Search

Approximately 80% of breast cancer (BC) cases are estrogen receptor positive (ER+) and sensitive to hormone treatment; Tamoxifen is a prodrug, and its main plasmatic active metabolites are 4-hydroxytamoxifen (4-OH Tam) and endoxifen. Despite the effectiveness of tamoxifen therapy, resistance can be developed. An increment in eukaryotic initiation factor-4A complex (eIF4A) activity can result in tamoxifen-resistant tumor cells. For this work, we developed a cell variant resistant to 4-OH Tam and endoxifen, denominated MCF-7Var E; then, the aim of this research was to reverse the acquired resistance of this variant to tamoxifen metabolites by incorporating the natural compound auraptene. Combination treatments of tamoxifen derivatives and auraptene successfully sensitized the chemoresistant MCF-7Var E. Our data suggest a dual regulation of eIF4A and ER by auraptene. Joint treatments of 4-OH Tam and endoxifen with auraptene identified a novel focus for chemoresistance disruption. Synergy was observed using the auraptene molecule and tamoxifen-derived metabolites, which induced a sensitization in MCF-7Var E cells and ERα parental cells that was not observed in triple-negative breast cancer cells (TNBC). Our results suggest a synergistic effect between auraptene and tamoxifen metabolites in a resistant ER+ breast cancer model, which could represent the first step to achieving a pharmacologic strategy. [ABSTRACT FROM AUTHOR]

AIM: To evaluate the effect of auraptene (AUR) treatment in forms of free and encapsulated in niosome nanoparticles by investigating the mRNA expression level of vascular endothelium growth factor (VEGF)-A and platelet-derived growth factors (PDGFs) in human retinal pigment epithelium (RPE) cell line. METHODS: Niosome nanocarriers were produced using two surfactants Span 60 and Tween 80. RPE cell line was treated with both free AUR and niosome-encapsulated. Optimum dosage of treatments was calculated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Expression of VEGF-A and PDGF-A, PDGF-B, PDGF-C, PDGF-D genes was measured after total RNA extraction and cDNA synthesis, using real-time polymerase chain reaction (RT-PCR). RESULTS: The highest entrapment efficiency (EE) was achieved by Span 60:cholesterol (1:1) with 64.3%. The half maximal inhibitory concentration (IC50) of free and niosome-encapsulated AUR were 38.5 and 27.78 µg/mL, respectively. Release study revealed that niosomal AUR had more gradual delivery to the cells. RT-PCR results showed reduced expression levels of VEGF-A, PDGF-A, PDGF-B, PDGF-C, and PDGF-D after treatment with both free and niosomal AUR. CONCLUSION: Niosomal formulation of Span 60: cholesterol (1:1) is an effective drug delivery approach to transfer AUR to RPE cells. VEGF-A, PDGF-A, PDGF-B, PDGF-C, and PDGF-D are four angiogenic factors, inhibiting which by niosomal AUR may be effective in age-related macular degeneration.

Auraptene (AUT) is widely known to possess both antioxidant and anti-inflammatory properties. This study attempted to evaluate the protective effects of AUT in dextran sodium sulfate (DSS)-induced colitis in mice and to determine the underlying molecular mechanisms. Our results suggest that AUT substantially minimizes the severity and worsening of DSS-induced colitis in mice, indicated by the lengthening of the colon, lower disease activity index, reduced oxidation levels, and attenuated inflammatory factors. Molecular studies revealed that AUT reduces the nuclear translocation of nuclear factor-κB (NF-κB), thereby inhibiting the expression of inflammatory factors. Additionally, AUT promotes the diversity of the intestinal flora in mice with colitis by increasing the number of beneficial bacteria such as Lactobacillaceae and lowering the number of harmful bacteria. In conclusion, AUT mitigates DSS-induced colitis by maintaining the integrity of the intestinal barrier and modulating the levels of the intestinal microbial species. TOC Graphic. Diagram summarizing the study findings. Auraptene mitigates dextran sulfate sodium-induced colitis in mice by regulating specific intestinal flora and repairing the intestinal barrier. [ABSTRACT FROM AUTHOR]

The natural product auraptene can influence tumor cell proliferation and invasion, but its effect on hepatocellular carcinoma (HCC) cells is unknown. Here, we report that auraptene can exert anti-tumor effects in HCC cells via inhibition of cell proliferation and ferroptosis induction. Auraptene treatment induces total ROS and lipid ROS production in HCC cells to initiate ferroptosis. The cell death or cell growth inhibition of HCC cells induced by auraptene can be eliminated by the ROS scavenger NAC or GSH and ferroptosis inhibitor ferrostatin-1 or Deferoxamine Mesylate (DFO). Mechanistically, the key ferroptosis defense protein SLC7A11 is targeted for ubiquitin–proteasomal degradation by auraptene, resulting in ferroptosis of HCC cells. Importantly, low doses of auraptene can sensitize HCC cells to ferroptosis induced by RSL3 and cystine deprivation. These findings demonstrate a critical mechanism by which auraptene exhibits anti-HCC effects via ferroptosis induction and provides a possible therapeutic strategy for HCC by using auraptene or in combination with other ferroptosis inducers. [ABSTRACT FROM AUTHOR]

Background: Paclitaxel administration causes peripheral neuropathy. Auraptene is a natural bioactive monoterpene with anti-inflammatory and anti-neuropathic effects that is widely used. Objectives: We aimed to study auraptene effects on paclitaxel-induced neuropathy. Materials and Methods: This study was comprised of two steps of evaluation of the preventive and treatment effects of auraptene in mice. In the first step, mice were randomly allocated into three groups of six animals, including the negative control (NEG CTL): animals injected with paclitaxel (PTX) together with normal saline, PTX (paclitaxel 2 mg/kg given on days 1, 3, 5, and 7), and PREVENTION: PTX + auraptene 100 mg/kg on days 1, 3, 5, and 7. In the second step, animals were allocated into six groups of six: NEG CTL (normal saline), PTX (paclitaxel 10 mg/kg given on days 1, 3, 5, and 7), PTX AUR (PTX + auraptene 50, 75, and 100 mg/kg), and a positive control (PTX-treated animals receiving imipramine 10 mg/kg). Intraperitoneal injection of PTX 2 mg/kg on days 1, 3, 5, and 7 was used in order to induce neuropathy. In both steps of the study, a hot plate test was done on day 7 in order to determine the response to heat. After the scarification of animals, the interleukin-6 (IL-6) level in the sciatic nerve was assessed by western blotting. Results: In the preventive group, auraptene could reduce hyperalgesia significantly. In the treatment step, the AUR 100 mg/kg compared to NEG CTL groups had significantly increased heat latency. The expression of IL-6 protein in the sciatic nerve was remarkably decreased in both the preventive and treatment groups compared to NEG CTL. Conclusion: Taken together, our results confirmed that AUR could decrease paclitaxel-induced hyperalgesia in mice and IL-6 protein content in sciatic nerve samples. [ABSTRACT FROM AUTHOR]

Abstract Auraptene (AUR) and umbelliprenin (UMB) are naturally occurring prenylated coumarins that have demonstrated promising anticancer effects across various human cancer cell lines. This meta-analysis aimed to systematically assess, compare, and quantify the anticancer efficacy of AUR and UMB by synthesizing evidence from in vitro studies. A comprehensive literature search identified 27 eligible studies investigating AUR or UMB against cancer cells. Mixed-effects models revealed significant negative associations between coumarin dose and viability for AUR (est. = − 2.27) and UMB (est. = − 3.990), underscoring their dose-dependent cytotoxicity. Meta-regression indicated slightly higher potency for UMB over AUR, potentially due to increased lipophilicity imparted by additional isoprenyl units. Machine learning approaches identified coumarin dose and cancer type as the most influential determinants of toxicity, while treatment duration and the specific coumarin displayed weaker effects. Moderate (AUR) to substantial (UMB) between-study heterogeneity was detected, although the findings proved robust. In summary, this meta-analysis establishes AUR and UMB as promising natural anticancer candidates with clear dose-toxicity relationships across diverse malignancies. The structural insights and quantifications of anticancer efficacy can inform forthcoming efforts assessing therapeutic potential in pre-clinical models and human trials.

Objective: The present work examined the anti-metastatic effects of auraptene and their underlying mechanisms of action in U87 Glioblastoma multiforme (GBM) cells.Materials and Methods: To test the hypothesis, cell culture, Matrigel invasion assay, scratch wound healing assay, gelatin zymography assay, qRT-PCR, and western blot analysis were conducted.Results: At sublethal concentrations of 12.5 and 25 µg/ml, auraptene exhibited a significant reduction in cell invasion and migration of U87 cells, as assessed using scratch wound healing and Transwell tests, respectively. The qRT-PCR and zymography experiments demonstrated a significant decrease in both mRNA expression and activities of MMP-2 and MMP-9 following auraptene treatment. Western blot analysis also showed that the total protein level of MMP-2 as well as phosphorylation of crucial metastasis-related proteins, including p-JNK and p-mTOR, decreased in auraptene-treated cells. The molecular docking studies consistently demonstrated that auraptene exhibits a significant affinity towards MMP-2/-9, the ATP binding site of mTOR and JNK1/2/3.Conclusion: Auraptene effectively inhibited the migration and invasion of GBM cells. This inhibitory effect was induced by modulating specific mechanisms, including suppressing MMPs, JNK, and mTOR activities. Auraptene might serve as a potential anti-metastatic agent against malignant GBM.

Objective: The present work examined the anti-metastatic effects of auraptene and their underlying mechanisms of action in U87 Glioblastoma multiforme (GBM) cells. Materials and Methods: To test the hypothesis, cell culture, Matrigel invasion assay, scratch wound healing assay, gelatin zymography assay, qRT-PCR, and western blot experiments were conducted. Results: At sublethal concentrations of 12.5 and 25 µg/ml, auraptene exhibited a significant reduction in cell invasion and migration of U87 cells, as assessed using scratch wound healing and Transwell tests, respectively. The qRT-PCR and zymography experiments demonstrated a significant decrease in both mRNA expression and activities of MMP-2 and MMP-9 following auraptene treatment. Western blot analysis also showed that MMP-2 protein level and phosphorylation of metastasis-related proteins (p-JNK and p-mTOR) decreased in auraptene-treated cells. Molecular docking studies consistently demonstrated that auraptene exhibits a significant affinity towards MMP-2/-9, the ATP binding site of mTOR and JNK1/2/3. Conclusion: Auraptene inhibited the migration and invasion of GBM cells. This inhibitory effect was induced by modulating specific mechanisms, including suppressing MMPs, JNK, and mTOR activities. [ABSTRACT FROM AUTHOR]

Phytochemical profiling followed by antimicrobial and anthelmintic activity evaluation of the Australian plant Geijera parviflora, known for its customary use in Indigenous Australian ceremonies and bush medicine, was performed. In the present study, seven previously reported compounds were isolated including auraptene, 6′-dehydromarmin, geiparvarin, marmin acetonide, flindersine, and two flindersine derivatives from the bark and leaves, together with a new compound, chlorogeiparvarin, formed as an artefact during the isolation procedure and isolated as a mixture with geiparvarin. Chemical profiling allowed for a qualitative and quantitative comparison of the compounds in the leaves, bark, flowers, and fruit of this plant. Subsequently, a subset of these compounds as well as crude extracts from the plant were evaluated for their antimicrobial and anthelmintic activities. Anthelmintic activity assays showed that two of the isolated compounds, auraptene and flindersine, as well as the dichloromethane and methanol crude extracts of G. parviflora, displayed significant activity against a parasitic nematode (Haemonchus contortus). This is the first report of the anthelmintic activity associated with these compounds and indicates the importance of such fundamental explorations for the discovery of bioactive phytochemicals for therapeutic application(s). [ABSTRACT FROM AUTHOR]

Approximately 80% of breast cancer (BC) cases are estrogen receptor positive (ER+) and sensitive to hormone treatment; Tamoxifen is a prodrug, and its main plasmatic active metabolites are 4-hydroxytamoxifen (4-OH Tam) and endoxifen. Despite the effectiveness of tamoxifen therapy, resistance can be developed. An increment in eukaryotic initiation factor-4A complex (eIF4A) activity can result in tamoxifen-resistant tumor cells. For this work, we developed a cell variant resistant to 4-OH Tam and endoxifen, denominated MCF-7Var E; then, the aim of this research was to reverse the acquired resistance of this variant to tamoxifen metabolites by incorporating the natural compound auraptene. Combination treatments of tamoxifen derivatives and auraptene successfully sensitized the chemoresistant MCF-7Var E. Our data suggest a dual regulation of eIF4A and ER by auraptene. Joint treatments of 4-OH Tam and endoxifen with auraptene identified a novel focus for chemoresistance disruption. Synergy was observed using the auraptene molecule and tamoxifen-derived metabolites, which induced a sensitization in MCF-7Var E cells and ERα parental cells that was not observed in triple-negative breast cancer cells (TNBC). Our results suggest a synergistic effect between auraptene and tamoxifen metabolites in a resistant ER+ breast cancer model, which could represent the first step to achieving a pharmacologic strategy.

The natural product auraptene can influence tumor cell proliferation and invasion, but its effect on hepatocellular carcinoma (HCC) cells is unknown. Here, we report that auraptene can exert anti-tumor effects in HCC cells via inhibition of cell proliferation and ferroptosis induction. Auraptene treatment induces total ROS and lipid ROS production in HCC cells to initiate ferroptosis. The cell death or cell growth inhibition of HCC cells induced by auraptene can be eliminated by the ROS scavenger NAC or GSH and ferroptosis inhibitor ferrostatin-1 or Deferoxamine Mesylate (DFO). Mechanistically, the key ferroptosis defense protein SLC7A11 is targeted for ubiquitin–proteasomal degradation by auraptene, resulting in ferroptosis of HCC cells. Importantly, low doses of auraptene can sensitize HCC cells to ferroptosis induced by RSL3 and cystine deprivation. These findings demonstrate a critical mechanism by which auraptene exhibits anti-HCC effects via ferroptosis induction and provides a possible therapeutic strategy for HCC by using auraptene or in combination with other ferroptosis inducers.

Citrus hassaku extract reportedly activates AMPK. Because this extract contains an abundance of auraptene, we investigated whether pure auraptene activates AMPK and inhibits proliferation using prostate cancer cell lines. Indeed, auraptene inhibited the proliferation and migration of LNCaP cells and induced phosphorylation of AMPK or its downstream ACC in LNCaP, PC3, and HEK-293 cells, but not in DU145 cells not expressing LKB1. In addition, the mTOR-S6K pathway, located downstream from activated AMPK, was also markedly suppressed by auraptene treatment. Importantly, it was shown that auraptene reduced androgen receptor (AR) and prostate-specific antigen (PSA) expressions at both the protein and the mRNA level. This auraptene-induced downregulation of PSA was partially but significantly reversed by treatment with AMPK siRNA or the AMPK inhibitor compound C, suggesting AMPK activation to, at least partially, be causative. Finally, in DU145 cells lacking the LKB1 gene, exogenously induced LKB1 expression restored AMPK phosphorylation by auraptene, indicating the essential role of LKB1. In summary, auraptene is a potent AMPK activator that acts by elevating the AMP/ATP ratio, thereby potentially suppressing prostate cancer progression, via at least three molecular mechanisms, including suppression of the mTOR-S6K pathway, reduced lipid synthesis, and AR downregulation caused by AMPK activation. [ABSTRACT FROM AUTHOR]

AbstractObjectiveMethodsResultsConclusionDespite significant advances that have been made in the treatment of traumatic brain injury (TBI), it remains a global health issue. This study aimed to investigate the synergistic effects of 17-β estradiol (E2) and auraptene (AUR) on TBI treatment.In total, 70 adult male Wistar rats were divided randomly into ten main groups: Sham, TBI, TBI + DMSO, TBI + AUR (4 mg/kg), TBI + AUR (8 mg/kg), TBI + AUR (25 mg/kg), TBI + E2 group, TBI + AUR (4 mg/kg) + E2 group, TBI + AUR (8 mg/kg) + E2 group and TBI + AUR (25 mg/kg) + E2 group. Diffuse TBI was caused by the Marmarou process in male rats. The brain’s tissues were harvested to check the parameters of oxidative stress and levels of inflammatory cytokine.The finding revealed that TBI induced a significant increase in brain edema, pro-inflammatory cytokines and oxidant levels [MDA and NO], and also a decrease in the brain’s antioxidant biomarkers [GPx, SOD]. We also found that E2 and AUR (25 mg/kg) significantly preserved the levels of these biomarkers. The combination of AUR concentrations and E2 showed that this treatment efficiently preserved the levels of these biomarkers. Furthermore, the combination of E2 and AUR (25 mg/kg) c could cause the most effective synergistic interaction.AUR could act synergistically with E2 to treat brain injury complications. [ABSTRACT FROM AUTHOR]

Phytochemical profiling followed by antimicrobial and anthelmintic activity evaluation of the Australian plant Geijera parviflora, known for its customary use in Indigenous Australian ceremonies and bush medicine, was performed. In the present study, seven previously reported compounds were isolated including auraptene, 6′-dehydromarmin, geiparvarin, marmin acetonide, flindersine, and two flindersine derivatives from the bark and leaves, together with a new compound, chlorogeiparvarin, formed as an artefact during the isolation procedure and isolated as a mixture with geiparvarin. Chemical profiling allowed for a qualitative and quantitative comparison of the compounds in the leaves, bark, flowers, and fruit of this plant. Subsequently, a subset of these compounds as well as crude extracts from the plant were evaluated for their antimicrobial and anthelmintic activities. Anthelmintic activity assays showed that two of the isolated compounds, auraptene and flindersine, as well as the dichloromethane and methanol crude extracts of G. parviflora, displayed significant activity against a parasitic nematode (Haemonchus contortus). This is the first report of the anthelmintic activity associated with these compounds and indicates the importance of such fundamental explorations for the discovery of bioactive phytochemicals for therapeutic application(s).

Acute myeloid leukemia is one of the most commonly identified hematological malignancies with poor prognosis. This research was planned to identify the cytotoxic effects of Auraptene on HL60 and U937 cell lines. The cytotoxic effects of Auraptene were measured by AlamarBlue assay (Resazurin) after 24- and 48-h treatments with different doses of Auraptene. The inductive effects of Auraptene on cellular oxidative stress were investigated by determining cellular ROS levels. The cell cycle progression and cell apoptosis were also evaluated by flow cytometry method. Our findings revealed that Auraptene decreased HL60 and U937 cellular proliferation by downregulation of Cyclin D1. Auraptene also induces cellular oxidative stress by upregulation of cellular ROS levels. Auraptene induces cell cycle arrest the early and late phases of apoptosis by upregulation of Bax and p53 proteins. Our data suggest that the anti-tumor function of Auraptene can be mediated by promoting apoptosis and cell cycle arrest and inducing cellular oxidative stress in HL60 and U937 cell lines. These results support that Auraptene may be used as a potent anti-tumor agent against hematologic malignancies in the further studies. [ABSTRACT FROM AUTHOR]

Auraptene (7-geranyloxycoumarin) is the abundant prenyloxycoumarin found in the fruits of Citrus spp. Auraptene has a variety of pharmacological and therapeutic functions, such as anticancer, antioxidant, immunomodulatory, and anti-inflammation activities, with excellent safety profiles. In this study, we evaluated the anticoronaviral activity of auraptene in HCoV-OC43-infected human lung fibroblast MRC-5 cells. We found that auraptene effectively inhibited HCoV-OC43-induced cytopathic effects with 4.3 μM IC50 and 6.1 μM IC90, resulting in a selectivity index (CC50/IC50) of >3.5. Auraptene treatment also decreased viral RNA levels in HCoV-OC43-infected cells, as detected through quantitative real-time PCR, and decreased the expression level of spike proteins and nucleocapsid proteins in virus-infected cells, as detected through the Western blot analysis and immunofluorescence staining. Time-of-addition analysis showed auraptene's inhibitory effects at the post-entry stage of the virus life cycle; however, auraptene did not induce the antiviral interferon families, IFN-α1, IFN-β1, and IFN-λ1. Additionally, auraptene-treated MRC-5 cells during HCoV-OC43 infection decreased the MMP-9 mRNA levels which are usually increased due to the infection, as auraptene is a previously reported MMP-9 inhibitor. Therefore, auraptene showed antiviral activity against HCoV-OC43 infection, and we suggest that auraptene has the potential to serve as a therapeutic agent against human coronavirus. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer is the second most prevalent and the fifth deadliest cancer among men worldwide. To improve radiotherapy outcome, we investigated the effects of 7-geranyloxycoumarin, also known as auraptene (AUR), on radiation response of prostate cancer cells. Methods and results: PC3 cells were pretreated with 20 and 40 µM AUR for 24, 48 and 72 h, followed by X-ray exposure (2, 4 and 6 Gy). After 72 h recovery, cell viability was determined by alamar Blue assay. Flow cytometric analysis was performed to assess apoptosis induction, clonogenic assay was carried out to investigate clonogenic survival, and the expression of P53, BAX, BCL2, CCND1 and GATA6 was analyzed by quantitative polymerase chain reaction (qPCR). Cell viability assay indicated that toxic effects of radiation was enhanced by AUR, which was also confirmed by increased numbers of apoptotic cells and reduced amount of survival fraction. The qPCR results demonstrated significant induction of P53 and BAX, while the expression of BCL2, GATA6, and CCND1 was significantly downregulated. Conclusion: The findings of the present study indicated, for the first time, that AUR improved radio sensitivity in prostate cancer cells, and thus, has the potential to be used in future clinical trials. [ABSTRACT FROM AUTHOR]

Objectives: Auraptene is the most abundant natural prenyloxycoumarin. Recent studies have shown that it has multiple biological and therapeutic properties, including antioxidant properties. Erythrocytes are constantly subjected to oxidative damage that can affect proteins and lipids within the erythrocyte membrane and lead to some hemoglobinopathies. Due to the lack of sufficient information about the antioxidant effects of auraptene on erythrocytes, this study intended to evaluate the potential of this compound in protecting radical-induced erythrocytes damages.Methods: The antioxidant activity of auraptene was measured based on DPPH and FRAP assays. Notably, oxidative hemolysis of human erythrocytes was used as a model to study the ability of auraptene to protect biological membranes from free radical-induced damage. Also, the effects of auraptene in different concentrations (25-400 μM) on AAPHinduced lipid/protein peroxidation, glutathione (GSH) content and morphological changes of erythrocytes were determined.Results: Oxidative hemolysis and lipid/protein peroxidation of erythrocytes were significantly suppressed by auraptene in a time and concentration-dependent manner. Auraptene prevented the depletion of the cytosolic antioxidant GSH in erythrocytes. Furthermore, it inhibited lipid and protein peroxidation in a time and concentration-dependent manner. Likewise, FESEM results demonstrated that auraptene reduced AAPH-induced morphological changes in erythrocytes.Conclusion: Auraptene efficiently protects human erythrocytes against free radicals. Therefore, it can be a potent candidate for treating oxidative stress-related diseases.

Abstract Background Auraptene (AUR) and naringenin (NAR) are citrus-derived phytochemicals that influence several biological mechanisms associated with cognitive decline, including neuronal damage, oxidative stress and inflammation. Clinical evidence of the efficacy of a nutraceutical with the potential to enhance cognitive function in cohorts at risk of cognitive decline would be of great value from a preventive perspective. The primary aim of this study is to determine the cognitive effects of a 36-week treatment with citrus peel extract standardized in levels of AUR and NAR in older adults experiencing subjective cognitive decline (SCD). The secondary aim is to determine the effects of these phytochemicals on blood-based biomarkers indicative of neuronal damage, oxidative stress, and inflammation. Methods Eighty older persons with SCD will be recruited and randomly assigned to receive the active treatment (400 mg of citrus peel extract containing 0.1 mg of AUR and 3 mg of NAR) or the placebo at a 1:1 ratio for 36 weeks. The primary endpoint is a change in the Repeatable Battery for the Assessment of Neuropsychological Status score from baseline to weeks 18 and 36. Other cognitive outcomes will include changes in verbal and nonverbal memory, attention, executive and visuospatial functions. Blood samples will be collected from a consecutive subsample of 60 participants. The secondary endpoint is a change in interleukin-8 levels over the 36-week period. Other biological outcomes include changes in markers of neuronal damage, oxidative stress, and pro- and anti-inflammatory cytokines. Conclusion This study will evaluate whether an intervention with citrus peel extract standardized in levels of AUR and NAR has cognitive and biological effects in older adults with SCD, facilitating the establishment of nutrition intervention in people at risk of cognitive decline. Trial registration The trial is registered with the United States National Library of Medicine at the National Institutes of Health Registry of Clinical Trials under the code NCT04744922 on February 9th, 2021 ( https://www.clinicaltrials.gov/ct2/show/NCT04744922 ).

Background: Auraptene is a coumarin derivative extracted from citrus species, such as lemon, grapefruit, and orange. To date, auraptene has shown antioxidant, antibacterial, anti-inflammatory, antiproliferative, antiapoptotic, and antitumor activities. Among these, antitumor activity has become more important over the recent years, while its underlying mechanism is not fully understood. The current study was conducted to evaluate the antiproliferative effect of auraptene and its mechanisms on MCF7 cell line.Method: This experimental study investigated whether hesperidin affected the proliferation of MCF-7 human breast cancer cells. MCF7 cells were cultured in DMEM medium with 10% fetal bovine serum, 100 μg/ml streptomycin, and 100 units/ml penicillin. The cells were incubated in order to be treated with different concentrations of auraptene and time points. Subsequently, the amount of cytotoxicity and apoptosis was measured utilizing MTT and PI staining.Results: The MTT assay revealed that auraptene had a significant effect on cell viability and induced apoptosis in MCF7 cells at concentrations of 75, 100, 130, 170, and 200 μM.Conclusion: In this study, through the induction of apoptosis, auraptene prevented the growth and inhibited the proliferation of MCF7 cells at high concentrations in a dose-dependent manner. However, further investigation is needed to reveal the mechanisms of auraptene concerning apoptosis induction.

Oxyprenylated secondary metabolites of plant, fungal, and microbial origin have emerged as biologically active natural compounds with a great potential for the next future. While originally obtained from the respective sources merely by conventional techniques of the phytochemical practice like maceration, percolation, and Soxhlet extractions, during the last five years novel and alternative experimental protocols to get such chemicals in higher yields and purity degree and/or in form of enriched phytopreparations have been developed. Such new processes include ultrasounds and microwaves assisted extractions, use of auxiliary agents like deep eutectic solvents and QuEChERS, employment of novel extractive solvents like supercritical CO2 and subcritical butane, accelerated solvent extractions, and finally extractions in the heterogeneous phase using solid supports. All these new methodologies proved to be very powerful and efficient in terms of yields and selectivity in concentrating classes of secondary metabolites from the respective matrices, comparing favorably to the already and widespread "classic" extraction techniques. All the developed processes can be framed in a green chemical context stating the employment of nontoxic, non-pollutant, environmentally friend, recyclable, easy to handle and to store solvents and reagents. The aim of this review article is to make a detailed survey of these alternative extraction processes for oxyprenylated secondary metabolites providing not only the most relevant examples of the recent literature, but also concrete suggestions and addresses to accomplish future research activities in the same field. [ABSTRACT FROM AUTHOR]

A series of five naturally occurring oxyprenylated phenylpropanoids, namely, the coumarins auraptene (7-geranyloxycoumarin) 1 and 7-isopentenyloxycoumarin 2, and the coumaric acid and ferulic acid derivatives, 4'-isopentenyloxycoumaric acid 3, boropinic acid 4, and 4'-geranyloxyferulic acid 5 were tested for their effects on mitochondrial functionality using the organophosphate pesticides glyphosate and chlorpyrifos, and resveratrol, as the reference. While not showing an appreciable in vitro antioxidant activity, and virtually no or a little effect on the viability of non-cancer cell lines BEAS-2B and SHSY-5Y, all phytochemicals exhibited a marked protective effect on mitochondrial potential and activity, with values that were comparable to resveratrol. Auraptene 1 and 7-isopentenyloxycoumarin 2 were seen to be the most effective secondary metabolite to this concern, in particular in being able to completely abolish the decrease of mitochondrial potential induced by increasing concentration of both glyphosate and chlorpyrifos. All the compounds tested also exhibited a protective effect on mitochondrial activity. The potency displayed will shed more light on the molecular basis of the beneficial effects of auraptene, 7-isopentenyloxycoumarin, and structurally related oxyprenylated phenylpropanoids reported to date in the literature. [ABSTRACT FROM AUTHOR]

Decrease in quality of postovulatory aged oocytes occurs due to oxidative stress and leads to low fertilization and development competence. It is one of the main causes that exerting detrimental effect on the success rate in assisted reproductive technology (ART). Auraptene (AUR), a citrus coumarin, has been reported to possess an antioxidant effects in other tissues. In this study, we aimed to confirm the potential of AUR to delay the oocyte aging process by alleviating oxidative stress. Superovulated mouse oocytes in metaphase of second meiosis (MII) were exposed to 0, 1 or 10 μM AUR for 12 h of in vitro aging. AUR addition to the culture medium recovered abnormal spindle and chromosome morphology and mitigated mitochondrial distribution and mitochondrial membrane potential (ΔΨ) in aged oocytes. AUR-treated aged oocytes also showed suppressed oxidative stress, with lower reactive oxygen species (ROS) levels, higher glutathione (GSH) levels and increased expression of several genes involved in antioxidation. Furthermore, AUR significantly elevated the fertilization and embryo developmental rates. Oocytes aged with 1 μM AUR exhibited morphokinetics that were very similar to those of the control group. Altogether, these data allowed us to conclude that AUR improved the quality of aged oocytes and suggest AUR as an effective clinical supplement candidate to prevent postovulatory aging. [ABSTRACT FROM AUTHOR]

Aims: The association of auraptene (AUR), a 7-geranyloxycoumarin, on osteoporosis and its potential pathway was predicted by network pharmacology and confirmed in experimental osteoporotic mice. Methods: The network of AUR was constructed and a potential pathway predicted by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) terms enrichment. Female ovariectomized (OVX) Institute of Cancer Research mice were intraperitoneally injected with 0.01, 0.1, and 1 mM AUR for four weeks. The bone mineral density (BMD) level was measured by dual-energy X-ray absorptiometry. The bone microstructure was determined by histomorphological changes in the femora. In addition, biochemical analysis of the serum and assessment of the messenger RNA (mRNA) levels of osteoclastic markers were performed. Results: In total, 65.93% of the genes of the AUR network matched with osteoporosis-related genes. Osteoclast differentiation was predicted to be a potential pathway of AUR in osteoporosis. Based on the network pharmacology, the BMD and bone mineral content levels were significantly (p < 0.05) increased in the whole body, femur, tibia, and lumbar spine by AUR. AUR normalized the bone microstructure and the serum alkaline phosphatase (ALP), bone-specific alkaline phosphatase (bALP), osteocalcin, and calcium in comparison with the OVX group. In addition, AUR treatment reduced TRAP-positive osteoclasts and receptor activator of nuclear factor kappa-B ligand (RANKL)+nuclear factor of activated T cells 1 (NFATc1)+ expression in the femoral body. Moreover, the expressions of initiators for osteoclastic resorption and bone matrix degradation were significantly (p < 0.05) regulated by AUR in the lumbar spine of the osteoporotic mice. Conclusion: AUR ameliorated bone loss by downregulating the RANKL/NFATc1 pathway, resulting in improvement of osteoporosis. In conclusion, AUR might be an ameliorative cure that alleviates bone loss in osteoporosis via inhibition of osteoclastic activity. Cite this article: Bone Joint Res 2022;11(5):304–316.

Citrus hassaku extract reportedly activates AMPK. Because this extract contains an abundance of auraptene, we investigated whether pure auraptene activates AMPK and inhibits proliferation using prostate cancer cell lines. Indeed, auraptene inhibited the proliferation and migration of LNCaP cells and induced phosphorylation of AMPK or its downstream ACC in LNCaP, PC3, and HEK-293 cells, but not in DU145 cells not expressing LKB1. In addition, the mTOR-S6K pathway, located downstream from activated AMPK, was also markedly suppressed by auraptene treatment. Importantly, it was shown that auraptene reduced androgen receptor (AR) and prostate-specific antigen (PSA) expressions at both the protein and the mRNA level. This auraptene-induced downregulation of PSA was partially but significantly reversed by treatment with AMPK siRNA or the AMPK inhibitor compound C, suggesting AMPK activation to, at least partially, be causative. Finally, in DU145 cells lacking the LKB1 gene, exogenously induced LKB1 expression restored AMPK phosphorylation by auraptene, indicating the essential role of LKB1. In summary, auraptene is a potent AMPK activator that acts by elevating the AMP/ATP ratio, thereby potentially suppressing prostate cancer progression, via at least three molecular mechanisms, including suppression of the mTOR-S6K pathway, reduced lipid synthesis, and AR downregulation caused by AMPK activation.

Abstract Background Depression is one of the most common mental illnesses worldwide. Nitric oxide (NO) is involved in the pathophysiology of depression. Auraptene (a coumarin derivative) has been shown to possess pharmacological effects on neurological diseases. Purpose The present study aimed to investigate the possible role of the NO pathway in Auraptene antidepressant effects in male mice. Methods Behavioral tests were used to assess depression-like behaviors. The mice received Auraptene at 10, 30, and 100 mg/kg, the combination of the sub-effective (ineffective) dose of Auraptene (10 mg/kg) and L-NAME, and the combination of the effective dose of Auraptene (30 mg/kg) and L-arginine. Finally, OFT, TST, FST, brain, serum MDA level, antioxidant capacity, hippocampus, and serum NO level were measured. Results The data analysis showed that Auraptene (30 mg/kg) improved depression-like behaviors. Auraptene (30 mg/kg) also significantly reduced serum NO levels (P

Purpose: Auraptene (AUR) is a monoterpene coumarin compound with several biological activities specifically anti-cancer. The bioavailability of AUR in biological fluids is negligible, thus, the cytotoxicity of this compound for the target cells is low. Herein, the synthesis of AUR-coated Fe3O4 nanoparticles is presented as a strategy to increase the cytotoxicity of AUR on PC3, DU145, and LNCaP prostate cancer cells.Methods: Fe3O4 nanoparticles were synthesized via co-precipitation method, coated with AUR and stabilized by dextran. They were characterized by X-ray diffraction spectroscopy (XRD), Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), dynamic light scattering (DLS) analysis, and vibrating sample magnetometry (VSM). In vitro release test for coated nanoparticles was performed in both physiologic (pH= 7.4) and acidic (pH= 5.5) environments. Cytotoxicity for prostate cancer cells was evaluated by AlamarBlue assay and the results were analyzed by one-way and two-way ANOVA tests.Results: Characterization outcomes represented the formation of magnetic nanoparticles with good crystalline structure, relatively spherical shape and superparamagnetic properties. AUR release profile from nanoparticles demonstrated that coated nanoparticles are able to inhibit burst release of this compound. AUR release was remarkably higher in acidic medium that can be advantageous for treating tumor regions. Cytotoxicity results indicated that AUR had a very low toxicity against prostate cancer cells at the tested concentrations. In contrast, AUR-coated Fe3O4 nanoparticles were significantly cytotoxic on all the cell lines.Conclusion: The coating of AUR on the surface of Fe3O4 nanoparticles was a successful approach to enhance the efficacy and cytotoxicity of this compound.

Objective(s): In this work, we loaded Auraptene (AUR) into nanostructured lipid carriers (NLCs) and performed an assessment on inhibitory activities of the obtained AUR-NLCs on melanogenesis. Materials and Methods: AUR-NLCs were prepared through a high shear homogenization and ultrasound method. Results: Entrapment efficiency and Particle size of the optimized formulation were 103.1±4.9 nm and 89.56±3.75. The TEM outcomes exhibited the spherical shape of our nanoparticles, while the DSC analysis revealed the lack of any drug-lipid incompatibility throughout the formulations. A prolonged drug-release was observed from AUR-NLCs when compared to the AUR-solution. According to results, this product can significantly attenuated the activity of cellular tyrosinase and ROS content with minimal cytotoxic effects in B16F10 cell line, which in contrast to AUR-solution. Moreover, the western blotting analysis was indicative of AUR-NLCs ability to inhibit melanogenesis through the suppression of MITF and act much more efficiently than AUR-solution.Conclusion: AUR-NLCs can offer merits as a natural anti-tyrosinase agent for the treatment of hyperpigmentory disorders.

Background: Auraptene (AUR) and naringenin (NAR) are citrus-derived phytochemicals that influence several biological mechanisms associated with cognitive decline, including neuronal damage, oxidative stress and inflammation. Clinical evidence of the efficacy of a nutraceutical with the potential to enhance cognitive function in cohorts at risk of cognitive decline would be of great value from a preventive perspective. The primary aim of this study is to determine the cognitive effects of a 36-week treatment with citrus peel extract standardized in levels of AUR and NAR in older adults experiencing subjective cognitive decline (SCD). The secondary aim is to determine the effects of these phytochemicals on blood-based biomarkers indicative of neuronal damage, oxidative stress, and inflammation.Methods: Eighty older persons with SCD will be recruited and randomly assigned to receive the active treatment (400 mg of citrus peel extract containing 0.1 mg of AUR and 3 mg of NAR) or the placebo at a 1:1 ratio for 36 weeks. The primary endpoint is a change in the Repeatable Battery for the Assessment of Neuropsychological Status score from baseline to weeks 18 and 36. Other cognitive outcomes will include changes in verbal and nonverbal memory, attention, executive and visuospatial functions. Blood samples will be collected from a consecutive subsample of 60 participants. The secondary endpoint is a change in interleukin-8 levels over the 36-week period. Other biological outcomes include changes in markers of neuronal damage, oxidative stress, and pro- and anti-inflammatory cytokines.Conclusion: This study will evaluate whether an intervention with citrus peel extract standardized in levels of AUR and NAR has cognitive and biological effects in older adults with SCD, facilitating the establishment of nutrition intervention in people at risk of cognitive decline.Trial Registration: The trial is registered with the United States National Library of Medicine at the National Institutes of Health Registry of Clinical Trials under the code NCT04744922 on February 9th, 2021 ( https://www.Clinicaltrials: gov/ct2/show/NCT04744922 ). [ABSTRACT FROM AUTHOR]

Auraptene (7-geranyloxycoumarin) is the abundant prenyloxycoumarin found in the fruits of Citrus spp. Auraptene has a variety of pharmacological and therapeutic functions, such as anticancer, antioxidant, immunomodulatory, and anti-inflammation activities, with excellent safety profiles. In this study, we evaluated the anticoronaviral activity of auraptene in HCoV-OC43-infected human lung fibroblast MRC-5 cells. We found that auraptene effectively inhibited HCoV-OC43-induced cytopathic effects with 4.3 μM IC50 and 6.1 μM IC90, resulting in a selectivity index (CC50/IC50) of >3.5. Auraptene treatment also decreased viral RNA levels in HCoV-OC43-infected cells, as detected through quantitative real-time PCR, and decreased the expression level of spike proteins and nucleocapsid proteins in virus-infected cells, as detected through the Western blot analysis and immunofluorescence staining. Time-of-addition analysis showed auraptene’s inhibitory effects at the post-entry stage of the virus life cycle; however, auraptene did not induce the antiviral interferon families, IFN-α1, IFN-β1, and IFN-λ1. Additionally, auraptene-treated MRC-5 cells during HCoV-OC43 infection decreased the MMP-9 mRNA levels which are usually increased due to the infection, as auraptene is a previously reported MMP-9 inhibitor. Therefore, auraptene showed antiviral activity against HCoV-OC43 infection, and we suggest that auraptene has the potential to serve as a therapeutic agent against human coronavirus.

Dyslipidemia is described as a hallmark of metabolic syndrome, promoting a stage of metabolic inflammation (metainflammation) that could lead to misbalances in energetic metabolism, contributing to insulin resistance, and modifying intracellular cholesterol pathways and the renin–angiotensin system (RAS) in pancreatic islets. Low-density lipoprotein (LDL) hypercholesterolemia could disrupt the tissue communication between Langerhans β-cells and hepatocytes, wherein extracellular vesicles (EVs) are secreted by β-cells, and exposition to LDL can impair these phenomena. β-cells activate compensatory mechanisms to maintain insulin and metabolic homeostasis; therefore, the work aimed to characterize the impact of LDL on β-cell cholesterol metabolism and the implication on insulin secretion, connected with the regulation of cellular communication mediated by EVs on hepatocytes. Our results suggest that β-cells can endocytose LDL, promoting an increase in de novo cholesterol synthesis targets. Notably, LDL treatment increased mRNA levels and insulin secretion; this hyperinsulinism condition was associated with the transcription factor PDX-1. However, a compensatory response that maintains basal levels of intracellular calcium was described, mediated by the overexpression of calcium targets PMCA1/4, SERCA2, and NCX1, together with the upregulation of the unfolded protein response (UPR) through the activation of IRE1 and PERK arms to maintain protein homeostasis. The LDL treatment induced metainflammation by IL-6, NF-κB, and COX-2 overexpression. Furthermore, LDL endocytosis triggered an imbalance of the RAS components. LDL treatment increased the intracellular levels of cholesterol on lipid droplets; the adaptive β-cell response was portrayed by the overexpression of cholesterol transporters ABCA1 and ABCG1. Therefore, lipotoxicity and hyperinsulinism induced by LDL were regulated by the natural compound auraptene, a geranyloxyn coumarin modulator of cholesterol-esterification by ACAT1 enzyme inhibition. EVs isolated from β-cells impaired insulin signaling via mTOR/p70S6Kα in hepatocytes, a phenomenon regulated by auraptene. Our results show that LDL overload plays a novel role in hyperinsulinism, mechanisms associated with a dysregulation of intracellular cholesterol, lipotoxicity, and the adaptive UPR, which may be regulated by coumarin-auraptene; these conditions explain the affectations that occur during the initial stages of insulin resistance. [ABSTRACT FROM AUTHOR]

Background: Auraptene is a coumarin derivative extracted from citrus species, such as lemon, grapefruit, and orange. To date, auraptene has shown antioxidant, antibacterial, anti-inflammatory, antiproliferative, antiapoptotic, and antitumor activities. Among these, antitumor activity has become more important over the recent years, while its underlying mechanism is not fully understood. The current study was conducted to evaluate the antiproliferative effect of auraptene and its mechanisms on MCF7 cell line. Method: This experimental study investigated whether hesperidin affected the proliferation of MCF-7 human breast cancer cells. MCF7 cells were cultured in DMEM medium with 10% fetal bovine serum, 100 µg/ml streptomycin, and 100 units/ml penicillin. The cells were incubated in order to be treated with different concentrations of auraptene and time points. Subsequently, the amount of cytotoxicity and apoptosis was measured utilizing MTT and PI staining. Results: The MTT assay revealed that auraptene had a significant effect on cell viability and induced apoptosis in MCF7 cells at concentrations of 75, 100, 130, 170, and 200 µM. Conclusion: In this study, through the induction of apoptosis, auraptene prevented the growth and inhibited the proliferation of MCF7 cells at high concentrations in a dose-dependent manner. However, further investigation is needed to reveal the mechanisms of auraptene concerning apoptosis induction. [ABSTRACT FROM AUTHOR]

• LPS combined with uCMS exacerbated depression-like behaviors and inflammatory challenges. • Auraptene ameliorate the behavioral phenotype of mice induced by intermittent LPS injection combined with uCMS. • Auraptene can balance the expression of hippocampal inflammatory cytokines via the polarization phenotype transition from M1 to M2 in the microglia. An inflammatory response is one of the pathogeneses of depression. The anti-inflammatory and neuroprotective effects of auraptene have previously been confirmed. We established an inflammatory depression model by lipopolysaccharide (LPS) injection combined with unpredictable chronic mild stress (uCMS), aiming to explore the effects of auraptene on depressive-like behaviors in adult mice. Mice were divided into a control group, vehicle group, fluoxetine group, celecoxib group, and auraptene group. Then, behavioral tests were conducted to evaluate the effectiveness of auraptene in ameliorating depressive-like behavior. Cyclooxygenase-2 (COX-2), C-reactive protein (CRP), tumor necrosis factor (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) were examined by ELISA. Interleukin-10 (IL-10), interleukin-4 (IL-4), and transforming growth factor-β (TGF-β) were examined by protein chip technology. The morphology of microglia was observed by the immunohistochemical method. The data showed that, compared with the control group, the vehicle group mice exhibited a depressive-like behavioral phenotype, accompanied by an imbalance in inflammatory cytokines and the activation of microglia in the hippocampus. The depressive behaviors of the auraptene group's mice were significantly alleviated, along with the decrease in pro-inflammatory factors and increase in anti-inflammatory factors, while the activation of microglia was inhibited in the hippocampus. Subsequently, we investigated the role of auraptene in vitro-cultured BV-2 cells treated with LPS. The analysis showed that auraptene downregulated the expression of IL-6, TNF-α, and NO, and diminished the ratio of CD86/CD206. The results showed that auraptene reduced the excessive phagocytosis and ROS production of LPS-induced BV2 cells. In conclusion, auraptene relieved depressive-like behaviors in mice probably via modulating hippocampal neuroinflammation mediated by microglia. [ABSTRACT FROM AUTHOR]

• The binding ability of auraptene (AUR) with DNA has been evaluated for the first time. • The moderate fluorescence enhancement observed upon binding of AUR to DNA Fluorescence dynamic activation mechanism was prominent in AUR-DNA interaction. • Auraptene spontaneously binds to the minor groove of DNA. • Docking studies indicated that AUR fits into the minor groove via dodecamer base pairs. In this study, various spectroscopic methods, including UV-Vis spectrophotometry, fluorescence (competitive and non-competitive studies and binding thermodynamic parameters determine) and Fourier transform infrared (FT-IR) spectroscopies, viscometry, and molecular docking simulation, have been used to study the interaction of the bioactive 7-geranyloxycoumarin, auraptene (AUR), with calf thymus DNA (CT-DNA) as a model. According to the data, the AUR-CT-DNA association constant (K b) is around 7.3×104 M−1, which is appropriate for the groove binding mode. Fluorescence experiments showed that the AUR-CT-DNA complex formation process has a dynamic fluorescence-enhancing mechanism. The observed thermodynamic values imply that a crucial part of the binding reaction between AUR and CT-DNA is played by hydrogen bonds. Additionally, a competitive MB binding experiment using fluorescence spectroscopy demonstrated that AUR binds to CT-DNA in a non-intercalative manner. Additionally, FT-IR investigations revealed that AUR attaches to backbone sugar molecules in a minor groove. Following the interaction of AUR with CT-DNA, minor alterations were noted based on viscosity measurement. According to experimental and molecular docking data, AUR is a powerful ligand with a high affinity for the minor groove of CT-DNA. [ABSTRACT FROM AUTHOR]

Auraptene and umbelliprenin are among the most abundant naturally occurring prenyloxy umbelliferone derivatives. Both have been mainly isolated from plants belonging to numerous genera of the Rutaceae (in particular auraptene in Citrus spp.) and Apiaceae (in particular umbelliprenin in Ferula spp.) families, comprising different and widely used medicinal plants and in general plants having beneficial effects to human welfare as well as edible fruits and vegetables. Although known for quite a long time (nearly a century for auraptene and 50 years for umbelliprenin), only in the last two decades the two title natural compounds were revealed to possess valuable and promising pharmacological properties as dietary feeding active cancer chemopreventive, anti-bacterial, anti-protozoal, anti-fungal, anti-inflammatory, neuroprotective, and anti-oxidant agents among the activities best detailed in the recent literature. The aim of this comprehensive review is to outline in detail the effects described in the very last years for auraptene and umbelliprenin and what has been reported about the mechanisms of action underlying the observed pharmacological activities of these oxyprenylated secondary metabolites. In view of the herein described data suggestions on how to address the future research about both natural products in the best ways according to Authors will be also provided. [ABSTRACT FROM AUTHOR]

Angiogenesis is the most important challenge in breast cancer treatment. Recently, scientists become interesting in rare natural products and intensive researches was performed to identify their pharmacological profile. Auraptene shows helpful effects such as cancer chemo-preventive, anti-inflammatory, anti-oxidant, immuno-modulatory. In this regard, we investigated the anti-angiogenesis effect of Auraptene in in-vitro and in-vivo model of breast cancer. In this study, 4T, MDA-MB-231 and HUVEC cell lines were used. The proliferation study was done by MTT assay. For tube formation assay, 250 matrigel, 1 × 104 HUVEC treated with Auraptene, 20 ng/mL EGF, 20 ng/mL bFGF and 20 ng/mL VEGF were used. Gene expression of important gene related to angiogenesis in animal model of breast cancer was investigated by Real-time PCR. Protein expression of VCAM-1 and TNFR-1 gene related to angiogenesis in animal model of breast cancer was investigated by western-blot. Auraptene treatment led to reduction in cell viability of MDA-MB-231 in a concentration-dependent manner. Also, we observed change in the number of tubes or branches formed by cells incubated with 40 and 80 μM Auraptene. Auraptene effect the gene expression of important gene related to angiogenesis (VEGF, VEGFR2, COX2, IFNɣ). Moreover, the western blot data exhibited that Auraptene effect the protein expression of VCAM-1 and TNFR-1. Overall, this study shows that Auraptene significantly suppressed angiogenesis via down-regulation of VEGF, VEGFR2, VCAM-1, TNFR-1, COX-2 and up-regulation of IFNγ. [ABSTRACT FROM AUTHOR]

Farnesoid X receptor (FXR) has been considered as a promising target for nonalcoholic steatohepatitis (NASH), while existing FXR agonists suffer from serious side effects. Thus, it is very necessary to identify novel FXR agonists with good safety. Auraptene (AUR) is a new FXR agonist with excellent safety and extensive pharmacological activities, while the lactone of AUR is vulnerable to esterolysis. In this study, the lactone of AUR was converted to metabolically stable amide moiety, and the obtained analog SU5 revealed comparable activity and better metabolic stability than that of AUR. In NASH model, SU5 showed stronger efficacy than AUR on fatty liver by upregulating gene expressions related to FXR in vivo. Moreover, SU5 improved lipid metabolism by downregulating the gene expressions of lipid synthesis, while upregulating the gene expressions of fatty acid β‐oxidation and triglyceride metabolism. Besides, the inflammation‐related genes were significantly decreased in SU5‐treated group. These positive results highlighted the pharmacological potential of SU5 for the treatment of NASH. [ABSTRACT FROM AUTHOR]

Background: Depression is one of the most common mental illnesses worldwide. Nitric oxide (NO) is involved in the pathophysiology of depression. Auraptene (a coumarin derivative) has been shown to possess pharmacological effects on neurological diseases. Purpose: The present study aimed to investigate the possible role of the NO pathway in Auraptene antidepressant effects in male mice. Methods: Behavioral tests were used to assess depression-like behaviors. The mice received Auraptene at 10, 30, and 100 mg/kg, the combination of the sub-effective (ineffective) dose of Auraptene (10 mg/kg) and L-NAME, and the combination of the effective dose of Auraptene (30 mg/kg) and L-arginine. Finally, OFT, TST, FST, brain, serum MDA level, antioxidant capacity, hippocampus, and serum NO level were measured. Results: The data analysis showed that Auraptene (30 mg/kg) improved depression-like behaviors. Auraptene (30 mg/kg) also significantly reduced serum NO levels (P < 0.05) and significantly increased serum MDA (10 mg/kg, P < 0.05). Auraptene at 30 mg/kg also increased serum antioxidant capacity (P < 0.01). Co-administration of L-NAME and the sub-effective dose of Auraptene enhanced the effects of Auraptene. However, co-administration of the effective dose of Auraptene and L-arginine reduced the impacts of Auraptene. Conclusions: The results showed that Auraptene causes antidepressant effects in a dose-dependent manner and acts as a prooxidant at 100 mg/kg, and exacerbates oxidative stress. The antidepressant effects of this active molecule are exerted by reducing the NO level in the hippocampus and serum, increasing the antioxidant capacity, and reducing the MDA level in the serum. [ABSTRACT FROM AUTHOR]

Objective(s): Auraptene (AUR) is a monoterpene coumarin compound with several biological activities specifically anti-cancer. The bioavailability of AUR in biological fluids is negligible, thus, the cytotoxicity of this compound for the target cells is low. Herein, the synthesis of AUR-coated Fe3O4 nanoparticles is presented as a strategy to increase the cytotoxicity of AUR on PC3, DU145, and LNCaP prostate cancer cells. Materials and Methods: Fe3O4 nanoparticles were synthesized via co-precipitation method, coated with AUR and stabilized by dextran. They were characterized by X-ray diffraction spectroscopy (XRD), Fouriertransform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), dynamic light scattering (DLS) analysis, and vibrating sample magnetometry (VSM). In vitro release test for coated nanoparticles was performed in both physiologic (pH= 7.4) and acidic (pH= 5.5) environments. Cytotoxicity for prostate cancer cells was evaluated by AlamarBlue assay and the results were analyzed by one-way and two-way ANOVA tests. Results: Characterization outcomes represented the formation of magnetic nanoparticles with good crystalline structure, relatively spherical shape and superparamagnetic properties. AUR release profile from nanoparticles demonstrated that coated nanoparticles are able to inhibit burst release of this compound. AUR release was remarkably higher in acidic medium that can be advantageous for treating tumor regions. Cytotoxicity results indicated that AUR had a very low toxicity against prostate cancer cells at the tested concentrations. In contrast, AUR-coated Fe3O4 nanoparticles were significantly cytotoxic on all the cell lines. Conclusion: The coating of AUR on the surface of Fe3O4 nanoparticles was a successful approach to enhance the efficacy and cytotoxicity of this compound. [ABSTRACT FROM AUTHOR]

Objective(s): In this work, we loaded Auraptene (AUR) into nanostructured lipid carriers (NLCs) and performed an assessment on inhibitory activities of the obtained AUR-NLCs on melanogenesis. Materials and Methods: AUR-NLCs were prepared through a high shear homogenization and ultrasound method. Results: Entrapment efficiency and Particle size of the optimized formulation were 103.1±4.9 nm and 89.56±3.75. The TEM outcomes exhibited the spherical shape of our nanoparticles, while the DSC analysis revealed the lack of any drug-lipid incompatibility throughout the formulations. A prolonged drug-release was observed from AUR-NLCs when compared to the AUR-solution. According to results, this product can significantly attenuated the activity of cellular tyrosinase and ROS content with minimal cytotoxic effects in B16F10 cell line, which in contrast to AUR-solution. Moreover, the western blotting analysis was indicative of AUR-NLCs ability to inhibit melanogenesis through the suppression of MITF and act much more efficiently than AUR-solution. Conclusion: AUR-NLCs can offer merits as a natural anti-tyrosinase agent for the treatment of hyperpigmentory disorders. [ABSTRACT FROM AUTHOR]

Cervical cancer is characterized by the cellular transformation caused by Human Papillomavirus (HPV), favoring cell proliferation, migration, invasion, and metastasis. Cervical cancer is conventionally treated with radiation therapy, and chemotherapy focused on the destruction of tumor cells. However, chemoresistance and low selectivity between tumor and non-tumor cells have been reported, causing side effects in patients. Metabolites of natural origin have shown selectivity against tumor cells, suggesting their use for reducing the side effects caused by drugs used in conventional therapy. Among these compounds, several natural coumarins stand out, such as auraptene, scopoletin, osthole, and praeruptorin, of which antiproliferative, anti-migratory, and anti-invasive activity have been reported. Auraptene, scopoletin, osthole, and praeruptorin show a cytotoxic or antiproliferative effect on cervical tumor cells, arresting the cell cycle by inducing the overexpression of negative regulators of the cell cycle, or inducing cell death by increasing the expression of pro-apoptotic proteins and decreasing that of anti-apoptotic proteins. On the other hand, auraptene, scopoletin, and praeruptorin inhibit the capacity for migration, invasion, and metastasis of cervical tumor cells, mainly by inhibiting the expression and activity of matrix metalloproteinase-2 and -9. The PI3K/Akt signal pathway appears to be central to the anti-tumor activity of the coumarins analyzed in this review. In addition, auraptene, osthole, and praeruptorin are useful in sensitizing tumor cells to radiotherapy or chemotherapeutic molecules, such as FOLFOX, cisplatin, or DOX. Coumarins offer an excellent possibility for developing new drugs as complementary medicine with an integrative approach against cervical cancer. [ABSTRACT FROM AUTHOR]

Objective(s): Despite advances in the treatment of adult T-cell leukemia/lymphoma (ATLL), the survival rate of this malignancy remains significantly low. Auraptene (AUR) is a natural coumarin with broad-spectrum anticancer activities. To introduce a more effective therapeutic strategy for ATLL, we investigated the combinatorial effects of AUR and arsenic trioxide (ATO) on MT-2 cells. Materials and Methods: The cells were treated with different concentrations of AUR for 24, 48, and 72 hr, and viability was measured by alamarBlue assay. Then, the combination of AUR (20 µg/ml) and ATO (3 µg/ml) was administrated and the cell cycle was analyzed by PI staining followed by flow cytometry analysis. In addition, the expression of NF-κB (REL-A), CD44, c-MYC, and BMI-1 was evaluated via qPCR. Results: Assessment of cell viability revealed increased toxicity of AUR and ATO when used in combination. Our findings were confirmed by accumulation of cells in the sub G1 phase of the cell cycle and significant down-regulation of NF-κB (REL-A), CD44, c-MYC, and BMI-1. Conclusion: Obtained findings suggest that combinatorial use of AUR and ATO could be considered for designing novel chemotherapy regimens for ATLL. [ABSTRACT FROM AUTHOR]

Traumatic Brain Injury (TBI) is widely acknowledged as a significant risk factor for death and disability. Our goal in this experiment was to see if Auraptene (AUR) could help rats recover from TBI-induced disability by measuring of oxidative stress parameters. Adult male Wistar rats were randomly assigned to one of six groups: sham, TBI, Vehicle (DMSO), TBI+ AUR (4 mg/kg), TBI + AUR (8 mg/kg), TBI + AUR (25 mg/kg). The animals were anesthetized. After that, diffuse TBI was done by Marmarou model in male rats. Then, the brain tissues were harvested. Some of oxidative stress parameters, and TNFα levels were evaluated. TBI-induced brain damage was significantly inhibited by AUR (25 mg/kg), as evidenced by decreased Malondialdehyde (MDA) and Nitric Oxide (NO) levels, oxidative stress inhibition and reduced levels of pro-inflammatory cytokine tumor necrosis factor (TNF-α) in the brain. This study showed that probably the AUR prevents complications of TBI through decreases in brain edema, modulating oxidative stress, and reductions in the levels of inflammatory cytokines. • Auraptene administration improved brain edema and neurologic injury after TBI. • The reduction of oxidative stress parameters was appeared by auraptene in TBI. • The increase in inflammatory cytokines level alleviated following auraptene administration post-TBI. [ABSTRACT FROM AUTHOR]

Zhiwen Cao,1 Wen Li,1 Rui Liu,1 Chenxi Li,1 Yurong Song,1 Guangzhi Liu,1 Youwen Chen,1 Cheng Lu,2 Aiping Lu,3 Yuanyan Liu1 1School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, People’s Republic of China; 2Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, People’s Republic of China; 3School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hongkong, People’s Republic of ChinaCorrespondence: Yuanyan Liu; Aiping Lu Tel +86 10 84738658Email yyliu_1980@163.com; lap64067611@126.comIntroduction: Auraptene (AUR), a natural bioactive prenyloxy coumarin, is a highly pleiotropic molecule that can bind to the MT1 receptor and can effectively reduce the proliferation and migration of breast cancer cells. Cisplatin (CDDP), as the first synthetic platinum-based anticancer drug, is widely used in the clinic due to its definite mechanism and therapeutic effect on diverse tumors. However, both of AUR and CDDP exhibit some disadvantages when used alone, including poor solubility, low bioavailability, lack of selectivity and systemic toxicity when they are used singly.Methods: Therefore, the biodegradable materials hyaluronic acid (HA) and β-cyclodextrin derivative (mono-(6-amino-mono-6-deoxy)-β-CD, CD) were employed as carriers to load AUR and CDDP to form nanogel (CDDPHA-CD@AUR) capable of dual-targeted delivery and synergistic therapy for breast cancer and cell imaging.Results: With the help of the CDDP-crosslinked CD-loaded structure, the newly synthesized nanogel exhibited excellent physiological stability and fluorescence effects. The release of AUR and CDDP was affected by the pH value, which was beneficial to the selective release in the tumor microenvironment. Cell experiments in vitro demonstrated that the nanogel could be selectively internalized by MCF-7 cells and exhibited low cytotoxicity to HK-2 cells. Antitumor experiments in vivo showed that the nanogel have better antitumor effects and lower systemic toxicity.Conclusion: Based on these, the nanogel loaded with AUR and CDDP have the potential for targeted delivery against breast cancer.Keywords: auraptene, cisplatin, cell imaging, tumor targeting, pH-responsive

A series of five naturally occurring oxyprenylated phenylpropanoids, namely, the coumarins auraptene (7-geranyloxycoumarin) 1 and 7-isopentenyloxycoumarin 2, and the coumaric acid and ferulic acid derivatives, 4’-isopentenyloxycoumaric acid 3, boropinic acid 4, and 4’-geranyloxyferulic acid 5 were tested for their effects on mitochondrial functionality using the organophosphate pesticides glyphosate and chlorpyrifos, and resveratrol, as the reference. While not showing an appreciable in vitro antioxidant activity, and virtually no or a little effect on the viability of non-cancer cell lines BEAS-2B and SHSY-5Y, all phytochemicals exhibited a marked protective effect on mitochondrial potential and activity, with values that were comparable to resveratrol. Auraptene 1 and 7-isopentenyloxycoumarin 2 were seen to be the most effective secondary metabolite to this concern, in particular in being able to completely abolish the decrease of mitochondrial potential induced by increasing concentration of both glyphosate and chlorpyrifos. All the compounds tested also exhibited a protective effect on mitochondrial activity. The potency displayed will shed more light on the molecular basis of the beneficial effects of auraptene, 7-isopentenyloxycoumarin, and structurally related oxyprenylated phenylpropanoids reported to date in the literature.

Decrease in quality of postovulatory aged oocytes occurs due to oxidative stress and leads to low fertilization and development competence. It is one of the main causes that exerting detrimental effect on the success rate in assisted reproductive technology (ART). Auraptene (AUR), a citrus coumarin, has been reported to possess an antioxidant effects in other tissues. In this study, we aimed to confirm the potential of AUR to delay the oocyte aging process by alleviating oxidative stress. Superovulated mouse oocytes in metaphase of second meiosis (MII) were exposed to 0, 1 or 10 μM AUR for 12 h of in vitro aging. AUR addition to the culture medium recovered abnormal spindle and chromosome morphology and mitigated mitochondrial distribution and mitochondrial membrane potential (ΔΨ) in aged oocytes. AUR-treated aged oocytes also showed suppressed oxidative stress, with lower reactive oxygen species (ROS) levels, higher glutathione (GSH) levels and increased expression of several genes involved in antioxidation. Furthermore, AUR significantly elevated the fertilization and embryo developmental rates. Oocytes aged with 1 μM AUR exhibited morphokinetics that were very similar to those of the control group. Altogether, these data allowed us to conclude that AUR improved the quality of aged oocytes and suggest AUR as an effective clinical supplement candidate to prevent postovulatory aging.

Aim: To evaluate the effect of auraptene (AUR) treatment in forms of free and encapsulated in niosome nanoparticles by investigating the mRNA expression level of vascular endothelium growth factor (VEGF)-A and platelet-derived growth factors (PDGFs) in human retinal pigment epithelium (RPE) cell line., Methods: Niosome nanocarriers were produced using two surfactants Span 60 and Tween 80. RPE cell line was treated with both free AUR and niosome-encapsulated. Optimum dosage of treatments was calculated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Expression of VEGF-A and PDGF-A , PDGF-B , PDGF-C , PDGF-D genes was measured after total RNA extraction and cDNA synthesis, using real-time polymerase chain reaction (RT-PCR)., Results: The highest entrapment efficiency (EE) was achieved by Span 60:cholesterol (1:1) with 64.3%. The half maximal inhibitory concentration (IC 50 ) of free and niosome-encapsulated AUR were 38.5 and 27.78 µg/mL, respectively. Release study revealed that niosomal AUR had more gradual delivery to the cells. RT-PCR results showed reduced expression levels of VEGF-A , PDGF-A , PDGF-B , PDGF-C , and PDGF-D after treatment with both free and niosomal AUR., Conclusion: Niosomal formulation of Span 60: cholesterol (1:1) is an effective drug delivery approach to transfer AUR to RPE cells. VEGF-A, PDGF-A, PDGF-B, PDGF-C, and PDGF-D are four angiogenic factors, inhibiting which by niosomal AUR may be effective in age-related macular degeneration., Competing Interests: Conflicts of Interest: Vahidi A, None; Khosravi T, None; Dastaviz F, None; Sheikh Arabi M, None; Khosravi A, None; Oladnabi M, None., (International Journal of Ophthalmology Press.)

Breast cancer is a common malignant tumor in women with limited treatment options and multiple side effects. Today, the anti-cancer properties of natural compounds have attracted widespread attention from researchers worldwide. In this study, we treated 4T1 tumor-bearing Balb/c mice with intraperitoneal injection of Auraptene, paraffin oil, and saline as two control groups. Body weight and tumor volume were measured before and after treatment. Hematoxylin and eosin (H & E) staining and immunohistochemistry of Ki-67 were used as markers of proliferation. In addition, ELISA assays were performed to assess serum IFN-γ and IL-4 levels. There was no significant change in body weight in all animal groups before and after treatment. 10 days after the last treatment, Auraptene showed its anti-cancer effect, which was confirmed by the smaller tumor volume and H & E staining. In addition, Ki-67 expression levels were significantly reduced in tumor samples from the Auraptene-treated group compared to the paraffin oil and saline-treated groups. In addition, in tumor-bearing and normal mice receiving Auraptene treatment, IL-4 serum production levels were reduced, while serum levels of IFN-γ were significantly up-regulated in tumor-bearing mice after Auraptene treatment. In the case of inhibition of tumor volume and Ki-67 proliferation markers, Auraptene can effectively inhibit tumor growth in breast cancer animal models. In addition, it might increases Th1 and CD8 + T cell responses after reducing IL-4 serum levels and IFN-γ upregulation, respectively. However, further research is needed to clarify its mechanism of action. [ABSTRACT FROM AUTHOR]