Effect of Phenolics from Aeonium arboreum on Alpha Glucosidase, Pancreatic Lipase, and Oxidative Stress; a Bio-Guided Approach.

Metabolic syndrome (MetS) is a global issue affecting over a billion people, raising the risk of diabetes, cardiovascular disorders, and other ailments. It is often characterized by hypertension, dyslipidemia and/or obesity, and hyperglycemia. Chemical investigation of Aeonium arboreum (L.) Webb & Berthel led to the isolation of six compounds, viz. ß-sitosterol, ß-sitosterol glucoside, myricetin galactoside, quercetin rhamnoside, kaempferol rhamnoside, and myricetin glucoside. Interestingly, A. arboreum's dichloromethane (DCM), 100 and 50% MeOH Diaion fractions and the isolated compound (quercetin-3-rhamnoside) revealed potent α-glucosidase inhibitory activity, especially 50% Diaion fraction. In addition, they also showed very potent antioxidant potential, especially the polar fractions, using DPPH, ABTS, FRAP, ORAC, and metal chelation assays. Notably, the 50% Diaion fraction had the highest antioxidant potential using DPPH and ORAC assays, while the 100% Diaion fraction and quercetin-3-rhamnoside showed the highest activity using ABTS, FRAP, and metal chelation assays. Also, quercetin-3-rhamnoside showed a good docking score of -5.82 kcal/mol in comparison to acarbose. In addition, molecular dynamic stimulation studies illustrated high stability of compound binding to pocket of protein. Such potent activities present A. arboreum as a complementary safe approach for the management of diabetes mellitus as well as MetS.

UPLC-MS-Based Metabolomics Profiling and Chemometric Analysis for Hypericum sinaicum Boiss and the Endophytic Aspergillus foetidus in Comparison to Hypericum perforatum L.

One of the endangered plant species in Saint Catherine protectorate is Hypericum sinaicum Boiss which is endemic to Egypt, Jordan, and Saudi Arabia. The fungus-host relationship can assist in the investigation of bioactive compounds produced by H. sinaicum paving the way for economic and medicinal implications. Therefore, a comprehensive metabolic approach via MS and chemical analysis was used to track and compare metabolites from H. sinaicum and Aspergillus foetidus var. pallidus, the endophytic fungus, with Hypericum perforatum. Metabolomics analysis revealed the presence of 25 metabolites distributed among samples and the discovery of new chemotaxonomic compounds, i. e., phloroglucinols and xanthones, allowing the discrimination between species. A. foetidus extract is considered a reliable source of furohyperforin and naphthodianthrone derivatives. In conclusion, using A. foetidus as an in vitro technique for producing potential phytoconstituents was cost effective, having easier optimization conditions and faster growth with fewer contamination rates than other in vitro methods.

Characterization and anti-aging effects of Opuntia ficus-indica (L.) Miller extracts in a D-galactose-induced skin aging model.

Opuntia ficus-indica (L.) Miller (OFI), belonging to the family Cactaceae, is widely cultivated not only for its delicious fruits but also for its health-promoting effects, which enhance the role of OFI as a potential functional food. In this study, the in vitro collagenase and elastase enzyme inhibitory effects of extracts from different parts of OFI were evaluated. The most promising extracts were formulated as creams at two concentrations (3 and 5%) to investigate their effects on a D-galactose (D-gal)-induced skin-aging mouse model. The ethanolic extracts of the peel and cladodes exhibited the highest enzyme inhibitory effects. Cream made from the extract of OFI peel (OP) (5%) and cream from OFI cladodes extract (OC) (5%) significantly decreased the macroscopic aging of skin scores. Only a higher concentration (5%) of OC showed the normalization of superoxide dismutase (SOD) and malondialdehyde (MDA) skin levels and achieved significant improvements as compared to the vitamin E group. Both OC and OP (5%) showed complete restoration of the normal skin structure and nearly normal collagen fibres upon histopathological examination. The Ultra-Performance Liquid Chromatography High Resolution Mass Spectrometry (UHPLC-ESI-TOF-MS) metabolite profiles revealed the presence of organic acids, phenolic acids, flavonoids, betalains, and fatty acids. Flavonoids were the predominant phytochemical class (23 and 22 compounds), followed by phenolic acids (14 and 17 compounds) in the ethanolic extracts from the peel and cladodes, respectively. The anti-skin-aging effects could be attributed to the synergism of different phytochemicals in both extracts. From these findings, the OFI peel and cladodes as agro-waste products are good candidates for anti-skin-aging phytocosmetics.

Eurycomanol and eurycomanone as potent inducers for cell-cycle arrest and apoptosis in small and large human lung cancer cell lines.

Eurycoma longifolia Jack is one of traditional herbal medicines in South-East Asia. This study evaluated the anticancer, cell-cycle arrest, and apoptotic induction potentials of eurycomanone (EONE) and eurycomanol (EOL), highly oxygenated quassinoids previously isolated from its roots, against large (H460) and small (A549) lung cancer cells. EOL and EONE exhibited IC50 of 386 and 424 µg/mL on normal human lung cell line. EONE exhibited higher anticancer activity with an IC50 of 1.78 µg/mL and 20.66 µg/mL than EOL which exhibited an IC50 of 3.22 µg/mL and 38.05 µg/mL against H460 and A549, respectively. Both reduced the viability of H460 and A549 and arrested G0/G1 phase. The increase in the apoptotic rates was mainly in the percentage of late apoptosis. Moreover, they inhibited A549 by inducing the accumulation of S and G2/M phases. This study revealed EOL and EONE potential as novel leads exhibiting cell-cycle arrest and apoptosis induction potentials.

An overview and update on the chemical composition and potential health benefits of Opuntia ficus-indica (L.) Miller.

Opuntia ficus-indica (OFI), widely recognized as prickly pear, is native to Mexico and it is distributed in many areas of the world because of its socioeconomic, agronomic, and ecological benefits, besides its large amounts of functional, nutraceutical, and biological activities. Various parts of this plant including the fruit pulp and peel, cladode, and seeds are scientifically proven to have therapeutic potentials and are safe for human use. The contents of phytochemical compounds in each part of the OFI are different. Each pharmacological activity depends on the phytochemical compounds, the components used, and the extraction type. In this review, we summarize the active constituents from different parts of OFI and their pharmacological effects including the antioxidant, wound healing, skin protective, hepatoprotective, anticancer, antidiabetic, antihypercholesterolemic, and anti-obesity activities. Besides its effects on the bone health, cardiovascular system, kidneys, and gastrointestinal tract, its gastroprotective, anti-ulcer, anti-inflammatory, antiviral, neuroprotective, sedative, analgesic, anxiolytic and antimicrobial effects and effects on cognitive and memory function are also mentioned. PRACTICAL APPLICATIONS: Over the past few decades, the health benefits of Opuntia ficus-indica (OFI) have received much attention. All parts of the plant, including the fruit pulp and peel, cladode, and seeds have found use in the treatment of many diseases. The chemical composition of OFI provides both a high nutritional value and various health benefits. Therefore, the aim of this review is to present the up-to-date research carried out on OFI phytochemicals, showing the most important biological activities reported.

Impact of different processing methods on the phenolics and neuroprotective activity of Fragaria ananassa Duch. extracts in a D-galactose and aluminum chloride-induced rat model of aging.

Age-related diseases, including dementia, are a major health concern affecting daily human life. Strawberry (Fragaria ananassa Duch.) is the most eaten fruit worldwide due to its exceptional aroma and flavor. However, it's rapid softening and decay limit its shelf-life. Freezing and boiling represent the well-known conservation methods to extend its shelf-life. Therefore, we aimed to discover the phytochemical content differences of fresh and processed strawberries associated with investigating and comparing their neuroprotective effects in a rat model of aging. Female Wistar rats were orally pretreated with fresh, boiled, and frozen F. ananassa methanolic extracts (250 mg kg-1) for 2 weeks, and then these extracts were concomitantly exposed to D-galactose [65 mg kg-1, subcutaneously (S/C)] and AlCl3 (200 mg kg-1, orally) for 6 weeks to develop aging-like symptoms. The results of UPLC/ESI-MS phytochemical profiling revealed 36 secondary metabolites, including phenolics, flavonoids, and their glycoside derivatives. Compared with boiled and frozen extracts, the fresh extract ameliorated the behavioral deficits including anxiety and cognitive dysfunction, upregulated brain HO-1 and Nrf2 levels, and markedly reduced caspase-3 and PPAR-γ levels. Moreover, LDH and miRNA-9, 124 and 132 protein expressions were reduced. The histological architecture of the brain hippocampus was restored and glial fibrillary acidic protein (GFAP) immunoexpression was downregulated. In conclusion, the fresh extract has neuroprotective activity that could have a promising role in ameliorating age-related neurodegeneration.

Antiinflammatory and antioxidant activity of Hypericum sinaicum Boiss. growing widely in Egypt.

Methanol extract of the flowering aerial parts of Hypericum sinaicum Boiss. (ME) growing in Saint Catherine Protectorate (SKP), Egypt was analysed for its phenolic compounds profiling using HPLC and colorimetric methods. The total phenol content of ME was 158.60 ± 0.74 (µg GAE/mg D.E.), while the total flavonoid content was 70.91 ± 0.01 (µg QE/mg D.E.). HPLC analysis revealed that the highest flavonoid was naringenin (50.31 mg/g), while the highest phenolic acid was syringic acid (0.37 mg/g). The scavenging activity of ME was evaluated using DPPH assay with SC50 22.9 µg/ml and ABTS with SC50 13.10 µg/ml. ME produced dose - dependent and significant inhibition of edema at 4 hour of dose 200 mg/kg (78.55%) and 100 mg/kg (72.89%) to that of standard drug Indomethacin (86.94%). The current study interprets the anti-inflammatory and antioxidant potency of H. sinaicum.

Secondary metabolites from Lantana camara L. flowers extract exhibit in vivo anti-urolithiatic activity in adult Wistar albino rats.

The present study aims at evaluating potential of the ethanol extracts of L. camara leaves (LE), flowers (FlE) and roots (RE) in the treatment of renal calculi and characterising the secondary metabolites in the active extract. The results revealed that the FlE had significantly reduced the levels of kidney parameters (calcium, creatinine, urea, and uric acid) against ethylene glycol (EG) injuries, and restored the activity of glutathione peroxidase (GPx), superoxide dismutase and lipid peroxide malondialdehyde to the normal level. In addition, FlE significantly attenuated iNOS tissue expression caused by EG. The results obtained in this study suggest the potential value of the L. camara L. flowers as an antiurolithiatic agent.

Immunomodulatory effect of Noni fruit and its isolates: insights into cell-mediated immune response and inhibition of LPS-induced THP-1 macrophage inflammation.

Morinda citrifolia L. is a plant of the family Rubiaceae and is known as Indian mulberry or Noni in India. It is a perennial herb native to Southeast Asia and has been used over the years as a food supplement and medicinal plant. Noni fruits are reported to possess anticancer, fungicidal, antiviral and antiarthritic effects. The objective of our study is the screening of the immunomodulatory activity of the total extract, fractions, and isolated compounds of Noni fruits to identify their bioactive compounds. To achieve our goal, an ethanol extract (EE) was prepared from Noni fruits. Fractionation and purification of the EE were accomplished. The cell-mediated immune (CMI) response in prednisolone-induced immunosuppression rats was evaluated. The toxicity of the EE, fractions and isolated compounds on the differentiated THP-1 macrophage was assessed using the MTT viability assay. Moreover, the inflammation-related immune responses in lipopolysaccharide (LPS)-induced THP-1 macrophage activation were evaluated. Fractionation of the EE gave three fractions, dichloromethane (DCMF), water (WF) and methanol (MF). Purification of DCMF yielded stigmast-7-ene-3-ol (M1), 28-hydroxy-3ß-acetoxy-9-dehydrogramisterol (M2), 3ß-acetoxy-taraxast-20(30)-ene-21-ol (M3), 22-dehydroclerosterol (M4) and 22-dehydroclerosterol-3-O-ß-d-glucopyranoside (M5), while purification of MF yielded quercetin (M6), hesperidin (M7), naringin (M9) and gallic acid (M8). The results revealed that DCMF elicited an increase in paw edema to the extent of 35.8%. All the tested samples had no cytotoxic effect on THP-1 macrophages. Co-treatment of the LPS-induced macrophages with DCMF, M2, M3, and M6 decreased the production of TNF-α, IL-1ß, and IL-6/IL-10. The expression of iNOS, COX-2, and NF-κB decreased to 0.14 ± 0.02, 0.15 ± 0.02, and 0.17 ± 0.03, respectively, after co-treatment with LPS and DCMF. M2 attenuated the expression of iNOS and NF-κB to 0.18 ± 0.03 and 0.17 ± 0.03, respectively. Additionally, M3 attenuated the expression of iNOS to 0.18 ± 0.03, and after co-treatment with M6 and LPS, the expression of COX-2 and NF-κB was down-regulated to 0.2 ± 0.03. Our study proves the immunomodulatory effect of Noni fruits and specifies for the first time the compounds responsible for their activity.

Optimization of an Extraction Solvent for Angiotensin-Converting Enzyme Inhibitors from Hibiscus sabdariffa L. Based on Its UPLC-MS/MS Metabolic Profiling.

Hibiscus species (Malvaceae) have been long used as an antihypertensive folk remedy. The aim of our study was to specify the optimum solvent for extraction of the angiotensin-converting enzyme inhibiting (ACEI) constituents from Hibiscus sabdariffa L. The 80% methanol extract (H2) showed the highest ACEI activity, which exceeds that of the standard captopril (IC50 0.01255 ± 0.00343 and 0.210 ± 0.005 µg/mL, respectively). Additionally, in a comprehensive metabolomics approach, an ultra-performance liquid chromatography (UPLC) coupled to the high resolution tandem mass spectrometry (HRMS) method was used to trace the metabolites from each extraction method. Interestingly, our comprehensive analysis showed that the 80% methanol extract was predominated with secondary metabolites from all classes including flavonoids, anthocyanins, phenolic and organic acids. Among the detected metabolites, phenolic acids such as ferulic and chlorogenic acids, organic acids such as citrate derivatives and flavonoids such as kaempferol have been positively correlated to the antihypertensive potential. These results indicates that these compounds may significantly contribute synergistically to the ACE inhibitory activity of the 80% methanol extract.

In-depth hepatoprotective mechanistic study of Phyllanthus niruri: In vitro and in vivo studies and its chemical characterization.

Phyllanthus niruri L. is a widespread tropical plant which is used in Ayurvedic system for liver and kidney ailments. The present study aims at specifying the most active hepatoprotective extract of P. niruri and applying a bio-guided protocol to identify the active compounds responsible for this effect. P. niruri aerial parts were extracted separately with water, 50%, 70% and 80% ethanol. The cytoprotective activity of the extracts was evaluated against CCl4-induced hepatotoxicity in clone-9 and Hepg2 cells. Bioassay-guided fractionation of the aqueous extract (AE) was accomplished for the isolation of the active compounds. Antioxidant activity was assessed using DPPH (1, 1-diphenyl-2-picrylhydrazyl) radical scavenging method and ferric reducing antioxidant power (FRAP). The in vivo hepatoprotective activity of AE was evaluated in CCl4-induced hepatotoxicity in rats at different doses after determination of its LD50. Pretreatment of clone-9 and Hepg2 with different concentrations of AE (1, 0.1, 0.01 mg/ml) had significantly reduced the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) against CCl4 injures, and restored the activity of the natural antioxidants; glutathione (GSH) and superoxide dismutase (SOD) towards normalization. Fractionation of AE gave four fractions (I-IV). Fractions I, II, and IV showed a significant in vitro hepatoprotective activity. Purification of I, II and IV yielded seven compounds; corilagin C1, isocorilagin C2, brevifolin C3, quercetin C4, kaempferol rhamnoside C5, gallic acid C6, and brevifolin carboxylic acid C7. Compounds C1, C2, C5, and C7 showed the highest (p< 0.001) hepatoprotective potency, while C3, C4, and C6 exhibited a moderate (p< 0.001) activity. The AE exhibited strong antioxidant DPPH (IC50 11.6 ± 2 µg/ml) and FRAP (79.352 ± 2.88 mM Ferrous equivalents) activity. In vivo administration of AE in rats (25, 50, 100 and 200 mg/kg) caused normalization of AST, ALT, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), total cholesterol (TC), triglycyrides (TG), total bilirubin (TB), glucose, total proteins (TP), urea and creatinine levels which were elevated by CCl4. AE also decreased TNF-α, NF-KB, IL-6, IL-8, IL10 and COX-2 expression, and significantly antagonizes the effect of CCl4 on the antioxidant enzymes SOD, catalase (CAT), glutathione reductase (GR), and glutathione peroxidase (GSP). The histopathological study also supported the hepatoprotective effect of AE. P. niruri isolates exhibited a potent hepatoprotective activity against CCl4-induced hepatotoxicity in clone-9 and Hepg2 cell lines through reduction of lipid peroxidation and maintaining glutathione in its reduced form. This is attributable to their phenolic nature and hence antioxidative potential.

Brain Cortical and Hippocampal Dopamine: A New Mechanistic Approach for Eurycoma longifolia Well-Known Aphrodisiac Activity and Its Chemical Characterization.

Eurycoma longifolia Jack (Fam.: Simaroubaceae), known as Tongkat Ali (TA), has been known as a symbol of virility and sexual power for men. Metabolic profiling of the aqueous extract of E. longifolia (AEEL) using UPLC-MS/MS in both positive and negative modes allowed the identification of seventeen metabolites. The identified compounds were classified into four groups: quassinoids, alkaloids, triterpenes, and biphenylneolignans. AEEL is considered safe with oral LD50 cut-off >5000 mg/kg. Oral administration of 50, 100, 200, 400, or 800 mg/kg of AEEL for 10 consecutive days to Sprague-Dawley male rats caused significant reductions in mounting, intromission, and ejaculation latencies and increased penile erection index. AEEL increased total body weight and relative weights of seminal vesicles and prostate. Total and free serum testosterone and brain cortical and hippocampal dopamine content was significantly elevated in treated groups with no significant effects on serotonin or noradrenaline content.

Rho-Kinase II Inhibitory Potential of Eurycoma longifolia New Isolate for the Management of Erectile Dysfunction.

Background. Eurycoma longifolia Jack (Fam.: Simaroubaceae), known as Tongkat Ali (TA), has been known as a symbol of virility and sexual power. The aim of the study was to screen E. longifolia aqueous extract (AE) and isolates for ROCK-II inhibition. Results. The AE (1-10 µg/ml) showed a significant inhibition for ROCK-II activity (62.8-81%) at P < 0.001 with an IC50 (651.1 ± 32.9 ng/ml) compared to Y-27632 ([(+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl)cyclohexanecarboxamide dihydrochloride]) (68.15-89.9 %) at same concentrations with an IC50 (192 ± 8.37 ng/ml). Chromatographic purification of the aqueous extract (AE) allowed the isolation of eight compounds; stigmasterol T1, trans-coniferyl aldehyde T2, scopoletin T3, eurycomalactone T4, 6α- hydroxyeurycomalactone T5, eurycomanone T6, eurycomanol T7, and eurycomanol-2-O-ß-D-glucopyranoside T8. This is the first report for the isolation of T1 and T3 from E. longifolia and for the isolation of T2 from genus Eurycoma. The isolates (at 10 µg/ml) exhibited maximum inhibition % of ROCK-II 82.1 ± 0.63 (T2), 78.3 ± 0.38 (T6), 77.1 ± 0.11 (T3), 76.2 ± 3.53 (T4), 74.5 ± 1.27 (T5), 74.1 ± 2.97 (T7), 71.4 ± 2.54 (T8), and 60.3 ± 0.14 (T1), where the newly isolated compound trans-coniferyl aldehyde T2 showed the highest inhibitory activity among the tested isolated compounds and even higher than the total extract AE. The standard Y-27632 (10 µg/ml) showed 89.9 ± 0.42 % inhibition for ROCK-II activity when compared to control at P < 0.0001. Conclusion. The traditional use of E. longifolia as aphrodisiac and for male sexual disorders might be in part due to the ROCK-II inhibitory potential.

The hidden mechanism beyond ginger (Zingiber officinale Rosc.) potent in vivo and in vitro anti-inflammatory activity.

ETHNOPHARMACOLOGICAL RELEVANCE: Ginger (Zingiber officinale Roscoe) is a well known anti-inflammatory drug in the Egyptian, Indian and Chinese folk medicines, yet its mechanism of action is unclear. AIM OF THE STUDY: To explore its mechanism of action and to correlate it to its biophytochemicals. MATERIALS AND METHODS: Various extracts viz. water, 50%, 70%, 80%, and 90% ethanol were prepared from ginger rhizomes. Fractionation of the aqueous extract (AE) was accomplished using Diaion HP-20. In vitro anti-inflammatory activity of the different extracts and isolated compounds was evaluated using protein denaturation inhibition, membrane stabilization, protease inhibition, and anti-lipoxygenase assays. In vivo anti-inflammatory activity of AE was estimated using carrageenan-induced rat paw edema in rats at doses 25, 50, 100 and 200mg/kg b.wt. RESULTS: All the tested extracts showed significant (p< 0.1) in vitro anti-inflammatory activities. The strongest anti-lipoxygenase activity was observed for AE that was more significant than that of diclofenac (58% and 52%, respectively) at the same concentration (125µg/ml). Purification of AE led to the isolation of 6-poradol (G1), 6-shogaol (G2); methyl 6- gingerol (G3), 5-gingerol (G4), 6-gingerol (G5), 8-gingerol (G6), 10-gingerol (G7), and 1-dehydro-6-gingerol (G8). G1, G2 and G8 exhibited potent activity in all the studied assays, while G4 and G5 exhibited moderate activity. In vivo administration of AE ameliorated rat paw edema in a dose-dependent manner. AE (at 200mg/kg) showed significant reduction in production of PGE2, TNF-α, IL-6, monocyte chemoattractant protein-1 (MCP-1), regulated upon activation, normal T-cell expressed and secreted (RANTES), myeloperoxidase (MPO) activity by 60%, 57%, 60%, 41%, 32% and 67%, respectively. AE at 100 and 200mg/kg was equipotent to indomethacin in reduction of NOx level and in increasing the total antioxidant capacity (TAC). Histopathological examination revealed very few inflammatory cells infiltration and edema after administration of AE (200mg/kg) prior to carrageenan. CONCLUSIONS: Ginger anti-inflammatory activity is mediated by inhibiting macrophage and neutrophils activation as well as negatively affecting monocyte and leukocyte migration. This was evidenced by the dose-dependent decrease in pro-inflammatory cytokines and chemokines and replenishment the total antioxidant capacity.

In vitro evaluation of cytotoxic activity of the ethanol extract and isolated compounds from the corms of Liatris spicata (L.) willd on HepG2.

Investigation of the ethanol extract of the corms of Liatris spicata (L.) willd led to the isolation of two sterols: stigmasterol and its 3-O-glucoside, a triterpene: obtusifoliyl acetate, two benzofurans: euparin and 6-hydroxy-3-methoxytremetone, three phenolic acids: protocatechuic, vanillic and ferulic acid and a sesquiterpene lactone igalan. The structures of the isolated compounds were established on the basis of physicochemical properties and spectral analysis (IR, EI/MS, 1H NMR and 13C NMR). The ethanol extract and its isolated compounds evidenced cytotoxic activities against human liver cancer cell line (HepG2), where igalan showed the highest potency (3.83 ± 0.043) µg/mL, its effect was comparable to that of the standard drug doxorubicin® (3.73 ± 0.036) µg/mL.

A new acylated flavonol from the aerial parts of Asteriscus maritimus (L.) Less (Asteraceae).

Phytochemical investigation of the flowering aerial parts of Asteriscus maritimus (L.) Less (Asteraceae) led to the isolation of a new compound: patuletin 7-O-ß-D-[(2″'S) 6″(3″'-hydroxy-2″'-methyl-propanoyl)] glucopyranoside, together with five known metabolites; ß-sitosterol 2, chlorogenic acid 3, P-hydroxy -methylbenzoate 4, luteolin 5 and protocatechuic acid 6. The structures of the isolated compounds were determined by comprehensive analyses of its 1D and 2D NMR, HRMS and compared with previously known analogues. The ethanolic extract of the flowering aerial parts of A. maritimus was found to be safe (LD50 = 4.6 mg/kg) and possess significant antioxidant and anti-inflammatory activities and this was in accordance with its high phenolic content (107.36 ± 0.051 mg GAE/g extract).