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Received: 19 October 2016 | Revised: 22 February 2017 | Accepted: 28 February 2017

DOI: 10.1111/jfbc.12376

REVIEW

Apigenin: A current review on its beneficial biological activities

Xiang Zhou1 | Feng Wang1 | Ruijun Zhou1 | Xiuming Song2 | Meilin Xie1

1
Department of Pharmacology, Jiangsu Key
Laboratory of Preventive and Translational
Abstract
Medicine for Geriatric Diseases, College of Apigenin, identified as 40 ,5,7-trihydroxyflavone, is a natural flavonoid compound present in a vari-
Pharmaceutical Sciences, Soochow ety of fruits, vegetables, functional foods, and medicinal plants. Many studies have revealed that
University, Suzhou, Jiangsu Province,
apigenin has the cytostatic and cytotoxic effects on the various cancer cells, prevents the athero-
215123, China
2
genesis, hypertension, cardiac hypertrophy, ischemia/reperfusion-induced heart injury, and
Lianyungang Runzhong Pharmaceutical Co,
Ltd., Lianyungang, Jiangsu Province, 222069, autoimmune myocarditis, protects the chemicals- and ischemia/reperfusion-induced liver injury,
China inhibits the asthma, bleomycin-induced pulmonary fibrosis, abnormal behavior, and oxygen and
glucose deprivation/reperfusion-induced neural cell apoptosis, improves the pancreatitis, type 2
Correspondence
diabetes and its complication, osteoporosis, and collagen-induced arthritis. These biological effects
Meilin Xie, Department of Pharmacology,
Jiangsu Key Laboratory of Preventive and suggest that apigenin may be a potential health promoting agent. In the article, we will review
Translational Medicine for Geriatric these effects and possible biochemical mechanisms.
Diseases, College of Pharmaceutical
Sciences, Soochow University, 199 Renai Practical applications
Road, Suzhou Industrial Park, Suzhou Apigenin-rich chamomile, propolis, and garlic oil have been used in the prevention ane cure of
215123, Jiangsu Province, China.
hypertension and chemicals-induced liver injury as food supplements. However, their bioactive
Email: xiemeilin@suda.edu.cn
components and mechanisms have not been fully elucidated. Apigenin may be a common effective
Funding information component and play an important role in the process of therapy. In addition, apigenin itself may
Science and Technology Funds of Jiangsu also be considered as a potential functional food, but the further development will be needed to
Province, Grant/Award Number:
apply to the prevention and treatment of some-related diseases in the future.
BY2015039-09

KEYWORDS
apigenin, biological activity, natural products, plant flavonoids

1 | INTRODUCTION These beneficial effects of apigenin have aroused intense interest in


the development of health promoting agent in recent years. Therefore,
Apigenin, identified as 40 ,5,7-trihydroxyflavone (Figure 1), is a natural it is necessary to summarize these biological effects for being applied to
flavonoid compound present in a variety of fruits, vegetables, func- the prevention and treatment of some-related diseases in the future.
tional foods, and medicinal plants, such as oranges, garlic, propolis, and
chamomile. Its amount is particularly high in the parsley and celery
(Tsanova-Savova & Ribarova, 2013; Zhang, Zhou, Chen, Cao, & 2 | ANTITUMOR EFFECT
Tan, 2011). Literature data have revealed that apigenin has some
unique biological effects. In the lipopolysaccharide (LPS)-stimulated The data show that in a minute, there have been six people diagnosed
RAW264.7 macrophages, apigenin treatment may inhibit the TRAIL-R1 as cancer and five people died of this disease in China (Chen et al.,
expression, and the effect is more effective than that of flavonoid com- 2016b). The cancer chemoprevention has emerged as one of the major
 l,
pound chrysin or acacetin (Warrat, Szliszka, Korzonek-Szlacheta, Kro approaches (Steward & Brown, 2013). Some epidemiological studies
& Czuba, 2014). Also, apigenin intake, unlike the flavonoid compounds have proved that the civilians with a diet mainly containing the meat
myricetin, kaempferol, quercetin, and luteolin, can decrease the risk of are much more prone to the risk of breast cancer compared with the
ovarian cancer (Gates et al., 2009). Additionally, daily consumption of people who mainly consume the fruits and vegetables (Potentas,
5 g dried parsley containing 84 mg apigenin does not affect the platelet Witkowska, & Zujko, 2015).
aggregation in human volunteers, which is different from the 220 g Recent studies have demonstrated that apigegin may be a cancer
onions containing 114 mg quercetin (Janssen et al., 1998). chemopreventive agent (Shukla & Gupta, 2010), and the apigenin-rich

J Food Biochem. 2017;e12376. wileyonlinelibrary.com/journal/jfbc V


C 2017 Wiley Periodicals, Inc. | 1 of 11
https://doi.org/10.1111/jfbc.12376
2 of 11 | ZHOU ET AL.

and G2/M phase for myeloid HL60 cell (Ruela-de-Sousa et al., 2010),
and induce the DNA damage through downregulation of some related
genes involved in cell cycle control and DNA repair (Arango et al.,
2012). In addition, apigenin can suppress the adenine nucleotide
translocase-2 to enhance the Apo2L/TRAIL-induced apoptosis in pros-
tate cancer cells (Oishi et al., 2013) and downregulate the hypoxia
inducible factor-1a and VEGF expressions to inhibit the tumor angio-
genesis in human pancreatic cancer cells, prostate cancer cells, and
ovarian cancer cells (Fang et al., 2007; Melstrom et al., 2011).
FIGURE 1 Chemical structure of apigenin Recent studies have observed that apigenin may inhibit the tumor
proliferation via the alteration of energy metabolism and androgen bio-
diet also has the lower risks of breast cancer in women (Yap, 2015) and synthesis. The former is mainly related to the inhibition of glucose
prostate cancer in men (Labbe et al., 2015). Apigenin has cytostatic and transporter-1 expression in cultured cancer cells, and the antitumor
cytotoxic effects on various cancer cells at different doses (Table 1), effect of apigenin may be reversed by glucose transporter-1 overex-
including pancreatic cancer BxPC-3, PANC-1, AsPc-1, Panc-1, and pression and galactose supplementation (Fang, Bao, Zhou, & Fan,
MiaPaCa-2 cells (Johnson & de Mejia, 2013; Wu et al., 2014); prostate 2015; Lee et al., 2016). The latter shows that apigenin may be an inhib-
cancer DU145, LNCaP, and PC-3 cells (Oishi et al., 2013; Shukla, Fu, & itor of steroidogenic enzymes and subsequently result in the reduction
Gupta, 2014); breast cancer MDA-MB-231, MDA-MB-453, MBA-MB- of androgen production (Wang et al., 2016), which is beneficial for the
468, MCF-7, MCF-10A, and SK-BR-3 cells (Bai, Jin, Yang, Zhu, & Cai, treatment of prostate tumor. Conversely, apigenin may also inhibit the
2014; Harrison, Coombs, Delaney, & Hoskin, 2014; Seo et al., 2014); tumor cell proliferation, invasion, and metastasis by reducing the Wnt/-
ovarian cancer SKOV3 cell (Suh, Jo, Lee, & Lee, 2015); cervical cancer catenin and STAT3 signaling pathways and their downstream target
HeLa, CaSki, and C33A cells (Oh et al., 2008; Zheng, Chiang, & Lin, genes VEGF, metalloproteinase-2/9, and Twist1 (Cao et al., 2016; Liu
2005); lung cancer H1299, H460, and H2030 cells (Lee et al., 2016); et al., 2015b; Santos et al., 2015; Xu et al., 2016). Zhu et al. (2015)
glioma and glioblastoma C6, U251, and GL-15 cells (Santos et al., 2015; have demonstrated that apigenin can inhibit the epithelial-
Wang et al., 2013); osteosarcoma U2OS and MG63 cells (Liu et al., mesenchymal transition in prostate cancer, which also contributes to
2015b); papillary thyroid carcinoma BCPAP cell (Zhang et al., 2015a); its antimetastatic effect.
bladder cancer T-24 cell (Shi, Shiao, Lee, & Shih, 2015); colorectal can- These potential antitumor mechanisms are illustrated in Figure 2.
cer cells (Xu et al., 2016); and leukemia cells (Ruela-de-Sousa et al., Although apigenin may induce the autophagy of papillary thyroid carci-
2010). The antitumor effect of apigenin has also been validated in vivo noma BCPAP cell (Zhang et al., 2015a), a decreased autophagy is also
experiments, indicating that it can significantly prolong the survival observed in malignant neuroblastoma after the combinative application
time and suppress the tumor growth (Chen, Landis-Piwowar, Chen, & of N-4-hydroxyphenyl retinamide and apigenin (Mohan, Banik, & Ray,
Dou, 2007; Shukla et al., 2015b). 2011). Therefore, how the apigenin affects the autophagy is a valuable
The antitumor effect of apigenin may result from a complex inter- issue to research further.
play. Many data have shown that apigenin may block the phosphoryla-
tion and degradation of IjB a by inhibiting IKK activation, which in
turn lead to the suppression of nuclear factor (NF)-jB activation and 3 | EFFECT ON CARDIOVASCULAR SYSTEM
subsequent downregulation of NF-jB-mediated genes involved in the
proliferation (cyclin D1 and cyclooxygenase-2 [COX-2]), anti-apoptosis It estimates that nearly 90% of cardiovascular diseases are preventable.
(Bcl-2 and Bcl-xL), and angiogenesis (vascular endothelial growth factor The civilians with the habitual intake of flavonoids including apigenin
[VEGF] of cancer cells) (Johnson & de Mejia, 2013; Seo et al., 2014; have a smaller portion of hypertension, suggesting that apigenin-rich
Shukla et al., 2014, 2015a, 2015b; Wang et al., 2013; Wu et al., 2014). diet may prevent the cardiovascular disease (Cassidy et al., 2011; Jen-
Apigenin may also decrease the levels of cyclin A, cyclin B1, cyclin E, nings et al., 2012). It is reported that the olive extract containing apige-
CDK2, Cdc2, and Cdc25C to block the cell cycle progression (subG1 nin can block the calcium channel (Gilani, Khan, Shah, Connor, &
phase accumulation), and increase the levels of Bax, Bad, Bak, caspase- Jabeen, 2005), which contributes to the endothelial relaxation.
3, caspase-7, and caspase-9 to strengthen the caspase-dependent apo- The beneficial effect of apigenin itself on cardiovascular system is
ptosis in human bladder cancer T-24 cell (Shi et al., 2015). Apigenin presented in Table 2. Apigenin may protect the vascular endothelium
may act on the restoration of p53 nuclear localization and blockage of via the increment of nitric oxide level in the aorta (Jin et al., 2009), and
the CRM1-p53 association (Cai & Liu, 2008). It has been reported that it possesses the direct reduction of blood pressure via the inhibition of
the molecular targets of apigenin action may be the GTPase activation, angiotensin-conventing enzyme activity (Salah, Dongmo, Kamanyi,
membrane transport, and mRNA metabolism/alternative splicing Bopelet, & Wagner, 2001) and improvement of cardiac hypertrophy
(Arango et al., 2013). Apigenin may also block the leukemia cell prolifer- and abnormal myocardial glucolipid metabolism in hypertensive rats
ation through cell-cycle arrest in G0/G1 phase for erythroid TF1 cell (Zhu, Gao, Huang, Xue, & Xie, 2016).
ZHOU ET AL. | 3 of 11

TA BL E 1 Antitumor effect of apigenin

Dose and route Duration of


Type of test of administration experiment Major findings References

PC-3, DU145, OVCAR-3, 20–40 lM, in vitro 15 hr Decrease in HIF-1a and VEGF Fang et al. (2007)
HCT-8, MCF-7, and LNCaP cells expressions

MDA-MB-231 cell 25–100 lM, in vitro 24 hr Induction of cell apoptosis Chen et al. (2007)

TF1 and HL60 cells 50–200 lM, in vitro 5–24 hr Cell cycle arrest Ruela-de-Sousa et al.
(2010)

S2-013 and CD18 cells 25–50 lM, in vitro 24 hr Down-regulation of HIF-1a, Melstrom et al. (2011)
GLUT-1, and VEGF

SH-SY5Y, SK-N-BE2, 50 lM, in vitro 24 hr Promotion of cell apoptosis Mohan et al. (2011)
and IMR-32 cells

BxPC-3 and PANC-1 cells 10–50 lM, in vitro 24–48 hr Induction of cell apoptosis via Johnson and de Mejia
inhibition of GSK-3b/NF-jB (2013)
pathway

C6 glioma and PC12 cells 12.5–50 lM, in vitro 12–36 hr Activation of caspase-3 and 8, Wang et al. (2013)
increase in Bak expression and
decrease in Bcl-xL expression

DU145 and LNCaP cells 5–20 lM, in vitro 24 hr Enhancement of Apo2L/TRAIL- Oishi et al. (2013)
induced apoptosis

MCF-7 and MCF-10A cells 20–100 lM, in vitro 24–48 hr Production of ROS and induction of Bai et al. (2014)
apoptosis

AsPc-1, Panc-1, and MiaPaCa-2 cells 10–80 lM, in vitro 24 hr Inhibition of NF-jB signaling Wu et al. (2014)
pathway and Ku70-Bax interaction
to induce apoptosis

BALB/c nude mice 15–30 mg/kg, p.o. 6 weeks

PC-3 and DU145 cells 5–40 lM, in vitro 24 hr Inhibition of Bcl-2, Bcl-xL, and Shukla et al. (2014)
Ku70-Bax interaction to induce
apoptosis

athymic nude mice 20–50 lg/mouse, p.o. 8 weeks

MDA-MB-453 cell 20–100 lM, in vitro 24–72 hr Inhibition of STAT3 signaling path- Seo et al. (2014)
way

MDA-MB-231, MBA-MB-468, 10–50 lM, in vitro 24-72 hr Production of ROS and reduction of Harrison et al. (2014)
MCF-7, and SK-BR-3 cells Akt phosphorylation

C57BL/TGN TRAMP mice 20–50 lg/mouse, p.o. 20 weeks Inhibition of NF-jB- mediated gene Shukla et al. (2015b)
expression through IŒBa and IKK
pathway

WI-38, HT-1376, T-24, and PC-3 cells 1–50 lM, in vitro 24 hr Cell cycle arrest and inducing apop- Shi et al. (2015)
tosis

ACC‑2 cell 10–160 lM, in vitro 1–5 days Inhibition of glucose transporter-1 Fang et al. (2015)

GL-15, U251, and TG-1 cells 50 lM, in vitro 12–48 hr Regulation of extracellular matrix Santos et al. (2015)
metalloproteinases

SKOV3 and SKOV3/TR cells 10–40 lM, in vitro 1–10 days Inhibition of STAT3 signaling path- Suh et al. (2015)
way

HeLa cell 18.5–74 lM, in vitro 12–72 hr Induction of apoptosis via p53- Zheng et al. (2005)
dependent pathway

HeLa, CaSki, and C33A cells 3.125–25 lM, in vitro 24 hr Induction of apoptosis Oh et al. (2008)

U2OS and MG63 cells 25–100 lM, in vitro 24–96 hr Repression of Wnt/b-catenin path- Liu et al. (2015b)
way

DU145 cell 10–80 lM, in vitro 24-48 hr Repression of epithelial mesenchy- Zhu et al. (2015)
mal transition

BCPAP cell 12.5–50 lM, in vitro 24 hr Promotion of autophagic cell death Zhang et al. (2015a)
(continues)
4 of 11 | ZHOU ET AL.

TA BL E 1 (continued)

Dose and route Duration of


Type of test of administration experiment Major findings References

H1299, H460, H2030, A549, A375, 5–20 lM, in vitro 24 hr Inhibitions of glutamine metabolism Lee et al. (2016)
HCT116, and SW480 cells and glucose transporter-1

Rat immature Leydig cell 100 lM, in vitro 3 hr Repression of androgen biosynthetic Wang et al. (2016)
enzyme

SW480, HCT15, and HEK293T cells 5–80 lM, in vitro 48 hr Inhibition of Wnt/b-catenin path- Xu et al. (2016)
way

A375, G361, and B16F10 cells 5–40 lM, in vitro 24 hr Inhibition of STAT3 signaling path- Cao et al. (2016)
way

C57BL/6 mice 150 mg/kg, p.o. 24 days

THP-1 cell 50 lM, in vitro 3 hr induction of DNA damage Arango et al. (2012)

U2OS and IMR32 cells 40 lM, in vitro 3 hr Inhibition of Thr-55 phosphorylation Cai & Liu (2008)

PC3 and 22Rv1 cells 2.5–20 lM, in vitro 4–16 hr Blockage of IKKa activation Shukla et al. (2015a)

It is acknowledged that LDL, especially oxidized LDL, plays a major fusion injury, and its mechanisms are associated with the upregula-
role in the initiation of cardiovascular diseases due to the increment of tion of Bcl-2 expression and reduction of p38 mitogen-activated
inflammatory cell infiltration and subsequent cascade response in protein kinase signaling pathway (Chen et al., 2016a; Hu et al.,
endothelium. Apigenin can reduce the expressions of cell adhesion 2015; Yang et al., 2015). In LPS-induced model of heart injury, api-
molecules, including vascular cell adhesion molecule-1 and E-selectin in genin treatment decreases the serum inflammatory cytokines TNF-a,
oxidized LDL-stimulated human umbilical vein endothelial cells (Lii IL-1b, and IL-6 by inhibiting the SphK1/S1P signaling pathway
et al., 2010). Apigenin can also decrease the atherogenesis via the (Zhang, Yan, Juan, Wang, & Yang, 2015c), showing a protective
induction of macrophage apoptosis in ApoE(–/–) mice, which leads to effect. Apigenin also attenuates the experimental autoimmune myo-
the reduction of inflammatory cytokines, such as tumor necrosis carditis by modulating the Th1/Th2 cytokine balance in mice (Zhang
factor-a (TNF-a), interleukin (IL)21b, and IL-6 (Wang et al., 2015). et al., 2016) and acute myocardial infarction by inhibiting the matrix
The experimental data both in vivo and in vitro have confirmed metalloprotease-9 and inflammatory response in rats (Du, Hao, Liu,
that apigenin may protect heart/myocardium against ischemia/reper- Lu, & Yang, 2015).

FIGURE 2 Potential antitumor mechanisms of apigenin


ZHOU ET AL. | 5 of 11

TA BL E 2 Beneficial effect of apigenin on cardiovascular system

Dose and route of Duration of


Type of test administration experiment Major findings References

Sprague-Dawley rat 0.5–72 lM, in vitro 30 min Increase in nitric oxide Jin et al. (2009)
thoracic aorta

Human umbilical vein 20–50 lM, in vitro 16 hr Decrease in cell adhesion molecules Lii et al. (2010)
endothelial cells

ApoE(-/-) mice 100 mg/kg, p.o. 8 weeks Reduction of atherogenesis via induction of Wang et al. (2015)
macrophage apoptosis

Isolated rat heart 5 lM, in vitro 10 min Decrease in ischemia/reperfusion-induced Hu et al. (2015)
heart injury by inhibiting p38 MAPK signaling

Sprague-Dawley rats 5 mg/kg, i.v. None Decrease in ischemia/reperfusion-induced Yang et al. (2015)
heart injury by inhibiting p38 MAPK signaling

Wistar rats 10–40 mg/kg, i.p. 24 hr Decrease in acute myocardial infarction by Du et al. (2015)
inhibiting inflammatory response

H9c2 cell 10–40 lM, in vitro 5 min Decrease in inflammatory cytokines via SphK1/ Zhang et al. (2015c)
S1P pathway

Rats 50–100 mg/kg, p.o. 1 hr

Sprague-Dawley rats 50–100 mg/kg, p.o. 4 weeks Decrease in cardiac hypertrophy and abnormal Zhu et al. (2016)
myocardial glucolipid metabolism

H9c2 cell 10–80 lM, in vitro 24 hr Improvement of anoxia/reoxygenation -in- Chen et al. (2016a)
duced myocardial injury via Bcl-2 pathway

BALB/c mice 20–200 mg/kg, p.o. 21 days Reduction in autoimmune myocarditis by mod- Zhang et al. (2016)
ulating the balance of Th1/Th2 cytokines

4 | EFFECT ON LIVER et al., 2015). These findings suggest that apigenin possesses the
excellent scavenging reactive oxygen species (ROS) and inhibiting
Liver has various biological functions, such as metabolism of drug, inflammatory effects, indicating its potential ability as a food supple-
synthesis of protein, and regulation of glucolipid metabolism. Some ment to protect against toxicity from the residue pesticide in the
research data have demonstrated that apigenin may exert a foods. In addition, apigenin is also reported having the protective
protective effect on liver (Table 3). It may inhibit some chemicals- effect on ischemia/reperfusion-induced rat hepatic necrosis through
induced liver injury, such as acetaminophen, furan, and N- the regulation of Fas/FasL pathway (Tsalkidou et al., 2014).
nitrosodiethylamine (Ali, Rahul, Naz, Jyoti, & Siddique, 2014; Wang, However, it is noteworthy that apigenin treatment with 100 or
Chen, Hu, & Yuan, 2014a; Yang, Wang, Xue, Gu, & Xie, 2013), and 200 mg/kg once by intraperitoneal administration in Swiss mice may
the mechanisms may be related to the increment of hepatic antioxi- result in the increments of serum alanine aminotransferase, aspartate
dant ability including antioxidant glutathione and antioxidant aminotransferase, and alkaline phosphatase, and final hepatic damage
enzyme superoxide dismutase, and the reduction of hepatic inflam- (Singh, Mishra, Noel, Sharma, & Rath, 2012). The authors thought that
matory cytokines including TNF-a, IL-1b, and IL-6. After treatment the hepatotoxicity of apigenin may be from the enhancement of oxida-
of hepatoma HepG2 cells with apigenin, the expression levels of tive stress. Therefore, more specific study of apigenin on hepatic effect
Nrf2-mediated antioxidant genes also increase (Paredes-Gonzalez will be needed to clarify this issue.

TA BL E 3 Beneficial effect of apigenin on liver

Dose and route Duration of


Type of test of administration experiment Major findings References

Kunming mice 100–200 mg/kg, p.o. 7 days Increase in activity of hepatic glutathione Yang et al. (2013)
reductase

Wistar rats 1–4% solution, p.o. 21 days Protection of NDEA-induced hepatotoxicity Ali et al. (2014)

BALB/c mice 5–20 mg/kg, p.o. 7 days Protection of furan-induced hepatotoxicity Wang et al. (2014a)

Wistar rats 15 mg/kg, i.p. Once Decrease in ischemia/reperfusion-induced Tsalkidou et al. (2014)
hepatic necrosis via Fas/FasL pathway

HepG2 cell 1.56–6.25 lM, in vitro 6–12 hr Induction of Nrf2-mediated antioxidant Paredes-Gonzalez et al.
gene expression (2015)
6 of 11 | ZHOU ET AL.

TA BL E 4 Beneficial effect of apigenin on respiratory system

Dose and route of Duration of


Type of test administration experiment Major findings References

BALB/c mice 5–10 mg/kg, p.o. 6 days Inhibition of the Th17 cells Li & Zhang (2013)

THP-1 and 6.25–25 lM, in vitro 2 hr Decrease in inflammation by suppressing COX-2 Wang et al. (2014b)
J774A.1 cells and NF-jB pathway

THP-1 and 6.25–25 lM, in vitro 2 hr Inhibition of caspase-1 and ERK 1/2 activation Zhang et al. (2014b)
J774A.1 cells

Kunming mice 25–100 mg/kg, p.o. 7 days Inhibition of NF-jB-mediated lung inflammation Luan et al. (2016)

A549 cell 10–100 lM, in vitro 24 hr Decrease in inflammation through pro-inflammatory Patil et al. (2016)
mediators and AP-1 factors

ICR mice 20–200 mg/kg, p.o. 21 days Decrease in activities of lung matrix metalloproteinases Zhou et al. (2016)
and activation of lung TGF-b1

5 | EFFECT ON RESPIRATORY SYSTEM In the ovalbumin-induced model of asthma, apigenin may exert a pro-
tective effect via the inhibition of Th17 cells (Li & Zhang, 2013), indi-
The beneficial effect of apigenin on respiratory system is listed in cating that apigenin may correct the immune disorder of respiratory
Table 4. In animal models with asthma and acute lung injury, apigenin diseases via the regulation of T and B cell functions. However, much
shows an inhibitory effect on the infiltration of eosinophils in the lung works will need to do to fully elucidate the mechanisms of immune
tissue, consistent with the decreasing levels of inflammatory cytokines regulation.
including TNF-a, IL-6, and IL-1b (Li & Zhang, 2013; Luan, Meng, &
Jiang, 2016; Wang et al., 2014b). Apigenin may also inhibit the LPS-
induced inflammatory response (Patil et al., 2016; Zhang, Wang, Gur- 6 | EFFECT ON ENDOCRINE SYSTEM
ley, & Zhou, 2014b). Furthermore, the lung NF-jB and COX-2 expres-
sions also reduce, indicating that apigenin can block the upstream of Pancreas, an important glandular and digestive organ, secretes several
the inflammation loop, subsequently inhibit the inflammatory cytokine critical hormones such as insulin, glucagon, and digestive enzymes, and
production. Our previous works have demonstrated that apigenin can its injury may induce the pancreatitis and metabolic disorder like diabe-
inhibit the activity of matrix metalloproteinase and activation of trans- tes. Recent literature data show that apigenin has many beneficial
forming growth factor-b1, which may result in the reduction of effects on endocrine system (Table 5). It may exert a protective effect
bleomycin-induced pulmonary fibrosis (Zhou, Gao, Jiang, & Xie, 2016). against pancreatitis (Lampropoulos et al., 2013; Mrazek et al., 2015). In

TA BL E 5 Beneficial effect of apigenin on endocrine system

Dose and route of Duration of


Type of test administration experiment Major findings References

PSC cell 30 lM, in vitro 24–78 hr Inhibition of pancreatic stellate cells by Wang et al. (2012)
inducing apoptosis

C57/BL6 mice 50 lg/mouse, p.o. 5 weeks

Wistar rats 5 mg/kg, p.o. 6–72 hr Reduction of pancreatic inflammatory cell Lampropoulos et al.
infiltration and necrosis (2013)

A549 cell 0.5–100 lM, in vitro. 4 hr Inhibition of NAD1ase CD38 Escande et al. (2013)

C57BL/6 mice 100 mg/kg, i.p. 7 days

PSC cell 5–50 lM, in vitro 48 hr Inhibition of pancreatic stellate cells Mrazek et al. (2015)

C57/BL6 mice 50 lg/mouse, p.o. 4 weeks

Wistar rats 10–40 mg/kg, i.p. 7 week Improvement of diabetes-associated cogni- Mao et al. (2015)
tive decline by suppressing oxidative stress
and nitric oxide synthase

Sprague-Dawley rats 50–100 mg/kg, p.o. 6 weeks Amelioration of glucolipid metabolism and Ren et al. (2016)
vascular dysfunction

C57BL/6J mice 0.005% solution, p.o. 16 weeks Regulation of glucolipid metabolism Jung et al. (2016)

C57BL/6J mice 10–50 mg/kg, i.p. 21 days Inhibition of obesity-related inflammation Feng et al. (2016)
ZHOU ET AL. | 7 of 11

TA BL E 6 Beneficial effect of apigenin on central nervous system

Dose and route of Duration of


Type of test administration experiment Major findings References

Sprague-Dawley rats 10–20 mg/kg, i.p. 3 days Protection of neural cells Zhang et al. (2014a)

PC12 cell 1–20 lM, in vitro 8 hr Decrease in intracellular ROS production Guo et al. (2014)

PC12 cell 3–12 lM, in vitro 4 hr Decrease in expressions of inducible nitric oxide Liu et al. (2015)
synthase and COX-2

Sprague-Dawley rats 20 mg/kg, i.p. 23.5 hr Protection of neural cells Zhang et al. (2015b)

Hippocampal 30 lM, in vitro 10 min Inhibition of glutamate release by reducing the Cav2.1 Chang et al. (2015)
synaptosome of rats and Cav2.2 channels

PC 12 cell 3–12 lM, in vitro 4 hr Improvement of oxidative damage and promotion of Liu et al. (2015a)
apoptosis through the mitochondrial pathway

ICR mice 20–50 mg/kg, i.p. 7 Days Reduction in production of inflammatory cytokines Li et al. (2015)

RAW 264.7 cell 50 lM, in vitro 16 hr Improvement of immune cells and immune system Arango et al. (2015)

C57BL/6J mice 50 mg/kg, i.p. 3 hr

C57BL/6 mice, None, i.p. 30 days Modulation of dendritic cell and other immune cell Ginwala et al. (2016)
functions

SJL/J mice 40 mg/kg, p.o. 42 days

ICR mice 20–40 mg/kg, s.c. 21 days Upregulation of the brain-derived neurotrophic factor Weng et al. (2016)

vitro, apigenin may inhibit the pancreatic stellate cells via the induction of PC12 cells by regulating the expressions of Bcl2, Bax, caspase-3,
of apoptosis in a time- and dose-dependent manner (Wang et al., and p53.
2012). In the pancreatitis animal models, apigenin may also inhibit the Besides, in the corticosterone- and LPS-induced depressive animal
inflammatory cell infiltration and necrosis (Lampropoulos et al., 2013). model, apigenin treatment may significantly attenuate the abnormal
Apigenin also is effective in improving type 2 diabetes and its com- behavior in the tail suspension test and open field test, and its mecha-
plication, including vascular dysfunction and cognitive decline (Mao, nisms may be related to the upregulation of brain-derived neurotrophic
Yu, Liu, & Zhou, 2015; Ren et al., 2016). It can reduce the blood glu- factor and inhibition of inflammatory cytokine production (Li, Zhao, Qu,
cose, serum lipid, and insulin resistance index, and finally improve the Fu, & Ma, 2015; Weng, Guo, Li, Yang, & Han, 2016). The anti-
abnormal glucose tolerance in high-fat diet-induced obese mice (Jung, inflammatory effect may be from the suppression of inducible nitric
Cho, & Choi, 2016). Apigenin may ameliorate the obesity-related oxide synthase and COX-2 expressions (Li et al., 2015).
inflammation via the activation of PPARg in mice (Feng et al., 2016). It At present, the neuro-immunology has aroused intense interest in
1
is noteworthy that apigenin is reported to be an inhibitor of NAD ase the neural science study. More and more evidences indicate that the
CD38, which is closely related to the metabolic syndrome (Escande neural diseases have a close relationship with the imbalance of neuro-
et al., 2013) and may be a therapeutic target of this disease. immunology in the central nervous system. Apigenin may affect the
biological functions of dendritic cells and other immune cells (Ginwala
et al., 2016). Arango et al also have demonstrated that apigenin can
restore the balance of immune system through the regulation of micro-
7 | EFFECT ON CENTRAL NERVOUS
RNAs (Arango et al., 2015).
SYSTEM

As shown in Table 6, apigenin has a protective effect on the neural 8 | EFFECTS ON BONE AND JOINT
cells (Guo et al., 2014; Liu et al., 2015a; Zhang, Li, & Chen, 2014a;
Zhang et al., 2015b). It may enhance the blood-brain barrier via the The effect of apigenin on bone metabolism shows a prospective out-
reduction of toll-like receptor 4/NF-jB-mediated inflammation (Zhang look in ovariectomy-induced osteoporosis murine (Goto, Hagiwara,
et al., 2015b), inhibit the glutamate release by reducing the Cav2.1 and Shirai, Yoshida, & Hagiwara, 2015; Park et al., 2008). The research
Cav2.2 channels in rat hippocampus nerve terminals (Chang et al., results indicate that apigenin can increase the mineral content and
2015), and decrease the lactate dehydrogenase release and intracellular bone density by activation of osteoblasts and inhibition of osteoclasts,
ROS level in 1-methyl-4-phenylpyridinium ion- or oxygen and glucose which mean a positive effect on bone turnover. Apigenin may delay
deprivation/reperfusion-treated PC12 cells (Guo et al., 2014; Liu et al., the onset and reduce the severity of arthritis in collagen-induced arthri-
2015a). The latter may be related to suppressing the apoptosis tis in mice, and the effect may result from the reduction of dendritic
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cell maturation, inflammatory cytokine secretion, and matrix metallo- apigenin-mediated anti-metastatic effect in melanoma. Scientific
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there are rarely research data elucidating its exact mechanisms on Cassidy, A., O’reilly, E. J., Kay, C., Sampson, L., Franz, M., Forman, J. P.,
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9 | CONCLUSION Chang, C. Y., Lin, T. Y., Lu, C. W., Wang, C. C., Wang, Y. C., Chou, S. S. P.,
& Wang, S. J. (2015). Apigenin, a natural flavonoid, inhibits glutamate
release in the rat hippocampus. European Journal of Pharmacology, 762,
The current literature data show that apigenin has many beneficial 72–81.
effects, including antitumor effect, biological organ protection (heart, Chen, D., Landis-Piwowar, K. R., Chen, M. S., & Dou, Q. P. (2007). Inhibi-
brain, liver, and lung), hypotension, hypoglycemia, lipid-lowering effect, tion of proteasome activity by the dietary flavonoid apigenin is asso-
antioxidation, anti-inflammation, anti-osteoporosis, and immune regula- ciated with growth inhibition in cultured breast cancer cells and
xenografts. Breast Cancer Research, 9, R80.
tion, which are helpful for understanding the health care functions of
Chen, C. J., He, H., Luo, Y., Zhou, M., Yin, D., & He, M. (2016a). Involve-
apigenin-rich foods. In addition, apigenin itself is also applied to the pre-
ment of Bcl-2 signal pathway in the protective effects of apigenin on
vention and treatment of some-related diseases as a potential functional anoxia/reoxygenation-induced myocardium injury. Journal of Cardio-
food, but much works remain to be done in detailing its exact mecha- vascular Pharmacology, 67, 152–163.
nisms. Considering the fact that high dosage of apigenin may induce the Chen, W. Q., Zheng, R. S., Baade, P. D., Zhang, S., Zeng, H., Bray, F., . . .
hepatotoxicity, future studies are still required to address its safety. He, J. (2016b). Cancer statistics in China, 2015. CA: A Cancer Journal
for Clinicians, 66, 115–132.
Du, H., Hao, J., Liu, F., Lu, J. C., & Yang, X. C. (2015). Apigenin attenu-
ACKNOWLEDG MENT ates acute myocardial infarction of rats via the inhibitions of matrix
metalloprotease-9 and inflammatory reactions. International Journal of
This work was supported by a grant from the Science and Technol-
Clinical and Experimental Medicine, 8, 8854–8859.
ogy Funds of Jiangsu Province (No. BY2015039-09), China.
Escande, C., Nin, V., Price, N. L., Capellini, V., Gomes, A. P., Barbosa,
M. T., . . . Chini, E. N. (2013). Flavonoid apigenin is an inhibitor of the
NAD(1)ase CD38 implications for cellular NAD(1) metabolism, pro-
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