A Review of Phototoxic Plants, Their Phototoxic Metabolites, and Possible Developments as Photosensitizers.

This study provides a comprehensive overview of the current knowledge regarding phototoxic terrestrial plants and their phototoxic and photosensitizing metabolites. Within the 435,000 land plant species, only around 250 vascular plants have been documented as phototoxic or implicated in phototoxic occurrences in humans and animals. This work compiles a comprehensive catalog of these phototoxic plant species, organized alphabetically based on their taxonomic family. The dataset encompasses meticulous details including taxonomy, geographical distribution, vernacular names, and information on the nature and structure of their phototoxic and photosensitizing molecule(s). Subsequently, this study undertook an in-depth investigation into phototoxic molecules, resulting in the compilation of a comprehensive and up-to-date list of phytochemicals exhibiting phototoxic or photosensitizing activity synthesized by terrestrial plants. For each identified molecule, an extensive review was conducted, encompassing discussions on its phototoxic activity, chemical family, occurrence in plant families or species, distribution within different plant tissues and organs, as well as the biogeographical locations of the producer species worldwide. The analysis also includes a thorough discussion on the potential use of these molecules for the development of new photosensitizers that could be used in topical or injectable formulations for antimicrobial and anticancer phototherapy as well as manufacturing of photoactive devices.

Carotenoids from Marine Microalgae as Antimelanoma Agents.

Melanoma cells are highly invasive and metastatic tumor cells and commonly express molecular alterations that contribute to multidrug resistance (e.g., BRAFV600E mutation). Conventional treatment is not effective in a long term, requiring an exhaustive search for new alternatives. Recently, carotenoids from microalgae have been investigated as adjuvant in antimelanoma therapy due to their safety and acceptable clinical tolerability. Many of them are currently used as food supplements. In this review, we have compiled several studies that show microalgal carotenoids inhibit cell proliferation, cell migration and invasion, as well as induced cell cycle arrest and apoptosis in various melanoma cell lines. MAPK and NF-ĸB pathway, MMP and apoptotic factors are frequently affected after exposure to microalgal carotenoids. Fucoxanthin, astaxanthin and zeaxanthin are the main carotenoids investigated, in both in vitro and in vivo experimental models. Preclinical data indicate these compounds exhibit direct antimelanoma effect but are also capable of restoring melanoma cells sensitivity to conventional chemotherapy (e.g., vemurafenib and dacarbazine).

Archaea Carotenoids: Natural Pigments with Unexplored Innovative Potential.

For more than 40 years, marine microorganisms have raised great interest because of their major ecological function and their numerous applications for biotechnology and pharmacology. Particularly, Archaea represent a resource of great potential for the identification of new metabolites because of their adaptation to extreme environmental conditions and their original metabolic pathways, allowing the synthesis of unique biomolecules. Studies on archaeal carotenoids are still relatively scarce and only a few works have focused on their industrial scale production and their biotechnological and pharmacological properties, while the societal demand for these bioactive pigments is growing. This article aims to provide a comprehensive review of the current knowledge on carotenoid metabolism in Archaea and the potential applications of these pigments in biotechnology and medicine. After reviewing the ecology and classification of these microorganisms, as well as their unique cellular and biochemical characteristics, this paper highlights the most recent data concerning carotenoid metabolism in Archaea, the biological properties of these pigments, and biotechnological considerations for their production at industrial scale.

Chemical Composition, Antibacterial Screening and Cytotoxic Activity of Chiliadenus antiatlanticus (Asteraceae) Essential Oil.

The chemical composition and in vitro antibacterial and cytotoxic activities of the essential oil (EO) of Chiliadenus antiatlanticus (Emb. & Maire) Gómiz, an asteraceous species endemic to the southwest of Morocco, were investigated. The EO yield was 1.07±0.28 %, twenty-seven metabolites were identified representing more than 96.4 % of the total composition. Camphor (35.7 %) and derivatives, borneol (4.9 %) and camphene (4.2 %) together with intermedeol (19.9 %), α-pinene (15.5 %) and (E)-pinocarveol (4.1 %) were the major constituents. An antibacterial activity was noticed against 24 strains (all Gram-positive) out of 71 at MICs values=100 µg/mL. The EO also showed significant toxicity towards liver HepG2 (55.8 % of cell viability) and melanoma B16 4A5 (41.6 % of cell viability) tumor cell lines at 100 µg/mL.

Chemical Composition and Biological Screening of the Essential Oils of Micromeria macrosiphon and M. arganietorum (Lamiaceae).

The chemical composition and in vitro biological activities of the essential oil (EO) of Micromeria macrosiphon Coss. and M. arganietorum (J. Emb.) R. Morales, two Lamiaceae endemic to south Morocco, were investigated. GC/MS analysis resulted in the identification of 36 metabolites from the EO of M. macrosiphon, 45 from M. arganietorum. Borneol was the major metabolite in both oils and together with related derivatives such as camphor, accounted for 2/3 of the EO of M. macrosiphon, 1/3 of those of M. arganietorum. Pinene and terpinene derivatives were also present in high proportions. From a chemotaxonomic point of view, the composition of the examined samples may be related to those of other species endemic to Macaronesia. Both EOs showed significant toxicity towards liver HepG2 and melanoma B16 4A5 tumor cell lines at 100 µg/mL; however, they were also cytotoxic towards S17 normal cell lines, with a selectivity index <1. No antibacterial activity was noticed against 52 strains at 100 µg/mL.

Correlation study on methoxylation pattern of flavonoids and their heme-targeted antiplasmodial activity.

A library of 33 polymethoxylated flavones (PMF) was evaluated for heme-binding affinity by biomimetic MS assay and in vitro antiplasmodial activity on two strains of P. falciparum. Stability of heme adducts was discussed using the dissociation voltage at 50% (DV50). No correlation was observed between the methoxylation pattern and the antiparasitic activity, either for the 3D7 chloroquine-sensitive or for the W2 chloroquine-resistant P. falciparum strains. However, in each PMF family an increased DV50 was observed for the derivatives methoxylated in position 5. Measurement of intra-erythrocytic hemozoin formation of selected derivatives was performed and hemozoin concentration was inversely correlated with heme-binding affinity. Kaempferol showed no influence on hemozoin formation, reinforcing the hypothesis that this compound may exert in vitro antiplasmodial activity mostly through other pathways. Pentamethoxyquercetin has simultaneously demonstrated a significant biological activity and a strong interaction with heme, suggesting that inhibition of hemozoin formation is totally or partially responsible for its antiparasitic effect.

A Nitrile Glucoside and Biflavones from the Leaves of Campylospermum excavatum (Ochnaceae).

The study of the MeOH extract of the leaves of Campylospermum excavatum led to the isolation of a nitrile glucoside, named campyloside C (1) and an original derivative of ochnaflavone, 7-O-methylochnaflavone (2), along with three known biflavonoids, amentoflavone, sequoiaflavone, and sotetsuflavone (3 - 5). The linkage site of the sub-units of 2 was confirmed by chemical correlation, after semi-synthesis of a trimethoxylated derivative of ochnaflavone (2a). The structures of these compounds as well as their relative and absolute configurations were assigned by 1D- and 2D-NMR experiments, HR-ESI-MS and Electronic Circular Dichroism (ECD) calculations. A low-pass J filter HMBC experiment was performed in order to define the configuration of the double bond of 1. All of the biflavonoids were evaluated against protozoan parasites. Amentoflavone moderately inhibited the promastigote form of Leishmania infantum.

HPLC-ELSD Quantification and Centrifugal Partition Chromatography Isolation of 8-O-Acetylharpagide from Oxera coronata (Lamiaceae).

INTRODUCTION: Iridoid glycosides possess highly functionalised monoterpenoid aglycon with several contiguous stereocentres. For the most common, they are often present in quantities reaching several percentage of the fresh plant weight, and thus they may be regarded as starting material for the synthesis of a number of new chiral and bioactive molecules. OBJECTIVE: To quantify and to isolate 8-O-acetylharpagide (AH) from several extracts of Oxera coronata R.P.J. de Kok, a Lamiaceae species endemic to New Caledonia, using HPLC-ELSD (evaporative light scattering detector) and centrifugal partition chromatography (CPC). METHODOLOGY: Oxera coronata produces high amounts of AH in leaves, twigs and fruits. Water and methanol extracts of these plant parts were prepared. The content of AH in each extract was quantified by HPLC-ELSD, using acetonitrile-water (+0.1% formic acid) gradient elution. The HPLC method was validated for precision, linearity, limit of detection (LOD), limit of quantification (LOQ) and accuracy. A ternary solvent system ethyl acetate/n-propanol/water (3:2:5, v/v/v) was selected and applied to recover the target compound using Spot CPC from the leaves aqueous extract. RESULTS: HPLC-ELSD analysis followed by CPC purification led to the efficient isolation of AH from O. coronata leaves aqueous extract. CONCLUSION: HPLC-ELSD has proven to be a well-adapted detection and quantification method for iridoid glycosides, while CPC confirmed to be an efficient technique for the isolation of polar compounds. Copyright © 2016 John Wiley & Sons, Ltd.

Three new trixane glycosides obtained from the leaves of Jungia sellowii Less. using centrifugal partition chromatography.

Jungia sellowii (Asteraceae) is a shrub that grows in Southern Brazil and polar extract of its leaves presents anti-inflammatory properties. Cyperane, guaiane, nortrixane, and trixane sesquiterpene types were reported as the main metabolites in Jungia species. This work aims to describe the isolation and identification of sesquiterpenes in the leaves of J. sellowii using liquid-liquid partition and centrifugal partition chromatography. Thus, the crude extract of fresh leaves of J. sellowii was partitioned with hexane, dichloromethane, ethyl acetate and butanol, respectively. The butanol fraction was then subjected to a selected ternary system optimized for the CPC (centrifugal partition chromatography): ethyl acetate-ethanol-water (9:2:10, v/v/v). The separation was carried out isocratically at a flow rate of 25 mL/min at 1200 rpm, affording seven fractions A to G. TLC of fractions B, C and F displayed a single spot corresponding to three new glycosylated sesquiterpenoids. Their structures were established by using spectroscopic data in comparison to those reported in the literature. Furthermore, the isolates were evaluated for their leishmanicidal and cytotoxic effects. No cytotoxic effect was observed against the three cancer cell lines (HL60, JURKAT and REH), but compound 1 showed a weak antiprotozoal activity. Liquid-liquid partition and CPC turned to be a versatile technique of glycoside purification which is environmentally friendly and requires a limited amount of organic solvents.

Isolation of Guttiferones from Renewable Parts of Symphonia globulifera by Centrifugal Partition Chromatography.

The aim of this study was to investigate the species Symphonia globulifera, a source of polycyclic polyprenylated acyl phloroglucinols such as guttiferone A, which is known to exhibit a variety of biological activities including noticeable antileishmanial properties. Our goal was the identification and the quantification of guttiferone A in different renewable parts of S. globulifera and its preparative isolation. To the best of our knowledge, there is no data concerning its mechanism of action. Consequently, it is particularly interesting to isolate it in gram quantities in order to establish structure activity relationship studies. After performing high-performance liquid chromatography profiles detecting the presence of guttiferone A and proceeding to its quantification, a centrifugal partition chromatography methodology using a two-phase solvent system of cyclohexane/ethyl acetate/methanol/water (20 :  1 :  20 : 1, v/v/v/v) was applied to each extract. In conclusion, a centrifugal partition chromatography system has been developed to ensure a fast, reliable, and scalable way to isolate, with a high level of purity, guttiferone A from five renewable parts of S. globulifera. Moreover, this methodology can be extended to the isolation of other polycyclic polyprenylated acyl phloroglucinols such as guttiferones B, C, and D.

Chemical and Biological Investigation of Olive Mill Waste Water - OMWW Secoiridoid Lactones.

Olive mill waste water is the major byproduct of the olive oil industry containing a range of compounds related to Olea europaea and olive oil constituents. Olive mill waste water comprises an important environmental problem in olive oil producing countries, but it is also a valuable material for the isolation of high added value compounds. In this study, an attempt to investigate the secoiridoid content of olive mill waste water is described with the aid of ultrahigh-performance liquid chromatography-electrospray ionization (±)-high-resolution mass spectrometry and centrifugal partition chromatography methods. In total, seven secoiridoid lactones were isolated, four of which are new natural products. This is the first time that a conjugate of hydroxytyrosol and a secoiridoid lactone has been isolated from olive mill waste water and structurally characterized. Furthermore, the range of isolated compounds allowed for the proposal of a hypothesis for the biotransformation of olive secoiridoids during the production of olive mill waste water. Finally, the ability of the representative compounds to reduce the intracellular reactive oxygen species was assessed with the dichlorofluorescein assay in conjunction with the known antioxidant agent hydroxytyrosol.

Antifungal ether diglycosides from Matayba guianensis Aublet.

Since the 1960s, fungal infections have become a major worldwide public health problem. Antifungal treatments have many limitations, such as toxicity and resistance. Matayba guianensis Aublet (Sapindaceae) was chemically investigated as part of our ongoing search for lead molecules against fungi in the Brazilian Cerrado biome. The ethanolic extract of M. guianensis root bark revealed the presence of two previously unreported ether diglycosides: matayoside E (1) and F (2) with anti Candida activity, along with two known compounds: cupanioside (3) and stigmasterol (4).

Antifungal activity of extracts from Justicia species against Fusarium graminearum.

Fusarium graminearum causes destructive ear rot diseases in maize and wheat. New antifungals are essential to combat this pathogen, and aerial parts of Justicia species (Acanthaceae) are a potential source. We investigated the antifungal activity of extracts from stems and leaves of five Justicia species native to Northwest Argentina. The aerial parts were subjected to sequential extractions with dichloromethane, ethyl acetate, and methanol. The resulting extracts were tested by the disc diffusion method against F. graminearum strains. Only the leaf and stem extracts from J. xylosteoides displayed inhibitory effects, with the dichloromethane leaf extract as the most active. The compounds involved were identified as the lignans hinokinin, savinin, and isohibalactone. Both the dichloromethane extract and hinokinin synergised with tebuconazole, and inhibited deoxynivalenol biosynthesis. The identified compounds warrant further research as additives to azole fungicides for F. graminearum control.

The protective effects of naringenin, a citrus flavonoid, non-complexed or complexed with hydroxypropyl-ß-cyclodextrin against multiorgan damage caused by neonatal endotoxemia.

BACKGROUND: Endotoxemia is a severe and dangerous clinical syndrome that results in elevated morbidity, especially in intensive care units. Neonates are particularly susceptible to endotoxemia due to their immature immune systems. There are few effective treatments for neonatal endotoxemia. One group of compounds with potential in the treatment of neonatal inflammatory diseases such as endotoxemia is the flavonoids, mainly due to their antioxidant and anti-inflammatory properties. Among these, naringenin (NGN) is a citrus flavonoid which has already been reported to have anti-inflammatory, antioxidant, anti-nociceptive and anti-cancer effects. Unfortunately, its clinical application is limited by its low solubility and bioavailability. However, cyclodextrins (CDs) have been widely used to improve the solubility of nonpolar drugs and enhance the bioavailability of these natural products. OBJECTIVE: We, therefore, aimed to investigate the effects of NGN non-complexed and complexed with hydroxypropyl-ß-cyclodextrin (HPßCD) on neonatal endotoxemia injuries in a rodent model and describe the probable molecular mechanisms involved in NGN activities. METHOD: We used exposure to a bacterial lipopolysaccharide (LPS) to induce neonatal endotoxemia in the mice. RESULTS: It was found that NGN (100 mg/kg i.p.) exposure during the neonatal period reduced leukocyte migration and decreased pro-inflammatory cytokine (TNF-α, IL-1ß and IL-6) levels in the lungs, heart, kidneys or cerebral cortex. In addition, NGN upregulated IL-10 production in the lungs and kidneys of neonate mice. The administration of NGN also enhanced antioxidant enzyme catalase and SOD activity, reduced lipid peroxidation and protein carbonylation and increased the reduced sulfhydryl groups in an organ-dependent manner, attenuating the oxidative damage caused by LPS exposure. NGN decreased ERK1/2, p38MAPK and COX-2 activation in the lungs of neonate mice. Moreover, NGN complexed with HPßCD was able to increase the animal survival rate. CONCLUSION: NGN attenuated inflammatory and oxidative damage in the lungs, heart and kidneys caused by neonatal endotoxemia through the MAPK signaling pathways regulation. Our results show that NGN has beneficial effects against neonatal endotoxemia and could be useful in the treatment of neonatal inflammatory injuries.

Deep Eutectic Solvents: An Eco-friendly Design for Drug Engineering.

Invited for this month's cover, the researchers from UTCBS and CiTCoM from Université Paris Cité (Paris, France), as well as Materia Nova (Mons, Belgium). The image emphasizes the deep eutectic solvent preparation thanks to hydrogen bond acceptor and donor interactions for drugs formulation and therapeutic applications. The Review itself is available at 10.1002/cssc.202300669.

Deep Eutectic Solvents: An Eco-friendly Design for Drug Engineering.

In the spirit of circular economy and sustainable chemistry, the use of environmentally friendly chemical products in pharmacy has become a hot topic. In recent years, organic solvents have been the subject of a great range of restriction policies due to their harmful effects on the environment and toxicity to human health. In parallel, deep eutectic solvents (DESs) have emerged as suitable greener solvents with beneficial environmental impacts and a rich palette of physicochemical advantages related to their low cost and biocompatibility. Additionally, DESs can enable remarkable solubilizing effect for several active pharmaceutical ingredients (APIs), thus forming therapeutic DESs (TheDESs). In this work, special attention is paid to DESs, presenting a precise definition, classification, methods of preparation, and characterization. A description of natural DESs (NaDESs), i. e., eutectic solvents present in natural sources, is also reported. Moreover, the present review article is the first one to detail the different approaches for judiciously selecting the constituents of DESs in order to minimize the number of experiments. The role of DESs in the biomedical and pharmaceutical sectors and their impact on the development of successful therapies are also discussed.

Chemical composition and antimicrobial activity of the essential oils of Anthospermum emirnense and Anthospermum perrieri (Rubiaceae).

The essential oils of Anthospermum emirnense Baker and Anthospermum perrieri Homolle ex Puff, obtained by hydrodistillation in 0.03 and 0.02% yield, respectively, were analyzed by GC/MS. In both cases, the major constituents consisted of sesquiterpene hydrocarbons and oxygenated sesquiterpenes. The two species showed an important qualitative similarity, with 40 compounds common to A. emirnense and A. perrieri, including ß-elemene, trans-ß-caryophyllene, caryophyllene oxide, and τ-cadinol, which were major components in both cases. When tested for antimicrobial activity, both essential oils showed similar profiles and exhibited interesting minimal-inhibitory-concentration (MIC) values towards Bacillus subtilis, Chryseobacterium indologenes, Flavimonas oryzihabitans, and Yersinia enterocolitica.

Detection, Isolation, and 1H NMR Quantitation of the Nitrile Glycoside Sarmentosin from a Bryophyllum pinnatum Hydro-Ethanolic Extract.

Bryophyllum pinnatum (Lam) Pers. (Crassulaceae) is widely used in folk medicine as leaf juice, aqueous, or hydro-ethanolic extracts. It is also listed as a medicinal plant in several countries such as France and Brazil. The main reported constituents are flavone glycosides, especially those with the rare 3-O-α-l-arabinopyranosyl-(1 → 2)-α-l-rhamnopyranoside moiety. Despite several phytochemical screenings indicating the presence of cyanide derivatives or alkaloids, there are no reports of nitrogenous metabolite characterization from this plant species. Nevertheless, the occurrence and the type of such compounds are of particular interest, as they may account for some of the numerous biological activities and ethnomedicinal uses described for B. pinnatum and could be regarded as chemical/taxonomic markers. Consequently, a hydro-ethanolic extract of B. pinnatum was investigated by using UHPLC-HRMS/MS and the nitrile glucoside sarmentosin was detected for the first time within the genus Bryophyllum/Kalanchoe. Considering the wide use of B. pinnatum and its closely related species for health purposes, the target metabolite was isolated by a combination of centrifugal partition chromatography in elution/extrusion mode and MPLC in order to confirm its structure. A linear, selective, precise, fast, and reliable 1H NMR quantitation method was then developed and validated and may become a tool for easy quality assessment of the plant species. The amount of sarmentosin was determined as 2.07% of the examined sample. Sarmentosin was also detected in Kalanchoe laciniata, confirming the occurrence of this compound within the genus.

In Vitro Anti-Trypanosoma cruzi Activity of Halophytes from Southern Portugal Reloaded: A Special Focus on Sea Fennel (Crithmum maritimum L.).

Marine halophytes are an outstanding reservoir of natural products and several species have anti-infectious traditional uses. However, reports about their potential use against neglected tropical ailments, such as Chagas disease, are scarce. This work evaluated for the first time the in vitro anti-Trypanosoma cruzi activity of extracts from the aromatic and medicinal species Helichrysum italicum subsp. picardii (Boiss. & Reut.) Franco (Asteraceae, everlasting) and Crithmum maritimum L. (Apiaceae, sea fennel). For that purpose, decoctions, tinctures, and essential oils from everlasting's flowers and sea fennel's stems, leaves, and flowers were tested against intracellular amastigotes of two T. cruzi strains. The extract from the sea fennel flower decoction displayed significant anti-trypanosomal activity and no toxicity towards the host cell (EC50 = 17.7 µg/mL, selectivity index > 5.65). Subsequent fractionation of this extract afforded 5 fractions that were re-tested in the same model of anti-parasitic activity. Fraction 1 was the most active and selective (EC50 = 0.47 µg/mL, selectivity index = 59.6) and was submitted to preparative thin-layer chromatography. One major compound was identified, falcarindiol, which was likely the one responsible for the observed anti-trypanosomal activity. This was confirmed using a commercially sourced molecule. Target-fishing studies showed falcarindiol as a ligand of T. cruzi spermidine synthase, pointing to a potential enzyme-inhibiting anti-trypanosomal mechanism of action. Overall, this work shows that sea fennel can provide effective anti-parasitic molecule(s) with potential pharmacological applications in the treatment of CD.

Bryophyllum pinnatum markers: CPC isolation, simultaneous quantification by a validated UPLC-DAD method and biological evaluations.

Bryophyllum pinnatum (Lam.) Oken (Crassulaceae) is widely used as leaf juice or extracts in traditional medicine all over tropical areas, especially in Brazil, to relieve inflammation-associated symptoms. Flavonol glycosides with unusual sugar moiety are among the major metabolites. Nevertheless, there are not enough quality control studies that can contribute to authentication of B. pinnatum and determination of their markers. As it is also used as medicinal plant in several countries, it is necessary to provide data related to safety, efficacy and quality. In this context, this work aims to isolate the major flavonoids from B. pinnatum hydroethanolic extract, to validate a method to quantify the content of chemical markers and to evaluate their xanthine oxidase inhibition and antioxidant activity. The extract was submitted to centrifugal partition chromatography (CPC). The solvents system CyHex-EtOAc-EtOH-H2O, 0.5:9:3:5.5, v/v/v/v was selected by shake-flask method. Four flavonoids (quercetin 3-O-α-L-arabinopyranosyl-(1→2)-O-α-L-rhamnopyranoside (1), kaempferol 3-O-α-L-arabinopyranosyl-(1→2)-O-α-L-rhamnopyranoside (2), quercetin 3-O-α-L-rhamnopyranoside (3) and kaempferol 3-O-α-L-rhamnopyranoside (4)) were isolated in a single and fast CPC run and their structures were confirmed by NMR analysis. An UPLC-DAD quantification method was established for the first time with validation of required parameters, according to RDC 166/2017. The calibration curves were linear with correlation coefficient ranging from 0.9996 to 0.9997 while the values of LOD (0.0077-1.984 ng.mL-1), LOQ (0.0263-6.012 ng.mL-1), recovery (≥ 80.7 %) and inter-day (%RSD ≤ 3.581) and intra-day precision (%RSD ≤ 2.628) were satisfactory. Quantitative analysis of these compounds showed that the proportion of 1, 2 and 3 were 2.43, 0.25 and 0.33 % (24.3 mg.g-1, 0.25 mg.g-1 and 0.33 mg.g-1 of extract), respectively. Moreover, in vitro xanthine oxidase (XO), DPPH and ABTS inhibition were evaluated for the extract and the major flavonoids. Compounds 2 (168 µM) and 3 (124 µM) moderately inhibited XO, while compounds 1 and 3 displayed average radical scavenging activity. In conclusion, our results suggest the flavonoid 1 as a specific marker which may be used for quality control of B. pinnatum hydroethanolic leaves extract.