Medicinal Importance, Pharmacological Activities, and Analytical Aspects of Engeletin in Medicine: Therapeutic Benefit Through Scientific Data Analysis.

BACKGROUND: Phytochemicals belonging to the class of flavonoids have been used in medicine for the treatment of different kinds of human health complications. Flavonoids have beneficial health aspects in medicine mainly due to their anti-microbial, anti-diabetic, anti-inflammatory, anticancer, and anti-carcinogenic activities. They have been scientifically investigated for their health benefit and pharmacological activities in medicine. Engeletin is a pure flavanonol class phytocompound present in the skin of white grapes and white wine. Engeletin has numerous pharmacological activities in medicine. METHODS: In order to know the beneficial health aspects of engeletin in medicine, scientific data on engeletin have been collected from different literature sources and analyzed in the present work. The present work summarized the important findings of engeletin with respect to its medicinal uses, pharmacological activities, and analytical aspects in medicine. All the scientific data were collected from PubMed, Google, Scopus, Science Direct and Google Scholar and analyzed in the present work. RESULTS: Scientific data analysis of research works revealed the biological importance and therapeutic benefit of engeletin in medicine. Engeletin has attracted scientific attention mainly due to its antiinflammatory and anti-tumor potential. Engeletin could inhibit the occurrence of cervical cancer and delay the development of liver damage and lung cancer in mice. Engeletin was found to inhibit lipopolysaccharides- induced endometritis in mice by inhibiting the inflammatory response. Pharmacological data analysis revealed the therapeutic importance of engeletin against acute lung injury, inflammatory diseases, liver injury, pulmonary fibrogenesis, Alzheimer's disease, endometritis, cervical carcinogenesis, lung cancer, and osteoarthritis. Analytical data signified the importance of modern analytical tools for separating, isolating, and identifying engeletin. CONCLUSION: Scientific data analysis revealed the biological importance and therapeutic benefit of engeletin in medicine and other allied health sectors.

Crystal Structure of an SSB Protein from Salmonella enterica and Its Inhibition by Flavanonol Taxifolin.

Single-stranded DNA (ssDNA)-binding proteins (SSBs) play a central role in cells by participating in DNA metabolism, including replication, repair, recombination, and replication fork restart. SSBs are essential for cell survival and thus an attractive target for potential anti-pathogen chemotherapy. In this study, we determined the crystal structure and examined the size of the ssDNA-binding site of an SSB from Salmonella enterica serovar Typhimurium LT2 (SeSSB), a ubiquitous opportunistic pathogen which is highly resistant to antibiotics. The crystal structure was solved at a resolution of 2.8 Å (PDB ID 7F25), indicating that the SeSSB monomer possesses an oligonucleotide/oligosaccharide-binding (OB) fold domain at its N-terminus and a flexible tail at its C-terminus. The core of the OB-fold in the SeSSB is made of a six-stranded ß-barrel capped by an α-helix. The crystal structure of the SeSSB contained two monomers per asymmetric unit, which may indicate the formation of a dimer. However, the gel-filtration chromatography analysis showed that the SeSSB forms a tetramer in solution. Through an electrophoretic mobility shift analysis, we characterized the stoichiometry of the SeSSB complexed with a series of ssDNA dA homopolymers, and the size of the ssDNA-binding site was determined to be around 22 nt. We also found the flavanonol taxifolin, also known as dihydroquercetin, capable of inhibiting the ssDNA-binding activity of the SeSSB. Thus, this result extended the SSB interactome to include taxifolin, a natural product with a wide range of promising pharmacological activities.

Flavanonol Glycosides from the Stems of Myrsine seguinii and Their Neuroprotective Activities.

The accumulation of amyloid beta (Aß) peptides is common in the brains of patients with Alzheimer's disease, who are characterized by neurological cognitive impairment. In the search for materials with inhibitory activity against the accumulation of the Aß peptide, seven undescribed flavanonol glycosides (1-7) and five known compounds (8-12) were isolated from stems of Myrsine seguinii by HPLC-qTOF MS/MS-based molecular networking. Interestingly, this plant has been used as a folk medicine for the treatment of various inflammatory conditions. The chemical structures of the isolated compounds (1-12) were elucidated based on spectroscopic data, including 1D and 2D nuclear magnetic resonance (NMR), high-resolution electrospray ionization mass spectrometry (HRESIMS) and electronic circular dichroism (ECD) data. Compounds 2, 6 and 7 showed neuroprotective activity against Aß-induced cytotoxicity in Aß42-transfected HT22 cells.

Bioactive secondary metabolites from roots of Cissus rheifolia planch.

Two new aromadendrin rhamnosides, cissusfoliate A (1) and 3-epi-cissusfoliate A (2) together with seven known compounds (3-9) were isolated from the roots of Cissus rheifolia Planch. Their structures were determined by extensive spectroscopic methods. The absolute configurations of compounds 1-5 were assigned by combination of the J coupling constant values of H-2 and H-3 and the comparison of their experimental ECD spectra with those reported in literature. Compounds 1, 3 and 5-8 showed antioxidant effects on ORAC, ATBS and DPPH assays as well as antibacterial activity against six pathogenic bacterial strains. Their cytotoxicity against Hela, KB, MCF-7, HepG2 and HT-29 cell lines were also evaluated.

Antiplasmodial and antileishmanial flavonoids from Mundulea sericea.

Five known compounds (1-5) were isolated from the extract of Mundulea sericea leaves. Similar investigation of the roots of this plant afforded an additional three known compounds (6-8). The structures were elucidated using NMR spectroscopic and mass spectrometric analyses. The absolute configuration of 1 was established using ECD spectroscopy. In an antiplasmodial activity assay, compound 1 showed good activity with an IC50 of 2.0 µM against chloroquine-resistant W2, and 6.6 µM against the chloroquine-sensitive 3D7 strains of Plasmodium falciparum. Some of the compounds were also tested for antileishmanial activity. Dehydrolupinifolinol (2) and sericetin (5) were active against drug-sensitive Leishmania donovani (MHOM/IN/83/AG83) with IC50 values of 9.0 and 5.0 µM, respectively. In a cytotoxicity assay, lupinifolin (3) showed significant activity on BEAS-2B (IC50 4.9 µM) and HePG2 (IC50 10.8 µM) human cell lines. All the other compounds showed low cytotoxicity (IC50 > 30 µM) against human lung adenocarcinoma cells (A549), human liver cancer cells (HepG2), lung/bronchus cells (epithelial virus transformed) (BEAS-2B) and immortal human hepatocytes (LO2).

Effects of Flavonoids and Its Derivatives on Immune Cell Responses.

BACKGROUND: Various pieces of evidence have shown that people who consume foods rich in polyphenolic and flavonoids compounds have a lower incidence of inflammatory, autoimmune diseases and cancer. OBJECTIVE: The study aimed to review the most potent compounds that affect the immune response and diseases associated with it. METHODS: Publications in PubMed and EmBase, from 1974-2018, and patents form Free patents online, Scifinder, Espacenet and Mendeley in which flavonoids, their semi-synthetic and synthetic derivatives are involved in immunosuppressive or immunostimulatory responses in vitro and in vivo. RESULTS: In vitro, flavonoids and their derivatives inhibit various transcriptional factors, which modulate differentiation, proliferation, activation of immune cells and enhance regulatory T cell generation. Some flavonoids exert anti-inflammatory effects through: Blockade of NF-κB, and NLRP3 inflammasome, inhibition of pro-inflammatory cytokine production, IL-1ß, IL-2, IL-6, TNF-α, IL-17A, down regulation of chemokines, and reduction of reactive oxygen and nitrogen species. Nevertheless, several reports have shown that some flavonoids enhance immune response by enhancing: oxygen and nitrogen radicals, antibody production, cytotoxic activity against tumours by increasing activating receptors and down regulating inhibitory receptors. In consequence, flavonoids may be potentially useful for treatment of infectious diseases and cancer. CONCLUSION: The most potent flavonoids in inflammation that modify immune responses are apigenin, quercetin and Epigallocatechin-3-Gallate (EGCG) although, other compounds are still under study and cannot be excluded. The most relevant patents concerning the use of flavones and other polyphenols were revised. A promising future of these compounds in different therapies is discussed.

An NADH-Dependent Reductase from Eubacterium ramulus Catalyzes the Stereospecific Heteroring Cleavage of Flavanones and Flavanonols.

The human intestinal anaerobe Eubacterium ramulus is known for its ability to degrade various dietary flavonoids. In the present study, we demonstrate the cleavage of the heterocyclic C-ring of flavanones and flavanonols by an oxygen-sensitive NADH-dependent reductase, previously described as enoate reductase, from E. ramulus This flavanone- and flavanonol-cleaving reductase (Fcr) was purified following its heterologous expression in Escherichia coli and further characterized. Fcr cleaved the flavanones naringenin, eriodictyol, liquiritigenin, and homoeriodictyol. Moreover, the flavanonols taxifolin and dihydrokaempferol served as substrates. The catalyzed reactions were stereospecific for the (2R)-enantiomers of the flavanone substrates and for the (2S,3S)-configured flavanonols. The enantioenrichment of the nonconverted stereoisomers allowed for the determination of hitherto unknown flavanone racemization rates. Fcr formed the corresponding dihydrochalcones and hydroxydihydrochalcones in the course of an unusual reductive cleavage of cyclic ether bonds. Fcr did not convert members of other flavonoid subclasses, including flavones, flavonols, and chalcones, the latter indicating that the reaction does not involve a chalcone intermediate. This view is strongly supported by the observed enantiospecificity of Fcr. Cinnamic acids, which are typical substrates of bacterial enoate reductases, were also not reduced by Fcr. Based on the presence of binding motifs for dinucleotide cofactors and a 4Fe-4S cluster in the amino acid sequence of Fcr, a cofactor-mediated hydride transfer from NADH onto C-2 of the respective substrate is proposed.IMPORTANCE Gut bacteria play a crucial role in the metabolism of dietary flavonoids, thereby contributing to their activation or inactivation after ingestion by the human host. Thus, bacterial activities in the intestine may influence the beneficial health effects of these polyphenolic plant compounds. While an increasing number of flavonoid-converting gut bacterial species have been identified, knowledge of the responsible enzymes is still limited. Here, we characterized Fcr as a key enzyme involved in the conversion of flavonoids of several subclasses by Eubacterium ramulus, a prevalent human gut bacterium. Sequence similarity of this enzyme to hypothetical proteins from other flavonoid-degrading intestinal bacteria in databases suggests a more widespread occurrence of this enzyme. Functional characterization of gene products of human intestinal microbiota enables the assignment of metagenomic sequences to specific bacteria and, more importantly, to certain activities, which is a prerequisite for targeted modulation of gut microbial functionality.

Antiplasmodial prenylated flavanonols from Tephrosia subtriflora.

The CH2Cl2/MeOH (1:1) extract of the aerial parts of Tephrosia subtriflora afforded a new flavanonol, named subtriflavanonol (1), along with the known flavanone spinoflavanone B, and the known flavanonols MS-II (2) and mundulinol. The structures were elucidated by the use of NMR spectroscopy and mass spectrometry. The absolute configuration of the flavanonols was determined based on quantum chemical ECD calculations. In the antiplasmodial assay, compound 2 showed the highest activity against chloroquine-sensitive Plasmodium falciparum reference clones (D6 and 3D7), artemisinin-sensitive isolate (F32-TEM) as well as field isolate (KSM 009) with IC50 values 1.4-4.6 µM without significant cytotoxicity against Vero and HEp2 cell lines (IC50 > 100 µM). The new compound (1) showed weak antiplasmodial activity, IC50 12.5-24.2 µM, but also showed selective anticancer activity against HEp2 cell line (CC50 16.9 µM).

Flavanonol glucosides from the aerial parts of Agrimonia pilosa Ledeb. and their acetylcholinesterase inhibitory effects.

Two new flavanonol glucoside isomers, (2R,3S)-dihydrokaempferol 3-O-ß-D-glucoside (1) and (2S,3R)-dihydrokaempferol 3-O-ß-D-glucoside (2), were isolated from the aerial parts of Agrimonia pilosa Ledeb., along with eight known flavanonol glucosides (3-10). Their structures were determined on the basis of spectroscopic analysis. In addition, these compounds were evaluated to determine their acetylcholinesterase inhibitory activities. The results indicated that these compounds have moderate inhibitory effects, with IC50 values ranging from 76.59 ± 1.16 to 97.53 ± 1.64 µM, except compounds 1 and 4 were inactive.

A pair of taxifolin-3-O-arabinofuranoside isomers from Juglans regia L.

Diaphragma juglandis Fructus has been known for its effect on tonifying kidney in traditional Uighur medicine. During our ongoing studies on the discovery of biologically active compounds from folk medicine, a pair of flavanonol glycoside isomers named (2S,3S)-taxifolin-3-O-α-d-arabinofuranoside (1) and (2S,3S)-taxifolin-3-O-α-l-arabinofuranoside (2) were isolated, among them, 1 was a new compound. It is the first report of taxifolin-3-O-arabinofuranosides in both α-d and α-l configuration forms in genus Juglans. Their structures were determined on the basis of spectroscopic analysis and chemical evidence, in combination with circular dichroism.

Engeletin Alleviates Lipopolysaccharide-Induced Endometritis in Mice by Inhibiting TLR4-mediated NF-κB Activation.

Engeletin (dihydrokaempferol 3-rhamnoside) is a flavanonol glycoside. It can be found in the skin of white grapes and white wine and is widely distributed in southeast Asia, and the leaves are used in a tea. Here, we explored the impact of engeletin against the inflammatory reaction in a lipopolysaccharide (LPS)-induced endometritis mouse model. Engeletin treatment significantly attenuated uterus damage and decreased myeloperoxidase activity. ELISA and qPCR assays showed that engeletin dose-dependently suppressed the expression of TNF-α, IL-1ß, and IL-6. Molecular studies also demonstrated that the levels of iNOS, COX-2, and TLR4, along with their downstream molecules MyD88, IRAK1, TRAF6, and TAK1, were also suppressed by engeletin. In addition, engeletin treatment inhibited NF-κB signaling-pathway activation. Moreover, immunofluorescence analysis demonstrated that engeletin suppressed NF-κB-p65 nuclear translocation. These data indicated the protective action of engeletin against LPS-stimulated endometritis in mice via negative regulation of pro-inflammatory mediators via the TLR4-regulated NF-κB pathway.

Flavanonol compounds from thorns of Gleditsie Spina and their cytotoxicity / 中草药

Objective: To study the flavonoids constituents from the thorns of Gleditsia sinensis and their cytotoxicity against tumor cells. Methods: The compounds were isolated by silica gel, Sephadex LH-20 column chromatography, and HPLC techniques. Their structures were elucidated on the basis of spectroscopic analyses. Results: Twelve flavonoids were obtained and identified as (2R,3R)-5,3',4'-trimethoxyl-7-hydroxyl-flavanonol (1), 5,7,3',4'-tetrahydroxyl-flavanonol (2), 5-methoxyl-3',4',7-trihydroxyl-flavanonol (3), dihydrokaempferol (4), epicatechin (5), 5,7,3',5'-tetrahydroxyl-flavanonol (6), fustin (7), (2R,3R)-7,3',5'-trihydroxyl-flavanonol (8), (2R,3R)-5,7,3'-trihydroxyl-4'-methoxyl-flavanonol (9), quercetin (10), 5,7,4'-trihydroxylflavone-8-C-glucopyranose (11), and 2,7-dimethyl-xanthone (12), respectively. Conclusion: Compound 1 is a new component named G. spina flavanonol A, and compounds 3,8,9, and 12 are isolated from the thorns of G. sinensis for the first time. The results of cytotoxicity test show that the dihydroflavonol compound 7 displays the stronger cytotoxicity against HepG2, A549, and EC109 cell strains, while compounds 1 and 3 have the effects on HepG2 and EC109, and compound 2 has the effect on EC109 cancer cells, respectively.