Emerging Utilization of Chrysin Using Nanoscale Modification

Jung, Joohee

doi:https://doi.org/10.1155/2016/2894089

Journal of Nanomaterials

On this page

Abstract Introduction Conclusions Abbreviations Acknowledgments References Copyright Related Articles

Special Issue

Nanoscale Biological Materials

View this Special Issue

Review Article | Open Access

Volume 2016 | Article ID 2894089 | https://doi.org/10.1155/2016/2894089

Emerging Utilization of Chrysin Using Nanoscale Modification

Joohee Jung^1,2

Academic Editor: Serdal Kirmizialtin

Received14 Dec 2015

Revised02 Mar 2016

Accepted18 Apr 2016

Published08 May 2016

Abstract

Chrysin is a flavone found in several plants, mushroom, and honeycomb. This constituent is broadly used in herbal medicine in Asia. Since its biological activities were identified in various studies, the focus has shifted to the development of chrysin as a complementary medicine for health promotion. Chrysin is known to have chemopreventive and therapeutic effects in skin aging, atherosclerosis, inflammation, diabetes, AIDS, and cancer. However, its poor bioavailability is a bottleneck for pharmaceutical applications. To overcome the limitations and enhance the bioactive effects, methods like nanoencapsulation or conjugation have been attempted. In this review, current trends of chrysin use in the biomedical field are summarized.

1. Introduction

Flavonoids including flavones, flavanols, and flavans possess various biological activities. Their effects are utilized in herbal medicines. Chrysin (5, 7-dihydroxyflavone, Figure 1) is a flavone contained in several plants (Passiflora caerulea [1], Passiflora incarnate [2], Oroxylum indicum [3, 4], Matricaria chamomilla [5], etc.) and natural products (Pleurotus ostreatus [6], propolis [7, 8], honey [9], etc.).

Recently, chrysin was reported as a bioactive ingredient. In this review, the effects of chrysin are briefly summarized (Figure 2) and its complementary application is discussed. Finally, emerging nanoscale modification of chrysin is introduced.

2. Biological Activities of Chrysin

2.1. Effect on Inflammation

Inflammation is a protective reaction of the body to infection, physiological stress, drugs, and so on and activates the immune system. Acute inflammation is induced by mediators including arachidonic acid, platelet-activating factor, prostanoids, leukotrienes, lipoxins, interleukins, histamine, serotonin, and lysosomal hydrolases. Chrysin alleviates inflammation through inhibition of COX-2 [10], prostaglandin-E2 [11], histamine [12], NF-γB pathway [13–15], tumor necrosis factor- (TNF-) alpha [16, 17], iNOS [16], and cytokines (interleukin-1β, interleukin-2, interleukin-6, and interleukin-12) [18] and activation of peroxisome proliferator-activated factor γ (PPARγ) [19]. These reports suggest that chrysin could be a good agent in inflammatory diseases. When acute inflammation does not clear up, inflammatory cells persist and chronic inflammation promotes organ dysfunction [16, 20, 21]. Disabling inflammatory diseases include Parkinson disease [22], cancer [13], cerebral ischemia [23], allergy [12], and autoimmune neuritis [18]. The anti-inflammatory mechanism of chrysin could prevent inflammation-related diseases.

2.2. Effect on Atherosclerosis

Atherosclerosis and hypercholesterolemia are risk factors for coronary heart disease, which is a major cause of mortality. In atherosclerosis, a fibroinflammatory lipid plaque consisting of inflammatory cells, smooth muscle cells, lipid, and connective tissue accumulates in arteries. The major factor in atherosclerosis is oxidative metabolism of plasma lipoproteins. Oxidation of low-density lipoproteins by oxygen free radicals generates reactive oxygen species (ROS). Thus, ROS play a central role in the incidence of atherosclerosis. Overproduction of ROS also injures endothelial cells. Originally, ROS are intermediate products in oxidative phosphorylation and are eliminated by sufficient levels of superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT). However, oxidative stress-induced ROS accumulate and impair cells when these enzymes are depleted. Chrysin can scavenge ROS as chrysin increases SOD, GPx, and CAT [11, 24, 25]. Furthermore, chrysin controls cholesterol efflux [26] and suppresses TNF-alpha-induced adhesion molecule expression [27]. These activities of chrysin could prevent atherosclerosis.

2.3. Effect on Diabetes

Diabetes, one of the lifestyle diseases, is described as a high glucose level in blood. Diabetes-induced complications depreciate the quality of the patient’s life and often become the cause of death. The ethanolic extract of Oroxylum indicum Kurz, which includes chrysin, inhibits the activities of α-glucosidase, thus decreasing glucose absorption in blood. It also induces GLUT-4 translocation in 3T3-L1 adipocyte cells, suggesting an increase of glucose uptake into those cells [28]. Several studies showed that chrysin has hypoglycemic effects on diabetic mice [29, 30]. Pancreatic beta cells, the function of which is important to prevent diabetes mellitus, are protected by the antioxidant activity of chrysin [31]. The antioxidant effect of chrysin can assuage the complications of diabetes. Chrysin decreases malondialdehyde and increases CAT, SOD, and glutathione. Its effect ameliorates cognitive deficits [32] and renal dysfunction [33] in diabetic animal models. Chrysin decreases total cholesterol, triglyceride, and low-density lipoprotein in streptozotocin-nicotinamide induced diabetic rats [34]. Nitric oxide-releasing chrysin attenuates diabetes-induced complications [35–38]. Because of these activities, chrysin derivatives have been synthesized for development as antidiabetes agents [38].

2.4. Effect on AIDS

Chrysin is known to inhibit casein kinase II involved HIV-1 transcription [39] and to suppress HIV replication in H9 cells [40]. Chrysin inhibits HIV expression in OM-10.1 cells or ACH-2 cells treated with TNF-alpha or phorbol myristate acetate (PMA) and 8E5 cultures [41]. Thus, chrysin has anti-HIV activity [41, 42].

2.5. Effect on Aging

Physiological functions degrade with advancing years. Among these functions, synthesis of sex hormones is important in the development of reproductive organs and maintenance of sexual function. With age, sex hormones decline and sexual function is enervated. Chrysin stimulates cyclic AMP-induced steroidogenesis in Leydig tumor cells and increases the expression of steroidogenic acute regulatory protein [43]. Moreover, chrysin ameliorates sexual functions in 2-year-old male rats, suggesting that chrysin can inhibit aromatase activities [44]. On the other hand, oral administration of chrysin to immature rats did not change sex hormone-induced uterine growth [45]. Urinary testosterone level was also measured in sportsmen drinking propolis including chrysin because aromatase inhibition can trigger the conversion of testosterone into estrogen. However, oral supplementation of propolis did not alter urinary testosterone levels [46]. These results may be due to poor absorption or bioavailability of chrysin in vivo. Nevertheless, chrysin was recently utilized as a testosterone booster supplement for bodybuilders and athletes [47].

Aged mouse brain shows memory declines, but chrysin prevents age-related cognitive decline by mitigating the decrease of brain-derived neurotrophic factor and ROS in the prefrontal cortex and hippocampus of aged mice [48].

Skin aging is also a matter of great interest. Ultraviolet (UV) exposure is a risk factor for skin aging. In particular, ROS promote photoaging by UV and induce cell damage. So ROS accumulation is observed in the aging process. Matrix metalloproteinase level is also increased by ROS. The antioxidant effect of chrysin inhibits the expression of matrix metalloproteinase and prevents UV-induced skin aging [49–51].

2.6. Effect on Cancer

Chrysin, a component of natural products, shows anticancer activities in various cancer cell lines [52, 53]. Several studies on chrysin have sought to explain the mechanisms of its anticancer effects, which include inhibition of the PI3K/Akt pathway, activation of caspase-3 and caspase-8 [54], and depletion of cellular glutathione [55]. Chrysin also increases mitochondrial membrane depolarization, Bax, and cleaved-PARP levels in cervical cancer cell lines [56]. Chrysin activates the transcription pathway mediated by TNF-alpha and TNF-beta via aryl hydrocarbon receptor in colorectal cancer cells [57]. Chrysin, as an HDAC inhibitor, arrests the cell cycle through induction of p21 [58, 59] and then suppresses cellular proliferation. Also, chrysin as an aromatase inhibitor potentially reduces tumor growth in estrogen receptor-positive breast cancer MCF-7 cells [60]. Chrysin derivatives have been synthesized and evaluated in the development of anticancer drugs [61].

In chemotherapy, metastasis is a problem that needs to be solved. Matrix metalloproteinase-9 (MMP-9) plays a key role in the metastatic cell invasion. Chrysin inhibits MMP-9 expression via suppression of ERK and JNK pathways in gastric cancer cells [62]. These activities of chrysin are of interest for its application in the pharmaceutical field. Furthermore, up to 3 g/day of chrysin showed no toxicity [47]. Although its advantages are attractive, chrysin has weaker therapeutic efficacy than commercial anticancer drugs. Generally, chrysin is ingested as a dietary food and utilized as a complementary medicine. Recently, the combination of chrysin and anticancer drug was shown to enhance cytotoxicity in various cancer cell lines and to be devoid of toxicity to normal cells. In human lung cancer H460 cell lines, chrysin improved the anticancer efficacy of doxorubicin and cisplatin by depletion of glutathione [63, 64]. In Hep G2 cells, the combination of chrysin and cisplatin enhanced p53 levels and induced apoptosis [65]. Also, chrysin increased the responsiveness in adriamycin-resistant cancer cells, indicating that chrysin could be developed as a chemosensitizer [66]. Moreover, the combination of chrysin and 1, 2, 3, 4, 6-penta-O-galloyl-β-D-glucose suppressed tumor growth through the reduction of S-phase kinase-associated protein 2 and low-density lipoprotein receptor-related protein 6 in triple-negative breast cancer [67].

3. Improvement Strategies for Chrysin

Although the bioactive effects of chrysin are diverse, its medicinal application is limited. One of the reasons is that chrysin has poor solubility as well as rapid metabolism and excretion [68]; the bioavailability of chrysin therefore needs to be enhanced. Nanoscale natural products are emerging as a good strategy. The nanoscale modification increases the ratio of surface area to volume and thus may improve solubility.

Bottom-up manufacturing method involves assembly of a nanoscale structure from small molecules (e.g., organic synthesis and self-assembly on protein) [69]. To improve the activities of chrysin, chemical conjugation with other chemicals was performed. Conjugation of chrysin with indole and barbituric acid increased the anti-inflammatory activity above that of chrysin itself [70]. Organogermanium had antioxidative activity like chrysin [71, 72]. And conjugation of chrysin-organogermanium had synergistic antioxidant effects and enhanced anticancer effects through apoptosis-associated mitochondrial function and antiangiogenesis [73]. Selenium containing chrysin showed significant cytotoxicity with 18-fold lower IC₅₀ than that of chrysin. Moreover, the cytotoxic activity of selenium containing chrysin was superior to that of cisplatin, a commercial anticancer drug [74]. These results suggest that chrysin and other chemicals that have similar biological activity elicit increasing therapeutic efficacy with conjugation.

The other method for overcoming the disadvantages of chrysin is the utilization of a drug delivery system (DDS). DDS have been used to solubilize a drug or modify the properties of a drug. Furthermore, DDS could be used to accumulate encapsulated drug at a target site (e.g., tumor). Nanoscale carriers include a drug reach and accumulate in tumor tissue much more than in normal tissues through the enhanced permeability and retention (EPR) effect [75]. Generally, this is called passive targeting. Recently, researchers have been concerned about manipulating nanoscale carriers in order to control drug release at the desired target site. Tumor specific antibodies or ligands are utilized in addition to the tumor microenvironment in order to achieve the active targeted delivery of drug. Eventually, DDS enhance the final concentration of drug at targeted site and improve the drug bioavailability. The technology of nanoscale modification as DDS is applied to infectious diseases as well as cancer therapy [76]. Use of natural products including chrysin as encapsulated materials has increased. Plant- or microorganism-derived materials are known to have biological activities and low toxicity compared to commercial drugs [77]. So natural products have been utilized as complementary medicine or preventive medicine. Recently, it was reported that nanoscale natural products are prospects for homeopathic medicine [69, 78–80]. Chrysin is also a good candidate for homeopathic medicine.

A successful strategy includes the selection of suitable carriers that could encapsulate the respective drugs. Based on the literature analysis, DDS for chrysin have utilized liposome [13], micelles [81], and nanoparticles [82–84] as carriers. Until now, chrysin-incorporated polymer as a nanoscale medicine was made from poly(ε-caprolactone) (PCL), polylactic-glycolic acid (PLGA), and polyethylene glycol (PEG). By improving the drug-loading contents, chrysin modified polymer increased chemotherapeutic efficacy. Chrysin interacted with PEG-PCL and formed polymer micelles composed of a single layer. With solubilization of chrysin, the micelle enhanced doxorubicin-induced cytotoxicity [81]. Moreover, chrysin was bound to the terminal group of methoxy PEG (mPEG) and doxorubicin was incorporated into mPEG-chrysin conjugate [82]. In micelles modified with chrysin, the chain lengths of their components were important. So mPEG (2 k)-PCL (5 k)-chrysin micelles were optimized to maximize the anticancer effect in vitro [85]. Chrysin has been used in attempts to enhance chemotherapeutic efficacy in various cancer cell lines.

To reduce the toxicity, carriers should be degradable in the body. One such carrier is PLGA-PEG, an FDA-approved polymer. Chrysin encapsulated into PLGA-PEG exhibited increased solubility and cytotoxicity in breast cancer T47D cells [83, 84]. The IC₅₀s of PLGA-PEG with chrysin and pure chrysin were 44.8 and 46.7 μM, respectively, in T47D cells [66]. Moreover, PLGA-PEG with chrysin decreased cyclin D1, a protooncogene, more than pure chrysin [66]. In Zarghami et al.’s study [83, 86], chrysin-curcumin in PLGA-PEG also inhibited the proliferation of breast cancer cells by decreasing cyclin D1 expression. This result with this technology suggests that bioavailability of chrysin is improved by PLGA-PEG [86].

Until now, chrysin has been modified for anticancer therapy in most studies, but various nanoparticles including chrysin, have the potential to be used for other applications. For example, PLGA-honeybee, a complex of chrysin and other components, was utilized for prevention of S. Typhimurium infection [87].

4. Conclusions

The technology of nanoscale modification could overcome obstacles in the development of functional dietary supplements and medicines. Nanoscale material changes the original material’s physicochemical properties, (especially, solubility). In this review, chrysin is described as a good example of nanoscale modification. Chrysin, a natural flavonoid, possesses various biological activities and shows promise as a complementary medicine. However, the limitations of chrysin (poor solubility in water and low stability in the body) are a hurdle in terms of application. To enhance the bioavailability, chemical conjugation using bottom-up manufacturing and encapsulation using nanoparticles were designed and applied (Table 1). These trials could be developed for the commercial exploitation of chrysin. Hereafter nanoscale modification could be increased in the pharmaceutical field, although scale-up processing and quality control remain to be solved.

Abbreviations

TNF:	Tumor necrosis factor
ROS:	Reactive oxygen species
SOD:	Superoxide dismutase
GPx:	Glutathione peroxidase
CAT:	Catalase
PPAR:	Peroxisome proliferator-activated receptor
PMA:	Phorbol myristate acetate
UV:	Ultraviolet
HIV:	Human immunodeficiency virus
HDAC:	Histone deacetylase
MMP-9:	Matrix metalloproteinase-9
PEG:	Polyethylene glycol
PLGA:	Polylactic-glycolic acid
PCL:	Poly-ε-caprolactone
DDS:	Drug delivery system.

Competing Interests

The author declares that there are no competing interests.

Acknowledgments

This work was supported by the Duksung Women’s University Research Grants of 2014 (300000211).

References

C. Wolfman, H. Viola, A. Paladini, F. Dajas, and J. H. Medina, “Possible anxiolytic effects of chrysin, a central benzodiazepine receptor ligand isolated from Passiflora coerulea,” Pharmacology, Biochemistry and Behavior, vol. 47, no. 1, pp. 1–4, 1994.
View at: Publisher Site | Google Scholar
E. Brown, N. S. Hurd, S. McCall, and T. E. Ceremuga, “Evaluation of the anxiolytic effects of chrysin, a Passiflora incarnata extract, in the laboratory rat,” AANA Journal, vol. 75, no. 5, pp. 333–337, 2007.
View at: Google Scholar
L.-J. Chen, D. E. Games, and J. Jones, “Isolation and identification of four flavonoid constituents from the seeds of Oroxylum indicum by high-speed counter-current chromatography,” Journal of Chromatography A, vol. 988, no. 1, pp. 95–105, 2003.
View at: Publisher Site | Google Scholar
Harminder, V. Singh, and A. K. Chaudhary, “A review on the taxonomy, ethnobotany, chemistry and pharmacology of Oroxylum indicum vent,” Indian Journal of Pharmaceutical Sciences, vol. 73, no. 5, pp. 483–490, 2011.
View at: Publisher Site | Google Scholar
P. Zanoli, R. Avallone, and M. Baraldi, “Behavioral characterisation of the flavonoids apigenin and chrysin,” Fitoterapia, vol. 71, no. 1, pp. S117–S123, 2000.
View at: Publisher Site | Google Scholar
R. Anandhi, T. Annadurai, T. S. Anitha et al., “Antihypercholesterolemic and antioxidative effects of an extract of the oyster mushroom, Pleurotus ostreatus, and its major constituent, chrysin, in Triton WR-1339-induced hypercholesterolemic rats,” Journal of Physiology and Biochemistry, vol. 69, no. 2, pp. 313–323, 2013.
View at: Publisher Site | Google Scholar
M. Debiaggi, F. Tateo, L. Pagani, M. Luini, and E. Romero, “Effects of propolis flavonoids on virus infectivity and replication,” Microbiologica, vol. 13, no. 3, pp. 207–213, 1990.
View at: Google Scholar
Z. Qiao and R. Chen, “Isolation and identification of antibiotic constituents of propolis from Henan,” Zhongguo Zhong Yao Za Zhi, vol. 16, no. 8, pp. 481–512, 1991.
View at: Google Scholar
I. Martos, F. Ferreres, and F. A. Tomás-Barberán, “Identification of flavonoid markers for the botanical origin of Eucalyptus honey,” Journal of Agricultural and Food Chemistry, vol. 48, no. 5, pp. 1498–1502, 2000.
View at: Publisher Site | Google Scholar
A. Rauf, R. Khan, M. Raza et al., “Suppression of inflammatory response by chrysin, a flavone isolated from Potentilla evestita Th. Wolf. in silico predictive study on its mechanistic effect,” Fitoterapia, vol. 103, pp. 129–135, 2015.
View at: Publisher Site | Google Scholar
G. K. Harris, Y. Qian, S. S. Leonard, D. C. Sbarra, and X. Shi, “Luteolin and chrysin differentially inhibit cyclooxygenase-2 expression and scavenge reactive oxygen species but similarly inhibit prostaglandin-E₂ formation in RAW 264.7 cells,” Journal of Nutrition, vol. 136, no. 6, pp. 1517–1521, 2006.
View at: Google Scholar
Y. Bae, S. Lee, and S.-H. Kim, “Chrysin suppresses mast cell-mediated allergic inflammation: involvement of calcium, caspase-1 and nuclear factor-κB,” Toxicology and Applied Pharmacology, vol. 254, no. 1, pp. 56–64, 2011.
View at: Publisher Site | Google Scholar
E. R. Kasala, L. N. Bodduluru, R. M. Madana, K. V. Athira, R. Gogoi, and C. C. Barua, “Chemopreventive and therapeutic potential of chrysin in cancer: mechanistic perspectives,” Toxicology Letters, vol. 233, no. 2, pp. 214–225, 2015.
View at: Publisher Site | Google Scholar
W. Dou, J. Zhang, E. Zhang et al., “Chrysin ameliorates chemically induced colitis in the mouse through modulation of a PXR/NF-κB signaling pathway,” Journal of Pharmacology and Experimental Therapeutics, vol. 345, no. 3, pp. 473–482, 2013.
View at: Publisher Site | Google Scholar
M. U. Rehman, M. Tahir, A. Q. Khan et al., “Chrysin suppresses renal carcinogenesis via amelioration of hyperproliferation, oxidative stress and inflammation: plausible role of NF-κB,” Toxicology Letters, vol. 216, no. 2-3, pp. 146–158, 2013.
View at: Publisher Site | Google Scholar
M. U. Rehman, N. Ali, S. Rashid et al., “Alleviation of hepatic injury by chrysin in cisplatin administered rats: probable role of oxidative and inflammatory markers,” Pharmacological Reports, vol. 66, no. 6, pp. 1050–1059, 2014.
View at: Publisher Site | Google Scholar
S. Lee, Y.-J. Kim, S. Kwon et al., “Inhibitory effects of flavonoids on TNF-α-induced IL-8 gene expression in HEK 293 cells,” BMB Reports, vol. 42, no. 5, pp. 265–270, 2009.
View at: Publisher Site | Google Scholar
J. Xiao, H. Zhai, Y. Yao et al., “Chrysin attenuates experimental autoimmune neuritis by suppressing immuno-inflammatory responses,” Neuroscience, vol. 262, pp. 156–164, 2014.
View at: Publisher Site | Google Scholar
X. Feng, H. Qin, Q. Shi et al., “Chrysin attenuates inflammation by regulating M1/M2 status via activating PPARγ,” Biochemical Pharmacology, vol. 89, no. 4, pp. 503–514, 2014.
View at: Publisher Site | Google Scholar
B. H. Ali, S. A. Adham, M. Al Za'abi et al., “Ameliorative effect of chrysin on adenine-induced chronic kidney disease in rats,” PLoS ONE, vol. 10, no. 4, Article ID e0125285, 2015.
View at: Publisher Site | Google Scholar
T. Kilic, O. Ciftci, A. Cetin, and H. Kahraman, “Preventive effect of chrysin on bleomycin-induced lung fibrosis in rats,” Inflammation, vol. 37, no. 6, pp. 2116–2124, 2014.
View at: Publisher Site | Google Scholar
Z. Zhang, G. Li, S. S. W. Szeto et al., “Examining the neuroprotective effects of protocatechuic acid and chrysin on in vitro and in vivo models of Parkinson disease,” Free Radical Biology and Medicine, vol. 84, pp. 331–343, 2015.
View at: Publisher Site | Google Scholar
Y. Yao, L. Chen, J. Xiao et al., “Chrysin protects against focal cerebral ischemia/reperfusion injury in mice through attenuation of oxidative stress and inflammation,” International Journal of Molecular Sciences, vol. 15, no. 11, pp. 20913–20926, 2014.
View at: Publisher Site | Google Scholar
R. Anandhi, P. A. Thomas, and P. Geraldine, “Evaluation of the anti-atherogenic potential of chrysin in Wistar rats,” Molecular and Cellular Biochemistry, vol. 385, no. 1-2, pp. 103–113, 2014.
View at: Publisher Site | Google Scholar
B. Bekdeşer, N. Durusoy, M. Özyürek, K. Güçlü, and R. Apak, “Optimization of microwave-assisted extraction of polyphenols from herbal teas and evaluation of their in vitro hypochlorous acid scavenging activity,” Journal of Agricultural and Food Chemistry, vol. 62, no. 46, pp. 11109–11115, 2014.
View at: Publisher Site | Google Scholar
S. Wang, X. Zhang, M. Liu et al., “Chrysin inhibits foam cell formation through promoting cholesterol efflux from RAW264.7 macrophages,” Pharmaceutical Biology, vol. 53, no. 10, pp. 1481–1487, 2015.
View at: Publisher Site | Google Scholar
S. B. Lotito and B. Frei, “Dietary flavonoids attenuate tumor necrosis factor α-induced adhesion molecule expression in human aortic endothelial cells. Structure-function relationships and activity after first pass metabolism,” The Journal of Biological Chemistry, vol. 281, no. 48, pp. 37102–37110, 2006.
View at: Publisher Site | Google Scholar
B. Dinda, I. Silsarma, M. Dinda, and P. Rudrapaul, “Oroxylum indicum (L.) Kurz, an important Asian traditional medicine: from traditional uses to scientific data for its commercial exploitation,” Journal of Ethnopharmacology, vol. 161, pp. 255–278, 2015.
View at: Publisher Site | Google Scholar
J.-S. Shin, K.-S. Kim, M.-B. Kim, J.-H. Jeong, and B.-K. Kim, “Synthesis and hypoglycemic effect of chrysin derivatives,” Bioorganic and Medicinal Chemistry Letters, vol. 9, no. 6, pp. 869–874, 1999.
View at: Publisher Site | Google Scholar
K. Batumalaie, R. Qvist, K. M. O. Yusof, I. S. H. Ismail, and S. D. E. Sekaran, “The antioxidant effect of the Malaysian Gelam honey on pancreatic hamster cells cultured under hyperglycemic conditions,” Clinical and Experimental Medicine, vol. 14, no. 2, pp. 185–195, 2014.
View at: Publisher Site | Google Scholar
T. Lapidot, M. D. Walker, and J. Kanner, “Antioxidant and prooxidant effects of phenolics on pancreatic β-cells in vitro,” Journal of Agricultural and Food Chemistry, vol. 50, no. 25, pp. 7220–7225, 2002.
View at: Publisher Site | Google Scholar
R. Li, A. Zang, L. Zhang et al., “Chrysin ameliorates diabetes-associated cognitive deficits in Wistar rats,” Neurological Sciences, vol. 35, no. 10, pp. 1527–1532, 2014.
View at: Publisher Site | Google Scholar
A. Ahad, A. A. Ganai, M. Mujeeb, and W. A. Siddiqui, “Chrysin, an anti-inflammatory molecule, abrogates renal dysfunction in type 2 diabetic rats,” Toxicology and Applied Pharmacology, vol. 279, no. 1, pp. 1–7, 2014.
View at: Publisher Site | Google Scholar
M. Torres-Piedra, R. Ortiz-Andrade, R. Villalobos-Molina et al., “A comparative study of flavonoid analogues on streptozotocin-nicotinamide induced diabetic rats: quercetin as a potential antidiabetic agent acting via 11β-Hydroxysteroid dehydrogenase type 1 inhibition,” European Journal of Medicinal Chemistry, vol. 45, no. 6, pp. 2606–2612, 2010.
View at: Publisher Site | Google Scholar
H. M. El-Bassossy, S. M. Abo-Warda, and A. Fahmy, “Chrysin and luteolin attenuate diabetes-induced impairment in endothelial-dependent relaxation: effect on lipid profile, AGEs and NO generation,” Phytotherapy Research, vol. 27, no. 11, pp. 1678–1684, 2013.
View at: Publisher Site | Google Scholar
X.-Q. Zou, S.-M. Peng, C.-P. Hu, L.-F. Tan, H.-W. Deng, and Y.-J. Li, “Furoxan nitric oxide donor coupled chrysin derivatives: synthesis and vasculoprotection,” Bioorganic and Medicinal Chemistry Letters, vol. 21, no. 4, pp. 1222–1226, 2011.
View at: Publisher Site | Google Scholar
X.-Q. Zou, S.-M. Peng, C.-P. Hu et al., “Synthesis, characterization and vasculoprotective effects of nitric oxide-donating derivatives of chrysin,” Bioorganic and Medicinal Chemistry, vol. 18, no. 9, pp. 3020–3025, 2010.
View at: Publisher Site | Google Scholar
Q.-Q. Wang, N. Cheng, W.-B. Yi, S.-M. Peng, and X.-Q. Zou, “Synthesis, nitric oxide release, and α-glucosidase inhibition of nitric oxide donating apigenin and chrysin derivatives,” Bioorganic and Medicinal Chemistry, vol. 22, no. 5, pp. 1515–1521, 2014.
View at: Publisher Site | Google Scholar
E. De Clercq, “Current lead natural products for the chemotherapy of human immunodeficiency virus (HIV) infection,” Medicinal Research Reviews, vol. 20, no. 5, pp. 323–349, 2000.
View at: Publisher Site | Google Scholar
C.-Q. Hu, K. E. Chen, Q. Shi, R. E. Kilkuskie, Y.-C. Cheng, and K.-H. Lee, “Anti-aids agents, 10. Acacetin-7-O-β-D-galactopyranoside, an anti-HIV principle from Chrysanthemum morifolium and a structure-activity correlation with some related flavonoids,” Journal of Natural Products, vol. 57, no. 1, pp. 42–51, 1994.
View at: Publisher Site | Google Scholar
J. W. Critchfield, S. T. Butera, and T. M. Folks, “Inhibition of HIV activation in latently infected cells by flavonoid compounds,” AIDS Research and Human Retroviruses, vol. 12, no. 1, pp. 39–46, 1996.
View at: Publisher Site | Google Scholar
H.-K. Wang, Y. Xia, Z.-Y. Yang, S. L. Morris Natschke, and K.-H. Lee, “Recent advances in the discovery and development of flavonoids and their analogues as antitumor and anti-HIV agents,” Advances in Experimental Medicine and Biology, vol. 439, pp. 191–225, 1998.
View at: Publisher Site | Google Scholar
K. Jana, X. Yin, R. B. Schiffer et al., “Chrysin, a natural flavonoid enhances steroidogenesis and steroidogenic acute regulatory protein gene expression in mouse Leydig cells,” Journal of Endocrinology, vol. 197, no. 2, pp. 315–323, 2008.
View at: Publisher Site | Google Scholar
K. Dhawan, S. Kumar, and A. Sharma, “Beneficial effects of chrysin and benzoflavone on virility in 2-year-old male rats,” Journal of Medicinal Food, vol. 5, no. 1, pp. 43–48, 2002.
View at: Publisher Site | Google Scholar
N. Saarinen, S. C. Joshi, M. Ahotupa et al., “No evidence for the in vivo activity of aromatase-inhibiting flavonoids,” Journal of Steroid Biochemistry and Molecular Biology, vol. 78, no. 3, pp. 231–239, 2001.
View at: Publisher Site | Google Scholar
C. Gambelunghe, R. Rossi, M. Sommavilla et al., “Effects of chrysin on urinary testosterone levels in human males,” Journal of Medicinal Food, vol. 6, no. 4, pp. 387–390, 2003.
View at: Publisher Site | Google Scholar
P. J. Tobin, P. Beale, L. Noney, S. Liddell, L. P. Rivory, and S. Clarke, “A pilot study on the safety of combining chrysin, a non-absorbable inducer of UGT1A1, and irinotecan (CPT-11) to treat metastatic colorectal cancer,” Cancer Chemotherapy and Pharmacology, vol. 57, no. 3, pp. 309–316, 2006.
View at: Publisher Site | Google Scholar
L. C. Souza, M. S. Antunes, C. B. Filho et al., “Flavonoid Chrysin prevents age-related cognitive decline via attenuation of oxidative stress and modulation of BDNF levels in aged mouse brain,” Pharmacology Biochemistry and Behavior, vol. 134, pp. 22–30, 2015.
View at: Publisher Site | Google Scholar
G.-S. Sim, B.-C. Lee, S. C. Ho et al., “Structure activity relationship of antioxidative property of flavonoids and inhibitory effect on matrix metalloproteinase activity in UVA-irradiated human dermal fibroblast,” Archives of Pharmacal Research, vol. 30, no. 3, pp. 290–298, 2007.
View at: Publisher Site | Google Scholar
K. V. Anand, M. S. Mohamed Jaabir, P. A. Thomas, and P. Geraldine, “Protective role of chrysin against oxidative stress in d-galactose-induced aging in an experimental rat model,” Geriatrics and Gerontology International, vol. 12, no. 4, pp. 741–750, 2012.
View at: Publisher Site | Google Scholar
N.-L. Wu, J.-Y. Fang, M. Chen, C.-J. Wu, C.-C. Huang, and C.-F. Hung, “Chrysin protects epidermal keratinocytes from UVA- and UVB-induced damage,” Journal of Agricultural and Food Chemistry, vol. 59, no. 15, pp. 8391–8400, 2011.
View at: Publisher Site | Google Scholar
B. Y. Khoo, S. L. Chua, and P. Balaram, “Apoptotic effects of chrysin in human cancer cell lines,” International Journal of Molecular Sciences, vol. 11, no. 5, pp. 2188–2199, 2010.
View at: Publisher Site | Google Scholar
M. Mandal and S. K. Jaganathan, “Antiproliferative effects of honey and of its polyphenols: a review,” Journal of Biomedicine and Biotechnology, vol. 2009, Article ID 830616, 13 pages, 2009.
View at: Publisher Site | Google Scholar
D. Sawicka, H. Car, M. H. Borawska, and J. Nikliński, “The anticancer activity of propolis,” Folia Histochemica et Cytobiologica, vol. 50, no. 1, pp. 25–37, 2012.
View at: Publisher Site | Google Scholar
R. Kachadourian and B. J. Day, “Flavonoid-induced glutathione depletion: potential implications for cancer treatment,” Free Radical Biology and Medicine, vol. 41, no. 1, pp. 65–76, 2006.
View at: Publisher Site | Google Scholar
S. Laishram, D. S. Moirangthem, J. C. Borah et al., “Chrysin rich Scutellaria discolor Colebr. induces cervical cancer cell death via the induction of cell cycle arrest and caspase-dependent apoptosis,” Life Sciences, vol. 143, pp. 105–113, 2015.
View at: Publisher Site | Google Scholar
S. M. Ronnekleiv-Kelly, M. Nukaya, C. J. Díaz-Díaz et al., “Aryl hydrocarbon receptor-dependent apoptotic cell death induced by the flavonoid chrysin in human colorectal cancer cells,” Cancer Letters, vol. 370, no. 1, pp. 91–99, 2016.
View at: Publisher Site | Google Scholar
J. R. Araújo, P. Gonçalves, and F. Martel, “Chemopreventive effect of dietary polyphenols in colorectal cancer cell lines,” Nutrition Research, vol. 31, no. 2, pp. 77–87, 2011.
View at: Publisher Site | Google Scholar
M. Pal-Bhadra, M. J. Ramaiah, T. L. Reddy et al., “Plant HDAC inhibitor chrysin arrest cell growth and induce p21WAF1 by altering chromatin of STAT response element in A375 cells,” BMC Cancer, vol. 12, article 180, 2012.
View at: Publisher Site | Google Scholar
J. A. van Meeuwen, N. Korthagen, P. C. de Jong, A. H. Piersma, and M. van den Berg, “(Anti)estrogenic effects of phytochemicals on human primary mammary fibroblasts, MCF-7 cells and their co-culture,” Toxicology and Applied Pharmacology, vol. 221, no. 3, pp. 372–383, 2007.
View at: Publisher Site | Google Scholar
H. A. Mohammed, L. A. Ba, T. Burkholz et al., “Facile synthesis of chrysin-derivatives with promising activities as aromatase inhibitors,” Natural Product Communications, vol. 6, no. 1, pp. 31–34, 2011.
View at: Google Scholar
Y. Xia, S. Lian, P. N. Khoi et al., “Chrysin inhibits tumor promoter-induced MMP-9 expression by blocking AP-1 via suppression of ERK and JNK pathways in gastric cancer cells,” PLoS ONE, vol. 10, no. 4, Article ID e0124007, 2015.
View at: Publisher Site | Google Scholar
H. M. Brechbuhl, R. Kachadourian, E. Min, D. Chan, and B. J. Day, “Chrysin enhances doxorubicin-induced cytotoxicity in human lung epithelial cancer cell lines: the role of glutathione,” Toxicology and Applied Pharmacology, vol. 258, no. 1, pp. 1–9, 2012.
View at: Publisher Site | Google Scholar
R. Kachadourian, H. M. Leitner, and B. J. Day, “Selected flavonoids potentiate the toxicity of cisplatin in human lung adenocarcinoma cells: a role for glutathione depletion,” International Journal of Oncology, vol. 31, no. 1, pp. 161–168, 2007.
View at: Google Scholar
X. Li, J.-M. Huang, J.-N. Wang, X.-K. Xiong, X.-F. Yang, and F. Zou, “Combination of chrysin and cisplatin promotes the apoptosis of Hep G2 cells by up-regulating p53,” Chemico-Biological Interactions, vol. 232, pp. 12–20, 2015.
View at: Publisher Site | Google Scholar
E. R. Kasala, L. N. Bodduluru, C. C. Barua, and R. Gogoi, “Chrysin and its emerging role in cancer drug resistance,” Chemico-Biological Interactions, vol. 236, pp. 7–8, 2015.
View at: Publisher Site | Google Scholar
C. Huang, Y. J. Chen, W.-J. Chen, C.-L. Lin, Y. X. Wei, and H. C. Huang, “Combined treatment with chrysin and 1,2,3,4,6-penta-O-galloyl-β-D-glucose synergistically inhibits LRP6 and Skp2 activation in triple-negative breast cancer and xenografts,” Molecular Carcinogenesis, vol. 54, no. 12, pp. 1613–1625, 2015.
View at: Publisher Site | Google Scholar
T. Walle, Y. Otake, J. A. Brubaker, U. K. Walle, and P. V. Halushka, “Disposition and metabolism of the flavonoid chrysin in normal volunteers,” British Journal of Clinical Pharmacology, vol. 51, no. 2, pp. 143–146, 2001.
View at: Publisher Site | Google Scholar
I. R. Bell, B. Sarter, M. Koithan et al., “Integrative nanomedicine: treating cancer with nanoscale natural products,” Global Advances in Health and Medicine, vol. 3, no. 1, pp. 36–53, 2014.
View at: Publisher Site | Google Scholar
P. Singh, J. Kaur, G. Singh, and R. Bhatti, “Triblock conjugates: identification of a highly potent antiinflammatory agent,” Journal of Medicinal Chemistry, vol. 58, no. 15, pp. 5989–6001, 2015.
View at: Publisher Site | Google Scholar
J. Jiang, S. Yao, H.-H. Cai, P.-H. Yang, and J. Cai, “Synthesis and synergetic effects of chrysin-organogermanium (IV) complex as potential anti-oxidant,” Bioorganic and Medicinal Chemistry Letters, vol. 23, no. 20, pp. 5727–5732, 2013.
View at: Publisher Site | Google Scholar
F. Yang, H. Jin, J. Pi et al., “Anti-tumor activity evaluation of novel chrysin-organogermanium(IV) complex in MCF-7 cells,” Bioorganic and Medicinal Chemistry Letters, vol. 23, no. 20, pp. 5544–5551, 2013.
View at: Publisher Site | Google Scholar
F. Yang, L. Gong, H. Jin et al., “Chrysin-organogermanium (IV) complex induced Colo205 cell apoptosis-associated mitochondrial function and anti-angiogenesis,” Scanning, vol. 37, no. 4, pp. 246–257, 2015.
View at: Publisher Site | Google Scholar
I. L. Martins, C. Charneira, V. Gandin et al., “Selenium-containing chrysin and quercetin derivatives: attractive scaffolds for cancer therapy,” Journal of Medicinal Chemistry, vol. 58, no. 10, pp. 4250–4265, 2015.
View at: Publisher Site | Google Scholar
Y. Matsumura and H. Maeda, “A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs,” Cancer Research, vol. 46, no. 12, part 1, pp. 6387–6392, 1986.
View at: Google Scholar
I. R. Bell, G. E. Schwartz, N. N. Boyer, M. Koithan, and A. J. Brooks, “Advances in integrative nanomedicine for improving infectious disease treatment in public health,” European Journal of Integrative Medicine, vol. 5, no. 2, pp. 126–140, 2013.
View at: Publisher Site | Google Scholar
R. Watkins, L. Wu, C. Zhang, R. M. Davis, and B. Xu, “Natural product-based nanomedicine: recent advances and issues,” International Journal of Nanomedicine, vol. 10, pp. 6055–6074, 2015.
View at: Publisher Site | Google Scholar
I. R. Bell, J. A. Ives, and W. B. Jonas, “Nonlinear effects of nanoparticles: biological variability from hormetic doses, small particle sizes, and dynamic adaptive interactions,” Dose-Response, vol. 12, no. 2, pp. 202–232, 2014.
View at: Publisher Site | Google Scholar
I. R. Bell and G. E. Schwartz, “Adaptive network nanomedicine: an integrated model for homeopathic medicine,” Frontiers in Bioscience, vol. 5, no. 2, pp. 685–708, 2013.
View at: Google Scholar
I. R. Bell, B. Sarter, L. J. Standish, P. Banerji, and P. Banerji, “Low doses of traditional nanophytomedicines for clinical treatment: manufacturing processes and nonlinear response patterns,” Journal of Nanoscience and Nanotechnology, vol. 15, no. 6, pp. 4021–4038, 2015.
View at: Publisher Site | Google Scholar
Y. Liang, X. Deng, L. Zhang et al., “Terminal modification of polymeric micelles with π-conjugated moieties for efficient anticancer drug delivery,” Biomaterials, vol. 71, pp. 1–10, 2015.
View at: Publisher Site | Google Scholar
H. Zheng, S. Li, Y. Pu, Y. Lai, B. He, and Z. Gu, “Nanoparticles generated by PEG-Chrysin conjugates for efficient anticancer drug delivery,” European Journal of Pharmaceutics and Biopharmaceutics, vol. 87, no. 3, pp. 454–460, 2014.
View at: Publisher Site | Google Scholar
E. Anari, A. Akbarzadeh, and N. Zarghami, “Chrysin-loaded PLGA-PEG nanoparticles designed for enhanced effect on the breast cancer cell line,” Artificial Cells, Nanomedicine, and Biotechnology, 2015.
View at: Publisher Site | Google Scholar
S. Mohammadinejad, A. Akbarzadeh, M. Rahmati-Yamchi et al., “Preparation and evaluation of chrysin encapsulated in PLGA- PEG nanoparticles in the T47-D breast cancer cell line,” Asian Pacific Journal of Cancer Prevention, vol. 16, no. 9, pp. 3753–3758, 2015.
View at: Publisher Site | Google Scholar
X. P. Yan Liang, Y. Chen, X. Deng et al., “Chain length effect on drug delivery of chrysin modified mPEG–PCL micelles,” RSC Advances, vol. 73, no. 5, pp. 59014–59021, 2015.
View at: Google Scholar
N. Zarghami, M. Mohammadinejad, A. Akbarzadeh, Y. Pilehvar-Soltanahmadi, and F. Zarghami, “Synergistic effects of chrysin-curcumin loaded in PLGA-PEG nanoparticles on inhibiting breast cancer cell line growth,” International Science Index, Chemical and Molecular Engineering, vol. 2, no. 12, 2015.
View at: Google Scholar
J.-A. Lee, B.-G. Jung, T.-H. Kim et al., “Poly d,l-lactide-co-glycolide (PLGA) nanoparticle-encapsulated honeybee (Apis melifera) venom promotes clearance of Salmonella enterica serovar Typhimurium infection in experimentally challenged pigs through the up-regulation of T helper type 1 specific immune responses,” Veterinary Immunology and Immunopathology, vol. 161, no. 3-4, pp. 193–204, 2014.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2016 Joohee Jung. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

3746

Downloads

1473

Citations