Establishing a link between the chemical composition and biological activities of Gladiolus italicus Mill. from the Turkish flora utilizing in vitro, in silico and network pharmacological methodologies.

OBJECTIVES: Five solvent extracts (n-hexane, ethyl acetate, ethanol, ethanol/water (70%), and water) of Gladiolus italicus Mill. from Turkey were evaluated for chemical and biological properties. METHODS: Antioxidant activities, inhibitory properties against key enzymes involved in the etiology of chronic diseases were tested, as well as cytotoxic effects on different cell lines. Chemical characterization was also carried out to determine the most abundant compounds of each extract. RESULTS: The highest total phenolic content (TPC) was observed in the water extract while highest TFC in ethanol/water extract. The most abundant compounds in the extracts were hyperoside (69041.06 mg kg-1), isoquercitrin (46239.49 mg kg-1), delphindin-3,5-diglucoside (42043.81 mg kg-1), myricetin (21486.61 mg kg-1), and kaempferol-3-glucoside (21199.76 mg kg-1). Molecular dynamic (MD) simulations confirmed the structural stability and dynamic conformational integrity of these complexes over a period of 100 ns. In network pharmacology, A total of 657 unique target genes were screened: 52 associated with programmed cell death-1 (PD-1), 85 with vascular endothelial growth factor receptor-2 (VEGFR2), and 130 with fibroblast growth factor receptor-2 (FGFR2), identifying crucial gene interactions for these proteins. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted, revealing significant interactions and pathways such as the advanced glycation end products (AGE) and their receptors (RAGE) signaling pathway in diabetic complications and T- helper 17 (Th17) cell differentiation, among others. This elucidation of complex networks involving key genes like AKT Serine/Threonine Kinase 1 (AKT1), MYC proto-oncogene (MYC), tumor protein 53 (TP53), Interleukin 6 (IL6), and tumor necrosis factor (TNF) provides a promising foundation for the development of targeted therapies in the treatment of non-communicable diseases. CONCLUSION: These results show that G. italicus could be a natural source of potent antioxidants and enzyme inhibitors which need to be further explored for the development of biopharmaceuticals.

Ethnomedicinal Plants for the Management of Diabetes Worldwide: A Systematic Review.

BACKGROUND: The increasing incidence of diabetes worldwide has urged researchers to explore novel antidiabetic agents from natural products. Ethnomedicinal field studies on diabetes have expanded across the globe, documenting large numbers of folk medicinal plants against diabetes. Nonetheless, a systematic review of these surveys has not been conducted so far. This study documents the medicinal plants traditionally used globally for managing diabetes. METHODS: Key databases including Sciencedirect, Medline/PubMed, and Google Scholar were scrutinized. The Plant List and The International Plant Names Index (IPNI) were used to validate the scientific plant names. RESULTS: 2004 traditionally used plants belonging to 1112 genera and 197 families were reported across 92 countries for the management of diabetes. Leguminosae (105 genera and 193 species), Compositae (97 genera and 188 species), and Lamiaceae (47 genera and 121 species) were the main plant families reported. Momordica charantia L., Syzygium cumini (L.) Skeels, Allium sativum L., Azadirachta indica A.Juss., Catharanthus roseus (L.) G.Don, Olea europaea L., Trigonella foenum-graecum L., Gymnema sylvestre (Retz.) R.Br. ex Sm., Aloe vera (L.) Burm.f., and Allium cepa L were the species mostly reported. Indeed, the antidiabetic properties of these main species have been evidenced by experimental studies. Several antidiabetic compounds acting via different mechanisms have been identified, including momordicoside, karaviloside, cucurbitacin, charantin, and charantoside from M. charantia, cuminoside from S. cumini, S-allyl cysteine sulfoxide from A. sativum, limonoids from A. indica, alkaloids including vindoline, vindolidine, vindolicine and vindolinine from C. roseus, oleuropein and oleanolic acid from O. europaea, flavone C-glycosides such as vicenin-1, isoschaftoside, and schaftoside from T. foenum-graecum seeds, gymnemosides, gymnemagenin, and pregnane glycosides from G. sylvestre, chysalodin from A. vera, and quercetin from A. cepa. CONCLUSION: This review is the first to provide a compiled list of traditional medicinal plants used worldwide against diabetes.

Chemical profiling and pharmaco-toxicological activity of Origanum sipyleum extracts: Exploring for novel sources for potential therapeutic agents.

The phytochemical, antiradical, and enzyme inhibition profile of three solvent extracts (ethyl acetate, methanol, water) of Origanum sipyleum were assessed. We also performed a pharmacological study in order to explore protective effects induced by extracts in inflamed colon. LC-MS analysis revealed that the extracts contained different classes of phenolics. The aqueous extract showed the highest antioxidant and acetylcholinesterase (AChE) inhibitory effects. Total phenol and flavonoid contents were highest in aqueous and ethyl acetate extract, respectively. All extracts were effective in reducing colon pro-oxidant and pro-inflammatory biomarkers. The extracts revealed also able to inhibit fungal and bacterial species involved in ulcerative colitis, including Candida albicans, Candida tropicalis, Staphylococcus aureus, and Staphylococcus thyphimurium. Finally, we also showed the antiproliferative effects exerted by the EA extracts on human colon cancer HCT116 cell line. Concluding, our results indicated that O. sipyleum extracts displayed promising therapeutic properties which warrants further validation. PRACTICAL APPLICATIONS: The present phytochemical and biological studies, including antioxidant, anti-inflammatory, and antimicrobic assessments, showed significant protective effects exerted by O. sipyleum extracts in an experimental model of ulcerative colitis. The results are intriguing and suggest potential applications O. sipyleum extracts as sources of natural agents for the management of clinical symptoms related to ulcerative colitis, characterized by increased burden of oxidative stress and microbiome dysbiosis.

New insights into the chemical profiling, cytotoxicity and bioactivity of four Bunium species.

Bunium species have been reported to be used both as food and in traditional medicines. The scientific community has attempted to probe into the pharmacological and chemical profiles of this genus. Nonetheless, many species have not been investigated fully to date. In this study, we determined the phenolic components, antimicrobial, antioxidant, and enzyme inhibitory activities of aerial parts of four Bunium species (B. sayai, B. pinnatifolium, B. brachyactis and B. macrocarpum). Results showed that B. microcarpum and B. pinnatifolium were strong antioxidants as evidenced in the DPPH, ABTS, CUPRAC, and FRAP assays. B. brachyactis was the most effective metal chelator, and displayed high enzyme inhibition against cholinesterase, tyrosinase, amylase, glucosidase, and lipase. The four species showed varied antimicrobial activity against each microorganism. Overall, they showed high activity against P. mirabilis and E. coli (MIC and MBC <1 mg mL-1). B. brachyactis was more effective against Aspergillus versicolor compared to the standard drug ketoconazole. B. brachyactis was also more effective than both ketoconazole and bifonazole against Trichoderma viride. B. sayai was more effective than ketoconazole in inhibiting A. fumigatus. B. sayai was most non-toxic to HEK 293 (cellular viability = 117%) and HepG2 (cellular viability = 104%). The highest level of TPC was observed in B. pinnatifolium (35.94 mg GAE g-1) while B. microcarpum possessed the highest TFC (39.21 mg RE g-1). Seventy four compounds were detected in B. microcarpum, 70 in B. brachyactis, 66 in B. sayai, and 51 in B. pinnatifolium. Quinic acid, chlorogenic acid, pantothenic acid, esculin, isoquercitrin, rutin, apigenin, and scopoletin were present in all the four species. This study showed that the four Bunium species are good sources of biologically active compounds with pharmaceutical and nutraceutical potential.

Protective effects of Cotoneaster integerrimus on in vitro and ex-vivo models of H2 O2 -induced lactate dehydrogenase activity in HCT116 cell and on lipopolysaccharide-induced inflammation in rat colon.

The present study evaluated the biological potential of methanol and aqueous extracts of the twigs and fruits of Cotoneaster integerrimus Medik. Lethality bioassays performed on Artemia salina showed that aqueous and methanol C. integerrimus extracts were non-toxic in the concentration range (0.1-20 mg/ml), with a LC50 ≥ 2.5 mg/ml, for each single extract. The protective effect of the extracts was assessed in vitro against hydrogen peroxide-induced lactate dehydrogenase (LDH) activity and tumor necrosis factor (TNF)α gene expression in colon cancer HCT116 cell line. All the extracts downregulated (H2 O2 )-induced TNFα gene expression, in HCT116. By contrast, it was observed that the lipopolysaccharide (LPS)-induced increase in colon nitrite, prostaglandin E2 , and 8-iso-PGF2α levels were counteracted mostly by the methanol twig extract. The present study showed protective effects induced by C. integerrimus in vitro and ex vivo, thus supporting potential application in the management of chronic inflammatory diseases. PRACTICAL APPLICATIONS: In the present study, protective effects of C. integerrimus are highlighted using in vitro and ex-vivo models of hydrogen peroxide-induced LDH activity in HCT116 cell and on LPS-induced inflammation in rat colon. Based on our results, this edible and traditionally used species could be considered as a valuable source of natural agents to combat inflammatory diseases, particularly ulcerative colitis. Results amassed herein advocates for further bioprospection of this species that could open new avenues for the development of nutraceuticals and functional foods geared toward the management of chronic inflammatory diseases.

Pharmacological and polyphenolic profiles of Phyllanthus phillyreifolius var. commersonii Müll. Arg: An unexplored endemic species from Mauritius.

Phyllanthus phillyreifolius var. commersonii Müll. Arg is an endemic plant of Mauritius. To date, no study has been performed concerning its polyphenolic profile and pharmacological properties. In this study, a decoction (water), ethyl acetate and methanol extracts of the aerial parts of P. phillyreifolius, obtained from different extraction procedures (maceration and Soxhlet), were studied for antibacterial, antioxidant, anticancer, and enzyme inhibitory properties along with their polyphenolic profile. The ethyl acetate macerated extract showed high antibacterial activity against B. cereus (MIC = 0.293 mg/mL) and E. coli (MIC = 0.417 mg/mL) while S. epidermidis was most susceptible to the ethyl acetate-Soxhlet extract (MIC = 0.521 mg/mL). The methanol-Soxhlet extract displayed the most potent cupric and ferric reducing power, and metal chelating effect, while the macerated methanolic extract was the most effective DPPH and ABTS scavenger, and BChE inhibitor. Only the ethyl acetate-Soxhlet extract exhibited α-glucosidase inhibition. All extracts exhibited a strong anti-tyrosinase activity, which was further investigated by molecular docking and molecular dynamic. After 48 h exposure to the extracts for HeLa cell lines, the ethyl acetate-Soxhlet extract showed the highest inhibition (IC50 = 533.1 µg/mL) while the decoction extract was more cytotoxic to MDA-MB-231 cells (IC50 = 337.4 µg/mL). Treatment of cancer cell lines with all P. phillyreifolius extracts resulted in a time-dependent reduction of cell viability for HeLa and dose-and time-dependent reduction for MDA-MB-231. Gene expression ratio of Bcl-2 to Bax was higher for all Soxhlet-extracts. Total phenolics (TPC) and flavonoids (TFC) content were highest in the decoction and methanol-Soxhlet extract, respectively (122.43 mg GAE/g extract and 31.28 mg RE/g extract, respectively). The extracts were abundant in ellagitannins, although phenolic acids and flavonoids were also detected. Granatin B was detected for the first time in Phyllanthus species. Overall, the aerial parts of P. phillyreifolius exemplify a potent reservoir of bioactive phytochemicals for therapeutic applications.

Paeonia arietina and Paeonia kesrounansis bioactive constituents: NMR, LC-DAD-MS fingerprinting and in vitro assays.

Paeonia species have been valued for their ethnomedicinal uses in various countries and received much interest among the scientific community for their therapeutic properties, including anti-microbial, anti-inflammatory, anti-cancer, nephroprotective and hepatoprotective effects. The multiple phytotherapeutical applications of Paeonia species inspired us to establish the phytochemical fingerprint and to evaluate the biological properties of ethyl acetate, methanol, and aqueous extracts from the roots and aerial parts of two Paeonia species (P. arietina G. Anderson and P. kesrounansis Thiébaut). Phytoconstituents of P. arietina and P. kesrounansis extracts were analyzed using 1D and 2D NMR and LC-DAD-ESI-MS. The total content of phenolics (TPC) and flavonoids (TFC) in the extracts was also evaluated. The antioxidant activity was profiled using DPPH, ABTS, CUPRAC, FRAP, phosphomolybdenum, and metal chelation assays. Enzyme inhibitory properties were evaluated against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), tyrosinase, α-amylase, and α-glucosidase. Phytochemical analysis of P. arietina and P. kesrounansis extracts showed the presence of galloyl esters of sugars, galloyl monoterpenes, and glycosylated flavonoids. The three solvent extracts presented different behavior in the bioassays. The highest antioxidant activity, tyrosinase and AChE inhibition were observed for the methanolic extract of the aerial parts of P. kesrounansis. In addition, the ethyl acetate extracts of the aerial parts of both plants were the most effective inhibitors of α-amylase. The highest BChE inhibition was observed for root methanolic extract of P. kesrounansis while the root ethyl acetate extract of P. arietina exerted the strongest inhibition of α-glucosidase. Methanol extract of P. kesrounansis aerial parts presented the highest TPC, while TFC was greatest in the corresponding extract of P. arietina. Our findings can be considered as a starting point for future studies to further validate the effectiveness and safety profiles of these plants in folk medicine.

A comprehensive appraisal on Crocus chrysanthus (Herb.) Herb. flower extracts with HPLC-MS/MS profiles, antioxidant and enzyme inhibitory properties.

In the quest for new drugs of herbal origin, the ethyl acetate (EAE), methanol (ME), and water (WE) extracts of Crocus chrysanthus (Herb.) Herb. flowers were analyzed for their polyphenolic composition, antioxidant, and enzyme inhibitory potential. WE showed the highest antioxidant activities in all assays including metal chelating, phosphomolybdenum, FRAP, CUPRAC, ABTS and DPPH. EAE was the most effective enzyme inhibitor, exhibiting the highest inhibition against some enzymes linked to Alzheimer's disease (cholinesterases), diabetes mellitus (α-glucosidase and α-amylase) and hyperpigmentation problems (tyrosinase). The highest total phenolics (34.99 mg GAE/g) and flavonoids content (77.58 mg RE/g) were observed in WE and ME, respectively. Eight compounds were identified in EAE, 24 in ME, and 15 in WE. Kaempferol 3-O glucoside was found in all extracts. In conclusion, C. chrysanthus flowers can be suggested as a source of bioactive components with potential use against chronic disorders caused by oxidative stress. Future in-depth studies are recommended to determine the biological effects of isolated compounds from C. chrysanthus to identify the main compounds modulating the observed activities.

HPLC-MS/MS chemical characterization and biological properties of Origanum onites extracts: a recent insight.

This study investigated into the phytochemical profile and biological properties of extracts (methanol and aqueous) of Origanum onites based on the antioxidant, enzyme inhibitory, and antibacterial activities. The aqueous extract exhibited higher antioxidant activities in the 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2'-azino-bis(3-ethylbenzothiazoline)-6-sulfonic acid (ABTS), ferric reducing antioxidant power, cupric reducing antioxidant capacity, phosphomolybdenum, and metal chelating assays, compared to the methanol extract. In contrast, the methanol extract was the most effective inhibitor of acetylcholinesterase, butyrylcholinesterase, tyrosinase, α-amylase, and α-glucosidase. The methanol extract also showed higher antibacterial activity with highest inhibition against Escherichia coli (MIC = 6.25 mg/mL). The total phenolic content was higher in the aqueous extract while the methanol extract possessed higher total flavonoid content. A total of 28 and 18 compounds (belonging to polyphenols, flavonoids, terpenoids, and ester classes) were identified from the methanol and water extracts, respectively. These findings suggest that O. onites could be helpful in the management of oxidative stress-associated diseases including diabetes and neurodegenerative complications. Abbreviations: ABTS: 2,2'-azino-bis(3-ethylbenzothiazoline)-6-sulfonic acid; ACAE: acarbose equivalent; AChE: acetylcholinesterase; AD: Alzheimer's disease; BChE: butyrylcholinesterase; CUPRAC: cupric reducing antioxidant capacity; DPPH: 1,1-diphenyl-2-picrylhydrazyl; EDTAE: EDTA equivalent; FRAP: ferric reducing antioxidant power; GAE: gallic acid equivalent; GALAE: galatamine equivalent; HPLC: high performance liquid chromatography; KAE: kojic acid equivalent; RE: rutin equivalents; TE: trolox equivalent; TPC: total phenolic content; TFC: total flavonoid content.

Scrophularia lucida L. as a valuable source of bioactive compounds for pharmaceutical applications: In vitro antioxidant, anti-inflammatory, enzyme inhibitory properties, in silico studies, and HPLC profiles.

The genus Scrophularia has received much interest with regards to its traditional uses against eczema, psoriasis, and mastitis. Yet, the medicinal properties of some species still need to be scientifically validated. The present study was designed to investigate into the biological properties of various solvent extracts (ethyl acetate, methanol, and aqueous) of the roots and aerial parts of Scrophularia lucida based on its antioxidant, anti-inflammatory, and enzyme inhibitory activities together with phytochemical screening. Our results revealed that the solvent extracts differed in their biological effectiveness. The root ethyl acetate extract showed the highest ABTS scavenging, FRAP, CUPRAC, and inhibitory activity against AChE and α-glucosidase. The ethyl acetate extract of the aerial parts displayed the highest BChE and α-amylase inhibition and antioxidant effect in the phosphomolybdenum assay, while the methanol extracts of both parts were the most effective DPPH• scavengers and tyrosinase inhibitors. The methanol extracts of the root and aerial parts also inhibited NO production in lipopolysaccharide (LPS)-stimulated murine leukemic monocyte-macrophage cell (4.99% and 10.77%, respectively), at 31.25 µg/mL concentration. The highest TPC (34.98 mg GAE/g extract) and TFC (48.33 mg RE/g extract) were observed in the ethyl acetate extract of the root and aerial parts, respectively. The most abundant compounds in the root ethyl acetate extract were luteolin (852 µg/g extract), rosmarinic acid (522 µg/g extract), and hesperidin (394 µg/g extract) while kaempferol was most abundant in the ethyl acetate extract of the aerial parts (628 µg/g extract). In silico experiments were conducted on tyrosinase and the higher docking values were observed for rosmarinic acid and hesperidin. The present findings provide base line information which tend to support the potential use of S. lucida in the management of several chronic diseases, including Alzheimer's disease and diabetes mellitus.

New pharmacological targets of three Asphodeline species using in vitro and ex vivo models of inflammation and oxidative stress.

This study explored the efficacy of the methanolic extract of three Asphodeline species (A. damascena subsp. rugosa, A. tenuior subsp. tenuiflora var. tenuiflora, and A. cilicica) to protect against hydrogen peroxide (H2O2)-induced lactate dehydrogenase (LDH) activity in HCT116 cells, and also any protective effects against lipopolysaccharides (LPS)-induced nitrite levels, prostaglandin E2 (PGE2) and 8-iso-prostaglandin F2α (8-iso-PGF2α) levels, 5HIAA/5-HT ratio, tumor necrosis factor (TNF)-α and interleukin (IL)-6 gene expression in rat colon specimens. Interestingly, A. tenuior extract was most effective in improving the tested biomarkers, by reducing LDH activity and nitrite level. On the other hand, A. damascena was the only species able to blunt LPS-induced TNF-α gene expression in rat colon specimens. The present findings highlighted the protective effects of Asphodeline extracts via in vitro and ex vivo models of inflammation and oxidative stress, adding new insights to the pharmacological actions of these medicinal plant species. Abbreviations: IBD: inflammatory bowel disease; LPS: lipopolysaccharide; LDH: lactate dehydrogenase; 5HIAA: 5-hydroxyindoleacetic acid; 5-HT: 5-hydroxytryptamine.

Combination of phenolic profiles, pharmacological properties and in silico studies to provide new insights on Silene salsuginea from Turkey.

The genus Silene is renowned in Turkey for its traditional use as food and medicine. Currently, there are 138 species of Silene in Turkey, amongst which have been several studies for possible pharmacological potential and application in food industry. However, there is currently a paucity of data on Silene salsuginea Hub.-Mor. This study endeavours to access its antioxidant, enzyme inhibitory, and anti-inflammatory properties. Besides, reversed-phase high-performance liquid chromatography-diode array detector (RP-HPLC-DAD) was used to detect phenolic compounds, and molecular docking was performed to provide new insights for tested enzymes and phenolics. High amounts of apigenin (534 µg/g extract), ferulic acid (452 µg/g extract), p-coumaric acid (408 µg/g extract), and quercetin (336 µg/g extract) were detected in the methanol extract while rutin (506 µg/g extract) was most abundant in the aqueous extract. As for their biological properties, the methanol extract exhibited the best antioxidant effect in the DPPH and CUPRAC assays, and also the highest inhibition against tyrosinase. The aqueous extract was the least active enzyme inhibitor but showed the highest antioxidant efficacy in the ABTS, FRAP, and metal chelating assays. At a concentration of 15.6 µg/mL, the methanol extract resulted in a moderate decrease (25.1%) of NO production in lipopolysaccharide-stimulated cells. Among the phenolic compounds, epicatechin, (+)-catechin, and kaempferol showed the highest binding affinity towards the studied enzymes in silico. It can be concluded that extracts of S. salsuginea are a potential source of functional food ingredients but need further analytical experiments to explore its complexity of chemical compounds and pharmacological properties as well as using in vivo toxicity models to establish its maximum tolerated dose.

A review of the traditional and modern uses of Salvadora persica L. (Miswak): Toothbrush tree of Prophet Muhammad.

ETHNOPHARMACOLOGICAL RELEVANCE: Salvadora persica L., also known as Arak (in Arabic) and Peelu (in Urdu), is the most common traditional source of tooth or chewing stick (miswak) highly recommended by Prophet Muhammad. To date, extensive studies have probed primarily into the validation of its traditional uses in oral care. Nonetheless, there is still a dearth of updated compilation and critical analysis of other potential ethnopharmacological properties of S. persica. This review therefore aims to provide an up-to-date detailed structured description of the traditional uses of S. persica and a critical analysis of its modern uses, highlighting its phytochemistry, pharmacological properties, and bioapplications. MATERIALS AND METHODS: Various databases (Science Direct, PubMed, Wiley Online Library, and Google Scholar), books, and relevant primary sources were probed, surveyed, analysed, and included in this review. The literature cited in this review dated from 1979 to 2017. RESULTS: S. persica was found to possess a plethora of bioactive compounds and broad pharmacological properties, including antimicrobial, antioxidant, enzyme inhibitory activity, antiulcer, anticonvulsant, sedative, analgesic, anti-inflammatory, hypoglycemic, hypolipidemic, antiosteoporosis, and antitumor activities. Studies also revealed the potential use of S. persica as a natural food preservative and a novel functional food ingredient. In addition, improvement in growth and reproductive performances have been observed by the introduction of S. persica in animal feed. Lastly, S. persica has also been used in the green synthesis of nanoparticles showing potential biotechnological applications. CONCLUSION: S. persica showed a wide scope of application and its uses have been extended far beyond the initial traditional uses of its roots, stems, and twigs in oral care. We found a number of other ethnopharmacological uses and potential bioapplications of different parts of S. persica that warrants further investigations. Though widely studied using several in vitro and in vivo models, and tested clinically for oral hygiene mainly, several gaps and research priorities have been identified which needs to be addressed in future.