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Inhibition of NLRP3 inflammasome activation produces potent therapeutic effects in a wide array of inflammatory diseases. Bergapten (BeG), a furocoumarin phytohormone present in many herbal medicines and fruits, exibits anti-inflammatory activity. In this study we characterized the therapeutic potential of BeG against bacterial infection and inflammation-related disorders, and elucidated the underlying mechanisms. We showed that pre-treatment with BeG (20 μM) effectively inhibited NLRP3 inflammasome activation in both lipopolysaccharides (LPS)-primed J774A.1 cells and bone marrow-derived macrophages (BMDMs), evidenced by attenuated cleaved caspase-1 and mature IL-1β release, as well as reduced ASC speck formation and subsequent gasdermin D (GSDMD)-mediated pyroptosis. Transcriptome analysis revealed that BeG regulated the expression of genes involved in mitochondrial and reactive oxygen species (ROS) metabolism in BMDMs. Moreover, BeG treatment reversed the diminished mitochondrial activity and ROS production after NLRP3 activation, and elevated the expression of LC3-II and enhanced the co-localization of LC3 with mitochondria. Treatment with 3-methyladenine (3-MA, 5 mM) reversed the inhibitory effects of BeG on IL-1β, cleaved caspase-1 and LDH release, GSDMD-N formation as well as ROS production. In mouse model of Escherichia coli -induced sepsis and mouse model of Citrobacter rodentium- induced intestinal inflammation, pre-treatment with BeG (50 mg/kg) significantly ameliorated tissue inflammation and injury. In conclusion, BeG inhibits NLRP3 inflammasome activation and pyroptosis by promoting mitophagy and maintaining mitochondrial homeostasis. These results suggest BeG as a promising drug candidate for the treatment of bacterial infection and inflammation-related disorders.

This study evaluated whether bergapten and methoxsalen could prevent diabetes-induced osteoporosis and its underlying mechanism. For 10 weeks, bergapten or methoxsalen (0.02%, w/w) was applied to diabetic mice that were provided with a high-fat diet and streptozotocin. Bone mineral density (BMD) and microarchitecture quality were significantly reduced in the diabetic control group; however, both bergapten and methoxsalen reversed serum osteocalcin, bone-alkaline phosphatase and femur BMD. These coumarin derivatives significantly increased bone volume density and trabecular number, whereas they decreased the structure model index of femur tissue in diabetic mice. Conversely, tartrate-resistant acid phosphatase 5 (TRAP) staining revealed that these derivatives reduced osteoclast numbers and formation in diabetic bone tissue. Additionally, both bergapten and methoxsalen tended to downregulate the expression of osteoclast-related genes such as receptor activator of nuclear factor kappa-B ligand (RANKL), nuclear of activated T-cells, cytoplasmic 1 (NFATc1) and TRAP in diabetic femurs, with NFATc1 and TRAP expression showing significant reductions. Our data suggest that both bergapten and methoxsalen prevent diabetic osteoporosis by suppressing bone resorption.

Bergapten (BP) or 5-methoxypsoralen (5-MOP) is a furocoumarin compound mainly found in bergamot essential oil but also in other citrus essential oils and grapefruit juice. This compound presents antibacterial, anti-inflammatory, hypolipemic, and anticancer effects and is successfully used as a photosensitizing agent. The present review focuses on the research evidence related to the therapeutic properties of bergapten collected in recent years. Many preclinical and in vitro studies have been evidenced the therapeutic action of BP; however, few clinical trials have been carried out to evaluate its efficacy. These clinical trials with BP are mainly focused on patients suffering from skin disorders such as psoriasis or vitiligo. In these trials, the administration of BP (oral or topical) combined with UV irradiation induces relevant lesion clearance rates. In addition, beneficial effects of bergamot extract were also observed in patients with altered serum lipid profiles and in people with nonalcoholic fatty liver. On the contrary, there are no clinical trials that investigate the possible effects on cancer. Although the bioavailability of BP is lower than that of its 8-methoxypsoralen (8-MOP) isomer, it has fewer side effects allowing higher concentrations to be administered. In conclusion, although the use of BP has therapeutic applications on skin disorders as a sensitizing agent and as components of bergamot extract as hypolipemic therapy, more trials are necessary to define the doses and treatment guidelines and its usefulness against other pathologies such as cancer or bacterial infections.

The objectives of this study were to investigate the melanogenetic potential of the psoralen derivatives 5-hydroxypsoralen, 5-methoxypsoralen, 8-hydroxypsoralen, 8-methoxypsoralen, and 5,8-dimethoxypsoralen in B16F10 melanoma cells. The results indicated that melanin production is significantly stimulated in B16F10 melanoma cells with 5-methoxypsoralen, 8-methoxypsoralen, and 5,8-dimethoxypsoralen, especially for 5-methoxypsoralen (bergapten), as reported previously. In addition, Western blot results showed that the protein levels of microphthalmia-associated transcription factor (MITF), tyrosinase, tyrosinase-related protein-1 (TRP-1), and tyrosinase-related protein-2 (TRP-2) increase after bergapten treatment for the first time. The results also showed that bergapten promotes the phosphorylation of Akt at Ser 473 and glycogen synthase kinase-3β at Ser 9. Moreover, bergapten increased the content of β-catenin in the cell cytoplasm and nucleus by reducing the phosphorylated β-catenin (p-β-catenin) content. The results also indicated that bergapten regulates melanogenesis by upregulating the phosphorylation of p38 and JNK-mitogen-activated protein kinase. Taken together, these findings suggest that the regulation of melanogenesis by bergapten may be mediated by the β-catenin and MAPK signaling pathways and that bergapten might provide new insights into the pathogenesis of pigmented diseases.

Using repositioning to find new indications for existing functional substances has become a global target of research. The objective of this study is to investigate the anti-inflammatory potential of psoralen derivatives (5-hydroxypsoralen, 5-methoxypsoralen, 8-hydroxypsoralen, and 8-methoxypsoralen) in macrophages cells. The results indicated that most psoralen derivatives exhibited significantly inhibited prostaglandin E2 (PGE2) production, particularly for 8-hydroxypsoralen (xanthotoxol) in lipopolysaccharide (LPS)-stimulated macrophage RAW 264.7 cells. In addition, xanthotoxol treatment decreased the PGE2, IL-6, and IL-1β production caused by LPS stimulation in a concentration-dependent manner. Moreover, Western blot results showed that the protein levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), which activated with LPS treatment, were decreased by xanthotoxol treatment. Mechanistic studies revealed that xanthotoxol also suppressed LPS-stimulated phosphorylation of the inhibitor of κBα (IκBα), p38 mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK) in RAW 264.7 cells. The Western blot assay results show that xanthotoxol suppresses LPS-induced p65 translocation from cytosol to the nucleus in RAW 264.7 cells. Moreover, we tested the potential application of xanthotoxol as a cosmetic material by performing human skin patch tests. In these tests, xanthotoxol did not induce any adverse reactions at a 100 μΜ concentration. These results demonstrate that xanthotoxol is a potential therapeutic agent for topical application that inhibits inflammation via the MAPK and NF-κB pathways.

The navel orangeworm (Amyelois transitella) and the fungus Aspergillus flavus constitute a facultative mutualism and pest complex in tree nut and fruit orchards in California. The possibility exists that the broad detoxification capabilities of A. flavus benefit its insect associate by metabolizing toxicants, including hostplant phytochemicals and pesticides. We examined this hypothesis by conducting laboratory bioassays to assess growth rates and survivorship of pyrethroid-resistant (R347) and susceptible (CPQ) larval strains on potato dextrose agar diet containing almond meal with and without two furanocoumarins, xanthotoxin and bergapten, found in several hostplants, and with and without two insecticides, bifenthrin and spinetoram, used in almond and pistachio orchards. Additionally, fungi were incubated in liquid diets containing the test chemicals, and extracts of these diets were added to almond potato dextrose agar (PDA) diets and fed to larvae to evaluate the ability of the fungus to metabolize these chemicals. Larvae consuming furanocoumarin-containing diet experienced higher mortality than individuals on unamended diets, but adding A. flavus resulted in up to 61.7% greater survival. Aspergillus flavus in the diet increased development rate > two-fold when furanocoumarins were present, demonstrating fungal enhancement of diet quality. Adding extracts of liquid diets containing xanthotoxin and fungus decreased mortality compared to xanthotoxin alone. On diets containing bifenthrin and spinetoram, however, mortality increased. These results support the hypothesis that A. flavus enhances navel orangeworm performance and contributes to detoxification of xenobiotics. Among practical implications of our findings, this mutualistic association should be considered in designing chemical management strategies for these pests.

Pure methoxyfuranocoumarins were isolated from a crude petroleum ether extract (CPE; Soxleth extraction efficiency 12.28%) from fruits of Peucedanum tauricum MB. (Apiaceae) by counter-current chromatography in a hydrostatic equilibrium system (centrifugal partition chromatography—CPC). The optimized biphasic solvent system composed of n-heptane-ethyl acetate-methanol-water (5:2:5:2; v/v/v/v) in the ascending mode of elution was used (3 mL/min, 1600 rpm). In the single run, peucedanin (P), 8-methoxypeucedanin (8MP), and bergapten (5MOP) were obtained as pure as 95.6%, 98.1%, and c.a. 100%, respectively. The carefully optimized and developed CPC was effectively transferred from the analytical to the semi-preparative scale (where 20 mg and 150 mg of CPE were loaded, respectively). Identification and quantitative analysis of methoxyfuranocoumarins was carried out in the plant material, in the CPE, and in individual CPC fractions by use of validated high-performance liquid chromatography with diode array detection and mass spectrometry (HPLC-DAD-ESI-MS). For the separation steps, the extraction/isolation recovery was calculated. In this case, CPC proved to be an effective tool for the simultaneous isolation and separation of P, 8MP, and 5MOP from a multicomponent plant matrix, without additional pre-purification steps. The high purity of the obtained plant metabolites makes it possible to consider their use in pharmacological or biological studies.

Non-small cell lung cancer (NSCLC) is a leading cause of cancer mortality worldwide, necessitating new treatment approaches with minimal side effects. In the present study, the potential of Bergapten (5-methoxypsoralen), a natural furanocoumarin compound, as a therapeutic agent against NSCLC was investigated by using network pharmacology, molecular docking and in vitro validation. Bergapten targets were identified using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform and SwissTarget databases, whilst lung cancer-related targets were sourced from GeneCards and DisGeNET. Protein-protein interaction analysis and molecular docking were performed to identify key targets. The inhibitory effects of Bergapten on lung cancer cells were assessed using Cell Counting Kit-8 assays, wound healing assays, cell migration experiments, flow cytometry and western blotting. SC79 was used to verify the regulation of Bergapten on the PI3K/AKT pathway. Network pharmacology identified 51 targets, one signaling pathway and four Gene Ontology projects associated with the action of Bergapten against NSCLC. Key targets identified included glycogen synthase kinase-3β, Janus kinase 2, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α and protein tyrosine kinase 2. In vitro experiments demonstrated that Bergapten significantly inhibited cell viability, promoted apoptosis, induced cellular senescence and inhibited the PI3K/AKT signaling pathway in NSCLC cells. In conclusion, Bergapten exerts its anti-NSCLC effects through the PI3K/AKT pathway, promoting cell senescence and inhibiting inflammation. These findings suggest that Bergapten has potential as a therapeutic agent for NSCLC.

The main purpose of the current study was to investigate the antitumor effects of 5-methoxypsoralen in U87MG human glioma cells along with studying its effects on cell cycle progression, autophagy and the PI3K/Akt signaling pathway. The cytotoxic effects of the drug were demonstrated by the MTS cell viability assay while its effects on cellular morphology associated with cell apoptosis were evaluated by phase contrast and fluorescence microscopic techniques. Effects of 5-methoxypsoralen on the cell cycle were studied by flow cytometry while effects on PI3K/Akt proteins were evaluated by western blot assay. The results indicate that 5-methoxypsoralen led to time-dependent as well as dose-dependent inhibitory effects on U-87MG human glioma cells. 5-Methoxypsoralen led to a substantial decrease of cell count along with distorted cell morphology. The molecule also led to DNA ladder formation which increased with increasing doses of 5-methoxypsoralen. 5-methoxypsoralen also led to dose-dependent G2/M phase cell cycle arrest. 5-Methoxypsoralen-treated cells also exhibited altered cell ultrastructure with the appearance of autophagic vacuoles and the number of these vacuoles increased with increasing drug dose. In brief, the results indicate that 5-methoxypsoralen exerted potent anticancer and apoptotic effects in U-87MG human glioma cells along with inducing cell cycle arrest, autophagy and m-TOR/PI3K/Akt signaling pathway inhibition.

Angelica dahurica (A. dahurica) has a wide range of pharmacological effects, including analgesic, anti-inflammatory and hepatoprotective effects. In this study, we investigated the effect of A. dahurica extract (AD) and its effective component bergapten (BG) on hepatic fibrosis and potential mechanisms. Hepatic fibrosis was induced by intraperitoneal injection with carbon tetrachloride (CCl 4 ) for 1 week, and mice were administrated with AD or BG by gavage for 1 week before CCl 4 injection. Hepatic stellate cells (HSCs) were stimulated by transforming growth factor-β (TGF-β) and cultured with AD, BG, GW4064 (FXR agonist) or Guggulsterone (FXR inhibitor). In CCl 4 -induced mice, AD significantly decreased serum aminotransferase, reduced excess accumulation of extracellular matrix (ECM), inhibited caspase-1 and IL-1β, and increased FXR expressions. In activated HSCs, AD suppressed the expressions of α-SMA, collagen I, and TIMP-1/MMP-13 ratio and inflammatory factors, functioning as FXR agonist. In CCl 4 -induced mice, BG significantly improved serum transaminase and histopathological changes, reduced ECM excessive deposition, inflammatory response, and activated FXR expression. BG increased FXR expression and inhibited α-SMA and IL-1β expressions in activated HSCs, functioning as GW4064. FXR deficiency significantly attenuated the decreasing effect of BG on α-SMA and IL-1β expressions in LX-2 cells. In conclusion, AD could regulate hepatic fibrosis by regulating ECM excessive deposition and inflammation. Activating FXR signaling by BG might be the potential mechanism of AD against hepatic fibrosis.