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Review ARTICLE
Pharmacological Activities of Psoralidin: A Comprehensive Review of the Molecular Mechanisms of Action
- 1Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- 2Science and Technology Application and Research Center (BITAUM), Bursa Uludag University, Bursa, Turkey
- 3Faculty of Chemistry and Chemical Technology, Al-Farabi Kazakh National University, Almaty, Kazakhstan
- 4Department of Medicinal and Aromatic Plants, University of Health Sciences, Istanbul, Turkey
- 5Department of Chemistry, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal, India
- 6Medical Ethics and Law Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- 7Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, Craiova, Romania
- 8Department of Toxicology, University of Medicine and Pharmacy of Craiova, Craiova, Romania
- 9Faculty of Allied Health Sciences, University Institute of Diet and Nutritional Sciences, The University of Lahore, Lahore, Pakistan
- 10Laboratorio de Análisis Químico, Departamento de Producción Vegetal, Facultad de Agronomía, Universidad de Concepción, Concepción, Chile
- 11Department of Botany, University of Fort Hare, Alice, South Africa
- 12Department of Nutrition and Dietetics, Faculty of Pharmacy, Centre for Healthy Living, University of Concepción, Concepción, Chile
- 13Unidad de Desarrollo Tecnológico, UDT, Universidad de Concepción, Concepción, Chile
Analysis of the most relevant studies on the pharmacological properties and molecular mechanisms of psoralidin, a bioactive compound from the seeds of Cullen corylifolium (L.) Medik. confirmed its complex therapeutic potential. In the last years, the interest of the scientific community regarding psoralidin increased, especially after the discovery of its benefits in estrogen-related diseases and as a chemopreventive agent. Growing preclinical pieces of evidence indicate that psoralidin has anticancer, antiosteoporotic, anti-inflammatory, anti-vitiligo, antibacterial, antiviral, and antidepressant-like effects. Here, we provide a comprehensive and critical review of psoralidin on its bioavailability, pharmacological activities with focus on molecular mechanisms and cell signaling pathways. In this review, we conducted literature research on the PubMed database using the following keywords: "Psoralidin" or "therapeutic effects" or "biological activity" or "Cullen corylifolium" in order to identify relevant studies regarding PSO bioavailability and mechanisms of therapeutic effects in different diseases based on preclinical, experimental studies. In the light of psoralidin beneficial actions for human health, this paper gathers complete information on its pharmacotherapeutic effects and opens new natural therapeutic perspectives in chronic diseases.
Used since ancient times in traditional medicine, Cullen corylifolium (L.) Medik. (syn. Psoralea corylifolia L.) has proven its therapeutic properties over the centuries. One of the main bioactive compounds is psoralidin (PSO), a coumestan derivative with a lot of pharmacological properties (Chopra et al., 2013). A diversity of pharmacological activities of PSO compound has been identified and described. PSO exerts therapeutic effects on cardiovascular and inflammatory diseases (Chopra et al., 2013; Yan et al., 2015).
PSO has a lot of beneficial health effects as an antibacterial against gram-negative and gram-positive germs (Borate et al., 2014), antioxidant (Xiao et al., 2010), anti-inflammatory modulating the inhibition of proinflammatory cytokines (Lee et al., 2012), antimycobacterial (Khushboo et al., 2010), antipsoriatic (Dwarampudi et al., 2012), and antidepressant (Yi et al., 2008). Besides, PSO possesses osteoblast proliferation-stimulating effects (Larsson and Fazzalari, 2014), estrogenic-like effects (Xin et al., 2019), and antitumor properties (Szliszka et al., 2011; Luo et al., 2013; Pal et al., 2017a; Badarau et al., 2019; Rusu et al., 2019). PSO is a natural phenolic coumarin in the same class with isopsoralen, psoralen, bakuchiol, bakuchalcone, flavones, and bavachinin (Zhang et al., 2016) isolated and identified from the seeds of the medicinal plant Cullen corylifolium. The plant is widely distributed in different regions of Asia, India and Europe (Zhang et al., 2019). PSO is a coumestan derivative with an isopentenyl group at the second carbon position of coumestrol (Liu et al., 2014) (Figure 1).
The insolubility of PSO in water is one of the main reason why in vivo studies are difficult to be conducted (Hao et al., 2014). However, dozens of studies have been performed (Figure 2) since 1961, when the first report of the structure of PSO was published by Khastgir (Xin et al., 2019). Initially, the studies focused on the evaluation of PSO cytotoxicity, but further in vivo showed its efficacy in preventing or reducing the progression of many pathologies.
FIGURE 2. Psoralidin citations that appear along the time from 1961 till 2019. The Pubmed database was searched by the use of "psoralidin" as a keyword. The plot shows the cumulative number of hits identified for each year after the first report of psoralidin (PSO).
The literature available in the PubMed database was researched for ethnomedicine uses, phytochemistry, pharmacological molecular mechanisms and PSO bioavailability by applying the following keywords: "Psoralea corylifolium," "Cullen corylifolium," "phytochemistry," "bioavailability," "anticancer," "Anti-osteoporosis," "Anti-inflammatory," "antibacterial," "SARS-CoV antiviral," "neuro-protective," "anti-vitiligo," "antiprotozoal," "vasodilatory," "anti-apoptotic," "antidepressant-like effects," and "mechanism of action" their titles corresponding to the medical subject (MeSH) using OR/AND conjunctions. The research focused on studies in ethnomedicine, phytochemical, preclinical and clinical reports available to understand the mechanisms of action. Searches were limited to works in extenso in English and did not include studies with homeopathic preparations.
Very few clinical studies have been found in the literature on the efficacy of PSO, so more clinical research is needed in the future. Highlighting the molecular pharmacological mechanisms of PSO is the strength of this study because it can lead to the development of useful pharmaceutical formulations in the treatment of many chronic diseases.
Bioavailability of Psoralidin
The bioavailability reflects the real available concentration at the site of drug action after absorption of these compounds from the gastrointestinal tract following oral administration of a dosage form (solution, suspension, tablet, capsule, powder, or elixir) (Chow, 2014; Salehi et al., 2019b). The percentage of a medicinal product absorbed unmodified in the systemic circulation represent the bioavailability of that product (Pandareesh et al., 2015; Salehi et al., 2020a).
PSO is an orally bioavailable natural compound. New pharmaceutical forms such as nanoencapsulation have been developed to increase the reduced bioavailability of PSO (Yi et al., 2008; Chen et al., 2017; Zhang et al., 2019). The results of Yin et al. (2016) demonstrate that nanoencapsulation of PSO (via chitosan and Eudragit S100) increased the oral delivery efficacy. By analyzing the pharmacokinetic profiles and some non-pharmacokinetic facings by the non-compartmental model of some suspensions of PSO and PSO-nanoencapsulated, it was found that the blood concentrations of the nanoencapsulated pharmaceutical forms are much higher at all moments of determination. The maximum concentration of nanoencapsulated PSO was 943 ng/ml compared to the simple PSO suspension whose concentration was 357 ng/ml, proving that nanoencapsulation favors the increased oral absorption of PSO more than conventional suspensions. Moreover, the peak time and the half-time remained the same, not being modified. The bioavailability of PSO in nanoencapsulated pharmaceutical forms was 339.02% higher compared to the control, a simple suspension with PSO. As a result, PSO pharmaceutical nanoformulations with chitosan and Eudragit S100 compounds have shown great potential for improving PSO bioavailability. It is still a need for further studies to improve the bioavailability of this promising compound.
Pharmacological Importance of Psoralidin: In Vitro and In Vivo Studies
The studies have proven that PSO has the next pharmacological properties: antidepressant (Farahani et al., 2015), modulator of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) signaling pathway (Rana et al., 2014) and it is an potential estrogen receptor modulator (Yang et al., 2019). The main therapeutic properties of PSO and its mechanisms of action are summarized in Figure 3.
FIGURE 3. Summarized scheme of the main pharmacological activities of psoralidin. ↑, increase; ↓, decrease; NF-κB, nuclear factor kappa beta; COX, cyclooxygenase; PGE2, prostaglandin E2.
In Vitro Studies
Cancer is one of the most feared diseases, and the fight against it has concentrated the efforts of thousands of medical researchers (Mishra et al., 2018; Salehi et al., 2019a). For hundreds of years, plants with anticancer effects have succeeded in improving the condition of the patients and, in some cases, to stimulate defense mechanisms of the body against certain types of cancer (Sharifi-Rad et al., 2020). It is not surprising that in recent years researchers have focused on the thesaurus of medicinal plant substances and have conducted research to identify compounds that are effective in anticancer therapies (Sani et al., 2017; Salehi et al., 2019a). PSO has been used in many in vitro models to evaluate its anticancerous effects and the underlying mechanisms (Xin et al., 2019). Determination of cytotoxicity after PSO contact with cells is done by calculating the percentage of dead cells and IC50 or the concentration of PSO that inhibited by 50% cell death (He et al., 2016).
PSO promotes cellular apoptosis and inhibits the cancer cells proliferation in prostate cancer (Szliszka et al., 2011; Das et al., 2014); breast cancer (Dwarampudi et al., 2012); liver cancer (Luo et al., 2013); colon cancer (Jin et al., 2016a); esophagal carcinoma (Jin et al., 2016b), or modulate the autophagy in the lung (Hao et al., 2014; Xin et al., 2019).
According to various studies, PSO has been recognized to inhibit forskolin-induced corticotrophin-releasing factor gene transcription (Chen et al., 2008). In a recent survey, it has shown potent in vitro activity against colon, gastric, breast and prostate cancer lines. It has been shown to exhibit a substantial effect on inhibiting protein tyrosine phosphatase 1B, a crucial metabolite involved in insulin signaling (Ren et al., 2019).
Different studies were conducted on the cytotoxicity of PSO suggested that it has shown the potential to induce cytotoxicity against breast (MCF-7) cancer, colon (HT-29), and gastric (SNU-1, SNU-16) cells. In prostate cancer cells, androgen-independent (DU-145, PC-3) androgen-dependent (LNCaP, C4-2B), the treatment with PSO also caused apoptosis. The growth of PC-3 xenograft tumor was also inhibited in nude mice by PSO (Srinivasan et al., 2010; Chiou et al., 2011; Hao et al., 2014).
Studies have been shown that PSO has a benefic role against diabetes complications, oxidative stress, obesity, osteoporosis, as well as on cell proliferation, autophagy, and apoptosis (Lim et al., 2011). PSO is implicated in the modulation of the autophagy process and inhibiting cadmium-transformed prostate epithelial cell xenograft growth thought placenta-specific 8 inhibition expression, reducing the levels nuclear factor kappa B (NF-κB) and B-cell lymphoma-2 (Bcl-2) expression and enhancing apoptotic gene expression (Pal et al., 2017a). Moreover, PSO has been found to decrease blood glucose, improve glucose tolerance and increase serum insulin levels (Seo et al., 2014).
PSO also has been found to promote the mineralization, suppress the adipocytes formation, increase the alkaline phosphatase activity, calcium nodule formation, and osteocalcin levels in bone marrow mesenchymal stem cells (BMSCs) whereas also down-regulated adipogenesis related factors. Moreover, PSO regulates the protein kinase B/glycogen synthase kinase 3β/β-catenin signaling pathway during the suppression of adipocyte differentiation (Cao et al., 2019). PSO significantly decreases cell proliferation and promotes apoptosis of Eca9706 cells in a dose-dependent manner. Moreover, it suppresses caspase-3 and NF-κB activities and also decreases the phosphatidylinositol-3-kinase (PI3K) and protein kinase B (Akt) protein expression dose-dependently (Jin et al., 2016b). Other in vitro studies on cell lines reported that PSO binds to both types of alpha and beta estrogen receptors, activating the classic estrogen receptor signaling pathway, thus explaining the effect of reducing bone loss as well as the antioxidant action (Liu et al., 2014). Furthermore, a very recent study has shown the dual beneficial antiosteoporotic effect of PSO by inhibiting adipogenesis and stimulating osteogenesis (Cao et al., 2019).
Researchers have used a mouse model of depression, and PSO has shown positive results in the forced swim test. 5-Hydroxyindole acetic acid and 5-hydroxytryptamine levels were significantly increased in the brain after PSO treatment, along with the changes in dopamine levels. Serum corticosterone, adrenal corticotropin-releasing hormone and corticotropin-releasing factor, hormones involved in stress control in mice, were reduced by PSO (Yi et al., 2008).
In Vivo Studies
According to the animal studies carried out in till now, PSO has shown a variety of biological activities including antidepressant (Yi et al., 2008), anti-inflammatory (Yang et al., 2011), anti-osteoclastogenic (Kong et al., 2017), and anti-osteoporotic (Zhai et al., 2018) (Table 1).
TABLE 1. The most relevant information, including the preclinical pharmacological activities and mechanism of action of PSO.
Yi et al. (2008) investigated the effect of PSO against depression in male mice. In this study, the forced swimming test was used to screen the antidepressant effect of PSO. PSO in doses 20, 40, and 60 mg/kg was administered to mice using as vehicle water 15 ml/kg by gastric gavage. The results revealed that administration of PSO significantly decreased immobility time and increased swimming behavior without altering climbing behavior in the mouse forced swimming test. Locomotor activity studied by the open-field test was not affected by PSO.
Moreover, the levels of monoamine neurotransmitters involved in the pathophysiology of depression as 5-hydroxytryptamine and 5-hydroxyindoleacetic acid (5-HIAA, the main metabolite of serotonin) increased significantly in various brain regions after PSO treatment. In mice exposed to forced swimming test, striatum dopamine levels were also changed. In mice, PSO also suppressed the increased level of serum corticotropin-releasing factor, adrenal corticotropin-releasing hormone and corticosterone concentrations induced by swimming stress. Overall, the results obtained in this study suggested that PSO antidepressant properties are mediated via the hypothalamic-pituitary-adrenal axis and monoamine neurotransmitter systems (Yi et al., 2008).
Inflammation acts as a significant limiting factor in the radiotherapy (Buga et al., 2019). In a study carried out a few years ago (Yang et al., 2011), the PSO (5 mg/kg) anti-inflammatory effect was investigated in IR-irradiated mouse lung (20 Gy at a dose rate of 0.81 Gy/min, for 12 h or 1 week). Twelve hours after treatment, PSO suppressed the radiation-increased mRNA levels of TNF-α, TGF-β, and ICAM-1 by half, and inhibited IL-6 and IL-1 α/β by one quarter. The PSO inhibitory effects were found to be more effective 1 week after irradiation. In conclusion, data obtained in this study suggested that PSO may regulate the inflammation process in the ionizing radiation-irradiated lung (Yang et al., 2011).
Regarding the osteoporosis, it occurs primarily in women with premature menopause, due to estrogen hormone deficiency (Salehi et al., 2020b). In the absence of this hormone, disorders occur in the assimilation and fixation of calcium which leads to weakening of the bones over time (Larsson and Fazzalari, 2014). Hormone replacement therapy has minimal indications due to severe side effects (thromboembolism, stroke, endometrial cancer, breast cancer, and cardiovascular disease) (Tsatsakis et al., 2019). Therefore, research has focused on finding natural estrogen analogues with more excellent therapeutic safety (He et al., 2017).
The similar structure of PSO with coumestrol, a phytoestrogen, allows PSO to bind efficiently to estrogen receptors. In vivo studies performed in ovariectomized rats showed that PSO could inhibit bone resorption of osteoclasts and stimulate the bone formation (Zhai et al., 2017).
In another study performed by Kong et al. (2017), the impact of PSO on osteoclastogenesis and bone loss was investigated in mice. A low (5 mg/kg) and high dose (50 mg/kg) PSO was administered orally before LPS injection (5 mg/kg) and then every other seven days. The femurs of mice were collected on day 10. The results showed that PSO treatment inhibited LPS-induced bone loss and osteoclastogenesis formation and markedly down-regulated inflammatory cytokines (TNF-α, IL-1β, and IL-6) expression.
In a similar study performed by Zhai et al. (2018), osteotropic activities of PSO from Cullen corylifolium and coumestrol from Medicago sativa L. were studied. PSO and coumestrol (at doses of 10 mg/kg body weight/day each) were administered to ovariectomized rats, and after 12 weeks of intervention, samples were collected. Both PSO and coumestrol suppressed ovariectomized bone loss in vivo. It was demonstrated that PSO suppresses bone loss and have better osteoprotective effects than coumestrol.
Clinical Studies
Regarding human clinical trials with PSO, there is a scarcity. There are only a few that have included a reduced number of patients with dermatological conditions such as acne and vitiligo.
A small clinical study included 76 adolescent and young patients diagnosed with grade II and III acne vulgaris, who received double medication for 1 month: oral tablets that had as active principle PSO from Cullen corylifolium and topical cream Clarine with antimicrobial, anti-inflammatory, healing, antioxidant, astringent, and emollient properties. The results showed that patients with grade II acne had an excellent response (56.3% of cases) and good response (43.8% of cases). Patients with grade III acne had a good response (only 38.3% of cases) and a good response in (56.7% of cases). Thus, the combination of the oral and topical preparations had a synergistic, beneficial anti-acne effect (Gopal et al., 2001; Khushboo et al., 2009).
In another study, the combination of PSO with trioxalene (a chemical derivative) and the exposure to solar ultraviolet is an effective psoriasis treatment. Another clinical study included 30 patients with lip vitiligo who topically applied an ointment with Cullen corylifolium as the main ingredient. Patients with mild forms of vitiligo showed maximum improvement in 1–10 months, while chronic cases with lip vitiligo showed an inadequate response. Exposure of the patient to sunlight (5–30 min daily) with oral administration of this for 1–7 weeks gave improved the beneficial effects (Sharma et al., 2005). Possible mechanism of action: PSO interacts with ultraviolet in the epidermis forming photosensitive fragments of DNA. The maximum activity is at a wavelength of 325 nm having as effects: 1) slowing down the proliferation of keratinocytes; 2) suppression of the immune skin reaction; and 3) affects melanocytes, fibroblasts, and endothelial cells (Chopra et al., 2013).
Although there are many treatments for vitiligo, none work unanimously for all patients. Patients with vitiligo have areas with completely pigment-free skin. PUVA phototherapy (PSO + UVA) has proven to be effective over time, but narrow-band UVB therapy is gaining ground as a safe and effective therapeutic option. A recent study aimed to statistically compare the effectiveness of PUVA and nb-UVB treatments (type B ultraviolet, narrow-band). A group of 69 vitiligo patients who were treated with PUVA or nb-UVB were retrospectively analyzed. The two groups of patients were compared regarding the stage of repigmentation, the number of treatments until complete repigmentation, the appearance of newly affected areas or the increase in the size of existing ones, adverse effects of therapy, stability of repigmentation, and matching of pigment color. It has been shown that in the group treated with PUVA (31 patients), nine showed complete repigmentation (23.6%) and 14 a moderate improvement (36.8%), while in the group of those treated with nb-UVB (31 patients), 13 showed complete repigmentation (41.9%), and a moderate improvement (32.2%). Increased stability of repigmentation and better matching of pigment color to the nb-UVB-treated group was observed. The conclusions of the study were that nb-UVB is a more effective therapeutic method and the repigmentation induced by nb-UVB is statistically more stable (Parsad et al., 2006).
The strong point of this study was that many systematic reviews were included that highlighted the mechanisms of PSO pharmacological activities in many chronic diseases. Thus, the article provides an up-to-date overview of the potential therapeutic applications of this natural compound.
Although, this study presented the beneficial pharmacological activities of PSO for human health, but the main clinical therapeutic limitation derives from low absorption. Several methods have been tried to improve PSO absorption, of which prenylation has been shown to be the most effective, as prenylated metabolite it has to be more bioavailable, increasing estrogenic activity and thus improving the anti-osteoporotic effects (Kretzschmar et al., 2010; Mukai et al., 2013) and antioxidant (Li et al., 2014).
Psoralidin is a prenylated coumestans derivative, with multiple therapeutic effects proven in preclinical studies, of which the most important and with the greatest clinical applicability as adjuvant therapies are: antiosteoporotic and anticancer.
Osteoporosis is a condition that manifests itself by decreased bone mass and damage to bone tissue. Thus, even bone fractures can occur as a result of minor traumas, the most affected being the spine, hip, forearm, ribs and hand joint (Salehi et al., 2020b). PSO has osteoprotective effects, promotes osteogenic differentiation, mineralization of osteoblasts, inhibits bone resorption by reducing osteoclast differentiation.
Cancer is a malignant tumor (Zlatian et al., 2015). Tumors appear when cells start to proliferate uncontrollably and can be benign or malignant (Elsebai et al., 2016). Unlike benign tumors, malignant tumors can differentiate (and lose their normal function), having the ability to invade neighboring tissues and to metastasize, that means to form tumors secondary to other parts of the body than the site of origin (Buga et al., 2019).
Carcinogenesis is a multi-stage and multi-factorial process during which profound changes occur, allowing cells to proliferate uncontrollably and ultimately invading other tissues. This process can be described in three major stages: initiation, promotion, and tumor progression. The results of our study showed that PSO could reduce the proliferation of malignant cells and stimulate apoptosis, thus being a potential adjunct in anticancer treatment.
Viral infections play an important role in human disease, and the recent COVID-19 pandemic in the emergence of globalization and ease of travel have highlighted their prevention as a critical issue in protecting public health (Alam Riaz et al., 2020; Docea et al., 2020; Goumenou et al., 2020; Tsatsakis et al., 2020). Despite advances in immunization and drug development, many viruses lack preventive vaccines and effective antiviral therapies, which are often caused by the generation of viral escape mutants (Calina et al., 2020a; Calina et al., 2020b). Thus, the identification of new antiviral alternative treatments is of critical importance, and bioactive natural compounds are an excellent source for such discoveries (Sarkar et al., 2020). In a recent study, it was shown that ethanolic extract from P. corylifolia seeds has good activity against papain-like protease (PLpro), an essential enzyme involved in SARS-CoV replication. The bioassay-guided fractionation of this extract identified six polyphenolic compounds as the bioactive compounds responsible for action against SARS-CoV PLpro. Of these, the most potent compounds that inhibited SARS-CoV PLpro were PSO and isobavachalcone (with IC50 ranging from 4.2 to 38.4 μM). The anti-SARS-CoV-2 mechanism is a type I, whereby PSO binds selectively to the free enzyme and not to the enzyme substrate. Based on these preliminary results it can be considered PSO as being one of the natural compound as potential agents against coronaviruses (Kim et al., 2014; Mani et al., 2020).
Although promising preclinical pharmacological studies have highlighted the mechanisms underlying PSO use as adjunctive therapy, long-term toxicity studies and data on possible interactions with other drugs are required. Besides, additional clinical trials are needed to confirm the clinical utility in medical practice.
The numerous bioactivities of PSO are summarized in this review outlining research approaches focusing on pharmacological activities and clinical trials. PSO has been proved to be a therapeutic option for cancer treatment. Based on this extensive research, we also suggest that PSO has potential as an antidepressant, anti-inflammatory, anti-osteoclastogenic, anti-osteoporotic and also bring beneficial effects in estrogen-related diseases. Regarding the bioavailability, we describe PSO as a non-toxic but low oral bioavailability compound; thus, new and further researches regarding the bioavailability of PSO as well as studies on pharmacokinetic are still required to improve the efficacy and delivery of PSO. The various therapeutic effects of PSO support its use as a potential drug in a wide range of medical conditions. Further research and studies are needed to confirm its benefits and efficacy in pharmaceutical formulations.
Author Contributions
JS-R, MM, and DC: conceptualization. SK, BY, AB, BS, and MAA: validation investigation. DC, AD, NA, and MM: resources. MI, NA, MERR, and JS-R: data curation. MM, DC, BS, AM, and JS-R: review and editing. All authors: writing. All authors read and approved the final manuscript and contributed equally to the manuscript.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
This work was supported by CONICYT PIA/APOYO CCTE AFB170007.
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Kim, Y., Lim, H.-S., Lee, J., and Jeong, S.-J. (2016). Quantitative analysis of Psoralea corylifolia Linne and its neuroprotective and anti-neuroinflammatory effects in HT22 hippocampal cells and BV-2 microglia. Molecules 21, 1076. doi: 10.3390/molecules21081076
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Kumar, R., Srinivasan, S., Koduru, S., Pahari, P., Rohr, J., Kyprianou, N., et al. (2009). Psoralidin, an herbal molecule, inhibits phosphatidylinositol 3-kinase-mediated akt signaling in androgen-independent prostate cancer cells. Cancer Prev. Res. 2, 234–243. doi: 10.1158/1940-6207.capr-08-0129
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Salehi, B., Lopez-Jornet, P., Pons-Fuster López, E., Calina, D., Sharifi-Rad, M., Ramírez-Alarcón, K., et al. (2019a). Plant-derived bioactives in oral mucosal lesions: a key emphasis to curcumin, lycopene, chamomile, aloe vera, green tea and coffee properties. Biomolecules 9, 106. doi: 10.3390/biom9030106
Salehi, B., Rescigno, A., Dettori, T., Calina, D., Docea, A. O., Singh, L., et al. (2020b). Avocado-soybean unsaponifiables: a panoply of potentialities to Be exploited. Biomolecules 10, 130. doi: 10.3390/biom10010130
Salehi, B., Sestito, S., Rapposelli, S., Peron, G., Calina, D., Sharifi-Rad, M., et al. (2019b). Epibatidine: a promising natural alkaloid in health. Biomolecules 9, 6. doi: 10.3390/biom9030106
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Keywords: Psoralea corylifolia, herbal medicine, psoralidin, bioavailability, biological properties, molecular mechanisms, cell signalling pathways
Citation: Sharifi-Rad J, Kamiloglu S, Yeskaliyeva B, Beyatli A, Alfred MA, Salehi B, Calina D, Docea AO, Imran M, Anil Kumar NV, Romero-Román ME, Maroyi A and Martorell M (2020) Pharmacological Activities of Psoralidin: A Comprehensive Review of the Molecular Mechanisms of Action. Front. Pharmacol. 11:571459. doi: 10.3389/fphar.2020.571459
Received: 10 June 2020; Accepted: 28 September 2020;
Published: 22 October 2020.
Edited by:Andrei Mocan, Iuliu Haţieganu University of Medicine and Pharmacy, Romania
Reviewed by:Claudio Ferrante, University "G. d'Annunzio" of Chieti-Pescara, Italy
Monica Paoliello, Albert Einstein College of Medicine, United States
Luigi Menghini, University "G. d'Annunzio"of Chieti-Pescara, Italy
Copyright © 2020 Sharifi-Rad, Kamiloglu, Yeskaliyeva, Beyatli, Alfred, Salehi, Calina, Docea, Imran, Anil Kumar, Eugenia Romero-Román, Maroyi and Martorell. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Javad Sharifi-Rad, email@example.com, Bahare Salehi, email@example.com, Daniela Calina email@example.com, Alfred Maroyi, email@example.com, Miquel Martorell, firstname.lastname@example.com


text:
Orders exceeding the stock on hand amount are processed as special orders, which require additional processing and shipping time and are not eligible for return.
EnduraTEX Resolve HTV is a premium economy heat transfer vinyl that doesn't compromise looks or performance. EnduraTEX Resolve heat transfer vinyl or t-shirt vinyl that can be applied to cotton, polyester, cotton/polyester blends, and acrylic fabrics It's thicker feel is ideal for heavy duty work wear as well as athletic apparel. EnduraTEX Resolve is extremely resistant and yet provides excellent flexibility making it easy to cut small letters and intricate detail.
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subset: commoncrawl


text:
Yesterday, European Union member states voted to pass the new Copyright Directive by just five votes, seeing the implementation of controversial Articles 11 and 13, now known as Articles 15 and 17 respectively. Some members of the European Parliament (MEPs) are now claiming to have voted for the proposition by …Read More »
European Parliament passes controversial Article 13 and Article 11
The European Parliament has repeatedly tried to implement Article 11 and Article 13 as a part of its Copyright Directive overhaul, with the former being a "link tax" and the latter is set to introduce an intrusive upload filter. After a number of delays and changes to the text, member …Read More »
European lawmakers struggle to finalise Article 13, with negotiations delayed once again
EU Member States have refused a compromise position on Article 13, further delaying negotiations of its final text.Read More »
Google News could disappear in Europe if the EU implements link tax
Google maintains that it might retract its News feature from Europe, should the EU push Article 11's "link tax."Read More »
EU votes in favour of amended Copyright Directive, retaining "link tax" and "upload filter"
In July, the European Parliament voted against the intrusive Copyright Directive, sending Article 11 and 13 back to the drawing board. Amended versions of both have since been approved, continuing to carry the controversial "link tax" and "upload filter" respectively. Easily the most heavily discussed portion of the Copyright Directive …Read More »
EU votes against Copyright Directive, sending Article 11 and 13 back to the drawing board
Two weeks ago, European Parliament sent the media world into a frenzy by pushing legislation that threatened to dismantle the internet as we currently know it. Fortunately, the all-important vote has seen both Article 11 and 13 thrown out, meaning copyright laws are to remain as they are for the …Read More »
EU Parliament votes in favour of legislation that could make the internet a "tool for control"
European Parliament has sent the tech industry into a frenzy this week as the JURI committee voted to pass Articles 11 and 13 of the EU Copyright Directive legislation. If enacted, the pair could dismantle the internet as we know it, filtering out uploaded content against copyrighted material. Article 11 …Read More »


text:
Vortex 3-9x50 Crossfire II Riflescope (Dead-Hold BDC)
Product Features
- 3.0-9.0x Magnification, 50mm Objective
- Fast Focus Eyepiece
- Fully Multicoated Optics
- 1" Diameter Tube Design
- Capped/Resettable W/E Turrets
Customer Reviews
Email me when stock arrives
Product Details
- Product: #80534
Read More: Overview Specifications More Info
The 3-9x50 Crossfire II Riflescope (Dead-Hold BDC) from Vortex Optics is a cost-effective yet durable variable power riflescope. The 3-9x magnification is ideal for close and mid-range hunting and target practice. A nitrogen purged and o-ring sealed aluminium housing is built to perform in driving rain and extreme humidity. This model of the Crossfire II is configured with a Dead-Hold BDC reticle and low-profile capped windage/elevation turrets. The wide 50mm objective lens features enhanced light gathering ability that is well-suited for performance in low light conditions. A fast focus eyepiece, fully multicoated optics, and generous eye relief make the Crossfire II a full-featured scope for sportsmen.
Key Features:
Dead-Hold BDC Reticle
Customised compensating reticle subtensions minimise guesswork on holdover and wind drift corrections, ideal for shooting at ranges where calculating accurate bullet drop is essential.
Anti-Reflective Lens Coating
Fully multicoated optics and an additional anti-reflective coating on the objective and the ocular lenses ensure transmission of bright detail-rich images throughout the entire magnification range.
Rugged Construction
The one-piece aerospace aluminium housing is anodised for a durable non-reflective finish. Each optical element is held in place by machined locking rings that ensure perfect lens alignment even after intense recoil and rapid fire. Additionally, the interior is nitrogen purged and o-ring sealed, preventing driving rain and extreme humidity from fogging the optics.
|3 to 9x
|Objective Lens Diameter
|50 mm
|Field of View
|3x: 12.9' @ 100 yd / 3.9 m @ 100 m
9x: >32' @ 100 yd / 9.7 m @ 100 m
|Eye Relief
|3.8 to 4.4" / 96 to 112 mm
|Reticle Type
|Dead-Hold BDC Reticle
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|1/4 MOA per Click
|Windage Adjustment
|Elevation Adjustment
|Parallax Correction
|Yes, 100 yd / 91.4 m
|Water Resistance
|Maintube Diameter
|Length: 12.7" / 32 cm
Objective Diameter: 2.2" / 5.7 cm
Eyepiece Diameter: 1.7" / 4.3 cm
|18.4 oz / 521 g


text:
02-Nov-2019 04:22
Visit Now, the first thing I'm gonna tell you about that's really gonna get your heart jumping like popcorn poppin' on the stove is that is free, and free in the true sense of the word, because if you want have a poke around to see what fine offerings are available for a touch of perusin', and what kind of gorgeous girl you're gonna be able to meet on the site, then you don't have to do a thing - and that includes signin' up.
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text:
Family Ties is the second PSA of Battle of Blood Gulch (Season Two). It is a crossover with Zeon1's series Moon Base.
"Allright," Natasha Killgrave said, looking over the small group of Moon Base Sector A: "Sandbox" soldiers that had decided to accompany her to visit her brother, "everyone here? Mikey?"
"Here!" chirped Red Team's marooned armored rookie.
"Issy- I mean, Captain Hawkings?"
"Die, ORKS!" came the half-drunken, half-whiny voice from their captain.
".... Thomas?"
"Okay, and finally, Noah?"
"I'm here!"
The pink-armored soldier smiled, and took a step back. She looked at the Pelican they had requested from command to visit her brother, and opened the hatch. The Reds and Blues began making their way in, each chattering about the new experience.
Jamous Killgrave yawned as he leaned back in his chair, hands crossed behind his head. The day had gone by slowly and, against normal occurences, nothing crazy had happened. No fights, random explosions, or even Rocket Shoes trying to kill Swanson. Yep, he was loving the day so far.
Of course, things can always go for the best even when it was the best (if that makes sense). Killgrave cracked an eye open, eyeing his office door. Boots were echoing down the hallway. He crossed his fingers and prayed it wasn't anything badly important. Maddox appeared, helmet under his arm and a piece of paper in another.
"Jamous!" Maddox said excitedly, "I've got great news!" The medic handed his friend the piece of paper. Killgrave looked at Maddox suspiciously for a minute, never seeing his friend so excited before, before opening it up and reading it's contents. A smile slowly formed on his face. He folded it back up, sat for a minute, and then stood to his feet.
More coming soon!


text:
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British Legal Technology Forum
The leading Legal Technology event in Europe, the day will attract experts from across both the legal and commercial technology sectors, looking at how IT infrastructure including systems, processes, strategies and platforms will help legal firms perform better and raise efficiency over the coming years.
Event Details:
Date: 8 March
Time: All day
Venue: The Old Billingsgate
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Let the Alante 31AL motor home by Jayco take you on your next great adventure! With double slides and a comfortable living area you are sure to enjoy all of the space that this motor home has to offer.
As you enter the motor home you will immediately notice the slide which has a three burner range, microwave, and sofa. Next to the slide there is a double kitchen sink. Located on the passenger side of the motor home there is a nice size dinette where you can enjoy your meals, and above the dinette there is a TV lift. Just past the dinette you will find the refrigerator, pantry, and large linen cabinet. Above the cab you can even choose to have an optional drop down bunk.
The bathroom has a shower, toilet, sink, and medicine cabinet.
In the rear bedroom you will find a queen bed with nightstands on either side of the bed. Across from the bed there is a slide with a wardrobe and an optional TV.
Throughout the inside of the motor home you will find plenty of overhead cabinets, and outside there is much exterior storage for all of your necessary items. Outside you will also find a 14' awning which adds so much shade.
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text:
When Doge on Kucoin? :')
All community want Doge in the best Exchange for the People!!
Just ask on Telegram!
➔ Kunjungi Kucoin sekarang dan memulai trading
3 Komentar
No official statement disclosed regarding this matter as of the moment. Please keep yourself posted for future announcements. Terima kasih!
We all want Doge on Kucoin
Queremos dogeeee en kucoin


text:
1.15 is an improvement based on 1.1:
The main reason is to increase the effective collision of the sub-warhead, making the V4 rocket shore-based anti-ship possible, and further improving the missile's flight speed and maneuverability. In the future, a dual- or even multiple-engine version of the launch vehicle may be developed, but considering the unit's prototype and the parts counts-friendly, we chose to retain the final design of this model.
The operation is the same as before.
Enjoy and fun!
General Characteristics
- Created On Android
- Wingspan 38.8ft (11.8m)
- Length 57.2ft (17.4m)
- Height 32.7ft (10.0m)
- Empty Weight -4,734,385lbs (-2,147,483kg)
- Loaded Weight 7,989lbs (3,624kg)
- Power/Weight Ratio 2.25
- Wing Loading 42.4lbs/ft2 (207.1kg/m2)
- Wing Area 188.4ft2 (17.5m2)
- Drag Points 57469
- Number of Parts 260
- Control Surfaces 8


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Yaesu FTM 100DR Interface Dayton 2015
See More: Link
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When searching for answers leave the letters that you don't know blank! E.g. B OTH R (BROTHER)
Actress Fisher from Confessions of a Shopaholic is a crossword clue for which we have 1 possible answer and we have spotted 1 times in our database. This crossword clue was last seen on 21 November 2020 in Daily Themed Crossword puzzle!


text:
Dryden Ugly Sweater 5K Run December 5, 2020 Dryden NY
START: 10:00am First Wave with 5 Waves
REGISTRATION: $32.50 Race Fee + $2.89 Sign Up Fee. Price increases to $37.50 after November 22, 2020 at 11:59pm EST
PLACE: 42 W Main St Dryden, NY US 13053
Come join us for the inaugural Dryden Ugly Sweater 5K set for Saturday, December 5th, 2020 in Dryden, NY. This event combines "fun" and "run" all into "one". Participants are not required but definitely encouraged to dress in costume (ugly sweaters) for this chilly run/walk. The event will start at the Historical Dryden Hotel (Built in 1844) with most of the run/walk on the new Dryden Rail Trail. This event will benefit the Dryden Rail Trail Revenue Fund as they continue to need funding to complete and improve this beautiful Trail. All donations and a portion of the race proceeds will help this cause!
Sign up at runsignup.com


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text:
- Is streaming considered a job?
- How much does a streamer get from bits?
- How much money do Twitch streamers make per viewer?
- How much does Ninja make a year?
- How do I cash out my twitch bits?
- How much does the average mixer streamer make?
- Who is the richest streamer?
- Who is the number 1 Twitch streamer?
- Is being a twitch streamer worth it?
- How much does a streamer with 1000 views make?
- Do streamers pay taxes?
- How much is 25000 bits on twitch?
- How much is 100 gifted subs worth?
- What is the max amount you can donate on twitch?
- How many streamers make a living?
- Do bits give streamers money?
- How much do 100 streamer viewers make?
- How do I become a successful streamer?
Is streaming considered a job?
If you want to make a living, or are already making a living off streaming, it is a job and should be treated as such.
As soon as someone pays you for it, it's a job.
Streaming is the same..
How much does a streamer get from bits?
No. In-fact they only receive $1.00, since each of those bits is worth a single penny, or cent for the streamers. That means on purchases of just 100 bits at a time, Twitch pulls in a whopping 40 per cent commission.
How much money do Twitch streamers make per viewer?
The rate streamers get paid for sponsored streams ranges from 1¢ to $1 per viewer per hour. If you get 10,000 viewers, that's $1,000 to $10,000 per hour of gameplay. You will also see streamers being sponsored by companies that make gaming equipment, from headsets to chairs to keyboards.
How much does Ninja make a year?
Ninja earns $500,000 a month from YouTube. He earns $550,000 per month from Twitch and $3.5 million a year from endorsements. This brings his total to $16.1 million and if you include merchandise and ad revenue, our calculations come to an eye-watering $18 million dollars per year.
How do I cash out my twitch bits?
Select Get Bits in the top right of the stream. Select the amount of Bits you want to buy and select a payment method. Pay the given amount and wait a few seconds for your inventory to be updated. The number of Bits you bought should appear.
How much does the average mixer streamer make?
This equates to $1,107 dollars per week, or $4,428 per month, or $53,136 per year. And that's just from the top donators, on average, not including the other currency, Sparks, which lets Mixer streamers earn more from Embers. Shroud makes just over $10,000 a year in Embers.
Who is the richest streamer?
The 10 Richest Twitch StreamersPewDiePie – Net Worth: $20 Million.Ninja – Net Worth: $10 Million. … TimTheTatman – Net Worth: $6.5 Million. … NightBlue3 – Net Worth: $6 Million. … Syndicate -Net Worth: $5 million. … Shroud – Net Worth; $4 Million. … PhantomLord – Net Worth: $4 Million. … Dr. … More items…
Who is the number 1 Twitch streamer?
TfueTop 10 Esports Twitch Streamers – All-Time & 2020 RankingsPlayerRank All-TimeTotal ViewersTfue1224,000,000Nickmercs3108,000,000Tyler12167,000,000Clix927,700,0006 more rows•Jul 8, 2020
Is being a twitch streamer worth it?
If you're going to be playing video games regardless you might as well stream them and if you make any money at all then I would consider that worth the effort. It's money you earned for something you were going to do for free anyway. Streamer Personality: This is the most important factor on twitch.
How much does a streamer with 1000 views make?
Sponsorships, which on Twitch often show up in the form of streams where gamers are paid to play specific games, can earn them anywhere from one cent to $1 per viewer per hour — so, someone who, like Wang, averages 10,000 viewers, can earn between $1,000 and $10,000 per hour, depending on the game he's playing.
Do streamers pay taxes?
Do Twitch Streamers Pay Tax? Yes, if you earned any money from Twitch or any other platform, you are required to pay taxes on your earnings in the United States. This includes revenue from ads, donations/tips, sponsorships, and any other method of payment.
How much is 25000 bits on twitch?
BitsDollars25000$250.0035000$350.0050000$500.0075000$750.0021 more rows
How much is 100 gifted subs worth?
100 gifted subs would be $499.00, depending on what payment method you use, and where you live, there may be a transaction fee.
What is the max amount you can donate on twitch?
Higher donations are given a bigger animated emote in chat and a percentage of the amount is donated directly to the streamer. The minimum purchase is $1.40, which gets the viewer 100 bits. The maximum sits at $308 for 25,000 bits.
How many streamers make a living?
On average, expert streamers can make between $3,000 to $5,000 each month playing around 40 hours a week. That specific number doesn't include ad revenue, which averages about $250 every 100 subscribers. If you put in the time and grow a respectable audience, Twitch can certainly be lucrative.
Do bits give streamers money?
Twitch Bits Bits are a type of virtual currency that gamers can "spend" on their favorite gamers' sites. Twitch pays their Affiliates and Partners one cent for every Bit fans use on their channels. A viewer can Cheer with his Bits.
How much do 100 streamer viewers make?
Ad Revenue However, once you get to this level, which won't be hard if you follow the advice below, the payoff can be huge. In fact, the average Twitch Streamer earns $250 in ad revenue for every 100 subscribers he or she has.
How do I become a successful streamer?
Ten tips to grow your creative community on TwitchKnow what you want to get out of streaming. … Look at what makes other streamers successful. … Look to maximize your audience reach from day one. … But don't expect to be an overnight success. … Observe the rules of supply and demand. … Interactivity is the key to a good stream. … Be prepared. … Consider your presentation style.More items…•


text:
Q. 205.0( 2 Votes )
Factorize each of the following algebraic expressions:
Answer :
(a – 4b)2- (5c)2
= (a – 4b + 5c) (a – 4b – 5c)
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10 Nov
The safety and security of our associates and applicants are our top priorities as we navigate the spread of the Coronavirus (COVID-19) and its impact on our work and personal lives. Consistent with public health guidance, we are promoting social distancing, and following all recommended precautions in our buildings to keep our people healthy including enhanced and more frequent cleaning measures at all our locations. Please note: all of our interviews are being conducted virtually during this time
About us:
Staples Business Advantage is the commercial, business to business division of Staples
We work with small to large sized companies to develop customized programs with specialized pricing,
dedicated account management, and a complete assortment of products and services at a low total delivered cost
Staples Business Advantage offers our clients: Facility Supplies, Breakroom Products, Technology Solutions, Furniture, Print Solutions, Promotional Products and more
To learn more about Staples Business Advantage visit us at: www.staplesbusinessadvantage.ca
We are currently looking for an outstanding Business to Business Outside Sales Representative to join our team! The focus of this position is new business development. This is an exciting opportunity for a sales professional that enjoys building relationships, achieving success, overcoming challenges, closing deals and securing contracts.
About the Job:
Your main responsibility is prospecting, cold calling and closing new deals with businesses in your assigned territory
You will sell our "one-stop solution" to customers enabling them to purchase their entire lines of business with our company
Responsibilities include scheduling appointments with key decision makers, giving solution-based presentations and closing new deals
You will work closely with your sales team, as well as utilize other company resources to ensure a smooth transition of new contracts to the Account Management Team
What you will be doing:
Research small to medium size businesses and qualify leads
Identify decision makers and key stakeholders
Prospect and cold call potential customers
Set appointments/build relationships to present our program solutions
Negotiate and close deals
Facilitate the transition of new contracts to the assigned Account Manager who will maintain and grow the business
Achieve/Exceed set Key Performance Indicators and sales objectives
We are looking for someone who has:
Previous experience in sales, new business development and other related fields
Strong communication/Interpersonal skills
Superior consultative selling skills with proven closing ability
Commitment to achieving key performance indicators - touchpoints, appointments and proposals
Familiarity with CRM platforms
Ability to function independently to achieve targets as well as work effectively in a team environment
Deadline and detail oriented with strong organizational skills
A proven background of hitting and exceeding sales targets
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A supportive environment that provides extensive sales training (in partnership with Miller Heiman) and career development potential
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Comprehensive medical and dental benefits, as well as RRSP matching
Partnership Benefits including discounts with gym memberships, retail stores, entertainment and more
****This is your opportunity to join a well Established North American company with endless opportunities and room for advancement**
Staples is committed to providing accommodation to people with disabilities throughout the job application and interview process to the point of undue hardship. If you require an accommodation during the application or interview process, please contact a Customer Care Representative at 1-(phone hidden).
Staples is an equal opportunity employer and an accommodation will be provided during the hiring process if requested.
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text:
William Kemp
Manuel, The Unfortunate
after Paula Rego's Last King of Portugal
Both sides of the story of your death
involve striped pyjamas, a maid and the deep rich red
of your bedroom wallpaper. Was your outpost
at Fullwell, Twickenham, private and secure enough
to keep at bay those Republican activists
who might by various means have poisoned you?
Or can we assume you over-exerted yourself
one too many times at tennis, and in so doing
activated some hereditary bronchial condition,
hitherto undetected, with fatal consequence?
None at Scotland Yard had strength or means
to piece together the evidence either way.
Good night, sweet prince.
Let acrylic, graphite and pastel on paper,
mounted on aluminium, be your epitaph.
William Kemp is a poet, broadcaster and arts professional from Plymouth, who works for the Dartington Hall Trust. He has written articles and reviews on a range of subjects, including jazz, folk and classical music, modern poetry and Shakespeare. He presents and produces a weekly arts show for Soundart Radio.


text:
The Island Will Sink
- $6.99
- $6.99
Publisher Description
In a not-too-distant future perpetually on the brink of collapse, catastrophe is our most popular entertainment.
The energy crisis has come and gone. EcoLaw is enforced by insidious cartoon panda bears and their armies of viral-marketing children. The world watches as Pitcairn Island sinks into the Pacific, wondering if this, finally, will be the end of everything. Amongst it all, Max Galleon, anxious family man and blockbuster auteur, lives a life that he cannot remember.
What happens when you can outsource your memories – and even edit them?
When death can be reversed through digitisation, what is the point of living?
If the lines between real and unreal are fully blurred, can you really trust anyone, even yourself?


text:
CHRIS SUTTON believes if Celtic were to sell Odsonne Edouard this late on in the window, it would be a slap in the face to the supporters – sending a warning to the powers that be.
The former Celtic striker believes the club owes the fans for their unwavering support during this potential ten in a row run and to sell the Frenchman would be an astonishing move at this stage.
"Odsonne Edouard is Celtic's striker, he's their main striker. He is so important to the team. I don't care what you say, the club actually owe the fans on this." Sutton told RecordSport.
"Would that not be a slap in the face for the supporters who have paid their hard earned money for years and years and years? Ploughed tens of thousands, millions of pounds into the football club, to get to this stage.
"I don't care what you say about history, it is so, so important and it's in touching distance. Therefore, for the club to sell their star player at this point in time… imagine the Rangers dressing room!"
Neil a Lennon has reiterated Eddy isn't for sale BUT did also admit there was a contingency plan in place should the club get a large bid this window.
With so much at stake for the club and the supporters, to let the frontman leave now would be gambling with ten in a row.
Celtic fans have already suffered a major blow with it increasingly unlikely they'll get into the ground to see any of this season. If Eddy was to go, it's going to make us sitting in our house watching the game feel just that bit more anxious.
The transfer window closes on October 5 and we expect there will be one or two twists between now and then.