Antiproliferative and Anti-Inflammatory Effects of the Polyphenols Phloretin and Balsacone C in a Coculture of T Cells and Psoriatic Keratinocytes.

Plaque psoriasis is a chronic inflammatory skin disease causing red inflamed lesions covered by scales. Leukocytes, including dendritic cells and T cells, participate in the inflammation of the skin by producing multiple cytokines, thus contributing to the hyperproliferation of keratinocytes. Lack of effectiveness and toxic side effects are the main concerns with conventional treatments, and research involving new antipsoriatic molecules is essential. In this study, the anti-inflammatory and antiproliferative effects of two natural polyphenols, phloretin and balsacone C, were investigated using the coculture of T cells and psoriatic keratinocytes. Phloretin exerted antiproliferative activity by regulating the expression of antigen Ki67 and proliferating cell nuclear antigen (PCNA). These effects were comparable to those of methotrexate, a reference treatment for moderate to severe psoriasis. With balsacone C, the expression of Ki67 was also reduced. Additionally, phloretin decreased the levels of multiple pro-inflammatory cytokines: monocyte chemoattractant protein-1 (MCP-1/CCL2), macrophage inflammatory protein-1α (MIP-1α), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-1 alpha (IL-1α), interleukin-1 beta (IL-1ß), interleukin-6 (IL-6), interleukin-17A (IL-17A), and tumor necrosis factor alpha (TNF-α). The increased interleukin-2 (IL-2) levels with phloretin and methotrexate also represented anti-inflammatory activity. Balsacone C and methotrexate decreased the levels of IL-1α and IL-1ß, but methotrexate exerted a higher reduction. In summary, the anti-inflammatory effects of phloretin were more pronounced than those of methotrexate and balsacone C. In addition, the expression of lymphocyte common antigen (CD45) was more similar to that of the healthy condition after using phloretin or methotrexate. Finally, phloretin stood out from the other compounds and appears promising for psoriasis treatment.

Synthesis and cytotoxicity evaluation of d- and l-sugar-containing mono- and bidesmosidic ursane-type saponins.

Ursolic acid and uvaol are naturally occurring triterpenoids that exhibit a broad spectrum of pharmacological activities, including cytotoxicity. However, a primary challenge in the development of ursane-type pentacyclic triterpenoids for pharmacological use is their poor aqueous solubility, which can impede their effectiveness as therapeutics agents. In this study, we present the facile synthesis of ursolic acid monodesmosides and uvaol bidesmosides, incorporating naturally occurring and water-soluble pentoses and deoxyhexose sugar moieties of opposite d- and l-configurations at the C3 or C3/C28 positions of the ursane core. The twenty synthetic saponins were evaluated in vitro for their cytotoxicity against lung carcinoma (A549) and colorectal adenocarcinoma (DLD-1) cell lines. Notably, all the bidesmosidic uvaol saponins were shown to be cytotoxic as compared to their non-cytotoxic parent triterpenoid. For each series of ursane-type saponins, the most active compounds were 3-O-α-l-arabinopyranosyl ursolic acid (3h) and 3,28-di-O-α-l-rhamnopyranosyl uvaol (4f), showing IC50 values in the low micromolar range against A549 and DLD-1 cancer lines.

Phenolic compounds from Limonium densiflorum: a multifaceted approach to antioxidant, anti-inflammatory, anticancer, and anti-influenza activities.

Exploration of the hydroethanolic extracts from the halophyte Limonium densiflorum, led to the isolation of seven phenolic compounds: gallic acid, epigallocatechin gallate (EGCG), quercitrin, a mixture of myricetin 3-O-α-rhamnopyranoside + myricetin 3-O-L-arabinofuranoside, dihydrokaempferol, pinoresinol, and trans-N-ferulolyl tyramine. These compounds were assessed for anticancer, anti-influenza A virus, antioxidant, and anti-inflammatory properties. The results indicated that these compounds do not exhibit toxicity towards healthy cells (WS-1 and MDCK). Furthermore, they displayed strong antioxidant properties. Among these compounds, gallic acid, the mixture of myricetin 3-O-α-rhamnopyranoside + myricetin 3-O-L-arabinofuranoside, dihydrokaempferol, and pinoresinol, showed significant cytotoxicity against colon cancer cells (IC50: 1-39 µg/mL). EGCG, gallic acid, dihydrokaempferol, pinoresinol, and trans-N-ferulolyl tyramine demonstrated potent anti-inflammatory activity by reducing nitric oxide (NO) production and also inhibited the replication of the influenza A virus. Biological activities varied based on compound structure, with phenolic acids and flavonoid aglycones showing stronger effects than glycosylated compounds and lignans.

Potential bio-functional properties of Citrus aurantium L. leaf: chemical composition, antiviral activity on herpes simplex virus type-1, antiproliferative effects on human lung and colon cancer cells and oxidative protection.

This study examined the antioxidant, anticancer and antiviral properties of the methanolic extracts from bigarade (Citrus aurantium L.) leaves at two development stages. Ferulic acid, naringin and naringenin were the principal phenolic components of young and old leaves. The highest total antioxidant capacity was obtained in young leaf extracts (YLE). These latter also exhibited the highest antiradical DPPH (1,1-diphenyl-2-picrylhydrazyl) and ABTS (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)) activities, while the highest iron chelating and reducing power activities were observed in old leaf extracts (OLE). The potent anticancer activity was observed in YLE for human lung carcinoma (A-549) and in OLE for colon adenocarcinoma (DLD-1) cells. YLE showed the highest virucidal effects as compared to OLE and the positive control acyclovir against herpes simplex virus type-1 (HSV-1) propagation in Vero cells during the absorption and replication periods. The young and old leaves might be a source of natural antioxidants and protective agents against oxidative damage.

Diphoterine, an amphoteric rinsing solution, reduces hydrofluoric acid injuries in an ex vivo pigskin model.

Hydrofluoric acid (HF) is a ubiquitous industrial chemical that is particularly hazardous because of the potential for systemic effects and the induction of severe cutaneous necrosis after contact with the skin. Minimizing skin injury requires decontaminating the affected area promptly with an emergency rinsing solution. Few experimental studies have objectively characterized rinsing solutions such as Diphoterine (DP). Here we develop an ex vivo pigskin model to study and compare the efficacy of rinsing solutions as initial decontaminating agents to stop the progression of skin lesions after HF splashing. The pigskin model shows an immediate local response to HF at varying concentrations and exposure times. We then exposed the pigskin biopsies to 3.75% HF for 1 min and rinsed them with different solutions, including water, 0.9% NaCl solution (saline), 10% calcium gluconate (CaG), Hexafluorine (HXF), and DP. We found DP to be a more effective agent for decontaminating HF lesions than water, saline, and CaG. DP had a similar efficacy as HXF, an emergency rinsing solution used specifically for decontaminating HF-exposed skin. This study shows that skin exposed to HF must be treated quickly from the first minute of exposure.

Phytochemical investigation, antioxidant, anti-inflammatory and cytotoxic activities of Tunisian medicinal Tamarix africana Poir.

The current study aimed to evaluate Tunisian Tamarix africana Poir biological activities. In this study, novel biological activities of the shoot extracts related to their phenolics investigated. Secondary metabolite contents, antioxidant, anti-inflammatory and cytotoxic activities of four extracts (hexane, dichloromethane, methanol and water) were investigated. Antioxidant activities were assessed via in vitro and ex vivo assays. Besides, anticancer activity was investigated against human lung carcinoma (A-549) and colon adenocarcinoma (DLD-1) cells. The anti-inflammatory ability was evaluated via inhibition of LPS-induced NO production in RAW 264.7 macrophage cell lines. Methanol and water extracts displayed the highest antioxidant (IC50 = 3.3 and 4.3 µg/mL respectively), which are correlated activities correlated with phenolic contents. Hexane extract exhibited an important anti-inflammatory effect inhibiting NO ability by 100% at 80 µg/mL. Besides, T. africana extracts were found to be active against A-549 lung carcinoma cells with IC50 values ranging from 20 to 34 µg/mL. These results suggested that T. africana is considered as a potential source of readily accessible natural molecules with a promising effect on human health and diseases.

Synthesis and Cytotoxicity of Monomethylated Betulinic Acid 3-O-α-l-Rhamnopyranosides.

Three original derivatives of the cytotoxic betulinic acid 3-O-α-l-rhamnopyranoside featuring a monomethylated rhamnoside residue were synthesized. An improved catalytic procedure was involved to functionalize the O-3 position of the monosaccharide in a site-selective fashion. The cytotoxicity of the novel compounds was evaluated in vitro to highlight the moderate impact of carbohydrate monomethylation on the biological activity of betulinic acid 3-O-α-l-rhamnopyranoside.

Phytochemical analysis, antioxidant, anticancer and anti-inflammatory activities of Lycium europaeum fruits.

Lycium europaeum is used as a medicinal herb in many countries. In this study, cyclohexane, dichloromethane, ethyl acetate, methanol and water were used as solvents in the extraction of L. europaeum fruits. The contents of total phenolics, total flavonoids, total tannins and condensed tannins as well as the biological activities of these extracts were investigated using various in vitro and ex vivo assays. Results showed that all solvent extracts of L. europaeum had no anticancer activity against cancerous (A-549 and DLD-1) and non-cancerous (WS-1) human cells. Methanol and ethyl acetate were the most effective solvent for extraction of phenolic compounds and also exhibited the highest antioxidant and anti-inflammatory activities. The methanol extract of L. europaeum fruits was the richest in phenolic compounds with the predominance of ferulic acid, catechin and narengin. These results supported the use of L. europaeum fruit as natural source of bioactive compound for pharmaceutical applications.

Effect of the Chromone Core Substitution of Dirchromone on the Resultant Biological Activities.

Dirchromone is a bioactive vinyl sulfoxide-bearing chromone first isolated from the shrub Dirca palustris. Altogether, 32 of its derivatives were prepared to assess the effect of substitution of its chromone core upon activities against cancer cell lines, Gram-positive bacteria, and fungi (such as Candida albicans). All compounds were synthesized following a synthetic strategy involving Pummerer and soft-enolization Baker-Venkataraman rearrangements. Substituent position changes induced little variability on the activities tested. There was no correlation between cytotoxic and antibacterial effects, suggesting different underlying mechanisms of action. In particular, hydroxy group and cyanide substituents diminished cytotoxicity, with the latter featuring enhanced antibacterial activity. Higher homologues of 6-alkoxydirchromones also exhibited progressively emerging antifungal activity. Other modifications had moderate effects on cytotoxicity with some derivatives leading to increased potency. This behavior highlights the robustness of the natural dirchromone pharmacophore toward decoration, thus paving the way for more elaborate future drug design.

Bio-Guided Fractionation of Retama raetam (Forssk.) Webb & Berthel Polar Extracts.

The fractionation of the methanolic extract (MeOH-E) of Retama raetam (Forssk.) Webb & Berthel and further analysis by thin layer chromatography resulted in four fractions (F1, F2, F3 and F4) that, in parallel with the MeOH-E, were screened for antioxidant, cytotoxic, antidiabetic and antibacterial properties. In addition, chemical characterization of their bioactive molecules was performed using LC-DAD-ESI/MSn. The results indicated that F3 was the most promising regarding antioxidant and cytotoxicity abilities, possibly due to its richness in flavonoids class, particularly isoflavones. In turn, F1 was characterized by the presence of the most polar compounds from MeOH-E (organic acids and piscidic acid) and showed promising abilities to inhibit α-amylase, while F4, which contained prenylated flavonoids and furanoflavonoids, was the most active against the tested bacteria. The gathered results emphasize the distinct biological potentials of purified fractions of Retama raetam.

Total Synthesis of a Chimeric Glycolipid Bearing the Partially Acetylated Backbone of Sponge-Derived Agminoside E.

We describe the total synthesis of a chimeric glycolipid bearing both the partially acetylated backbone of sponge-derived agminoside E and the (R)-3-hydroxydecanoic acid chain of bacterial rhamnolipids. The branched pentaglucolipid skeleton was achieved using a [3 + 2] disconnection approach. The ß-(1 → 2) and ß-(1 → 4)-glycosidic bonds were synthesized through a combination of NIS/Yb(OTf)3- and TMSOTf-mediated stereoselective glycosylations of thiotolyl, N-phenyltrifluoroacetimidate, and trichloroacetimidate donors. Late-stage pentaacetylation, Staudinger reduction of a (2-azidomethyl)benzoyl group, followed by continuous-flow microfluidic hydrogenolysis completed the total synthesis of the structurally simplified glycolipid, whose partial acetylation pattern on the glycan part was identical to agminoside E. Our study lays the foundation for the total synthesis of sponge-derived agminosides and the understanding of their biological functions in sponges.

Antioxidant, Anti-Inflammatory, and Anti-Aging Potential of a Kalmia angustifolia Extract and Identification of Some Major Compounds.

Skin aging is the most visible element of the aging process, giving rise to a major concern for many people. Plants from the Ericaceae family generally have antioxidant and anti-inflammatory properties, making them potential anti-aging active ingredients. This study aimed to evaluate the safety and anti-aging efficacy of a Kalmia angustifolia extract using reconstructed skin substitutes. The safety evaluation was performed using a 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay, while the efficacy was determined by assessing antioxidant and anti-inflammatory activity and analyzing skin substitutes reconstructed according to the self-assembly method by histology and immunofluorescence staining (elastin, collagen-1, collagen-3, aquaporin-3). The cell viability assay established the safety of the extract at a concentration up to 200 µg/mL. The Oxygen Radical Absorbance Capacity (ORAC) assay and a cell-based assay using 2',7'-dichlorofluorescein-diacetate (DCFH-DA) revealed a strong antioxidant activity with an ORAC value of 16 µmol Trolox Equivalent/mg and a half-maximal inhibitory concentration (IC50) of 0.37 ± 0.02 µg/mL, while an interesting anti-inflammatory activity was found in the inhibition of NO production, with an inhibition percentage of NO production of 49 ± 2% at 80 µg/mL. The isolation and characterization of the extract allowed the identification of compounds that could be responsible for these biological activities, with two of them being identified for the first time in K. angustifolia: avicularin and epicatechin-(2ß-O-7, 4ß-6)-ent-epicatechin. Histological analyses of skin substitutes treated with the extract showed an increase in dermal thickness compared with the controls. K. angustifolia extract enhanced the expression of elastin and collagen-1, which are usually decreased with skin aging. These results suggest that K. angustifolia has promising antioxidant efficacy and anti-aging potential.

Phenolic Extract from Aralia nudicaulis L. Rhizomes Inhibits Cellular Oxidative Stresses.

UV-B and IR-A radiation are important inducers of biological changes in skin involving ROS generation. The overloading of antioxidant defense mechanisms by ROS production could lead to photoaging and photocarcinogenesis processes. Various traditional usages are reported for Aralia nudicaulis L. extracts, including treatment of dermatological disorders. Antioxidant and anti-inflammatory properties have already been reported for other Aralia species possibly due to the presence of phenolic compounds. However, the phenolic composition and the potential activity of A. nudicaulis rhizomes extract against oxidative stress and UV/IR damages have not been investigated. The main aims of this study were to prepare a fraction enriched in phenolic compounds (FEPC) from A. nudicaulis rhizomes, to identify its major phenolic compounds and to assess its potential for protective effects against oxidative stress induced by UV-B, IR-A or inflammation. A quantitative LC-MS study of FEPC shows that chlorogenic, caffeic and protocatechuic acids are the main phenolic compounds present, with concentrations of 15.6%, 15.3% and 4.8% of the total composition, respectively. With a validated analytical method, those compounds were quantified over different stages of the growing period. As for biological potential, first this extract demonstrates antioxidant and anti-inflammatory activities. Furthermore, ROS generation induced by IR-A and UV-B were strongly inhibited by A. nudicaulis extract, suggesting that Aralia nudicaulis L. rhizome extract could protect dermal cells against oxidative stress induced by UV-B and IR-A.

The Biological Activity of Monarda didyma L. Essential Oil and Its Effect as a Diet Supplement in Mice and Broiler Chicken.

The use of growth-promoting antibiotics in livestock faces increasing scrutiny and opposition due to concerns about the increased occurrence of antibiotic-resistant bacteria. Alternative solutions are being sought, and plants of Lamiaceae may provide an alternative to synthetic antibiotics in animal nutrition. In this study, we extracted essential oil from Monarda didyma, a member of the Lamiaceae family. We examined the chemical composition of the essential oil and then evaluated the antibacterial, antioxidant, and anti-inflammatory activities of M. didyma essential oil and its main compounds in vitro. We then evaluated the effectiveness of M. didyma essential oil in regard to growth performance, feed efficiency, and mortality in both mice and broilers. Carvacrol (49.03%) was the dominant compound in the essential oil extracts. M. didyma essential oil demonstrated antibacterial properties against Escherichia coli (MIC = 87 µg·mL-1), Staphylococcus aureus (MIC = 47 µg·mL-1), and Clostridium perfringens (MIC = 35 µg·mL-1). Supplementing the diet of mice with essential oil at a concentration of 0.1% significantly increased body weight (+5.4%) and feed efficiency (+18.85%). In broilers, M. didyma essential oil significantly improved body weight gain (2.64%). Our results suggest that adding M. didyma essential oil to the diet of broilers offers a potential substitute for antibiotic growth promoters.

Hemisynthesis and Biological Evaluation of Cinnamylated, Benzylated, and Prenylated Dihydrochalcones from a Common Bio-Sourced Precursor.

Several families of naturally occurring C-alkylated dihydrochalcones display a broad range of biological activities, including antimicrobial and cytotoxic properties, depending on their alkylation sidechain. The catalytic Friedel-Crafts alkylation of the readily available aglycon moiety of neohesperidin dihydrochalcone was performed using cinnamyl, benzyl, and isoprenyl alcohols. This procedure provided a straightforward access to a series of derivatives that were structurally related to natural balsacones, uvaretin, and erioschalcones, respectively. The antibacterial and cytotoxic potential of these novel analogs was evaluated in vitro and highlighted some relations between the structure and the pharmacological properties of alkylated dihydrochalcones.

Total synthesis, isolation, surfactant properties, and biological evaluation of ananatosides and related macrodilactone-containing rhamnolipids.

Rhamnolipids are a specific class of microbial surfactants, which hold great biotechnological and therapeutic potential. However, their exploitation at the industrial level is hampered because they are mainly produced by the opportunistic pathogen Pseudomonas aeruginosa. The non-human pathogenic bacterium Pantoea ananatis is an alternative producer of rhamnolipid-like metabolites containing glucose instead of rhamnose residues. Herein, we present the isolation, structural characterization, and total synthesis of ananatoside A, a 15-membered macrodilactone-containing glucolipid, and ananatoside B, its open-chain congener, from organic extracts of P. ananatis. Ananatoside A was synthesized through three alternative pathways involving either an intramolecular glycosylation, a chemical macrolactonization or a direct enzymatic transformation from ananatoside B. A series of diasteroisomerically pure (1→2), (1→3), and (1→4)-macrolactonized rhamnolipids were also synthesized through intramolecular glycosylation and their anomeric configurations as well as ring conformations were solved using molecular modeling in tandem with NMR studies. We show that ananatoside B is a more potent surfactant than its macrolide counterpart. We present evidence that macrolactonization of rhamnolipids enhances their cytotoxic and hemolytic potential, pointing towards a mechanism involving the formation of pores into the lipidic cell membrane. Lastly, we demonstrate that ananatoside A and ananatoside B as well as synthetic macrolactonized rhamnolipids can be perceived by the plant immune system, and that this sensing is more pronounced for a macrolide featuring a rhamnose moiety in its native 1 C 4 conformation. Altogether our results suggest that macrolactonization of glycolipids can dramatically interfere with their surfactant properties and biological activity.

On the role of the vinylsulfoxide side chain of dirchromone towards its bioactivities.

Analogs of dirchromone were prepared to shed light on the pivotal role of its peculiar vinylsulfoxide side chain towards its cytotoxic and antimicrobial properties, especially dependant upon the presence and oxidation state of sulfur. The reaction of dirchromone with cysteamine revealed a surprising Michael acceptor behavior with elimination of the methylsulfinyl moiety and redox transformation of the sulfur atom that could be involved in the mode of action of dirchromone within cells.

Pili Tree (Canarium ovatum) Resin's Antibacterial Essential Oil and Hydrosol as Rich Sources of (S)-Phellandrenes Derivatives.

Five batches of resin from the Pili tree (Canarium ovatum Engl.) were distilled, and their essential oils and hydrosols were analyzed by gas chromatography. The oils, obtained in yields of 13.4-19.7 % v/m, featured α-phellandrene in high proportions (50-65 %), alongside limonene, ß-phellandrene and para-cymene. Chiral GC analysis confirmed that both phellandrenes were in fact >95 % (S)-(+) enantiomers, while the other monoterpenes featured less pronounced enantiomeric excesses. The hydrosols were rich in α-phellandrene oxidation products including cis-α-phellandrene epoxide and a series of para-menth-5-ene-1,2-diol isomers. Both essential oils and hydrosols were tested for their antibacterial activity against Escherichia coli and Staphylococcus aureus and exhibited MIC90 of less than 5 and 0.5 mg/mL of total volatiles, respectively. The essential oil features some potential as a source of readily available natural (S)-(+)-α-phellandrene.

Chemical composition and antibacterial activity of Tussilago farfara (L.) essential oil from Quebec, Canada.

The chemical composition of Tussilago farfara L. essential oil from the Saguenay-Lac-St-Jean region of Quebec, Canada was analyzed by gas chromatography-flame ionisation detector (GC-FID) and gas chromatography-mass spectrometry (GC-MS), and the antibacterial activity of the oil was tested against Escherichia coli and Staphylococcus aureus. Forty-five (45) compounds were identified from the GC profile. The main components were 1-nonene (40.1%), α-phellandrene (26.0%) and ρ-cymene (6.6%). The essential oil demonstrated antibacterial activity against E. coli (MIC50 = 468 µg·mL-1; MIC90 = 6869 µg·mL-1) and S. aureus (MIC50 = 368 µg·mL-1; MIC90 = 773 µg·mL-1). Dodecanoic acid was found to be active against both bacteria having a MIC50 and MIC90 of 16.4 µg·mL-1 and 95 µg·mL-1, respectively for E. coli and a MIC50 and MIC90 of 9.8 µg·mL-1 and 27.3 µg·mL-1, respectively for S. aureus. In addition, 1-decene and (E)-cyclodecene were also found to be active against E. coli.

Balsacone C, a New Antibiotic Targeting Bacterial Cell Membranes, Inhibits Clinical Isolates of Methicillin-Resistant Staphylococcus aureus (MRSA) Without Inducing Resistance.

New options are urgently needed for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. Balsacone C is a new dihydrochalcone extracted from Populus balsamifera that has been reported previously as being active against Staphylococcus aureus. Here, we evaluate the antibacterial activity of balsacone C against MRSA. Thirty-four (34) MRSA isolates were obtained from hospitalized patients; these isolates were then characterized for their resistance. Most of these MRSA (>85%) were resistant to penicillin, amoxicillin/clavulanic acid, ciprofloxacin, moxifloxacin, levofloxacin, clindamycin, erythromycin, and cefoxitin as well as being sensitive to linezolid, trimethoprim/sulfamethoxazole, rifampicin, and gentamicin. When tested against all MRSA isolates and various gram-positive bacteria, the antibacterial activity of balsacone C produced a MIC of 3-11.6 mg/mL. We observed no resistant isolates of MRSA (against balsacone C) even after 30 passages. Microscopy fluorescence showed that bacteria cell membrane integrity was compromised by low concentrations of balsacone C. Scanning electron microscope (SEM) confirmed balsacone C-provoked changes in the bacterial cell membrane and we find a dose-dependent release of DNA and proteins. This loss of cellular integrity leads to cell death and suggests a low potential for the development of spontaneous resistance.