Research Progress of Luteolin Biological Activity

Luteolin is a 3′,4′,5,7-tetrahydroxyflavone compound,which mainly exists in the chrysanthemum,travertine,goat milk,speranskia grass,honeysuckle and other plants,research in recent years found that it has a high biological activity.Now the research progress of luteolin in antitumor, cardioprotective effects, respiratory effects, immune regulation, anti-inflammatory effects and other aspects in recent years will be summarized below.

1 Anti-tumor effect
Fangfang Zhang et al[1] pointed out that luteolin is a plant flavonoid and anti-tumor promoter,which has a significant inhibitory effect on a variety of solid tumors, ascites cancer and leukemia cells. Luteolin also sensitizes a variety of apoptotic factors,which has multi-target antitumor potential.Liangzhen Cai[2] observed the effect of luteolin on protein kinase C activity in HL-60 cells,the result indicates that luteolin could significantly inhibit PKC activity in HL-60 cells and present dose-dependent relationship.The IC 50 was 2.38μmol / L, the effect is better than the positive control drug quercetin (IC50 = 2.54μmol / L).Luteolin,as a intracellular PK C inhibitor, has the potential value of anti-tumor clinical application.
It has been demonstrated that luteolin is a topoisomerase inhibitor that inhibits the proliferation of tumor cells.Dakai Xiao et al[3] studied the effect of luteolin on the in vitro invasive ability of ovarian cancer cell line HO-8910PM,the result shows that after luteolin treatment,the in vitro invasion and exercise capability of HO-8910PM cell presents a dose-dependent decline.The secretion of MMP-9 in HO-8910PM cells decreased and the expression of ERK2 protein decreased significantly, but the mRNA levels in TIM P-1 and NM 23 did not change significantly.It indicated that luteolin inhibited the transfer ability of ovarian cancer cell HO-8910PM in a dose-dependent manner in vitro, which was related to the inhibitory effect of luteolin on the secretion of MMP-9 and the down-regulation expression of ERK2 .At present, most of the studies on luteolin stay in vitro, so it is necessary to further study the anticancer effect of luteolin in vitro, as well as the efficacy, chemotherapy combined effect,mechanism and conditions of use and so on,these lay the foundation for the clinical application of luteolin anti-tumor effect[1].
2 Cardiovascular protection
Yuzhou He et al[4] firstly demonstrated the antagonistic effect of luteolin on H2O2-induced endothelial cell injury in vitro, and explored its possible mechanism for the first time.Luteolin reduces the inhibitory rate of H2O2 on endothelial cell growth in a dose-dependent manner, reduces the amount of MDA, LDH,increases the content of NO-2/NO-3,and significantly inhibits caspase-3 expression and decreases the amount of apoptotic cells.The result explains that luteolin can antagonize and repair hydrogen peroxide-induced vascular endothelial cell damage,its function is related to anti-oxidation,promote release and inhibition of caspase-3 expression.Guantao Du et al[5] established a H2O2 injury model in neonatal rat cardiomyocytes and observed the effects of different concentrations of luteolin (1×10 -6, 3×10 -6, 1×10 -5 mol/L) on the activity of hydrogen peroxide, the activity of superoxide dismutase (SOD) and the content of malondialdehyde (MDA).Compared with the normal group,the activity of LDH and the content of MDA in the model group increased ,the activity of SOD decreased( P <0. 01) . Compared with the model group,different concentrations of luteolin can reduce cell LDH activity and MDA content, increase the SOD activity.Results of the above experiments show that luteolin has a protective effect on H2O2 -induced cardiomyocytes injury in suckling rat.Yanling Mou et al[6] demonstrated through experiments that luteolin can significantly increase the cell viability of H2O2-injured cells, increase the activity of intracellular superoxide dismutase (SOD) and decrease the production of malondialdehyde (MDA) and intracellular reactive oxygen species (ROS) ,meanwhile,reduces intracellular calcium content.Results show that luteolin has an obvious protective effect on H2O2-induced oxidative injury of cardiomyocytes. The mechanism may be related to increasing free radical scavenging enzyme activity, protecting myocardial cell membrane integrity, maintaining the balance between antioxidative defense mechanism and free radicals and reducing intracellular Calcium overload.Qingfeng Yan et al[7] observed the influence and anti-oxidation effect of luteolin on lipid metabolism in experimental hyperlipidemic rats.The results showed that luteolin can significantly reduce the content of cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C) and serum lipid peroxide (MDA) in serum of hyperlipidemic rats, raise the content of high-density lipoprotein cholesterol (HDL-C) and decrease the arteriosclerosis index (AI). The results showed that it may increase the hyperlipidemic rat peripheral tissue cells of cholesterol transport to the liver,in order to reduce the accumulation of cholesterol in peripheral tissue cells and extensive damage to vascular endothelial cells to prevent the formation of atherosclerosis.In the experiment, luteolin was found to significantly inhibit the increase of MDA ,and increase the activity of serum superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in hyperlipidemic rats by gavage.The results indicated that luteolin could protect the activity of antioxidant enzymes in hyperlipidemia body and correct the disorder of free radical metabolism in various tissues,thereby maintaining the body’s oxidation and antioxidant system dynamic balance,reducing the toxic side effects of free radicals,further reducing the damage of lipid peroxidation on cardiovascular, which plays anti-atherosclerotic effect.Huidi Jiang et al[8] studied diastolic action of rat aorta and related mechanisms,the result indicates that Luteolin produces a non-endothelium-dependent relaxation in the aorta of rats,its mechanism may be related to inhibition of receptor-operated calcium channels (ROC), voltage-dependent calcium channel (VDC), decrease of intracellular calcium release and activation of K+ channel, but not with α receptor and β receptor.The vasodilatation of luteolin may be the main mechanism of its hypotensive effect.Xiaoping Chen et al [9] studied the correlation between collagen fibers and aldose reductase in the myocardium of early diabetic rats,the result showed that the aldose reductase in myocardial homogenate of diabetic rats was significantly higher than that of the normal group,and aldose reductase in myocardial homogenate decreased after luteolin treatment.Collagen fibers became more and thicker in myocardium tissue of rats after suffering from diabetes for 30days and 60 days,and collagen fibers became thinner after luteolin treatment.The changes of collagen fibers in the myocardium of early tested diabetic rats were related to the changes of the amount of aldose reductase.,luteolin could protect cardiomyocytes by inhibiting the activity of aldose reductase (A R).
3 Respiratory system effects
Guoqing Gong et al[10-11] observed the effects of luteolin at different doses on lung weight index, malondialdehyde content, hydroxyproline content and histological changes of bleomycin-induced pulmonary fibrosis in rats.The results showed that the above indicators of model rats had different degrees of inhibition, its morphology was also be significantly improved.Further study of the effect of luteolin on Transforming growth factor TGF-β1mRNA expression in lung tissue of lung fibrosis rat , the results show that the anti-pulmonary fibrosis of luteolin is related to the inhibition of TGF-β1 mRNA expression in lung tissue.Wenhui Fan et al[12-13] established the model of airway remodeling in asthma and used dexamethasone and luteolin respectively to intervene,observed the changes of levels of Interleukin-5 and Interferon-γ in bronchoalveolar lavage fluid.After repeated antigen challenge, the levels of interleukin-5 in asthmatic group were significantly higher than those in normal control group, dexamethasone group and luteolin group, but the levels of interferon-γ in asthma group were significantly lower than those in normal control group, dexamethasone group,luteolin group,bronchial wall thickness and smooth muscle thickness in asthma group were significantly higher than those in normal control group, dexamethasone group and luteolin group,indicating that luteolin has a significant anti-airway remodeling function.The further study of its mechanism of action shows that it achieves may be through the reduction of interleukin-5 secretion and the augment of the secretion of γ-interferon.The effects of luteolin on airway remodeling and airway Interleukin-13 receptorα2 ( IL-13Rα 2) expression in asthmatic mice were also observed.Studies found that the effect of luteolin inhibiting airway remodeling was similar to glucocorticoid,and there was a common mechanism – inhibition of IL-13Rα2 expression.Some scholars have reported that luteolin can inhibit the role of TNF-α, the latter can stimulate the expression of IL-13Rα2 together with IL-13[14-15].Some studies have found that luteolin can alleviate airway hyperresponsiveness and airway inflammation in asthmatic mice.Previous experiments found that Luteolin also participates in the regulation of immune responses and inflammation through other mechanisms,such as inhibiting NF-kB-mediated gene expression,Inhibiting the histamine release from murine mast cells and human basophils,to affect the function of some enzymes(such as tyrosine proteases,serine-threonine proteases)[17-18].AS a consequence,luteolin may be an effective drug intervention in asthma research or for the treatment of glucocorticoid-resistant and glucocorticoid-dependent asthma patients.
4 Immunomodulatory effect
VerbeekR[19] and other studies in vitro found that luteolin can inhibit the autoimmune T cell antigen-specific proliferation in rats and human and the production of IFN-γ.Luteolin can reduce the phagocytic function of macrophage and lysozyme activity in vivo in mice, and has a certain immunomodulatory effect.Hanjun Wu et al[21] further confirmed the proliferation and activation of the T cells in mice through the research, and reduced the biological activity of T cells by inhibiting the expression of IL-2mRNA and INF-γ mRNA.
5 Anti-inflammatory effects
Some studies have shown that the anti-inflammatory function of luteolin is associated with the release of inflammatory mediators and gene expression mediated by kB (NF-kB).Yi Zhang et al[22] observed the effect of luteolin on expression of nuclear factor kB(NF-kB) and cyclooxygenase2 (COX-2) inRAW264.7 cells (mouse monocyte/macrophage cell line) induced by lipopolysaccharide(LPS), and on the binding activity of NF -κB DNA,the result found that luteolin could significantly inhibit the LPS-induced PGE2 production in RAW264.7 cells, decrease the DNA binding activity of NF-κB, and down-regulate the expression of COX-2mRNA, NF-κB and COX-2 proteins induced by LPS.Xuguang Wang et al[23] then used enzyme immunoassay (EIA) to detect the effect of luteolin on PGE2 production,the expression of COX-2 and mPGES-1 mRNA by reverse transcription-polymerase chain reaction (RT-PCR) and the expression of COX-2 and mPGES-1 protein by western blotting,the result found that luteolin inhibited LPS-induced PGE2 production in RAW 264.7 cells and down-regulated LPS-induced COX-2 and mPGES-1 mRNA proteins expression in RAW264.7 cells,indicating that luteolin could inhibit the expression of two induced enzyme COX-2 and mPGES-1 in the PGE2 synthesis pathway,so as to down-regulate the biosynthesis of PG E 2, which may be one of the main mechanisms of luteolin anti-inflammatory.