Siraitia grosvenorii / Monkfruit (sweeter than sugar)

General features: Siraitia grosvenorii (SG) is the botanical name. It is widely known as monk fruit and is famed as a low-calorie sugar substitute, sweeter than any natural sugar; in addition, it has immense medicinal properties. The plant is primarily found in the mountainous regions of southern China, especially in Guangxi province. It is a perennial woody vine in the genus Siraitia and the Cucurbitaceae, or gourd family.  In Chinese, it is called Luo han guo, meaning “to achieve Nirvana” (liberation from the endless cycle of rebirth). In Buddhism, in ancient times,  ‘Arhat’ was a legendary monk in Buddhist mythology who gained enlightenment and longevity by consuming it daily. Historically, it has been cultivated for more than 300 years for medicinal needs, particularly to treat respiratory illnesses [1]. But its major use is directed to extracting the juice from ripened fruits and using it as a low-calorie sugar substitute, which is about 250 – 300 times sweeter than sucrose, a naturally available normal sugar molecule used in daily life [2]. The extract of SG/monk fruit contains a few mogroside derivatives (triterpene glycosides), which provide an extremely sweet taste, and is currently used as a low-calorie sugar substitute in foods and drinks. Among them, mogroside V provides the sweetest sensation [2].

Normally, the plant reaches 10 – 16 ft in length, climbing by using tendrils. The leaves are narrow and heart-shaped, 4 – 8 inches long. The fruits are oblong and 2 – 3 inches in diameter when ripe, turning to a yellow-brown color with a brittle cover-shell, 0.04 inches thick. The inside pulp is edible, and the seeds are pale yellow and ovate-shaped. The fruit possesses a pleasant sweetness, while its outer shell is primarily utilized for the preparation of tea [3]. The seeds take several months to germinate. The plant prefers shady surroundings covered by mist, protecting it from the direct sun. It is rarely found in the wilderness since it has been carefully cultivated for hundreds of years, mainly in southern China, such as in Guangxi and Guangdong provinces [4]. The plant is difficult to grow elsewhere in the world since it requires a very specific climatic condition. The commercial preparation for using it as a sweetener was patented in 1995 by Procter & Gamble. In recent days, SG/monkfruit has earned its reputation as a low-calorie sugar substitute for foods and drinks, and is nontoxic, and much sweeter (~300 times) than sugar. The fruit is also a good source of trace elements e,g, K (12.3 g/Kg), Ca (667 mg/Kg), Mg (550 mg/Kg), and vitamin C (~5100 mg/Kg) [5].

History: The fruit has a centuries-old history, recorded in the Buddhist monastery around the 13^th century in the mountainous regions of Southern China. The plant has been planted and cultivated mostly by the Buddhist monks for medicinal purposes as a remedy for cough, sore throat, or digestive problems, and also for healing other ailments. Its use as a natural sweetener has been reported in traditional Chinese medicine. The plant thrives in the subtropical, misty climate. So, besides China, SG also grows in northern Thailand. In the Chinese language, it is called “Luo han guo,” or “immortal fruit,” historically associated with longevity, named after the Luo Han Buddhist monks who inhabited those regions, and used it from the very early period. In the seventies and eighties, research on SG/monkfruit identified a few phytocomponents, mogrosides, that can act as natural sweeteners and are much sweeter than sucrose. Around 1993, a Japanese entrepreneur, while searching for a sugar-free alternative, discovered this fruit in China, which led to the modern-day extraction procedure. In 2010, the extract earned approval from the FDA (USA) to use in foods and drinks [6]. Later, in 2019, it also received approval from the European Commission [7]. Factually, Siraitia grosvenorii has been named after the President of the National Geographic Society, who supported the 1930 expedition to properly identify and locate its source [8].

Physiology behind the sweet sensation of mogrosides: Studies have already established that T1R2 and T1R3 are the receptors residing on taste buds of the tongue, responsible for sensing the sweet taste, also triggering pleasure pathways in the brain. The receptors are normally activated by interacting with the natural sugars such as sucrose, fructose, or lactose. Binding to these molecules triggers the receptor-linked G-proteins, signaling the pleasure center inside the brain, leading to sweet taste. The artificial or naturally occurring non-caloric sugar substitutes also act in a similar way [9,10]. In SG, mogrosides IV and V mostly create the major sweet sensation, directly activating the human sweet taste receptors T1R2/T1R3. The triterpene structure of mogroside V tends to bind to the receptor(s) with high affinity and with greater efficiency than other sugar moieties, evoking an intense signal. After binding to mogroside, the ligand-receptor complex activates intracellular signaling cascades, sending signals via cranial nerves VII, IX, and X to the brain [11]. Unlike sucrose, these receptors trigger a sweet taste without affecting sugar metabolism or an increase in blood sugar or insulin levels.  Interestingly, the intensity of the sweet sensation is seen to depend on the number of glycosylations on the triterpene molecule, mogrosides. The derivative mogroside V has greater glycosylation than the others, thereby producing a stronger sweet sensation [12]. Advantageously, mogrosides cause less aftertaste feeling compared to other sweeteners, including the artificial ones [13].

Traditional uses: Monkfruit has been traditionally used in China for several centuries. It is deeply rooted in traditional Chinese medicine and often used in healthy beverages or sweet desserts to provide a ‘cooling’ effect on the body, alleviating respiratory problems, sore throats, and coughs. As per folk medicine, it was also used as an anti-inflammatory to treat inflammation, fever, constipation, and heat stroke. Recent research has shown its potent antioxidant role. The fruit extract was largely used as a natural sugar substitute, intending not to elevate glucose or insulin levels in the blood. Possibly in that way, it controls diabetes [14]. In recent years, it has been mostly used as a sugar substitute.

Phytocomponents in SG/monkfruit: A large number of versatile phytochemicals have been identified in SG, which include flavonoids, polysaccharides, amino acids, and proteins [15]. Among those, the triterpene saponins attract more attention for their potent anti-inflammatory and antioxidant activities [16].

These triterpene saponins are considered to be the main active ingredients providing excellent sweet taste and flavor, and are known as mogrosides. They are unique cucurbitane-type tetracyclic triterpene glycosides exhibiting versatile pharmacological properties, such as anti-inflammatory, antitumor, antioxidant, and hypoglycemic. Uniquely, these mogrosides are the major source of sweetness. In this family, mogroside IV, V, and Siamenoside I exert the highest sweet sensation [17]. On the other hand, the flavonoids in SG are mostly quercetin and kaempferol, and their different glycoside derivatives, such as grosvenorine, which is also a major flavonoid in SG [18]. It inhibits the intestinal bacteria, affecting the pharmacological roles [15]. The total flavonoid content is 5 – 10 mg in a single fresh fruit. It has been proven that the flavonoid fraction of SG shows antibacterial, antioxidant, and blood glucose-lowering effects. Additionally, it also exhibits anti-aging, hepatoprotective, and anti-atherosclerosis activities [19,20].

The polysaccharides of SG are important bioactive compounds. Besides adding sweetness and a flavorful taste, they exert physiologically crucial regulatory roles by enriching the nutritional values, making it a good, healthy food ingredient. Until now, SGPS1, SGPS2, and SGP have been isolated. SGPS1 is an acidic heteropolysaccharide made of glucose, rhamnose, xylose, and arabinose. SGPS2 is composed of rhamnose and glucuronic acid. They show antioxidant and immunomodulatory roles and downregulate histamine in mast cells and can antagonize the immunosuppressive effects produced by cyclophosphamide [21,22]. These components also promote the proliferation of RAW264.7 cells (murine macrophage cell line), and significantly promote NO, IL-6, and TNF-α secretion, enhancing phagocytosis, and exerting potent immunomodulatory activity, affecting immune function, and regulating free radical levels [23,24]. The protein and amino acid content of dried fruits is 8.7–13.35%, and they lack tryptophan but are enriched in aspartic and glutamic acids. The others are threonine, leucine, isoleucine, lysine, and methionine. In a way, SG fruits are good sources of protein [25]. Further, a significant amount (27–33%) of grease or fatty matter is isolated from the dry seeds. Farnesol is seen as the major constituent. Besides farnesol, hexanal, glutaraldehyde, nonanal, and palmitic acid are also other components. On average, among them, farnesol accounts for ~ 52.4%. Additionally, squalene has also been isolated in a considerable amount (~12.5%). Physiologically, it resists hypoxia and promotes skin health [26]. Several other components have been identified in the SG extract. They are 1-acetyl-carboline (potent anti-inflammatory), maltol (flavoring), magnolol (neuroprotective), β-damascenone (flavoring, antagonist to estrogen receptor), benzoxazine derivative (anticancer, anti-proliferative), and vanillic acid (flavoring) [26].

Physiological and pharmacological effects: In general, SG/monkfruit shows a variety of beneficial effects, which include metabolic control, immunity, the respiratory system, and antitumor effects.

Metabolic control/anti-diabetic effect – Studies have shown that SG/monkfruit has great potential to control diabetes, mostly owing to mogrosides, enabling to reduce the blood sugar levels by inhibiting the conversion of glucose in the diet [27]. Mogrosides alleviate oxidative stress-related damage in diabetic rats by activating the Keap1-Nrf2/ARE pathway while protecting the pancreas [28]. They also improve glucose and lipid toxicity of pancreatic β-cells and inhibit their apoptosis. Research further indicates that these triterpene glycosides also reduce total cholesterol, triglycerides, and low-density lipoproteins while increasing the levels of high-density lipoproteins. It inhibits obesity, improves glucose tolerance and insulin sensitivity, and lowers adipose tissue inflammation [29,30]. Besides mogrosides, several other ingredients like polysaccharides and polyphenolics can also reduce the blood glucose level and promote insulin secretion, inhibit intestinal glucose absorption, and enhance the utilization of sugar by the tissues [31].

Antioxidant effect – The antioxidant activities of SG protect cells from any oxidative damage, while slowing down aging, reducing the risks of cardiovascular disease, cancer, and diabetes [32]. The mogrosides, polysaccharides, phenolics, and vitamin C exert strong antioxidant activity, potently scavenging the generated free radicals, delaying cellular aging, and protecting the cells from cellular damage. The aqueous extract of SG and mogrosides considerably enhances the actions of glutathione peroxidase and superoxide dismutase in a high-fat mouse model, simultaneously lowering the level of malondialdehyde [33]. Mogrosides alone dose-dependently (0.1 – 10 µg/ml) alleviate oxidative stress-induced reduction of PC12 cell viability and enhance the antioxidative capacity of the cells [34].

Anti-inflammatory effect – The extracts of SG show potent anti-inflammatory actions, controlling the release of mediators and blocking the inflammatory pathways, thereby minimizing the tissue damage owing to inflammation [35,36]. It has been observed that mogroside V can inhibit the activation, production, and expression of NF-κB, human CCAAT enhancer-binding protein δ, reactive oxygen species, and activator protein-1/heme oxygenase. It prevents the production of TNF-α, IL-1β, IL-2, IL-6, and NO, and the expression of p—P65, COX–2, and iNOS in ovalbumen-induced asthmatic mice and the LPS-treated RAW264.7 macrophage cell line [37]. Whereas the mogroside IIE shows the improvement of pancreatitis in mice and other cell models, downregulating the leukotriene receptor-interacting pathway [38].

Antitumor effect – Studies have shown that SG extract has an antitumor effect. Extraction by alcohol prevents the proliferation of the prostate cancer DU145, lung cancer A549, liver cancer HepG2, and nasopharyngeal cancer CNE1 and CNE2 cells [39]. The effects are dose-dependent and caused by elevating pro-apoptotic genes like caspase-3 and Bax proteins, and simultaneously, inhibiting anti-apoptotic genes like lymphoma/leukemia-2 and survivin B in cancer cells [40,41]. Additionally, extract enriched with mogrosides has shown anticancer activities toward prostate cancer PC-3 and bladder cancer T24 cell lines, lowering cell viability and inducing apoptosis [42]. The molecular docking analysis indicates that mogroside V can be used as a therapeutic agent [43].

Preventing pulmonary fibrosis – Mogrosides are noted to prevent pulmonary fibrosis [44,45]. Mogroside IIIE efficiently inhibits pulmonary fibrosis by modulating Toll-like receptor 4 (TL-4R)/myeloid differentiation factor-88/NF-κβ signaling pathway, preventing pulmonary inflammation and extracellular matrix deposition. On the other hand, mogroside IVE prevents liver fibrosis by inhibiting TL-4R signaling and hypoxia-inducible factor-1α [46].

Hepatoprotective effect – The hepatoprotective activities include anti-inflammatory, antioxidant, antifibrotic, and detoxifying effects, as well as stimulation of liver cell regeneration. Overall, these actions help maintain healthy liver function, reducing the risk of liver diseases. Besides the anti-fibrotic effect, mogrosides have shown a strong protective role on the injured liver induced by CCl₄ in laboratory mice and rats [46].

Effect on constipation – Consumption of SG efficiently can moisten the intestine, relieving constipation. The aqueous extract produces a laxative effect on normal and constipated animals. It also exerts antispasmodic effects on isolated intestines. It is noticed that mogrosides enhance the frequency, expediting bowel movements [47].

Effect on the nervous system – Studies have indicated that SG/monkfruit has a beneficial role on the nervous system, particularly owing to the presence of mogroside V and its other metabolite 11-oxo-mogroside V. Both of them can inhibit the neuronal damage created by dextromethorphan malate (cough medicine and a neurotoxin, a NMDA receptor antagonist) while promoting neurite growth and preventing cell apoptosis [48]. Additionally, mogroside V reduces rotenone-induced (rotenone, a phytogenic insecticide neural damage (experimentally induced Perkinson’s disease model) by lowering mitochondrial dysfunction by upregulating Sirtuin3 (SIRT3) [49].

Anti-fatigue effect – The fruit shows a prominent anti-fatigue effect. Its extract is effective in lowering fatigue while significantly increasing hepatic and muscle glycogen contents in fatigued mice [50]. In a laboratory model using weight-loaded swimming rats, it enhances the testosterone level, the body’s metabolism, and subsequently lowers fatigue. It is further noticed that mogroside V reduces erythropoietin level but enhances mitochondrial function [26].

Uses in food and nutrition: SG is mostly used as an excellent sweetener, substituting natural sugar. It is about 250 – 300 times sweeter than sucrose or lactose. Considering its nutritional ability, it is low in calories and rich in antioxidants. The major sweetening agent is mogroside V. Although there are mogroside derivatives that also taste sweet, but varying in their capacities. Numerous studies have proven that, besides acting as a natural sweetener, SG has superb pharmacological roles while acting as an antioxidant, anti-diabetic, anti-inflammatory, lipid lowering agent. All of the effects are highly beneficial to health. In overall considerations, SG is a highly nutritious fruit that also helps provide good health. Research also shows that it bears no significant toxicity [26].

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