Research Progress on Biological Activity of Sciadopitysin

Wenbo ZUO, Yannan LI, Hui XUE, Tong ZHANG, Yu ZHANG, Anqi WANG, Yue TENG, Yinghua LUO, Chenghao JIN*

1. College of Life Science & Technology, Heilongjiang Bayi Agricultural University, Daqing 163319, China; 2. College of Animal Science & Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing 163319, China

Abstract Sciadopitysin (SP) belongs to flavonoids. Recent studies showed that sciadopitysin has anti-tumor, anti-oxidation, treatment of osteoporosis, diabetic osteopathy, Alzheimer’s disease and other effects. This study will review the biological activity and related action mechanism of the sciadopitysin in recent years, in order to provide theoretical basis and reference for the future research and drug development of the sciadopitysin.

Key words Sciadopitysin, Anti-tumor, Anti-oxidation, Osteoporosis, Diabetic osteopathy, Alzheimer’s disease

1 Introduction

Sciadopitysin (SP) is a flavonoid found in gymnosperms such asCyperusrotundusL.,Cryptomeriafortunei,Podocarpusmacrophyllus,TaxusL., andGinkgobiloba. Molecular formula of sciadopitysin is C33H24O10, and molecular weight is 580.54, and the appearance is yellow crystal. It is soluble in acetone and ethyl acetate, slightly soluble in petroleum ether and water, and should be stored in a dark and cool place[1]. In recent years, the bioactivity of sciadopitysin has been gradually explored. Studies have shown that sciadopitysin has many pharmacological effects, such as anti-tumor, anti-oxidation, reducing blood glucose and blood lipid. In this paper, the bioactivity and action mechanism of sciadopitysin are reviewed.

2 Anti-tumor effect

Lung cancer is one of the malignant tumors that seriously threaten human life and health. With the acceleration of industrialization and environmental pollution, the mortality and incidence rate of lung cancer is increasing[2]. When non-small cell lung cancer is diagnosed, radiotherapy can be used to improve the survival rate, and G2/M phase is the most sensitive period of radiotherapy. Some studies have shown that paclitaxel can block the proliferation cycle of tumor cells in G2/M phase, improve the effect of tumor radiotherapy, enhance the ability to induce apoptosis of tumor cells or kill tumor cells directly[3]. However, when dosage of paclitaxel is too large, it will lead to drug resistance and side effects, which limits its clinical application. Sciadopitysin can reduce the adverse reactions caused by paclitaxel and promote paclitaxel inducing apoptosis of lung cancer A549 cells[4]. Via reverse transcription-polymerase chain reaction and western blotting, Zhao Xuemeietal.[5]found that sciadopitysin combining with paclitaxel could obviously up regulate the activity of protein caspase-3, promote the expression of Bax mRNA, and inhibit the expression of Bcl-2 mRNA. It is inferred that the combination of sciadopitysin and paclitaxel could enhance the effect of paclitaxel on Bcl-2 family at the levels of gene and protein, and further activate caspase-3, thereby promoting the effect of paclitaxel inducing apoptosis of A549 cells. It shows that sciadopitysin has an important value in lung cancer treatment, and opens up new ideas for clinical chemotherapy of lung cancer.

3 Anti-oxidation effect

Free radicals are normal metabolites of human body. When a small amount of it exists, it helps to maintain energy and eliminate inflammation. But when there are too many free radicals, it will lead to a series of diseases. Li Yingetal.[6]found that there are seven substances with significant antioxidant activity inTaxusLinn., containing sciadopitysin. Zhang Jialietal.[7]determined clearance rate andIC50value of DPPH and ABTS+free radical by sciadopitysin at 517 and 734 nm, and the results found that sciadopitysin had obvious antioxidant activity. Using 1, 1-diphenyl-2-picryhydrazy (DPPH), Lu Ruilietal.[8]studied scavenging activity of free radical in more than 60 gymnosperms. Sciadopitysin was found in some plants, and it was proved that sciadopitysin had stronger scavenging activity of free radical. This showed that sciadopitysin had antioxidant effect on some gymnosperms. In another animal experiment, Suhetal.[9]found that if sciadopitysin was used for the pretreatment of pancreas β cells and rat insulinoma cell line RIN-m5F, it can protect cells from methylglyoxal (MG)-induced cell death and impaired insulin secretion, and prevent interleukin-1β causing oxygen free radicals and cardiolipin peroxidation in cells, increase the activities of adenylate phosphate protein kinase and glyoxase I in RIN-m5F cells, and reduce the formation of MG-protein adducts. These results show that sciadopitysin has a certain protective effect on cell injury.

4 Effect on bone

4.1 Anti-osteoporosis effectBone tissue is in the dynamic process of continuous growth and reconstruction. The bone formation of osteoblast and the bone absorption of osteoclast commonly maintain the dynamic balance of bone. When osteoclasts over differentiate, it will lead to bone diseases, such as osteoporosis. Throughinvitroandinvivoexperiments, Cao Jinjin[10]explored the effect of sciadopitysin on anti osteoporosis. It was found that sciadopitysin could inhibit the activation of NF-κB signal path in a dose-dependent manner, and the transcription of osteoclast related genesCts-K,MMP-9,TRAP,NFATc1 andC-Fos, and further inhibit osteoclast differentiation and bone resorption activity. LPS is an important component of outer wall of gram negative bacteria. After intraperitoneal injection of LPS into mice, it was found that sciadopitysin could improve an increase in the number of osteoclasts caused by LPS, thereby proving that sciadopitysin has a significant therapeutic effect on LPS induced bone loss in mice[11]. Through pharmacological studiesinvivoandinvitro, Zhang Leietal.[12]found that sciadopitysin has estrogen like effect, which can significantly increase the bone mineral density, bone ash weight, bone calcium and bone phosphorus content of middle femur in rats with osteoporosis caused by retinoic acid. Liu Jinpeng[13]isolated sciadopitysin from the branches and leaves ofCunninghamialanceolata, and combined osteosarcoma cell MG-63-PERE with rat osteoporosis model induced by retinoic acid. It was found that sciadopitysin has better estrogen like effect and anti osteoporosis effect. These researches prove that sciadopitysin has a significant effect on the treatment of osteoporosis.

4.2 Protection of osteoblast functionSuhetal.[4]used osteoblast MC3T3-E1 to study the effect of sciadopitysin on osteoblast function and cell injury induced by antimycin A. It was found that when osteoblast MC3T3-E1 was directly exposed to antimycin A, the function of osteoblasts decreased significantly. However, pretreatment of osteoblast MC3T3-E1 with sciadopitysin peroxidase can maintain the level of adenosine triphosphate (ATP), inhibit the release of reactive oxygen species (ROS) and the increase of nitrotyrosine by preventing the decrease of mitochondrial membrane potential (MMP), thereby significantly reducing the cell injury induced by antimycin A, the generation of tumor necrosis factor TNF-α and oxidative stress. It can also increase the phosphorylation level of CREB inhibited by antimycin A. Moreover, sciadopitysin could significantly improve alkaline phosphatase activity, collagen synthesis, osteocalcin production and mineralization, and glutathione content, and the increase of these substances can promote the formation of mineralized stones. These results show that sciadopitysin could protect mitochondria from oxidative stress and activate CREB to protect osteoblasts MC3T3-E1 from antimycin A-induced cell damage by improving mitochondrial function.

4.3 Anti diabetic bone diseaseDiabetes mellitus (DM) is a kind of metabolic diseases of chronic hyperglycemia, and the number of people who die from diabetes every year is as high as 3.5 million[14]. Currently, various drugs used to treat diabetes often cause different side effects. Chen Jianweietal.[15]carried out the test of male Kunming mice. The experimental group was fed with high-fat diet, and the control group was fed with standard pellet diet. After four weeks, gavage and continuous administration were carried out. The results found that sciadopitysin could significantly inhibit the activity of α-glucosidase, decline blood glucose and blood lipid, and reduce the ratio of heart weight to body weight and abnormal histopathology in diabetic cardiomyopathy rats, and there were no adverse reactions. MG is the precursor of advanced glycation end products, and could lead diabetic complications including bone defects[16]. Choietal.[17]used osteoblast MC3T3-E1 to study the influence of sciadopitysin on cytotoxicity induced by MG, and found that sciadopitysin can play its therapeutic role by up regulating mitochondrial biosynthesis. The enhancement of mitochondrial biosynthesis may contribute to the protection of sciadopitysin on osteoblast MC3T3-E1 cells, and sciadopitysin can prevent diabetic bone disease by blocking MG mediated glycosylation system. This confirms that the sciadopitysin has certain effect in the treatment of diabetes and its complications, and lays a solid foundation for promoting its development as an effective drug for the prevention and treatment of diabetes.

5 Effect on Alzheimer’s disease

Alzheimer’s disease (AD) is a kind of progressive neurodegenerative diseases, and the main manifestations are behavioral disorders, deterioration of cognitive and memory functions, and continuous decline of daily living ability, accounting for 60%-80% of etiology of dementia. It is the most common cause of dementia known at present, often occurs in the elderly, and poses a serious threat to the life and health of the elderly[18]. The histopathological feature of Alzheimer’s disease is that extracellular amyloid-β (Aβ) peptides are deposited outside nerve cells to form neuroinflammatory plaques and intracellular nerve fiber tangles, and Aβ aggregates are neurotoxic substances in Alzheimer’s disease. Taking 95% ethanol extract ofTaxusLinn. as the material, Gu Qiongetal.[19]extracted five kinds of compounds, containing sciadopitysin. Using sulfur protein-fluorescence method, inhibition activity of the five kinds of compounds on Aβ accumulation was detected. It was found that sciadopitysin’s inhibitory effect on Aβ aggregation of primary cortical neurons and fibril formation is the most effective, and sciadopitysin could decline toxicity induced by Aβ, and increase survival capability of human neuroblastoma SH-SY5Y. It shows that sciadopitysin has great potential for the treatment of Alzheimer’s disease.

6 Drug interaction

It is well known that the combination of Chinese herbal medicine and western medicine can improve the curative effect, but the inhibition of drug metabolic enzymes by co-medication will also lead to drug-drug interaction (DDI). With the help ofinvitrometabolic incubation system, Wang Xinxinetal.[20]studied the inhibitory effect of sciadopitysin on 12 kinds of uridine diphosphate glucuronosyltransferases (UGTs). It was found that sciadopitysin had stronger inhibitory effect on UGT1A1, UGT1A3, UGT1A8 and UGT1A10. Moreover, when sciadopitysin combined with the drugs passing the metabolism of UGT1A1, UGT1A3, UGT1A8 and UGT1A10, all kinds of adverse reactions could be caused. For example, the combination of raloxifene and sciadopitysin could affect the reaction rate of glucuronidation binding, cause abnormal increase of blood drug concentration, and induce toxic reaction. However, when sciadopitysin combined with the drugs passing the metabolism of UGT1A1, UGT1A3, UGT1A8 and UGT1A10 but with higher treatment index, it can prolong the elimination half-life of drugs in vivo, so as to improve the curative effect. The results suggest that the combined application of sciadopitysin and clinical drugs can improve the therapeutic effect of drugs to a certain extent. But rational medication should be used, and it should pay attention to avoid adverse reactions caused by UGT inhibition.

7 Summary and prospect

Sciadopitysin mainly exists in gymnosperms, and its preparation method is simple and low cost[1]. After a number of studies, it is found that sciadopitysin has anti-tumor, antioxidant and other effects, and significant therapeutic effects on osteoporosis, diabetic bone disease and Alzheimer’s disease. This can avoid the disadvantage of drug resistance due to the single action mechanism of drugs. In order to further tap its higher use value, it is still necessary to conduct more in-depth research and discussion on sciadopitysin from the animal, cellular and molecular levels in combination with the relevant theories of traditional Chinese medicine, so as to make it more effectively used in clinic and play a therapeutic role.