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Oxygen heterocyclic compounds play a beneficial role in plants, and their presence in foods, such as Citrus fruits, cinnamon, carrots, and parsley, has been documented in recent years. Published research articles reported several extractions and chromatographic techniques for their determination. The aim of this review was to take into consideration the research articles published from 2016 to 2024 in which the authors developed extraction and chromatographic analysis methods of oxygen heterocyclic compounds in foods. The objective of this review was to assist researchers in choosing the best approach for their future work by identifying all the possible approaches to characterize coumarins, furocoumarins, and polymethoxyflavones in foodstuffs.

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Heracleum mantegazzianum is an invasive species in middle Europe. The mode of action of its invasiveness is still not known. Our study focuses on observation of potential allelopathic influence by the production and release of phytochemicals into its environment. Plant material was collected four times within one season (April, May, June, July 2019) at locality Lekárovce (eastern Slovakia) for comparison of differences in composition and potential allelopathy. Water extracts from collected samples were used for different biological assays. The total phenols and flavonoids were determined spectrophotometrically. The profile and content of phenolic components, including coumarins, were determined by two techniques of liquid chromatography along with in vitro evaluation of the free radical scavenging activity of extracts (DPPH, Hydroxyl, Superoxide, and FRAP). The changes in composition in extracts in different seasonal periods were evident as well as potential phytotoxic activity in some concentrations on specific model plants. The slight antioxidant activity was noted. The invasiveness of the current species could be supported by the excretion of its phytochemicals into its surroundings and by different modes of action influencing living organisms in its environment.

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Using the model of cyclophosphamide (CP)-induced immunosuppression in C57BL/6 mice, the hepatotropic effects of a conjugate of betulonic acid with 9-(4-methylpiperazin-1-ylmethyl)-2-(1,2,3-triazolyl) oreozelone (BABC) have been studied. In the liver of treated animals the expression of genes for cytochromes (CYP 1A1, CYP 1A2, CYP 3A44, CYP 2B10, CYP 2C29, CYP 17A1), PPARA, and cytokines (TNF-α, IL-1ß, IL-12α, IL-10) and the relative levels of NF-κB p65, GST-π, and NAT-1 proteins were determined. On day six after administration of the compound and CP to animals a significant (3.2-fold) increase in the expression of the CYP 2B10 as compared to the control group was observed. Treatment of mice with the compound and CP also caused a 2.4-fold increase in the mRNA level of the pro-inflammatory TNF-α gene as compared to the group of animals receiving CP. Administration of the studied compound to intact animals was accompanied by a 2.5-fold increase in the IL-1ß expression and a 1.8-fold decrease in the IL-10 expression as compared to the control group. An increase in the expression of pro-inflammatory cytokine genes in the liver of animals treated with the compound was accompanied by an increase in the content of NF-κB p65 (by 1.6 times), as well as an increase in the relative amount of NAT-1 protein (by 2.7 times) as compared to control animals.

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Epidemiological studies have found that high citrus fruit consumption was associated with higher risk of skin cancer. Citrus fruits and some vegetables contain furocoumarins, which may interact with ultraviolet radiation to induce skin cancer. We aimed to determine the effects of two furocoumarins, including 8-methoxypsoralen (8-MOP) and 6',7'-dihydroxybergamottin (DHB), on UVA-induced DNA damage in human epidermal melanocytes, the origin of melanoma. Our hypothesis was that these dietary furocoumarins increase UVA-induced DNA damage in melanocytes, compared to cells exposed to UV alone. We incubated melanocytes with 8-MOP or DHB, followed by exposure to physiological doses of UVA radiation. We used Western blots to quantify the UVA-induced DNA damage measured by the fraction of phosphorylated histone variant H2AX (γH2AX), which is a marker of DNA damage, relative to total H2AX (γH2AX/H2AX) in the presence or absence of furocoumarins. To quantify the UVA-induced change in γH2AX/H2AX, we calculated the UVA:Control ratio as the ratio of γH2AX/H2AX in UVA-exposed cells to that in cells without UVA (control). The mean UVA:Control ratios were borderline significantly higher for cells treated with 8-MOP and significantly higher for cells treated with DHB, compared to that of untreated cells. This study suggests that furocoumarins (particularly 8-MOP and DHB) enhance UVA-induced DNA damage in melanocytes, which is a potential novel mechanism for citrus and furocoumarins to elevate the risk of skin cancer.

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The immunomodulatory activity of a betulonic acid-based compound with furocoumarin (BABCF; 2-azido, 9-N-methylpiperazinomethyl oreozelone) has been investigated. Male C57BL/6 mice (aged 3 months) treated with the cytostatic agent cyclophosphamide (CP) and intact individuals served as experimental models. The expression of genes was studied in bone marrow (IL-12, IL-10, IL-1ß, TNF-α, TGF-ß, M-CSF, GM-CSF) or in the suspension of peritoneal cells (IL-12, IL-10; as the injection site). The surface markers of T-lymphocytes (CD3, CD4, and CD8) in fractions of venous blood mononuclear cells (MNCs) were determined by means of flow cytometry using antibodies. Histological and morphometric studies were performed to assess the impact of CP and BABCF on the thymus. BABCF caused a pronounced (about 3-fold) increase in relative expression of the GM-KSF gene. BABCF caused a local increase in the expression of IL-12 in the peritoneal cavity cells and restored the relative content of T-lymphocytes in the blood of CP-treated mice treated affecting mainly CD3⁺CD4⁺ lymphocytes. This substance reduced the tissue density of the thymic cortex and thymic medulla in CP-treated mice. Thus, results of this study suggest that BABCF exhibits a stimulating effect on the cellular link of immunity and promotes maintenance of the number of T-lymphocytes in the blood due to their migration from the central organs of the immune system.

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The aim of this research was to determine oxygen heterocyclic compounds in twenty-six Citrus- and cinnamon-flavoured foods using supercritical fluid chromatography in combination with triple-quadrupole mass spectrometry (SFC-QqQ-MS). According to the authors' knowledge, this is the first report on the determination of these molecules in foods by means of the SFC-QqQ-MS technique. The analytical technique normally used for their determination in foods is liquid chromatography coupled with a photodiode array detector. However, supercritical fluid chromatography is proving to be a valid alternative approach to investigating coumarins, furocoumarins and polymethoxyflavones. According to the results presented herein, each sample analysed showed the presence of molecules of interest. Coumarin was found in all the cinnamon-flavoured samples analysed in a low concentration. The presence of oxygen heterocyclic compounds in all the Citrus-flavoured samples, according to the label, comfirmed that the foods selected for this research article were prepared with Citrus fruits. Among the samples analysed, mandarin juice was the richest in bioactive compounds, representing a good source of polymethoxyflavones in a diet.

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Phytophotodermatitis, a condition that results from sequential skin exposure to phototoxic chemicals contained within plants, followed by exposure to solar ultraviolet radiation, has been described with several plants and plant-based foods, namely members of the Moraceaefamily, which include Ficus carica L. This tree's branches, leaves, and fruit skin exude a milky sap or latex containing proteolytic enzymes and furocoumarins known to be photoirritants, easily absorbed upon skin contact. Oxygen-dependent and independent toxic reactions subsequent to sun exposure promote cell membrane damage and oedema, consequently leading to cell death. The diagnosis is confirmed with a detailed anamnesis, and photopatch testing is often useful to rule out a differential diagnosis. It is typically a self-limited condition, with few cases requiring treatment with topical or systemic corticosteroids. We report on a 55-year-old male patient who, following picking figs and pruning a fig tree while exposed to sunlight, developed erythematous and pruritic maculopapular lesions that progressed to blisters with residual hyperpigmentation. The diagnosis was further corroborated through photopatch testing, and the patient was recommended to avoid this recreational activity without symptoms' relapse. This case highlights the importance of considering phytophotodermatitis as a differential diagnosis when evaluating cases of dermatitis on exposed body surfaces and the importance of an exhaustive anamnesis. Identification of specific plant triggers and the performance of photopatch tests are essential to help confirm the diagnosis and guide avoidance recommendations.

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During the Covid-19 pandemic, health agencies worldwide have recommended frequent handwashing and sanitizing. A variety of hand gel products were made available on the market, often with fragrances added to curtail the strong smell of alcohol. Commonly used Citrus fragrances contain volatile aroma constituents and non-volatile oxygen heterocyclic compounds (OHCs), consisting mostly of polymethoxyflavones, coumarins, and furocoumarins. The latter have long been investigated for their phototoxic properties, and their safety as cosmetic product ingredients has been debated recurrently. To this concern, twelve commercial Citrus-scented products were investigated in this study. An extraction method was optimized for thirty-seven OHC compounds, obtaining absolute mean recovery values in the 73.5-116% range with only few milliliters of solvent consumption. Analysis by ultra-high-pressure liquid chromatography with tandem mass spectrometry detection evidenced that three samples did not conform to the labeling requirements for fragrance allergens (coumarin) laid down by the European Union Regulation on Cosmetic Products. The total furocoumarin (FC) content of the samples investigated was in the 0.003-3.7ppm range, with some noteworthy exceptions. Specifically, in two samples, the total FCs were quantified as 89 and 219 ppm, thus exceeding the safe limits recommended up to a factor of 15. Finally, the consistency of the volatile fingerprint attained by gas chromatography allowed drawing conclusions on the authenticity of the Citrus fragrances labeled, and several products did not conform to the information reported on the label concerning the presence of essential oils. Besides the issue of product authenticity, analytical tools and regulatory actions for widespread testing of hand hygiene products are urgent, to protect consumers' health and safety.

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The genus Ruta in the family Rutaceae includes about 40 species, such as the well-known plants R. graveolens L. (common rue) or R. chalepensis L. (fringed rue), but also much lesser-known species such as R. angustifolia Pers. (narrow-leaved fringed rue). This rue specie, originating from the Mediterranean region, is well-distributed in Southeast Asia, notably in the Indo-Chinese peninsula and other territories. In some countries, such as Malaysia, the plant is used to treat liver diseases and cancer. Extracts of R. angustifolia display antifungal, antiviral and antiparasitic effects. Diverse bioactive natural products have been isolated from the aerial parts of the plant, notably quinoline alkaloids and furocoumarins, which present noticeable anti-inflammatory, antioxidant and/or antiproliferative properties. The present review discusses the main pharmacological properties of the plant and its phytoconstituents, with a focus on the anticancer activities evidenced with diverse alkaloids and terpenoids isolated from the aerial parts of the plant. Quinoline alkaloids such as graveoline, kokusaginine, and arborinine have been characterized and their mode of action defined. Arborinine stands as a remarkable inhibitor of histone demethylase LSD1, endowed with promising anticancer activities. Other anticancer compounds, such as the furocoumarins chalepin and rutamarin, have revealed antitumor effects. Their mechanism of action is discussed together with that of other bioactive natural products, including angustifolin and moskachans. Altogether, R. angustifolia Pers. presents a rich phytochemical profile, fully consistent with the traditional use of the plant to treat cancer. This rue species, somewhat neglected, warrant further investigations as a medicinal plant and a source of inspiration for drug discovery and design.

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This review summarizes and systematizes the literature on the anti-HIV activity of plant coumarins with emphasis on isolation and the mechanism of their antiviral action. This review summarizes the information on the anti-HIV properties of simple coumarins as well as annulated furano- and pyranocoumarins and shows that coumarins of plant origin can act by several mechanisms: inhibition of HIV reverse transcriptase and integrase, inhibition of cellular factors that regulate HIV-1 replication, and transmission of viral particles from infected macrophages to healthy ones. It is important to note that some pyranocoumarins are able to act through several mechanisms or bind to several sites, which ensures the resistance of these compounds to HIV mutations. Here we review the last two decades of research on the anti-HIV activity of naturally occurring coumarins.

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BACKGROUND: Primary photosensitization rarely occurs in horses and can easily be misinterpreted. Descriptions of the disease in horses after ingestion of parsnip are lacking. The aim of this case series was to describe the dermatological and ocular changes due to photosensitization and to raise awareness of parsnip being a possible aetiologic agent. CASE PRESENTATION: Nine horses from three different stables in Berlin and Brandenburg, Germany, presented variable degrees of erythema, scaling, crusting and necrosis of unpigmented skin at the head and prepuce. Horses were of different breeds with a median age of 15 ± 5.9 years. A mild leukocytosis was diagnosed in 1/9 horses at admission. Analyzed liver enzymes were within the reference ranges in all horses. Ocular changes were diagnosed as follows: blepharitis (3/9), conjunctivitis (7/9), corneal edema without additional signs of keratitis and/or uveitis (2/9), corneal edema with signs of uveitis (1/9) and photophobia (4/9). One horse developed a fluorescein positive corneal erosion. Skin biopsy (1/9) revealed a moderate to severe acute, eosinophilic and lymphocytic dermatitis with dermal edema and vasculitis. All stables housing these patients fed hay from the same distributer. Analyzed hay samples showed high contents of wild parsnip (plants, seeds, roots). Wild parsnip is widespread in Europe and contains furocoumarins, a family of photodynamic pigments, which may cause primary photodermatitis, keratoconjunctivitis and uveitis. Horses were treated according to severity of clinical symptoms systemically with flunixine meglumine (1.1 mg/kg BW 1-2x/day) or prednisolone (1 mg/kg BW 1x/day). Topically, either gentamicin (3x/day), dexamethasone (2-3x/day) and/or atropine (1x/day) were used. Skin care was provided with almond oil or dexpanthenol (2x/day). All horses were kept in a dark environment or were treated with sunscreen and facemasks. Duration of treatment varied from 6-30 days (median 11.3 days). CONCLUSION: Ingestion of wild parsnip (Pastinaca sativa) can induce primary photosensitization with dermatitis and ocular injury in horses. In times of extreme weather, hay may alter in botanical composition, resulting in high amounts of uncharacteristic plants causing novel problems.

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High biological activity of natural furocoumarins is often linked to a series of adverse side effects, e.g., genotoxicity. This makes it desirable to develop semi-synthetic derivatives with reduced negative activity while retaining or even enhancing the positive properties. Previously, we have studied the genotoxic activity of a library of twenty-one 1,2,3-triazolyl-modified furocoumarins and 2,3-dihydrofurocoumarins and identified modifications that minimize the negative properties. In the current article, we report on an investigation into the cytotoxic activity of the same library. We have aimed to rank the substances in order of the severity of their cytotoxicity and therefore to predict, with the use of statistical processing, the most promising substituents for the furocoumarin scaffold.

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The present study aims to determine the volatile compositions of 15 different accessions of native Sardinian populations of Bituminaria morisiana (Pignatti & Metlesics) Greuter, Bituminaria bituminosa (L.) C. H. Stirt. (B. b.), and Spanish native accessions of B. bituminosa. Furthermore, we particularly focused on the essential oil characterization of these accessions and discriminated within populations with low furocoumarin content useful for fodder production in Mediterranean environments or furocoumarin extraction for pharmaceutical utilization. The plant extracts were analyzed by GC/MS, showing great variability in the content and composition. No differences were found in Bituminaria bituminosa (L.) C.H. Stirt. var. bituminosa essential oils, while the varieties Bituminaria bituminosa (L.) C.H. Stirt. var. crassiuscula P. Méndez, Fern. Galván & A. Santos and Bituminaria bituminosa (L.) C.H. Stirt. var. albomarginata P. Méndez, Fern. Galván & A. Santos are characterized by the presence of a high concentration of long-chain alcohols and of salicylic acid benzylic ester. In B. bituminosa var. albomarginata, we observed a different profile with predominance of a large concentration of alcohols as dodecanol and tetradecanol. The endemic B. morisiana can be identified for the predominant presence of farnesene. In methanolic fractions, we detected the presence of maltol, methyl citrate, methyl cumarate, santonin, and methyl linoleate. B. morisiana showed a low content of psoralens, and the accession of B. morisiana, from Siliqua indicated the presence of apocynin.

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Official regulations concerning the maximum number of substances in food are introduced as a consequence of possible adverse effects, after oral administration. In this regard, analytical methods are necessary in order to determine specific targets. Among oxygen heterocyclic compounds (OHCs, that are furocoumarins, coumarins and polymethoxyflavones), only coumarin is subject to restriction by the Regulation (EC) No 1334/2008 of the European Parliament. Furocoumarins are known for their phototoxicity and other side effects due to their dietary intake; however, an official limit about the maximum content of these compounds in food is still missing. The lack of information about the real amount of these compounds in food is responsible for the conflicting opinions about the introduction of an official limit. The HPLC-MS/MS method here proposed, in combination with the linear retention index system, represents an innovative analytical strategy for the characterization of OHCs in citrus beverages. Several types of drinks were analysed in order to quantify 35 OHCs in total. This method is suitable for the quality control of OHCs in food and the obtained results may be considered as informative data useful for the regulatory authorities in the emission of new opinions and for a potential new regulation in this field.

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The aim of this study was to analyze the non-volatile composition and antioxidant differences of lemon essential oils (LEOs) obtained by cold-pressing vs. hydrodistillation. Pathological observations showed that LEO effectively inhibited liver injury caused by oxidative stress, and CPLEO was more effective than HDLEO. CPLEO increased serum T-AOC, SOD, GSH, and GSH-Px levels while decreasing NO, COX-2, IL-6, IL-1ß, IFN-γ, and TNF-α levels in mice with oxidative damage. The effects of CPLEO were stronger than those of HDLEO and similar to those of vitamin C. CPLEO upregulated mRNA and protein expressions of Cu/Zn-SOD, Mn-SOD, CAT, HO-1, Nrf2, and NQO1 while downregulating nNOS, iNOS, IL-1ß, COX-2, TNF-α, and NF-κB mRNA expression and nNOS, eNOS, iNOS, and COX-2 protein expression in mice with oxidative damage. The results demonstrate that LEO has good antioxidant effects and that CPLEO has a better antioxidant effect than HDLEO as it retains more active non-volatile substances.

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Photo-controlled or photo-regulated molecules, especially biologically active and operating in physiological conditions, are in steady demand. Herein, furocoumaric and furocoumarinic acids being (Z/E)-isomers relative to each other were obtained in two stages starting from psoralen: the alkaline solvolysis of psoralen led to furocoumaric acid, which was further Z → E photoisomerized (365 nm) to furocoumarinic acid. The kinetics of Z → E photoisomerization was monitored by HPLC and UV-vis spectrophotometry. Photophysical characteristics in the aqueous phase for both acids, as well as the reversibility of (Z/E) photoisomerization process, were also assessed. Furocoumarinic acid was found to be visibly fluorescent at pH 2.0-12.0, with the maxima of fluorescence emission spectra being pH-dependent. The reverse E → Z photoisomerization predicted by quantum chemistry calculations as energetically favorable for the monoanionic form of furocoumarinic acid was proved in the experiment while being complicated by pyrone ring closure back to psoralen in acidic and neutral conditions. The preparative synthesis of furocoumarinic acid outlined in this work is particularly valuable in view of a wide range of pharmacological effects previously predicted for this compound.

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Following a request from the European Commission, the EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the safety and efficacy of expressed lemon oil and distilled lemon oil from Citrus limon (L.) Osbeck and lime oil from Citrus aurantiifolia (Christm.) Swingle, when used as sensory additives in feed for all animal species. The use of the expressed lemon oil and its residual fraction and the use of lime oil in feed is not expected to increase the exposure to furocoumarins and methoxycoumarins and perillaldehyde of those target species that are already fed citrus by-products a relevant extent (< 10%). For companion animals and ornamental fish not normally exposed to citrus by-products, no conclusion can be drawn. For the other species and for the distilled fraction of expressed lemon oil, the FEEDAP Panel concludes that the additives under assessment are safe at the maximum proposed or at reduced use levels in complete feed. The Panel considers that the use in water for drinking is safe provided that the total daily intake of the additive does not exceed the daily amount that is considered safe when consumed via feed. No concerns for consumer safety were identified following the use of the additives at the maximum proposed use level in feed. The additives under assessment should be considered as irritants to skin and eyes and the respiratory tract and as skin sensitisers. Since expressed lemon oil and its fractions contain furocoumarins, they may cause phototoxicity. The use of the additives under the proposed conditions of use in animal feed is not expected to pose a risk for the environment. Since C. limon and C. aurantiifolia and their preparations are recognised to flavour food and its function in feed would be essentially the same as that in food, no further demonstration of efficacy is considered necessary.

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In the European Union, cosmetic products are regulated by the Cosmetics Regulation (EC) No. 1223/2009. The Analytical Working Group of the International Fragrance Association (IFRA) suggested that a new sensitive analytical method is needed to determine psoralens in finished cosmetic products. This research provides an HPLC-MS/MS method for the quality control of 20 furocoumarins, 8 coumarins and 7 polymethoxyflavones in cosmetics. Thanks to the high sensitivity of the tandem mass spectrometry detection in Multiple Reaction Monitoring mode, psoralens contained in trace have been quantified in different products. The Limits of Quantifications were in the range 0.3-74 µg L-1. A reliable identification was achieved combining the Linear Retention Index (LRI) system with the MS and MS/MS libraries. In particular, the attribution was based on the spectra similarity filtered by the LRI parameter. The robustness and reproducibility of the LRI approach was demonstrated by the comparison of the HPLC-MS/MS results here reported with those obtained in our previous study, by using an HPLC-PDA system. This method could be taken into account for quality control of furocoumarins in cosmetics, and by the main associations, such as IFRA, for the purpose of issuing new opinions.

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Phytophotodermatitis is a cutaneous reaction caused by direct contact with phototoxic agents and subsequent sunlight exposure. Furocoumarins and psoralens are 2 phototoxic agents that can cause this reaction, and these organic chemical compounds are found in many plant species consumed by humans. Following contact exposure to such foods and ultraviolet radiation exposure via direct sunlight, phytophotodermatitis can occur. Due to the etiology of these rashes relating closely to the outdoor consumption of margaritas, the rash may be known by patients as "margarita burn." There is a classically described sequence of rash progression: erythematous macules or patches, which later become vesicles and seem similar to second-degree burns, followed by an asymptomatic hyperpigmentation. This case presents a 26-year-old female diagnosed with phytophotodermatitis following use of citrus fruits for margaritas while outdoors in direct sunlight. The diagnosis of phytophotodermatitis is often made clinically but can be complicated due to its similarity in appearance to many other common cutaneous reactions. In this patient, the differential diagnosis included solar erythema, contact dermatitis (type IV hypersensitivity reaction), polymorphic light eruption, or drug-related photosensitivity. Careful history taking is essential in not only narrowing down the differential diagnosis but also in avoiding unnecessary tests or ineffective treatments.

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