Search Results (53)

Background/Objectives: Flavones, a class of plant-based flavonoids, have demonstrated conflicting anti-melanogenic activities in mouse and human melanocytes. Sinensetin (SNT), a polymethoxyflavone, has shown pro-melanogenic activity in B16F10 mouse melanoma (MM) cells, while eupatilin (EU) and jaceosidin (JAC), two flavones that are structural analogs of SNT, have not been evaluated for their effects on melanogenesis yet. Methods: Herein, the effects of SNT, EU, and JAC on melanogenesis in MNT-1 cells (human melanoma) and HEMn-DP cells (primary human melanocytes) have been examined. The mushroom tyrosinase (TYR) activity was tested in cell-free conditions, followed by examination of the cytotoxicity of the compounds via the Alamar Blue (AB) assay. Cellular melanin production and TYR activity were estimated in MNT-1 cells. The compounds were further examined in primary human melanocytes for melanin production, TYR activity, and protein levels. Results: Our findings show that SNT was a potent inhibitor of TYR activity in a cell-free assay, while EU and JAC had no effect. However, both SNT and EU were shown to exhibit anti-melanogenic activity (that was reversible) in human cells, while JAC was ineffective and cytotoxic. Conclusions: SNT and EU are potential novel candidates for hyperpigmentation treatment without cytotoxicity. Additional studies are warranted to elucidate the signaling mechanisms that govern their anti-melanogenesis action. Future research is necessary to assess the anti-melanogenic effectiveness of SNT/EU using 3D skin tissue equivalents and to select the optimal candidate. Full article

Phytochemicals, such as flavonoids, are bioactive compounds produced by plants, including citrus fruits, that exhibit antioxidant effects on mammalian cells and tissues. Polymethoxyflavones (PMFs) are a family of flavonoids found in the pulp and peel of citrus fruits, and have been reported to have potent antioxidant activity implicated in the prevention of human diseases. Several studies have shown that PMFs have a protective effect on bone resorption in mouse models of diseases, including osteoporosis, rheumatoid arthritis, and periodontal disease. PMFs significantly suppressed the differentiation of osteoclasts (bone resorptive cells) through indirect and direct mechanisms. The indirect effect of PMFs is the suppression of inflammatory mediator production, such as prostaglandin E2 (PGE2), and the reduction of osteoclastic inducers, such as the receptor activator of NF-κB ligand (RANKL), in osteoblasts (bone-forming cells). The direct effect of PMF suppresses osteoclast differentiation and function by inhibiting the NF-κB signaling pathway. In silico molecular docking studies indicated that PMFs target the ATP-binding pocket of IKKβ and inhibit the NF-κB signaling pathway. These findings suggest that PMFs protect against bone destruction by interfering with the NF-κB pathway in osteoblasts and osteoclasts. In this review, we summarize the latest findings regarding the effects of PMFs on various bone resorption-related diseases in mouse models. Full article

The huge amount of citrus peel produced worldwide represents an economic burden for society. However, this agricultural by-product is a rich source of natural molecules, potentially endowed with interesting pharmacological activities. In this regard, we decided to investigate if the polymethoxyflavones contained in citrus peel waste could be exploited as novel vasorelaxant agents. A hydroalcoholic blond orange (Citrus sinensis) peel extract, obtained by ultrasonication, was partitioned in dichloromethane. Column chromatography allowed for the isolation of four polymethoxyflavones, namely, scutellarein tetramethyl ether, nobiletin, tangeretin, and sinensetin, identified by nuclear magnetic resonance (NMR) spectroscopy and UPLC-HRMS/MS and confirmed by multivariate curve resolution of NMR fractional spectra. The four molecules showed interesting in vitro vasorelaxant activity, at least, in part, due to the blockade of smooth muscle Ca_V1.2 channels. Molecular modeling and docking analysis elucidated the binding mode of the polymethoxyflavones at the homology model of the rat Ca_V1.2c subunit and provided the structural basis to rationalise the highest activity of scutellarein tetramethyl ether in the set and the dramatic effect of the additional methoxy group occurring in nobiletin and sinensetin. In conclusion, citrus peel can be considered a freely available, valuable source of vasoactive compounds worthy of pharmaceutical and/or nutraceutical exploitation. Full article

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. Full article

In the framework of our studies on Citrus cultivars in Greece, the chemical composition of the essential oils (EOs) from the peels and leaves of orange, pummelo, and tangelo (mandarin × grapefruit hybrid) cultivated in Greece have been studied. All EOs have been analyzed through GC-MS, and a total of 47 and 87 metabolites were identified in the peels and leaves, respectively. These metabolites are classified into the chemical groups of terpenes, alcohols, aldehydes, esters, ketones, and organic acids. Limonene was the most abundant compound in the peel EOs. Moreover, bioactive polymethoxyflavones (PMFs) were isolated and structurally determined from the peels of orange and tangelo, highlighting them as a good potential source of natural PMFs. All EOs were evaluated for their antimicrobial activity against nine human pathogenic microorganisms (six bacteria and three fungi), showing an interesting profile. The EOs from the peels of all Citrus species exhibited a stronger antimicrobial activity compared to those from the leaves. The susceptibility of the assayed Gram-positive bacteria was observed to be greater than that of Gram-negative bacteria, while the fungi were also relatively less resistant than bacteria. The rootstock choice did not influence the EO profile of the fruit peel but exerted an influence on the chemical profile of the leaves. Full article

Polymethoxyflavones from Kaempferia parviflora rhizomes have been shown to effectively combat aging in skin cells and tissues by inhibiting senescence, reducing oxidative stress, and enhancing skin structure and function. This study assessed the anti-aging effects and safety of standardized K. parviflora extract (BG100), enriched with polymethoxyflavones including 5,7-dimethoxyflavone, 5,7,4′-trimethoxyflavone, 3,5,7,3′,4′-pentamethoxyflavone, 3,5,7-trimethoxyflavone, and 3,5,7,4′-tetramethoxyflavone. We evaluated BG100’s impact on skin rejuvenation and antioxidant properties using photoaged human 3D full-thickness skin models. The potential for skin irritation and sensitization was also assessed through studies on reconstructed human epidermis and clinical trials. Additionally, in vitro genotoxicity testing was performed following OECD guidelines. Results indicate that BG100 promotes collagen and hyaluronic acid production, reduces oxidative stress, and minimizes DNA damage in photoaged full-thickness 3D skin models. Furthermore, it exhibited non-irritating and non-sensitizing properties, as supported by tests on reconstructed human epidermis and clinical settings. BG100 also passed in vitro genotoxicity tests, adhering to OECD guidelines. These results underscore BG100′s potential as a highly effective and safe, natural anti-aging agent, suitable for inclusion in cosmeceutical and nutraceutical products aimed at promoting skin rejuvenation. Full article

Previous studies have revealed the microbial metabolism of dietary choline in the gut, leading to its conversion into trimethylamine (TMA). Polymethoxyflavones (PMFs), exemplified by tangeretin, have shown efficacy in mitigating choline-induced cardiovascular inflammation. However, the specific mechanism by which these compounds exert their effects, particularly in modulating the gut microbiota, remains uncertain. This investigation focused on tangeretin, a representative PMFs, to explore its influence on the gut microbiota and the choline–TMA conversion process. Experimental results showed that tangeretin treatment significantly attenuated the population of CutC–active bacteria, particularly Clostridiaceae and Lactobacillus, induced by choline chloride in rat models. This inhibition led to a decreased efficiency in choline conversion to TMA, thereby ameliorating cardiovascular inflammation resulting from prolonged choline consumption. In conclusion, tangeretin’s preventive effect against cardiovascular inflammation is intricately linked to its targeted modulation of TMA–producing bacterial activity. Full article

Tetramethoxyflavones (TMFs) found in the Citrus genus have garnered considerable interest from food scientists and the health food industry because of their promising biological properties. Nonetheless, there are currently limited data available regarding the effectiveness and bioavailability of “hydroxylated TMFs”, which are flavones known for their potential in disease prevention through dietary means. This study aims to provide insights into the chemical and biological properties of hydroxylated TMF and evaluates its effects on intestinal cell permeability and cytochrome P450 (CYP) inhibition. Liquid chromatography–mass spectrometry (LC-MS) and microsomes analyze the TMFs and hydroxylated TMFs, elucidating cell penetration and metabolic inhibition potential. 3H7-TMF shows the fastest (1-h) transport efficiency in intestinal cells. The Caco-2 cell model exhibits significant transport and absorption efficiency. Dissolved hydroxyl-TMF with hydrophilicity possibly permeates the gut. 3H7-TMF has higher transport efficiency (46%) 3H6-TMF (39%). IC₅₀ values of TMFs (78-TMF, 57-TMF, 3H7-TMF, 3H6-TMF) against CYP enzymes (CYP1A2, CYP2D6, CYP2C9, CYP2C19, CYP3A4) range from 0.15 to 108 μM, indicating potent inhibition. Hydroxyl groups enhance TMF hydrophilicity and membrane permeability. TMFs display varied inhibitory effects due to hydroxyl and methoxy hindrance. This study underscores the strong CYP inhibitory capabilities in these TMFs, implying potential food–drug interactions if used in medicines or supplements. These findings can also help with food nutrition improvement and pharma food developments through innovative approaches for Citrus waste valorization. Full article

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. Full article

We here investigated the anti-inflammatory activity of a polymethoxylated flavone-containing fraction (PMFF) from Citrus sinensis and of a prenylflavonoid-containing one (PFF) from Humulus lupulus, either alone or in combination (MIX). To this end, an in vitro model of inflammatory bowel disease (IBD), consisting of differentiated, interleukin (IL)-1β-stimulated Caco-2 cells, was employed. We demonstrated that non-cytotoxic concentrations of either PMFF or PFF or MIX reduced nitric oxide (NO) production while PFF and MIX, but not PMFF, also inhibited prostaglandin E₂ release. Coherently, MIX suppressed both inducible NO synthase and cyclooxygenase-2 over-expression besides NF-κB activation. Moreover, MIX increased nuclear factor erythroid 2–related factor 2 (Nrf2) activation, heme oxygenase-1 expression, restoring GSH and reactive oxygen and nitrogen species (RONs) levels. Remarkably, these effects with MIX were stronger than those produced by PMFF or PFF alone. Noteworthy, nobiletin (NOB) and xanthohumol (XTM), two of the most represented phytochemicals in PMFF and PFF, respectively, synergistically inhibited RONs production. Overall, our results demonstrate that MIX enhances the anti-inflammatory and anti-oxidative effects of the individual fractions in a model of IBD, via a mechanism involving modulation of NF-κB and Nrf2 signalling. Synergistic interactions between NOB and XTM emerge as a relevant aspect underlying this evidence. Full article

Polymethoxyflavones are flavonoids that are abundant in citrus fruit peels and have beneficial effects on human health. Previous studies have demonstrated that the polymethoxyflavones, namely sudachitin and nobiletin, ameliorate obesity and diabetes in humans and rodents. Although nobiletin induces lipolysis in adipocytes, lipolytic pathway activation by sudachitin has not been clarified in adipocytes. In this study, the effect of sudachitin on lipolysis was elucidated in murine 3T3-L1 adipocytes. Glycerol release into the medium and activation of the cyclic AMP (cAMP)/protein kinase A (PKA)/hormone-sensitive lipase (HSL) pathway was evaluated in 3T3-L1-differentiated adipocytes. Treatment with sudachitin and nobiletin for 24 and 48 h did not induce cytotoxicity at concentrations of up to 50 μM. Sudachitin and nobiletin at concentrations of 30 and 50 μM increased intracellular cAMP and medium glycerol levels in 3T3-L1 adipocytes. Western blotting revealed that sudachitin and nobiletin dose-dependently increased protein levels of phosphorylated PKA substrates and phosphorylated HSL. Sudachitin- and nobiletin-induced glycerol release, phosphorylation of PKA substrates, and HSL phosphorylation were suppressed by pharmacological inhibition of adenylate cyclase and PKA. These findings indicated that sudachitin, similar to nobiletin, exerts anti-obesogenic effects, at least in part through the induction of lipolysis in adipocytes. Full article

Mandarins are the second most farmed citrus. Consumers demand a mandarin fruit that is both tasty and excellent in quality. The fruit quality, flavonoid profile, antioxidant capacity and total carotenoid content of five varieties (‘Zorica’, ‘Chahara’, ‘Kawano Wase’, ‘Owari’ and ‘Saigon’) of Satsuma mandarins grown in Neretva valley (Croatia) were determined. In this research, the distribution of bioactive compounds was different for mandarin juice, dry pulp residue and dry peels. Dry peels showed higher levels of polyphenolic compounds and antioxidant activity. Total carotenoids were found to be in a greater concentration in dry pulp residue than in the dry peel. The highest levels of total carotenoids (543 μg β-carotene/g) were found in the dry pulp residue of ‘Owari’ and ‘Saigon’, while the lowest levels were in ‘Chahara’ (227.87 μg β-carotene/g). In dry mandarin peels, the highest levels of total carotenoids were in ‘Kawano Wase’ (227.58 μg β-carotene/g), and the lowest levels were in ‘Chahara’ (52.24 μg β-carotene/g). The most abundant component of polymethoxyflavones (PMFs) in mandarin dry peel was nobiletin, ranging from 0.204 mg/g (‘Chahara’) to 0.608 mg/g (‘Saigon’), followed by tangeretin, ranging from 0.133 mg/g (‘Chahara’) to 0.251 mg/g (‘Saigon’), and sinesestin (‘Zorica’), ranging from 0.091 mg/g to 0.353 mg/g (‘Saigon’). Full article

Citrus essential oil combines numerous components with many qualities and control issues. For example, how to monitor volatile components and nonvolatile substances simultaneously is a major problem. Therefore, the objective of this study was to develop a Gas chromatography/mass spectrometry (GC/MS) method for the compositional study of total constituents in cold-pressed essential oils from major orange species. A polysiloxane GC column (DB-1, nonpolar, low-bleeding) was used in this study; its fingerprint includes terpenoids (Section 1), long-chain hydrocarbons (Section 2), phytosterols, and polymethoxyflavones (Section 3). These markers are more effective in detecting adulteration of essential oil products than volatile components, and more effective than quantitative PMF by 5α-Cholestane for establishing authenticity. The study aims to use the analysis procedure as a routine quality control test for authenticity evaluation in cold-pressed orange essential oils (CP-OrEO). Full article

Hydroxylated polymethoxyflavones (PMFs) are a unique class of flavonoid compounds mainly found in citrus plants. We investigated the anti-inflammatory effects of one major 5-hydroxy PMF, namely 5-demethylnobiletin (5DN) and its metabolites 5, 3′-didemethylnobiletin (M1), 5, 4′-didemethylnobiletin (M2), and 5, 3′, 4′-tridemethylnobiletin (M3) in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells. The results showed that M2 and M3 produced stronger inhibitory effects on the production of nitric oxide (NO) than their parent compound at non-cytotoxic concentrations. Western blotting and real-time PCR analyses demonstrated that M2 and M3 significantly decreased iNOS and COX-2 gene expression. The results also showed that M1 and M3 induced heme oxygenase-1(HO-1) gene expression. Overall, our results demonstrated that metabolites of 5DN significantly inhibited LPS-induced inflammation in RAW 264.7 macrophage cells and generally possessed more potent anti-inflammatory activity than the parent compound, 5DN. Full article

The importance of the circadian clock in maintaining human health is now widely acknowledged. Dysregulated and dampened clocks may be a common cause of age-related diseases and metabolic syndrome Thus, circadian clocks should be considered as therapeutic targets to mitigate disease symptoms. This review highlights a number of dietary compounds that positively affect the maintenance of the circadian clock. Notably the polymethoxyflavone nobiletin has shown some encouraging results in pre-clinical experiments. Although many more experiments are needed to fully elucidate its exact mechanism of action, it is a promising candidate with potential as a chronotherapeutic agent. Full article