofen in biological fluids and pharmaceuticals.

The mixture of hyoscine N-butyl bromide (HBB) and ketoprofen (KTP) is commonly used for the handling of abdominal spasms and pain relief. There are two challenges that restrict the simultaneous assessment of HBB and KTP in biological fluids and pharmaceuticals. The first issue is the difficulty of elution of HBB and the second one is the presence of KTP as a racemic mixture in all pharmaceutical formulations, which obscures its appearance as a single peak. An ultrasensitive and highly efficient liquid chromatography-mass/mass spectrometric (LC-MS/MS) method is designed and validated for the first concurrent assessment of HBB and KTP in spiked human serum and urine, and pharmaceutical formulations. The estimated linearity ranges for HBB and KTP were respectively, 0.5-500 and 0.05-500 ng/ml, with excellent correlation coefficients. Validation results showed that the value of relative standard deviations were <2% for HBB and KTP. The mean extraction recoveries for HBB and KTP were, respectively, 91.04 and 97.83% in Spasmofen® ampoules; 95.89 and 97.00% in spiked serum; and 97.31 and 95.63% in spiked urine. The presented innovative chromatographic approach was utilized for the measurement of trace amounts of coexisting pharmaceuticals in pharmacokinetics studies and routine therapeutic medication monitoring.

Design, synthesis, and biological investigation of oxadiazolyl, thiadiazolyl, and pyrimidinyl linked antipyrine derivatives as potential non-acidic anti-inflammatory agents.

A novel series of 12 antipyrine derivatives containing 1,3,4-oxadiazoles (4a-d), 1,3,4-thiadiazoles (6a-d), and pyrimidines (8a-d), was preparedand assessed for its potential in vitro COX-2 inhibitors. Compared to Celecoxib, compounds 4b-d and 8d were the most potent derivatives c with a half-maximal inhibitory concentration range of 53-69 nM. Considering COX-2 selectivity index, compounds 4 b and 4c were chosen among these most potent derivatives for further investigation. The in vivo ability of compounds 4 b and 4c to counteract carrageenan-induced paw edoema has been assessed and their potential underlying mechanisms have been elucidated and the results have been further validated using molecular docking simulations.

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.

The Wound-Healing Potential of Olea europaea L. Cv. Arbequina Leaves Extract: An Integrated In Vitro, In Silico, and In Vivo Investigation.

Olea europaea L. Cv. Arbequina (OEA) (Oleaceae) is an olive variety species that has received little attention. Besides our previous work for the chemical profiling of OEA leaves using LC−HRESIMS, an additional 23 compounds are identified. An excision wound model is used to measure wound healing action. Wounds are provided with OEA (2% w/v) or MEBO® cream (marketed treatment). The wound closure rate related to vehicle-treated wounds is significantly increased by OEA. Comparing to vehicle wound tissues, significant levels of TGF-ß in OEA and MEBO® (p < 0.05) are displayed by gene expression patterns, with the most significant levels in OEA-treated wounds. Proinflammatory TNF-α and IL-1ß levels are substantially reduced in OEA-treated wounds. The capability of several lignan-related compounds to interact with MMP-1 is revealed by extensive in silico investigation of the major OEA compounds (i.e., inverse docking, molecular dynamics simulation, and ΔG calculation), and their role in the wound-healing process is also characterized. The potential of OEA as a potent MMP-1 inhibitor is shown in subsequent in vitro testing (IC50 = 88.0 ± 0.1 nM). In conclusion, OEA is introduced as an interesting therapeutic candidate that can effectively manage wound healing because of its anti-inflammatory and antioxidant properties.

Development of surface modified bilosomes for the oral delivery of quercetin: optimization, characterization in-vitro antioxidant, antimicrobial, and cytotoxicity study.

Quercetin (QT) is a flavonoid that exhibits anti-oxidant and chemo-preventive activity. This research work aimed to develop surface-modified bilosomes (BS) of QT. The BS was prepared by the solvent evaporation method and optimized by the Box-Behnken design. The optimized QT-BS (QT-BS3opt) displayed vesicle size (143.51 nm), PDI (0.256), zeta potential (-15.4 mV), and entrapment efficiency (89.52%). Further, the optimized QT-BS formulation was coated with chitosan (CS). The XRD diffractogram of CS-QT-BS3opt1 did not exhibit extensive peaks of QT, revealing that QT is properly encapsulated in the polymer matrix. The QT-BS3opt and CS-QT-BS3opt1 exhibited sustained-release (86.62 ± 3.23% and 69.32 ± 2.57%, respectively) up to 24 h with the Korsmeyer-Peppas kinetic model (R2 =0.9089). CS-QT-BS3opt1 exhibited significantly (P < .05) high flux, i.e. 4.20-fold more than pure QT dispersion and 1.27-fold higher than QT-BS3opt. CS-QT-BS3opt1 showed significantly greater bio-adhesion (76.43 ± 2.42%) than QT-BS3opt (20.82 ± 1.45%). The antioxidant activity showed that QT from CS-QT-BS3opt1 has more remarkable (P < .05) antioxidant activity at each concentration than pure QT. The CS-QT-BS3opt1 exhibited 1.61-fold higher cytotoxicity against MFC7 and 1.44-fold higher cytotoxicity against MDA-MB-231 than pure QT. The CS-QT-BS3opt1 displayed a significantly greater antimicrobial potential against E. coli than against S. aureus. From all these findings, it could be concluded that surface-modified QT-BS might be an effective approach for increasing the efficacy of QT in the treatment of certain ailments.

LC/MS Profiling and Gold Nanoparticle Formulation of Major Metabolites from Origanum majorana as Antibacterial and Antioxidant Potentialities.

Origanum majoranum L. is a Lamiaceae medicinal plant with culinary and ethnomedical applications. Its biological and phytochemical profiles have been extensively researched. Accordingly, this study aimed to investigate the chemical composition and the antibacterial and antioxidant properties of O. majoranum high features, as well as to search for techniques for activity optimization. A metabolomics study of the crude extract of O. majoranum using liquid chromatography-high-resolution electrospray ionization mass spectrometry (LC ± HR ± ESI ± MS) was conducted. Five fractions (petroleum ether, dichloromethane, ethyl acetate, n-butanol, and aqueous) were derived from the total extract of the aerial parts. Different chromatographic methods and NMR analysis were utilized to purify and identify the isolated phenolics (high features). Moreover, the antimicrobial, antibiofilm, and antioxidant activity of phenolics were performed. Results showed that metabolomic profiling of the crude extract of O. majoranum aerial parts revealed the presence of a variety of phytochemicals, predominantly phenolics, resulting in the isolation and identification of seven high-feature compounds comprising two phenolic acids, rosmarinic and caffeic acids, one phenolic diterpene, 7-methoxyepirosmanol, in addition to four flavonoids, quercetin, hesperitin, hesperidin, and luteolin. On the other hand, 7-methoxyepirosmanol (OM1) displayed the most antimicrobial and antioxidant potential. Such a phenolic principal activity improvement seems to be established after loading on gold nanoparticles.

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.

Bioactive Phytochemicals of Citrus reticulata Seeds-An Example of Waste Product Rich in Healthy Skin Promoting Agents.

Phytochemical investigation of Egyptian mandarin orange (Citrus reticulata Blanco, F. Rutaceae) seeds afforded thirteen known compounds, 1-13. The structures of isolated compounds were assigned using 1D and 2D NMR and HRESIMS analyses. To characterize the pharmacological activity of these compounds, several integrated virtual screening-based and molecular dynamics simulation-based experiments were applied. As a result, compounds 2, 3 and 5 were putatively identified as hyaluronidase, xanthine oxidase and tyrosinase inhibitors. The subsequent in vitro testing was done to validate the in silico-based experiments to highlight the potential of these flavonoids as promising hyaluronidase, xanthine oxidase and tyrosinase inhibitors with IC50 values ranging from 6.39 ± 0.36 to 73.7 ± 2.33 µM. The present study shed light on the potential of Egyptian mandarin orange's waste product (i.e., its seeds) as a skin health-promoting natural agent. Additionally, it revealed the applicability of integrated inverse docking-based virtual screening and MDS-based experiments in efficiently predicting the biological potential of natural products.

Chitosan Silver and Gold Nanoparticle Formation Using Endophytic Fungi as Powerful Antimicrobial and Anti-Biofilm Potentialities.

Nanotechnology is emerging as a new technology with encouraging innovations. Global antibiotic use has grown enormously, with antibiotic resistance increasing by about 80 percent. In view of this alarming situation, intensive research has been carried out into biogenic nanoparticles and their antibacterial, antifungal, and antitumor activities. Many methods are available to enhance stability and dispersion via peroration of conjugate with a polymer, such as chitosan, and other bioactive natural products. Two marine fungi were isolated and identified as Aspergillus sp. and Alternaria sp. via sequencing of the 16S rRNA gene. In this work, these strains were used to form the conjugation of biogenic silver nanoparticles (AgNPs) from Aspergillus sp. Silv2 extract and gold nanoparticles (AuNPs) from Alternaria sp. Gol2 extracts with chitosan to prepare chitosan-AgNPs and chitosan-AuNP conjugates. A variety of imaging and analytical methods, such as UV-vis, X-ray powder diffraction (XRD), FTIR spectroscopy, transmission electron microscopy (TEM), and scanning electron microscopy (SEM) were utilized to characterize biogenic nanoparticles and conjugates. The biosynthesized Ag and Au nanoparticles along with the prepared conjugates were evaluated for their antimicrobial effects on Gram-negative and Gram-positive bacterial isolates, including Escherichia coli and Staphylococcus aureus. Both chitosan-AgNP and AuNP showed powerful antimicrobial activities compared to the control. On the other hand, chitosan-AgNP conjugation had better antibacterial ctivity than chitosan-AuNPs, which exhibited moderate activity against S. aureus and very low activity against E. coli. Furthermore, the antibiofilm potentials of the prepared conjugates were tested against four biofilm-forming bacteria, including P. aeruginosa, B. subtilis, E. coli, and S. aureus. The obtained results indicate that the chitosan-AgNP showed a promising anti-biofilm activities on all strains, especially S. aureus, while chitosan-AuNP conjugates showed moderate anti-biofilm against B. subtilis and weak activities against the other three strains. These results showed the superiority of chitosan-AgNP as a promising antibacterial as well as biofilm formation inhibitors.

In Vitro Anti-Proliferative, and Kinase Inhibitory Activity of Phenanthroindolizidine Alkaloids Isolated from Tylophora indica.

The phenanthroindolizidine alkaloid (-)-tylophorine has been reported for its significant anticancer activity working through different biomechanistic pathways. The current study aimed to evaluate the anticancer activity of phenanthroindolizidine alkaloids isolated from Tylophora indica. Six phenanthroindolizidine alkaloid (compounds 1-6) in addition to septicine (7), chlorogenic acid (8), and chlorogenic acid methyl ester (9) were isolated from Tylophora indica using different chromatographic techniques including vacuum liquid chromatography (VLC) and preparative high performance liquid chromatography (HPLC). The isolated compounds structures' were determined using various spectro-analytical techniques, i.e., 1H-NMR, 13C-NMR, and mass spectrometry. The isolates' structural stereochemistry and structural geometries were determined with the help of chiroptical techniques together with comparisons with the available standard samples. The in vitro anti-proliferative activity on three different cell lines, MCF-7, HepG2, and HCT-116 were evaluated. Among all the isolated compounds, tylophorinidine (5) was the most active cytotoxic agent with the lowest IC50 values at 6.45, 4.77, and 20.08 µM against MCF-7, HepG2, and HCT-116 cell lines, respectively. The bioactivities were also validated by the in vitro kinase receptors inhibition assay. Compound (5) also exhibited the highest activity with lowest IC50 values (0.6 and 1.3 µM against the Aurora-A and Aurora-B enzymes, respectively), as compared with all the isolated alkaloidal products. The structure activity relationship on the molecular properties, molecular attributes, and bioactivity levels were analyzed, interrelated, and the molecular docking studies on two different receptors, Aurora-A and Aurora-B, were determined, which provided the confirmations of the bioactivity with receptor-ligand geometric disposition, energy requirements, lipophilicity, and detailed the binding pharmacophore involvements responsible for bioactivity elicitations.

Impact of highly phospholipid-containing lipid nanocarriers on oral bioavailability and pharmacodynamics performance of genistein.

Oxidative stress is a leading cause of different diseases. Genistein is a valuable bioflavonoid possessing antioxidant and anti-inflammatory activity but unfortunately, it suffers from low aqueous solubility, extremely poor bioavailability and first pass effect when used in its pure state. The aim of this work was to formulate and characterize genistein-loaded highly phospholipid-containing lipid nanocarriers to improve oral bioavailability and pharmacodynamic performance. Lipid nanocarriers were prepared by the emulsification/sonication technique. The influence of phospholipid percentage (1%-10%) on physicochemical properties, drug release and stability was investigated. The particle size, zeta potential and EE% were in ranges from 211.9 ± 21.6 to 342.3 ± 7.9 nm, -11.6 ± 1.7 to -19.4 ± 3.1 mV and 78.5 ± 4.7% to 92.2 ± 1.9%, respectively. Drug release was less predominant in the case of SLN formulations when compared to corresponding NLC formulations. High phospholipid percentage produced less stable formulations in terms of particle size growth, gelation and heterogeneous particle distributions. DSC, FT-IR and XRD tools revealed that genistein has existed in an amorphous form in NLC4. The bioavailability of NLC4 was approximately 2.6-fold greater than that of conventional suspension. Additionally, lipid peroxidation in liver homogenate and histopathological alterations in liver and kidney sections were particularly improved, providing a promising strategy for oral administration of genistein.

EGFR and COX-2 Dual Inhibitor: The Design, Synthesis, and Biological Evaluation of Novel Chalcones.

For most researchers, discovering new anticancer drugs to avoid the adverse effects of current ones, to improve therapeutic benefits and to reduce resistance is essential. Because the COX-2 enzyme plays an important role in various types of cancer leading to malignancy enhancement, inhibition of apoptosis, and tumor-cell metastasis, an indispensable objective is to design new scaffolds or drugs that possess combined action or dual effect, such as kinase and COX-2 inhibition. The start compounds A1 to A6 were prepared through the diazo coupling of 3-aminoacetophenone with a corresponding phenol and then condensed with two new chalcone series, C7-18. The newly synthesized compounds were assessed against both COX-2 and epidermal growth factor receptor (EGFR) for their inhibitory effect. All novel compounds were screened for cytotoxicity against five cancer cell lines. Compounds C9 and G10 exhibited potent EGFR inhibition with IC50 values of 0.8 and 1.1 µM, respectively. Additionally, they also displayed great COX-2 inhibition with IC50 values of 1.27 and 1.88 µM, respectively. Furthermore, the target compounds were assessed for their cytotoxicity against pancreatic ductal cancer (Panc-1), lung cancer (H-460), human colon cancer (HT-29), human malignant melanoma (A375) and pancreatic cancer (PaCa-2) cell lines. Interestingly, compounds C10 and G12 exhibited the strongest cytotoxic effect against PaCa-2 with average IC50 values of 0.9 and 0.8 µM, respectively. To understand the possible binding modes of the compounds under investigation with the receptor cites of EGFR and COX-2, a virtual docking study was conducted.

An In Vitro and In Silico Study of the Enhanced Antiproliferative and Pro-Oxidant Potential of Olea europaea L. cv. Arbosana Leaf Extract via Elastic Nanovesicles (Spanlastics).

The olive tree is a venerable Mediterranean plant and often used in traditional medicine. The main aim of the present study was to evaluate the effect of Olea europaea L. cv. Arbosana leaf extract (OLE) and its encapsulation within a spanlastic dosage form on the improvement of its pro-oxidant and antiproliferative activity against HepG-2, MCF-7, and Caco-2 human cancer cell lines. The LC-HRESIMS-assisted metabolomic profile of OLE putatively annotated 20 major metabolites and showed considerable in vitro antiproliferative activity against HepG-2, MCF-7, and Caco-2 cell lines with IC50 values of 9.2 ± 0.8, 7.1 ± 0.9, and 6.5 ± 0.7 µg/mL, respectively. The encapsulation of OLE within a (spanlastic) nanocarrier system, using a spraying method and Span 40 and Tween 80 (4:1 molar ratio), was successfully carried out (size 41 ± 2.4 nm, zeta potential 13.6 ± 2.5, and EE 61.43 ± 2.03%). OLE showed enhanced thermal stability, and an improved in vitro antiproliferative effect against HepG-2, MCF-7, and Caco-2 (IC50 3.6 ± 0.2, 2.3 ± 0.1, and 1.8 ± 0.1 µg/mL, respectively) in comparison to the unprocessed extract. Both preparations were found to exhibit pro-oxidant potential inside the cancer cells, through the potential inhibitory activity of OLE against glutathione reductase and superoxide dismutase (IC50 1.18 ± 0.12 and 2.33 ± 0.19 µg/mL, respectively). These inhibitory activities were proposed via a comprehensive in silico study to be linked to the presence of certain compounds in OLE. Consequently, we assume that formulating such a herbal extract within a suitable nanocarrier would be a promising improvement of its therapeutic potential.

Formulation of Genistein-HP ß Cyclodextrin-Poloxamer 188 Ternary Inclusion Complex: Solubility to Cytotoxicity Assessment.

The current study was designed to prepare the inclusion complex Genistein (GS) using Hydroxypropyl ß cyclodextrin (HP ß CD) and poloxamer 188 (PL 188). The binary inclusion complex (GS BC) and ternary inclusion complex (GS TC) were developed by microwave irradiation technique and evaluated for a comparative dissolution study. Further, the samples were assessed for FTIR, DSC, XRD, and NMR for the confirmation of complex formation. Finally, antioxidant and antimicrobial studies and cytotoxicity studies on a breast cancer (MCF-7) cell line were conducted. The dissolution study result showed a marked increment in GS dissolution/release after incorporation in binary (GS: HP ß CD, 1:1) and ternary (GS: HP ß CD: PL 188; 1:1:0.5) inclusion complexes. Moreover, the ternary complex exhibited a significant enhancement (p < 0.05) in dissolution than did the binary complexes. This might be due to the presence of PL 188, which helps in solubility enhancement of GS. DSC, XRD and SEM evaluation confirmed the modification in the structure of GS. FTIR and NMR results indicated the formation of an inclusion complex. The antioxidant and antimicrobial activity results revealed that GS TC has shown significant (p < 0.05) higher activity than pure GS. The cytotoxicity study results also depicted concentration-dependent cytotoxicity. GS TC exhibited significantly (p < 0.05) high cytotoxicity to cancer cells (IC50 = 225 µg/mL) than pure GS (IC50 = 480 µg/mL). Finally, it was concluded that a remarkable enhancement in the dissolution was observed after the inclusion of GS in the ternary complex and it therefore has significant potential for the treatment of breast cancer.