The Pharmacological Activities of Siraitia grosvenorii (Swingle): Comparison
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Siraitia grosvenorii (Swingle) C. Jeffrey ex Lu et Z. Y. Zhang is a unique economic and medicinal plant of Cucurbitaceae in Southern China. For hundreds of years, Chinese people have used the fruit of S. grosvenorii as an excellent natural sweetener and traditional medicine for lung congestion, sore throat, and constipation. It is one of the first species in China to be classified as a medicinal food homology, which has received considerable attention as a natural product with high development potential. Various natural products, such as triterpenoids, flavonoids, amino acids, and lignans, have been released from this plant by previous phytochemical studies. Pharmacological research of the fruits of S. grosvenorii has attracted extensive attention, and an increasing number of extracts and compounds have been demonstrated to have antitussive, expectorant, antiasthmatic, antioxidant, hypoglycemic, immunologic, hepatoprotective, antibacterial, and other activities.

  • Siraitia grosvenorii
  • Cucurbitaceae
  • chemical compounds
  • pharmacological effects

1. Antitussive, Expectorant and Anti-Asthmatic Activities

Antitussive, expectorant, and anti-asthmatic activities of S. grosvenorii have been widely reported. Aqueous extract of S. grosvenorii (SGA) significantly inhibited coughs induced by concentrated ammonia or sulfur dioxide (SO2) in mice, as well as increasing the secretion of phenolsulfonphthalein in mice and the excretion of sputum in rats, resulting in a visible expectorant activity [84][1]. Sung [85][2] et al. investigated the anti-asthmatic activity of S. grosvenorii residual extract (SGRE) against ovalbumin (OVA)-induced asthma in mice. The restudyearch showed that oral administration of SGRE significantly reduced Th2 cytokines (IL-4, IL-5, and IL-13) and increased the Th1cytokine IFN-γ in the BAL fluid and supernatant of splenocyte cultures. SGRE decreased the OVA-induced increase of IL-13, TARC, MUC5AC, TNF-a, and IL-17 expression in the lung. Mogrosides could inhibit ammoniainduced cough in mice and promote mucus movement in the esophagus of frogs. According to the studyresearch, mogrosides (50, 100, and 200 mg/kg) enhanced sputum secretion in mice in a dose-dependent manner, and topical application of mogrosides enhanced ciliary cell motility in the frog respiratory tract. The results from intragastric administration showed that the anti-cough activity achieved by mogrosides positively correlated with dose, at a minimum inhibitory concentration of 80 mg/kg [86][3].

2. Antioxidant

Mogrosides have specific scavenging activities on hydroxyl and superoxide anion free radicals, which could reduce the occurrence of erythrocyte haemolysis, inhibit malondialdehyde production in liver mitochondria and oxidative haemolysis in rat erythrocytes, inhibit lipid peroxidation in rat liver tissues, and protect liver tissues from peroxidative damage caused by ferrous ions and hydrogen peroxide. A bioactivity experiment on S. grosvenorii polysaccharide (SGP) (molecular weight 1.93 × 103 kDa), has indicated [87][4] promising antioxidant properties in vitro, particularly in scavenging DPPH radicals. Among H2O2 oxidation-damaged PC12 cells, SGP reduced ROS and the percentage of apoptotic and necrotic cells in a dose-dependent way. Clearly, mogroside V (16) and 11-oxomogroside V (43) exhibited inhibitory activities on reactive oxygen species (O2−, H2O2 and -OH) and DNA oxidative damage. As compared with 11-oxo-mogroside V (43), mogroside V (16) is more active in the scavenging of -OH, and 11-oxo-mogroside V (43) is more active in the scavenging of O2− and H2O2, 11-oxo-mogroside V (43) also inhibited OH-induced DNA damage [60][5]. Meanwhile, mogroside V (16) promotes the anti-oxidative stress capacity of skin fibroblasts by modulating the scavenging of free radicals with antioxidant enzymes, which could be used to prevent skin aging or lesions. In MSF treated with H2O2, mogrosides V (16) reduced ROS levels and MDA content, together with an increase in superoxide dismutase (SOD), glutathione peroxide (GSH-Px), and catalase (CAT) activities [47][6]. Furthermore, mogroside extracts (MGE) inhibited BSA glycation, as evidenced by the formation of fluorescent advanced glycation end products (AGEs) at 500 μg/ml with lower levels of protein carbonate and Ne-(carboxymethyl) lysine. MGE may be a potential anti-glycation treatment for diabetic problems by inhibiting protein glycation and sugar oxidation [6][7]. According to studies [88][8], mogroside IIIE (41) could decrease the levels of inflammatory cytokines and oxidative stress-related biomarkers. Furthermore, with intervention by mogroside IIIE (41), HG-induced apoptosis in podocytes was inhibited. Through activation of AMPK-SIRT1 signaling, mogroside IIIE (41) alleviates HG-induced inflammation and oxidative stress in podocytes. Ethanol extract of S. grosvenorii (SGE) significantly increased load swimming duration to exhaustion in mice. It could potentially suppress the reduction of HB and LD production during exercise and promote the HB synthesis and LD clearance in the recovery period, thus maintaining a high level of exercise capacity. The active ingredients could effectively promote the increase of SOD and GSH-Px activities in myocardial tissues of mice, and significantly inhibit the increase of MDA. Moreover, they can timely scavenge the excess free radicals produced during exercise during the recovery period and effectively prevent or resist lipid peroxidation in the body, which has obvious protective effects on the heart and other tissue damage caused by exercise. It has a positive effect on delaying the incidence and development of exercise fatigue [89][9].

3. Antidiabetic and Antihyperlipidemic Activies

The hypoglycemic activity of cucurbitanes has been discovered, yet the underlying mechanism has not yet been discovered. Four cucurbitacins isolated from bitter melon (Momordica charantia L.) exhibit several beneficial biological activities against diabetes and obesity, whose hypoglycemic activity is associated with the enhanced effects of AMPK, a key pathway mediating glucose uptake and fatty acid oxidation, causing a decrease in fasting glucose and improving glucose tolerance in normal animals, diabetic animals, and humans [90][10]. Mogrol (1), 3-hydroxymogrol (3) and 3-hydroxy-25-dehydroxy-24-oxo-mogrol (54) are efficient AMPK activators in the HepG2 cell line. Both mogrol (1) and 3-hydroxymogrol (3) play a role in the hypoglycemic and anti-hyperlipid activities of this plant in vivo [25][11]. The MGE-fed diabetic mice induced a marked decrease in fasting plasma glucose (FPG), glucosylated serum protein (GSP), serum insulin and HOMA-IR in a dose-dependent manner, whereas insulin sensitivity, glucose, and insulin tolerance increased significantly. Lipid accumulation and adipose deposition improved and recovered to nearly normal at high doses [91][12]. Activation of AMPK signaling is dose-dependent.Accordingly, mRNA levels of hepatic glycogenicity and lipogenicity genes are down-regulated, whereas lipoxidation-related genes are up-regulated.

4. Anti-Inflammatory

S. grosvenorii residual extract (NHGR) is an inexpensive raw material. Sung [92][13] et al. investigated NHGR anti-allergic activity using in vivo models of atopic dermatitis (AD) characterized by mite allergens, alongside with its effects on keratocytes and immune cells. Treatment with NHGR in vitro restored the effects of pro-inflammatory cytokines on the increased filaggrin expression and reduced Dermatophagoides farinae mite antigen extract (DfE) induced phosphorylation of ERK, JNK, and p38, resulting in anti-inflammatory activity. Additionally, SGA enhanced monocyte phagocytosis in hydrocortisone injured mice and enhanced immune function [93][14]. Mogroside IIIE (41) is a compound with excellent anti-inflammatory properties, which has an improved effect on glucose metabolism, insulin resistance, and reproductive outcomes in gestational diabetes mellitus (GDM) mice. As a complication of the gestational disease, GDM clinically affects the health of mothers and infants. The treatment reduced inflammatory factor expression and alleviated GDM symptoms by enhancing AMPK activation, inhibiting HDAC4 expression, and decreasing G6Pase production [40][15]. Similarly, mogroside IIIE (41) inhibited lung fibroblast collagen production by blocking the direct differentiation of lung pericytes and resident fibroblasts induced by TGF-β or LPS. These findings suggest that mogroside IIIE (41) is an effective pulmonary fibrosis inhibitor. In vitro and in vivo models have been utilized to demonstrate that mogroside IIIE (41) significantly eliminates fibrosis in a mouse model of bleomycin-induced pulmonary fibrosis [41][16]. Acute lung injury (ALI) has a high mortality rate, but there is no effective treatment available. Molecular studies have shown that mogroside IIIE (41) increases AMPK phosphorylation while inhibiting toll-like receptor 4 (TLR4) overexpression. In addition, compound C (a pharmacological AMPK inhibitor) reversed the anti-inflammatory activity of mogroside IIIE (41) in LPS-induced ALI mice [42][17]. Mogroside IIIE (41) has the greatest inhibitory activity on NO (an important inflammatory factor) release from LPS-induced RAW264.7 cells, eliminating pulmonary fibrosis and demonstrating a decrease in myeloperoxidase (MPO) activity, collagen deposition and pathology scores. The expression of several fibrosis markers, such as liver fibrosis, has been significantly inhibited [94][18]. The anti-fibrotic activity of mogroside IIIE (41) may be due to downregulation of TLR4 signaling from fibroblasts as a result of its inhibiting activation by fibroblasts and deposition of ECM [95][19]. In the same way, TLR is the main innate immune factor activated by LPS. In the last few years, some evidence has shown that TLR4 activation binds to adaptor protein MyD88 and activates NF-κB [96][20]. Song [97][21] et al. provided evidence that mogroside V (16) has anti-asthmatic activity against OVA-induced asthma in mice. Effectively, mogroside V (16) reduced OVA-induced airway hyperresponsiveness and the number of inflammatory cells in bronchoalveolar lavage fluid (BALF). On histological examination, mogroside V (16) reduced IgE and IgG production and rectified the balance between Th1 and Th2 cytokines in asthmatic mice, which could be beneficial to potential protective mechanisms against OVA-induced asthma. Several lines of evidence suggest that microglia play a key role in the brain of AD patients and are critical in the pathogenesis of the disease, as activation of microglia promotes the release of pro-inflammatory factors that largely influence AD pathogenesis [98][22]. In a recent study, mogrosides V (16) has been proven to be active against LPS-induced neuroinflammation in microglia, significantly reducing the expression of pro-inflammatory proteins [99][23]. Simultaneously, mogroside IIE (12) inhibited trypsin and cathepsin B activity induced by cerulein and LPS in pancreatic islet cells AR42J and primary acinar (AP) cells in a dose- and time-dependent manner. Also, mogroside IIE (12) lower IL-9 levels in AP mice and reverse the inhibition of cytoplasmic calcium and the regulation of autophagy mediated by it [100][24].

5. Liver Protection

In THP-1 cells, high-purity mogroside V (16) suppresses reactive oxygen species generation and increases the expression of sequestosome-1 (SQSTM1, p62). Thus, mogroside could help treat obesity and non-alcoholic fatty liver disease (NAFLD) by strengthening fat metabolism and antioxidant function [101][25]. Mogroside V (16) also significantly ameliorate hepatic steatosis in mice fed a high-fat diet. Likewise, in free fatty acid (FFA) cultured LO2 cells, mogroside V (16) down-regulated de novo lipogenesis and up-regulated steatolysis and fatty acid oxidation, thereby reducing fat accumulation, improving hepatic steatosis induced by HFD, and alleviating the imbalance between lipid acquisition and lipid clearance [102][26].

6. Antibacterial and Antiviral Activities

General research has shown that flavonoids with fewer sugar groups have better antibacterial activity [68][27]. All the flavonoids have an inhibitory activity on Gram-positive bacteria but no inhibitory activity on Gram-negative bacteria. The MIC values of grosvenorine (74) and its four metabolites against Gram-positive bacteria were all less than 70 mg/mL, indicating that grosvenorine (74) and its four metabolites had antibacterial activity against gram-positive bacteria, showing the best antibacterial activity with kaempferol (72). MSSA are sensitive microorganisms. Afzelin (79), a flavonoid glycoside, has shown significant inhibitory activity against MSSA and MRSA, as well as Enterococcus. It is well known that flavonoids are strongly hydrophobic and readily penetrate bacterial phospholipid membranes to exert intracellular inhibitory activity [103][28]. In recent studies, β-amyrin (68), ergosterol peroxide (87), aloe-emodin (82), aloe-emodin acetate (83), and 4-hydroxybenzoic acid (91), all isolated from the leaves of S. grosvenorii. It has been demonstrated in vitro that they inhibit the growth activities of oral bacterial species, such as Streptococcus mutans, Actinobacillus, Clostridium sclerotiorum, and Candida albicans. Among all the active compounds, aloe-emodin (93) had the highest effects against all the tested bacteria and yeast, with MIC values ranging from 1.22 to 12.20 mg/mL [75][29]. As for this, researchers have discovered that ethanol-eluting via 50%, 70%, and 95% parts of S. grosvenorii has different inhibition rates against Escherichia coli bacterial biofilms (BBF), respectively. Therefore, the ethanol-extracted fraction of S. grosvenorii showed significantly better antibacterial activity than the water-extracted fraction [104][30]. The borderless transmission of coronavirus remains uncontrolled globally. The undetected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant reduces the therapeutic efficacy of vaccines against coronavirus disease 2019 (COVID-19). Clinical observations suggest that tumor cases are highly infected with coronavirus, possibly due to immunologic injury, causing a higher COVID-19-related death toll [105,106][31][32]. Based on network pharmacology analysis, the current restudyearch identified 24 candidate targets and 10 core targets for mogroside V (16) for treating COVID-19 [107][33]. Mogroside V may treat COVID-19 by targeting JUN, IL2, HSP90AA1, AR, PRKCB, VEGF, TLR9, TLR7, STAT3, and PRKCA. Further analysis using molecular docking suggested potent binding scores between mogroside V (16) and the core target protein in COVID-19. VEGF, a core protein docked well with mogroside V (16), has been identified as a pharmacological target in mogroside V (16) treatment of COVID-19. Clinically, VEGF may induce vascular impairment in gastrointestinal cells infected with SARSCoV-2 [108][34].

7. Miscellaneous Activities

Mogroside V (16) has comprehensive anti-cancer activities. The natural sweet compound mogroside V (16) could inhibit the proliferation and survival of pancreatic cancer cells by focusing on multiple biological targets. In both in vitro and in vivo models of pancreatic cancer, mogroside V (16) has tumor growth inhibitory activity by promoting apoptosis and cell cycle arrest in pancreatic cancer cells (PANC-1 cells), possibly through modulation of the STAT3 signalling pathway, promoting cell proliferation (CCND1, CCNE1 and CDK2), while also upregulating cell cycle inhibitors (CDKN1A and CDKN1B) [109][35]. Mogroside V (16) inhibited hypoglycemic-induced lung cancer cell migration and invasion by reversing EMT and disrupting the cytoskeleton. In lung cancer cells cultured under hypoglycemic conditions, the metastatic efficiency of mogroside V (16) was compared with normoglycemia, which reversed hyperglycemia-induced invasion and migration by upregulating E-Cadherin expression and downregulating N-Cadherin, Vimentin, and Snail expression. Meanwhile, the expression levels of Rho A, Rac1, Cdc42 and p-PAK1 protein were decreased in a dose-dependent manner [110][36]. After injection of Aβ1-42, mice showed a distinct increase in escape latency and a distinct decrease in the number of times they crossed the target and time spent in the target quadrant. Mogrol (1) could significantly alleviate memory impairment caused by Aβ1-42, inhibit microglia overactivation and prevent hippocampus apoptosis, downregulate the high expression of IL1β, IL-6, NF-kB p65, TNF-a induced by Aβ1–42, reduce the neuroinflammation [5][37]. Likewise, this plant plays a role in anti-aging. Rats fed with S. grosvenorii showed a slower ageing process. The experimental group maintained a stationary LSK state, decreased ROS level, augmented hematopoietic stem cells, and reduced the number of β-gal positive cells associated with aging, thus lowering the expression of aging-related proteins and slowing the aging process in rats [111][38].

8. Summary of Pharmacologic Activities

In conclusion, S. grosvenorii has a wide range of pharmacological activities (Table 41). Modern pharmaceutical research mainly focuses on extracts and chemical components, indicating the prospects of S. grosvenorii in the treatment of such diseases.
Table 41.
Pharmacological activities of
S. grosvenorii
.
Activities Detail Extracts/Compounds Concentration/Dose In Vivo/In Vitro Ref.
Antitussive, expectorant and anti-asthmatic activities increased the secretion of phenolsulfonphthalein in mice and the excretion of sputum in rats SGA 4000 and 8000 mg/kg in vivo [84][1]
reduced Th2 cytokines (IL-4, IL-5, and IL-13) and increased the Th1cytokine IFN-γ SGRE 200 mg/kg in vivo [85][2]
enhanced sputum secretion in mice and ciliary cell motility in the frog respiratory tract mogrosides 50, 100, and 200 mg/kg in vivo [86][3]
Antioxidant decrease ROS in oxide injury PC12 cells and decrease apoptotic and necrotic cells SGP 0.5, 1.0, 1.5, 2.0 mg/mL in vitro [87][4]
reduced ROS levels and MDA content, increase SOD, GSH-Px and CAT activities mogroside V 30, 60, and 90 µg/mL in vitro [47][6]
scavenging of -OH mogroside V PC12 cells

EC50 = 48.44 μg/mL		 in vitro [60][5]
scavenging of O2 and H2O2, inhibited -OH induced DNA damage 11-oxomogroside V PC12 cells EC50 = 4.79 μg/mL, EC50 = 16.52 μg/mL, EC50 = 3.09 μg/mL in vitro [60][5]
inhibited BSA glycation MGE 500 μg/mL in vitro [6][7]
decrease the levels of inflammatory cytokines and oxidative stress-related biomarkers mogroside IIIE MPC-5 cells 1, 10, and 50 μM in vitro [88][8]
inhibited the reduction of HB and LD and inhibited the increase of MDA, promoted the synthesis of HB and the clearance of LD SGE 1500 mg/kg in vivo [89][9]
Hypoglycemic increase AMPK phosphorylation mogrol HepG2 cell line 1, 10, and 20 μM in vivo [25][11]
increase AMPK phosphorylation 3-hydroxymogrol HepG2 cell line

1, 10, and 20 μM		 in vivo [25][11]
increase AMPK phosphorylation 3-hydroxy-25-dehydroxy-24-oxo-mogrol HepG2 cell line

4 μM		 in vivo [25][11]
downregulated mRNA levels of hepatic gluconeogenic and lipogenic genes, upregulated fat oxidation-associated genes MGE 300 mg/kg in vivo [91][12]
Immunology and anti-inflammatory increased filaggrin expression and reduced DfE induced phosphorylation of ERK, JNK and p38 NHGR 200 or 400 mg/kg in vivo [92][13]
enhanced monocyte phagocytosis in hydrocortisone injured SGA 2500 and 5000 mg/kg in vivo [93][14]
decreased expression of

IL-1b, IL-6, and TNF-a		 mogroside IIIE GDM model 20.0 mg/kg in vivo [40][15]
inhibited LPS-induced

inflammatory		 mogroside IIIE RAW264.7 cells

10 μM		 in vitro [40][15]
inhibited LPS-induced

inflammatory		 mogroside IIIE RAW264.7 cells

1, 10 or 50 μM		 in vitro [42][17]
reduced the OVA-induced activation

of NF-κB		 mogroside V 2, 5, and 10 mg/kg in vivo [97][21]
inhibited LPS-induced

inflammatory		 mogroside V BV-2 cells

6.25, 12.5 and 25 μM		 in vitro [99][23]
inhibited the IL-9/IL-9R/calcium overload/cathepsin B activation/trypsinogen activation pathway mogroside IIE AR42J cells

5, 10 and 20 μM		 in vitro [100][24]
Liver protection inhibited reactive oxygen species production and

upregulated sequestosome-1 (SQSTM1, p62) expression		 mogroside V 200, 400, and 800 mg/kg in vivo [101][25]
activated AMPK ameliorates HFD-induced hepatic steatosis mogroside V LO2 cells

15, 30, 60, and 120 μM		 in vitro [102][26]
Antibacterial and anti-viral inhibitory effects against gram-positive bacteria grosvenorine MIC less than 70 μg/mL in vitro [68][27]
inhibitory effects against gram-positive bacteria kaempferitrin MIC less than 70 μg/mL in vitro [68][27]
inhibitory effects against gram-positive bacteria and MSSA kaempferol MIC less than 70 μg/mL in vitro [68][27]
inhibitory effects against MSSA and MRSA afzelin MIC less than 70 μg/mL in vitro [68][27]
inhibitory effects against Streptococcus mutans, Actinobacillus actinobacillus, Clostridium sclerotiorum, and Candida albicans β-amyrin MIC = 48.80, >100, 48.40, and >100 μg/mL in vitro [75][29]
inhibitory effects against Streptococcus mutans, Actinobacillus actinobacillus, Clostridium sclerotiorum, and Candida albicans ergosterol peroxide MIC = 4.88, 48.80, 48.80, and 12.20 μg/mL in vitro [75][29]
inhibitory effects against Streptococcus mutans, Actinobacillus actinobacillus, Clostridium sclerotiorum, and Candida albicans aloe-emodin MIC = 1.22, 6.10, 12.20, and 6.10 μg/mL in vitro [75][29]
inhibitory effects against Streptococcus mutans, Actinobacillus actinobacillus, Clostridium sclerotiorum, and Candida albicans aloe-emodin acetate MIC = 6.10, 12.20, >100, and 6.10 μg/mL in vitro [75][29]
inhibitory effects against Streptococcus mutans, Actinobacillus actinobacillus, Clostridium sclerotiorum, and Candida albicans 4-hydroxybenzoic acid MIC = 12.20, >100, 12.20, and 12.20 μg/mL in vitro [75][29]
inhibitory effects against Escherichia coli bacterial biofilms different ethanol-eluting parts of S. grosvenorii MIC = 55.58, 78.32, and 87.62% in vitro [103][28]
regulation of VEGF mogroside V - in vitro [107][33]
Miscellaneous activities inhibited expression of the STAT3 pathway mogroside V PANC-1 cells

10, 100, and 250 μM		 in vivo and in vitro [109][35]
inhibited expression levels of

Rho A, Rac1, Cdc42 and p-PAK1		 mogroside V A549 and H1299 cells

0–50 μM		 in vitro [110][36]
inhibited expression of IL1β, IL-6, NF-κB p65, TNF-a induced by Aβ1–42 mogrol 20, 40, 80 mg/kg in vivo [5][37]
decrease the intercellular levels of ROS extract of S. grosvenorii 200 mg/kg in vivo [111][38]

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