Advances in pharmacological action of bergamot lactone

XIE Shu-huan, FENG Ma-li

Shanxi Academy of Traditional Chinese Medicine, Taiyuan 030000, China

Keywords:

ABSTRACT Bergamot lactone has many pharmacological activities, such as anti-tumor, regulating blood sugar, improving insomnia, preventing osteoporosis, anti-aging, anti-inflammatory and anti-allergic, etc.In this paper, the main pharmacological effects of bergamot lactone are reviewed,which provides a theoretical basis and reference significance for the further study of bergamot lactone.

1.Introduction

Bergamot lactone, also known as 5 - metho xy supplement,molecular formula is : C12H8O4, is cou mar in compound, mainly exists in Qiang living, northern ginseng,Angelica dahurica,snake bed and other plants [1,2,3,4] , with anti - inflammatory,improve insomnia, anti - tumor, osteoporosis, anti-aging and other pharmacological effects[5].In recent years, the potential pharmacological effects of Bergamot has been further discovered.The study shows that Bergamot has inhibited liver cancer and nasopharyngeal cancer cells by regulating various sign aling path ways, and reviews the related role of Bergamot in recent years.

2.Anti-tumor action

In recent years, many scholars have found that Bergamot ester has a good effect in the treatment of tumors, so it has also become the focus of the researchers.Berg an ac tone acts on tumor cells in various ways and produces biological effects, but the drugs currently used to treat tumors have many side effects on the body, so seeking natural anti - tumor drugs has become the focus of future research.

2.1 Effects on nasopharyngeal carcinoma cells

Nasopharyngeal carcinoma is one of the high incidence diseases in China, There are a variety of clinical drugs for the treatment of nasopharyngeal carcinoma, In recent years, coumarins have been found to inhibit nasopharyngeal carcinoma cells, In contrast to the effects of several coumarin compounds on nasopharyngeal carcinoma cells, The Bergamot lactone can promote the apoptosis of CNE-2 and HONE-1 nasopharyngeal carcinoma cells, Apoptosis rate is more than 50%[6].Other studies have shown that Bergamot lactone can down-regulate mitochondrial membrane potential and mRNA and protein expression of BCL2 genes in nasopharyngeal carcinoma cells, Upregulation of mRNA and protein expression levels of BAX genes, TAT3 protein expression is constant, but downregulated the phosphorylation of its Y705 site, The mechanism of apoptosis may be related to down-regulation of BCL2 gene, upregulation of BAX gene and inhibition of STAT3 phosphorylation[7].studies such as Li Haiyun[8] found that low concentration of Bergamot lactone has a significant effect on inhibiting the specificity of tumor stem cells in nasopharyngeal carcinoma, may be associated with the activation of Hippo signaling pathways in tumor cells.

2.2 Effects on colon cancer cells

Colon cancer is a common and dangerous digestive tract disease,influenced by a series of factors such as body specificity, so that the application of chemotherapeutic drugs has been limited to a certain extent.However, some studies have shown that enzyme drugs can improve the [9] of adverse reactions of chemotherapeutic drugs to the body.5-fluorouracil (5-fluorouracil, 5-FU) is a fluorouracil analogue,it is widely used in the treatment of gastrointestinal and other related cancers.Studies have shown that Bergamot lactone enhances the sensitivity of colon cancer cells to 5-Fu.The mechanism may be [10]by inducing apoptosis, inhibiting EBI3/STAT3 signaling pathway and inhibiting the expression of CYP1B1 and MEKK2 related to drug resistance.

2.3 Effects on hepatoma cells

The liver is responsible for alcohol metabolism.In excess, the liver can't stop drinking alcohol after liver load, damage to liver tissue and function, severe liver cirrhosis and liver cancer.The proliferative activity of HepG2 and Hep3B cells treated with Bergamot lactone decreased significantly, concentrated, the expression of cysteine protease Caspase-3 and Caspase-8 protein was significantly increased.The expression of B lymphocytoma-2(Bcl-2) and PI3K protein decreased.The expression of PI3K and Akt mRNA also decreased to some extent, we hypothesized that Bergamot lactoneinduced apoptosis in HepG2 and Hep3B cells may be associated with [11] PI3K/Akt signaling pathway.p62/NF-κB signal axis is closely related to hepatoma apoptosis, low concentration of Bergamot lactone can promote apoptosis of hepatoma cells induced by cisplatin, may be associated with [12] inhibition of this pathway.

2.4 Effects on breast cancer cells

Breast cancer is a common gynecologic tumor, high incidence.According to statistics, at the first [13] of gynecologic malignancies,breast cancer is the result of multiple factors.Therefore, in the treatment also choose multi-target treatment.PTEN tumor suppressor gene, it is more likely to mutate in breast cancer and other female hormone related tumors.And showed a negative correlation with tumor development grade[15].PTEN encodes a protein/lipid phosphatase that controls phosphatidylinositol 3-kinase (PI3K)signaling, mediating autophagy in mammalian cells through its lipid phosphatase activity, to PI3K/AKT the inhibition of autophagy isolation of type III PI3- kinase by the pathway[17].In one study,Bergamot lactone induces autophagy in MCF7 and ZR-75 breast cancer cells, The expression level of Beclin1, PI3KIII, UVRAG,AMBRA was up-regulated to promote the transformation of LC3-I to LC3-II, thus showing the [18] of anti-inactivation reaction.

2.5 Effects on other tumors

Malignant glioblastoma is the most common, Bergamot lactone can significantly inhibit the growth of U87MG cells.It can also destroy its cell structure and make it appear autophagy vacuole, which is positively related to the dosage of administration, and the effect of high dose drugs on apoptosis is more obvious.The concentrationdependent inhibition of m-TOR and pm-TOR protein by Bergamot lactone treated tumor cells and the inhibition of PI3K/Akt protein expression were found in the test of related proteins by western blotting.The anticancer effect of Bergamot lactone may be related to[19,20] m-TOR/PI3K/Akt pathway.

3.Hypoglycemia

Diabetes is a chronic disease characterized by abnormal glucose metabolism due to endocrine disorders.According to its clinical manifestations and causes, it is divided into type 1 diabetes mellitus and type 2 diabetes mellitus.Type 1 diabetes is caused by heredity,because of the destruction of islet β cells.Type 2 is closely related to acquired factors.Multiple and impaired islet function and insufficient insulin secretion often lead to type 2 diabetes.The current treatment is mainly from the protection of islet β cells,improve insulin resistance, promote glycogen synthesis and other aspects of treatment [21].Hulu Ba Wan in "Taiping Huimin Hefang", for the classic treatment of intestinal gas.There are many active ingredients in fenugreek pill, among them, Bergamot lactone is one of the main components.In studying the relationship between Bergamot lactone and insulin, the hepatoma cells were cultured in a petri dish containing insulin, liver cancer cells treated with Bergamot lactone.Its glucose consumption and glycogen synthesis increased significantly.At the level of phosphorylation and transcription, the p85 regulatory subunits of estrogen receptor- (er ), akt/protein kinase B, phosphatidylinositol 3-kinase p85(pi3k85) were all significantly increased.We speculate that Bergamot lactone can activate PI3K/Akt pathway and reduce insulin resistance[22].But there are few studies on the hypoglycemic effects of Bergamot lactone.Its mechanism is unclear, the relationship between Bergamot lactone and blood glucose is a new direction in future research.

4.Improve insomnia

The increase of social pressure causes insomnia to expand,insomnia often appears fatigue, mental retardation and other symptoms, seriously affected people's daily life.Modern studies have shown that neurotransmitters in the brain play an important role in central regulation of sleep, with monoamine inhibitory neurotransmitter 5-hydroxytryptamine (HT) and amino acid neurotransmitter γ-aminobutyric acid (GABA).Modern pharmacological studies have shown that some coumarins have sedative and hypnotic effects and have a positive effect on neurotransmitters.Using p-chlorobenzalanine (PCPA) to establish a rat insomnia model, it is found that the latency of sleep in rats fed with Bergamot lactone is significantly lower than that in the model group and the sleep time is significantly, compared with the model group.The content of inhibitory neurotransmitter GABA increased and the content of excitatory neurotransmitter norepinephrine decreased.It is speculated that Bergamot lactone may improve sleep by regulating the[23,24] of neurotransmitters in the brain.

5.Prevention and treatment of osteoporosis

Both congenital and acquired factors can cause osteoporosis.Estrogen reduction is one of the main causes of the disease.As we get older, female estrogen secretion gradually decreased, inhibition of osteoclasts.Activation of osteoclasts leads to destruction and loss of normal bone cells, eventually lead to osteoporosis.Osteoporosis is a chronic disease, long-term use of estrogen is prone to adverse effects on the body.The rats were treated with Bergamot lactone.Cell 24, 48, 72 hours, the number of osteoblasts increased significantly, the expression levels of osteocalcin (BGP) and alkaline phosphatase (ALP) were significantly increased [25].Zheng and other[26] found that the built-in Buddhist function can significantly inhibit osteoclast formation, and bone resorption under lipopolysaccharidestimulated conditions.IL-1β can induce chondrocyte destruction in vitro, while Bergamot lactone was able to reverse this situation by inhibiting Il-1、Il-6、Tnf-α、Cox-2 and Mmp-13 expression [27].Other studies show that, dose response to mature osteoclast apoptosis after 24 h of Bergamot lactone was significantly enhanced [28].

6.Anti-aging effect

Aging is an essential stage of development in people growing up.The structural function of the tissues and organs is degenerative with age, until the end of the organ failure.It is irreversible.Although the effects of drugs does not prevent the process, but it can partly slow down the pace of aging.At present, most scholars' research on aging mostly starts with cells.Del aying aging can first starts with the cells.The mTOR pathway is closely related to the cells, play an important role in the various processes of its development.Model of hydrogen peroxide induced umbilical vein endo thelium aging found, pRb, of cells after Bergamot treatment.The pS6 protein expression levels have decreased, pAmpk, LC3-Ⅱ, Beclin-1 expression levels rise,positive number of stained cells and positive number of cell immun of luo res cence pS6 decreased.It provides a theoretical basis of [29]for activation of pAmpk-mTOR sign aling pathway.

7.Anti-inflammatory, anti-allergic effects

Inflammation is a common pathological process, can occur in various tissues and organs of the body.And it's double - sided,on the one hand, it plays a defensive role in external invasion, on the other hand, it damages the body.So anti-inflammatory is an essential step in the treatment of some diseases.Studies have shown that Bergamot extract Bergamot lactone has a significant inhibitory effect on interleukin-8[30].In vitro experiments, Bergamot lactone at concentrations of 10, 30, and 100 μg/mL for 15 minutes protects mast cells in rat mesenteric tissue, administration of Bergamot lactone at concentrations 3, 10, 30 mg/kg in vivo for 1 hour protects against 48/80-induced allergic reactions.Moreover, Bergamot lactone can significantly reduce pulmonary edema and congestion in bacterial lipopolysaccharide (LPS) mice [31].

8.Other

Bergamot lactone can present a dose-dependent reduction of liver tissue necrosis induced by paracetamol (APAP).Serum enzyme levels, liver pathology and factors related to oxidative stress such as malondialdehyde in mice treated with Bergamot lactone alone are in the normal range.It is speculated that Bergamot lactone has certain antioxidant properties and has protective effect on liver tissue [32].Besides, Bergamot lactone can promote melatonin secretion and increase the sensitivity of retina to light under certain conditions,and Bergamot lactone also has the function of inhibiting the enzyme responsible for melatonin metabolism, inhibiting melatonin metabolism.so that it can play the [33,34] of regulating circadian rhythm and regulating sleep in vivo.

9.Summary

Bergamot lactone, as a natural drug monomer, has a stable composition, has a wide range of pharmacological effects and has a good effect in many animal disease models.At present, most of the drugs in clinical use are difficult to develop, high cost and have great side effects on human body.Seeking natural drugs has become the trend of clinical use in the future.Bergamot lactone acts on the body through a variety of signaling pathways, exerting biological effects such as anti-cancer, improving insomnia, regulating blood sugar, improving osteoporosis, anti-inflammatory and anti-allergic,but the human body itself is a complex structure, and there may be corresponding links between the various pathways.This paper briefly reviews the pharmacological effects of Bergamot lactone in order to provide a theoretical basis for Bergamot lactone to become a new clinical drug.

Author's Contribution:

Xie Shu-huan: Paper Writing and Revision;Feng Mary: Proposed amendments.

All authors declare no conflict of interest.