What Are the Main Active Ingredients in Rosemary Extract?

Rosemary is a perennial shrub in the genus Rosmarinus officinalis of the family Labiatae of the order Dicotyledonaceae. Studies have shown that the main chemical constituents of rosemary extract are rosemarinol, rhamnol and rhamnolic acid, which are widely used in food industry, medicine and cosmetic field. Rosemary antioxidant is currently recognized as the best natural antioxidant in the world. The main chemical constituents and pharmacological effects of rosemary extracts are briefly described in order to provide reference for the efficient development and utilization of rosemary plant resources.

Rosemary (Rosmarinus oficinalis L.), also known as ayahuasca, is a shrub in the genus Rosmarinus of the family Labiatae of the order Dicotyledonaceae. Rosemary is native to the Mediterranean region of Europe and the Mediterranean coast of northern Africa, and is suitable for warm climates. In China, the earliest record of rosemary is found in "Gleanings from the Materia Medica". According to research, rosemary was introduced to China as far back as the Three Kingdoms period, and is now widely planted in the southern part of China[1] . 

The main demand for rosemary comes from the food industry and the fields of medicine and cosmetics[2-3] , of which the most important demand is in the food industry, which accounts for more than half of the total global demand for rosemary. The antioxidant extracted from rosemary is currently recognized as the best natural antioxidant in the world. Rosemary extract has astringent properties, can tighten the skin, promote blood circulation of the skin, so the demand for rosemary in the field of cosmetics is also large, accounting for about 32% of the total demand for rosemary. Modern research shows that rosemary has antibacterial, anti-AIDS, anti-tumor, anti-hepatitis, liver protection, antioxidant reduction, hypolipidemic, anti-inflammatory and analgesic, immunomodulatory, antiseptic, anti-thrombotic and so on[4-5] , and the demand in the field of medicine accounted for about 14% of the total demand of rosemary in the world. In this paper, the main chemical constituents of rosemary extracts and the pharmacological effects of rosemary are reviewed, and the effects of rosemary extracts in other fields are envisioned, in order to provide a reference for the efficient development and utilization of rosemary.

1 Chemical composition

The main chemical components of rosemary can be categorized into two major groups - volatile components (i.e. essential oils) and non-volatile components. Within the scope of this study, a variety of constituents such as terpenoids, flavonoids, organic acids, polybranched alkanes and amino acids have been extracted from rosemary[6] .

1.1 Terpenes

Terpenoids are the most complex and abundant components of rosemary[7] , including monoterpenes, sesquiterpenes, diterpenes and triterpenes.

1.1.1 Monoterpenes and Sesquiterpenes

Monoterpenoids and sesquiterpenoids are complex components that are mainly found in the essential oil of rosemary extracts. The essential oils of rosemary from different production areas are different due to the influence of the germplasm resources of rosemary and the soil environment, temperature, water and light during the growing process[8-10] . However, in general, its main components are α-pinene, camphene, β-pinene, 1,8-eudesmus, camphor, geranylgeranyl, verbenone, etc.[11] .

1.1.2 Diterpenes

The diterpenoids contained in rosemary will not decompose with water vapor distillation, and have high thermal stability, and can be divided into diterpene phenols and diterpene quinones. Among them, diterpene phenols are the main antioxidant components of rosemary, mainly rosemarinic acid, rosemarinol, rhamnol, rhamnolic acid, rhamnolic acid, methyl rhamnate, caffeic acid, coriander, etc.[12] . Among all the diterpene phenolic substances, rosemarinic acid is the most active[13] . The diterpene quinones of rosemary mainly include rosmariquione, royleanone, epitanshinone[14] , larch dikunone, 6, 7-dehydroroyleanone, 7-α-hydroxy-royleanone, and horimininone, etc. The diterpene quinones of rosemary include rosmariquione, rosmarinone, epitanshinone[15] , rosmariquione, 6, 7-hydroxy-royleanone, and horimininone.

1.1.3 Triterpenoids

The triterpenoids in rosemary are mostly triterpenoids, and their parent nuclei are ursane, oleanolic acid and lupane. Brieskorn et al.[15] found that the triterpenoids in rosemary stems and leaves included betulinol, betulinic acid, 19-α-hydroxyursolic acid, oleanolic acid, ursolic acid, epi-α-coumarinol, and 3β-hydroxyursolane-12,20-dien-17-oic acid. Chen Sili et al[16] experimentally isolated and identified seven constituents in rosemary, among which, the triterpenoids are 7, 24-tirucalladien-3β, 27-diol, tirucall-α-7, 24-dien-3β, 21, 23-triol, betulinol, and betulinic acid.

1.2 Flavonoids

Currently, more than 40 flavonoids have been extracted from rosemary. Studies have shown that terpenoids and flavonoids contain significant antioxidant activity in rosemary, with flavonoid content ranging from 2% to 3%[17] . The flavonoids mainly include quercetin, lignans, 6-methoxy lignans, apigenin, salicin, 8-methoxysorcinol, galangin, hesperidin, phegopolin, 5-hydroxy-7, 4-dimethoxy ketone, geraniol, and so on[18] .

1.3 Organic acids

The organic acids in rosemary accounted for about 5.55% of the extract, mainly including rosmarinic acid, caffeic acid, ferulic acid, chlorogenic acid, L-ascorbic acid, etc.[19-20] .

1.4 Other components

1.4.1 Trace elements

Wu et al.[21] used inductively coupled plasma-atomic emission spectrometry (ICP-AES) to determine the contents of nine trace elements in rosemary, and found that the contents of Fe, K, Mg, Mn, and Zn were relatively abundant. Yang Hongyun et al.[22] determined the trace elements in rosemary from Leishan County, Guizhou Province, and the results showed that the contents of Zn, Fe, Cu, and Mn in rosemary were high, and the toxic elements Cd and Pb were not detected.

1.4.2 Sugars and glycosides

Tiwalade et al.[23] isolated and identified 13 compounds from rosemary extract solution in 95% ethanol, among which the sugars and glycosides are (Z)-3-hexenyl glucoside, (Z)-3- hexenyl O-β-D-glucopyranosyl ( 1″ → 6 ′ ) -β-D- glucopyranoside, erythritol-1-O- ( 6-O-trans-caffeoyl ) -β-D-glucopyranoside, ( +) -syringaresinol, ( +) -syringaresinol, ( +) -syringarinol glucopyranoside, erythritol-1-O- ( 6-O-trans-caffeoyl ) - β-D-glucopyranoside, ( +) -syringaresinol-4 ′-O-β-D- glucopyranoside, 1, 2-di-O-β-D- glucopranosyl-4-ally- lbenzene, benzyl-O-β-D-apiofuranosyl- ( 1 → 2 ) -β- D-glucopyranoside and others.

Researchers have detected various fatty acids such as 10, 16-dihydroxyhexadecanoic acid, 9, 10, 18-trihydroxyoctadecanoic acid, and 6, 7, 160,000-trihydroxytetradecanoic acid in the stratum corneum of rosemary[24-25] , and some amino acids and multibranched alkanes have been detected in the extract of rosemary.

2 Pharmacological effects

2.1 Antimicrobial effects

A large number of scientific studies have shown that the main components of rosemary antibacterial are α-pinene, camphor and 1, 8-eudesmus, which belong to the essential oils of rosemary[26] . Liu Qian et al[27] used rosemary essential oil, tea tree essential oil and lavender essential oil as materials to conduct in vivo and ex vivo bacterial inhibition experiments on mice, and the results showed that the inhibitory effect of rosemary essential oil on Staphylococcus aureus, Streptococcus spp. and Escherichia coli was significantly higher than that of tea tree and lavender oils, and that different degrees of hemorrhages, blood spots, hard masses of lung tissue and other symptoms appeared on the lobes of the lungs of the mice infected with pneumonia, but after inhaling the essential oil of rosemary for 7 d, it was not possible to detect the symptoms of pneumonia. However, after inhaling rosemary essential oil for 7 d, the damaged parts of the lungs of the mice improved significantly, the hemorrhages and blood spots gradually decreased, and the hard tissues gradually became softer, approaching the morphology of the lungs of the mice in the negative control group. Zhang Zesheng et al[28] isolated petroleum ether fraction, ethyl acetate fraction, n-butanol fraction and water fraction from 80% ethanol extract of rosemary, and used these fractions to carry out bacterial inhibition experiments on seven kinds of bacteria, including Escherichia coli, Salmonella, and Staphylococcus aureus, etc. 

The results showed that, at the same concentration, petroleum ether and ethyl acetate fractions had strong inhibitory effects on the seven kinds of bacteria, and n-butanol fraction and water fraction had strong inhibitory effects on the seven kinds of bacteria. The results showed that at the same concentration, the petroleum ether and ethyl acetate fractions had a strong inhibitory effect on the seven bacteria, while the n-butanol and water fractions had a poorer inhibitory ability. Rosemary essential oil was encapsulated with oleic acid or chloroform to form microdroplets, and Chifiriuc et al[29] showed that these droplets were able to inhibit the adherence and biofilm formation of Candida albicans and Candida tropicalis, and Ojeda-Sana et al[30] found that the mechanism of the anticancer effect of rosemary was that 1,8-eudesmusine compounds disrupted the cell membranes of Escherichia coli. In addition, the non-essential oil constituents of Salvia divinorum are also currently recognized as having bacteriostatic effects[31] .

2.2 Antioxidant effects

Rosemary contains a variety of active ingredients, most of which have antioxidant properties and are natural and non-toxic antioxidants[32] . Zheng Qiuluo et al[4] dissolved 0.4% rosemary antioxidant in glycerol trioleate and compared it with blank glycerol trioleate, the peroxide value of glycerol trioleate with rosemary extract was lower than that of the blank, which indicated that rosemary has antioxidant effects on oils and fats. Lin Ruiyun[33] extracted the essential oil of rosemary from the shoots and leaves of rosemary by steam distillation, and tested the antioxidant activity of DPPH (1, 1-diphenyl-2-trinitrophenylhydrazine) against the common antioxidant Vitamin C (VC). The results showed that the scavenging rate of the essential oil of rosemary was higher than that of VC for the same concentration of DPPH radicals, and the scavenging rate was higher than that of VC, even when the concentration of the oil was diluted to 40%. Jongberg et al.[34] demonstrated that both rosemary essential oil and green tea extract have strong antioxidant activity and can effectively inhibit the oxidation of protein and fat.

It has been suggested that the antioxidant properties of rosemary are mainly due to the ability of its extracts to burst singlet oxygen, scavenge free radicals, cut off the chain reaction of lipid autooxidation, chelate metal ions, and the synergistic effect of organic acids, etc.[35] . The reducing substances contained in rosemarinic acid, such as phenolic hydroxyl groups, unsaturated double bonds and acids, have antioxidant effects when they are present individually, and synergistic antioxidant effects when they are combined together. It has been shown that the rhamnolic acid contained in rosemary can activate the silent mating type information regulator 2 homologous protein 1 pathway, thus reducing the oxidative damage of hydrogen peroxide on hepatocytes and inhibiting apoptosis[36] . Other studies have suggested that rosemary is an antioxidant because it reduces the production of reactive oxygen species, and also reduces the secretion or activity of caspase-3, caspase-9, and interleukin-6 (IL-6)[37] .

2.3 Antidepressant effects

Depression, also known as depressive disorder, is characterized by significant and persistent depressed mood. In mild cases, the depressed mood can range from sullenness to grief, low self-esteem and depression; in severe cases, pessimism or even suicide attempts or behaviors. Tong et al[38] investigated the antidepressant effects of two models of depression, namely, mouse tail suspension and mouse forced swimming, using different doses of rosemary and lemongrass essential oils as experimental groups, fluoxetine as a positive control group, and saline as a blank control group. The results of the mouse tail suspension test showed that compared with the blank control group, the medium dose of rosemary essential oil, low concentration of rosemary essential oil and high dose of lemongrass essential oil reduced the immobility time of mouse tail suspension, and the medium dose of rosemary essential oil had the best antidepressant effect; the results of the mouse forced swimming test showed that the medium dose of rosemary essential oil, low concentration of rosemary essential oil and high dose of lemongrass essential oil had the best antidepressant effect, and the medium dose of rosemary essential oil and high dose of lemongrass essential oil had the best antidepressant effect, and the medium dose of rosemary essential oil and high dose of rosemary essential oil had the best antidepressant effect. Ferlemi et al.[39] showed that rosemary tea was effective in reducing depressive and anxiety behaviors in rats, and that the active ingredients were silymarinic acid, caffeic acid, and lignoceroside 7-O-glucuronide. Rosemary tea has been shown to improve agitated depression in mice by reducing cholinesterase concentrations in the brain and liver. Comparatively, the cholinesterase inhibitors donepezil and galantamine have the same site of action as lignocaine 7-O-glucuronide, caffeic acid, rosmarinic acid, and acetylcholinesterase, and all of them can alleviate the depressive behaviors, which to some extent revealed the mechanism of antidepressant action of rosemary[12] .

2.4 Adjustment of the number of Bandai square meters

With the improvement of living conditions, people eat more and more abundantly, but sedentary, physical inactivity and other bad habits make the number of "three highs" (hyperlipidemia, hypertension, hyperglycemia) increasingly large. Shen Tingting et al[40] studied the effects of rosemary extract on the mechanisms of lipid regulation in hamsters fed a high-fat and high-cholesterol diet as an animal model. 

The experiment showed that compared with the control group, the triglyceride content of mice fed rosemary extract for 6 weeks decreased significantly, and the content of high-density lipoprotein (HDL) cholesterol increased, which indicated that the extract of rosemary was able to reduce the content of cholesterol in the livers of mice. Further analysis showed that rosemary extract could significantly reduce the expression level of mRNA of 3-hydroxy-3-methylglutaryl monoacyl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme for cholesterol synthesis, and increase the expression level of cholesterol 7-hydroxylase (CYP7A1), the rate-limiting enzyme for bile acid synthesis, in the livers of mice; thus, the ability of rosemary extract to lower blood lipids may be due to the inhibition of cholesterol synthesis and the increase in cholesterol levels in the liver. Therefore, the ability of rosemary extract to lower blood lipids may be realized by inhibiting cholesterol synthesis and enhancing the conversion of cholesterol to bile acids, thereby increasing cholesterol excretion.

Diabetic vasculopathy is partly caused by the elevation of monocyte chemotactic protein 1 (MCP1) and matrix metalloproteinase 9 (MMP9) in patients. Rosemary was first extracted with methanol, and then extracted with n-hexane, chloroform, ethyl acetate and n-butanol, and then applied to the smooth muscle cells and macrophages of rats, and it was found that the methanol and n-hexane extracts had the strongest inhibitory effects on MCP1 and MMP9. It was found that n-hexane extract had the strongest inhibitory effect on MCP1 and MMP9. The main component of n-hexane extract was rhamnosus acid[41] .

Rosemary extract can also inhibit the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ) and fatty acid-binding protein (FABP4) genes, thus inhibiting the proliferation and differentiation of mouse precursor adipocytes (3T3-L1). This suggests that rosemary can not only treat obesity, but also prevent obesity, and its main components of obesity inhibition are silymarinic acid and silybinol[42] .

2.5 Anti-neurological effects

Rosemary contains lignans, rhamnetin, and rosmarinic acid, which can reduce the expression of heat shock protein 74 in nerve cells, and may improve the damage and degeneration of nerve cells in stressful environments[43] . Alzheimer's disease is a neurodegenerative disease, which is accompanied by nerve cell damage and death. The pathological marker of Alzheimer's disease is the deformed deposition of β-amyloid, and the rhamnolipidic acid contained in rosemary can inhibit the formation of β-amyloid and the increase of poly(adenosine diphosphate) polymerase (PARP) induced by the enzyme[44-45] , suggesting that the rhamnolipidic acid contained in rosemary may have an intervening effect on Alzheimer's disease[46] .

2.6 Anti-inflammatory effects

Wu et al[47] concluded that one of the important causes of inflammation is the role of Nod-like receptor protein (NLRP) inflammasome.The mechanism of action of NLRP3 inflammasome is: after forming a protein complex-inflammasome, it first activates human cysteine protease-1, and then cytokine precursors, such as interleukin-1β, interleukin-18, etc., and then participates in cell death and inflammation[48] . The cell death and inflammatory responses are then involved[48] . In mice with oral ulcers modeled by applying rosemarinic acid powder to the ulcerated surface for 7 d, the ulcerated surface area of the mice with rosemarinic acid powder was significantly reduced compared with that of the control group, suggesting that rosemary has a role in anti-inflammation[49] .

 Linlin Zhang[49] used cellulase to extract the essential oils from the dried leaves of Dieffenbachia lilaca and used the extracted essential oils in an experiment on a mouse inflammation model. The results showed that the extracted essential oils were effective in resisting the acute inflammation of three kinds of diseases, namely, swelling of the auricle of mice caused by dimethylbenzene, hyper-permeability of the abdominal capillary vessels caused by acetic acid, and swelling of the feet caused by carrageenan gum. The extracted essential oils showed good resistance to these three acute inflammatory conditions in mice. Li Li et al[50] investigated the effects of rosemarinic acid on four models of inflammation, namely, swelling of mouse ear caused by xylene, hyperpermeability of mouse capillaries caused by acetic acid, granulomatous swelling of rat cotton balls, and adjuvant arthritis, and the results showed that rosemarinic acid had an inhibitory effect on the four models of inflammation. The activities of superoxide dismutase (SOD) and catalase (CAT) in the serum of mice with different types of inflammation increased with the increase of rosemary essential oil content, while the malondialdehyde (MDA) content in the tissues decreased with the increase of rosemary essential oil content. Accordingly, it has been suggested that the anti-inflammatory mechanism of rosemary may be related to free radicals.

2.7 Anti-tumor effects

It has been found that tumor cells are associated with ribonucleotide reductase (a key enzyme in the intracellular production of deoxyribonucleoside triphosphate), and that the activity of ribonucleotide reductase increases with the proliferation of tumor cells; therefore, in order to inhibit the proliferation of tumor cells, it is necessary to inhibit the activity of ribonucleotide reductase. Saiko et al[51] found that the activity of ribonucleotide reductase extracted from human leukemia cells treated with rosemarinic acid was significantly reduced. They believed that the mechanism of rosemarinic acid is to inhibit the activity of ribonucleotide reductase, reduce the production of dNTP, and thus inhibit the proliferation of tumor cells, and considered that rosemarinic acid has a very good effect on the prevention of tumors.

Another study found that the proliferation of cancer cells was related to the activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway and NF-κB pathway in activated B cells among the 11 signaling pathways of antitumor mechanism studied by Hong Zide et al [52]. Zhang Xiuying et al [53] investigated the effect of rosemarinic acid on human tongue cancer Tca8113 cells, and the results showed that rosemarinic acid had an inhibitory effect on Tca8113 cells, and the number of Tca8113 cells was significantly reduced with the increase of the concentration of rosemarinic acid. Cao Shujian et al.[54] studied the anti-breast cancer activity of the main antioxidant components of rosemary, and the results showed that the inhibitory effect on the proliferation of breast cancer cells was obvious, while the effect on normal mammary cells was almost non-existent, and it had a certain degree of selectivity.

2.8 Anti-aging effects

Wang Hong et al[55] used rosemary extract to conduct anti-aging experiments on the established D-galactose aging mouse model, and measured the SOD activity and MDA content as well as the hypoxia tolerance time of aging mice. The results showed that all doses of rosemary significantly increased the activity of serum and brain SOD and decreased the content of MDA in aging mice, and the time of hypoxia tolerance was significantly prolonged compared with that of aging mice, which indicated that the extract of rosemary has certain anti-aging effects.

2.9 Regulation of blood pressure

Clinical use of rosemary essential oil resulted in a significant increase in blood pressure in patients with essential hypotension, and when the drug was discontinued, the patient's blood pressure returned to the unadministered level without a rebound response[56] .

2.10 Anti-cirrhotic effect

When liver injury occurs, untreated liver fibrosis can lead to cirrhosis.Al-Attar et al[57] used rosemary leaf extract to investigate liver cirrhosis induced by thioacetamide (TAA) in mice, and the results showed that rosemary leaf extract could inhibit the liver physiology and pathohistological changes caused by TAA, and inhibit the development of cirrhosis.

3 Outlook

Rosemary plant contains phenols, acids, ketones, terpenes and other compounds, not only safe, non-toxic, easy to use, but also has the characteristics of light resistance, good temperature measurement, good stability, in the high-grade fats and oils, freeze-dried food, meat products, seafood, high-grade flavors, beverages, bakery products, oral liquid, royal jelly products and confectionery and other industries, it is recognized as the world's best natural antioxidant. In addition, rosemary is also a valuable spice plant, which can emit a fresh odor and has a refreshing effect. The essential oil extracted from rosemary can be used as a raw material for soaps, air fresheners, perfumes and other cosmetic products, as well as in shampoos and hair growth agents.

Rosemary is not only widely used in food and cosmetic industries, but also has good application prospects in medicine, with antibacterial, anti-AIDS activity, anti-tumor, anti-hepatitis, liver protection, antioxidant reductions, hypolipidemic, anti-inflammatory and analgesic, antiseptic, antithrombotic, antidepressant and so on, and it can provide the materials and ideas for the research and development of the relevant drugs.

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