Pharmacological Properties of Steviol Glycosides

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1		Adriana Orellana-Paucar	--	2153	2023-08-15 09:07:12	\|
2	references update	Fanny Huang	+ 1 word(s)	2154	2023-08-16 03:30:13	\|

This entry is adapted from the peer-reviewed paper 10.3390/molecules28031258

Stevia rebaudiana Bertoni (Asteraceae) is a small perennial herb endemic to South America. Dry stevia leaves have been used to sweeten traditional bitter drinks. Steviol glycosides exhibit a superior sweetener proficiency to that of sucrose and are noncaloric, noncariogenic, and nonfermentative. Scientific evidence encourages stevioside and rebaudioside A as sweetener alternatives to sucrose and supports their use based on their absences of harmful effects on human health. Moreover, these active compounds isolated from Stevia rebaudiana possess interesting medicinal activities, including antidiabetic, antihypertensive, anti-inflammatory, antioxidant, anticancer, and antidiarrheal activity.

stevia steviol glycosides S Stevia rebaudiana Stevia rebaudiana pharmacological properties

1. Introduction

Stevia rebaudiana Bertoni (Asteraceae) is a small perennial herb endemic to South America. Dry stevia leaves have been used to sweeten traditional bitter drinks such as mate tea ^[1]. Due to its sweetening and pharmacological qualities, stevia has attracted international commercial attention and scientific interest. Japan was the first nation outside of Latin America to cultivate and market stevia as a sucrose alternative. China, Malaysia, Singapore, South Korea, Taiwan, and Thailand are also merchandising it. Stevia plantations can now be found in Southeast Asia, the U.S., Canada, and Europe ^[2].

2. Pharmacological Properties of Steviol Glycosides

2.1. Antidiabetic Action

Diabetes is a chronic metabolic disease characterized by an insufficient amount of insulin due to pancreatic beta cell destruction (type 1 diabetes) or cell inability to effectively use insulin due to impaired responsiveness (type 2 diabetes) ^[3]. This disease affects around 536.6 million people worldwide ^[4]. Among the factors that contribute to type 2 diabetes mellitus (T2DM) are unhealthy dietary habits, poor physical activity, and genetic predisposition. In T2DM, glucose metabolism in the liver is impaired, and its peripheral tissues resist average insulin concentrations. Moreover, atherosclerosis development and cardiovascular disorders are the most common T2DM complications ^[5].

A study with and without stevioside was performed in type 2 diabetic Goto–Kakizaki (GK) and normal Wistar rats to better understand the hypoglycemic activity of stevioside ^[6]. In diabetic rats, stevioside (0.2 g/kg; i.v. administration) decreased glucose blood levels and increased insulin responses and reactions to an intravenous glucose tolerance test (IVGT). On the other hand, stevioside enhanced insulin levels above basal during the IVGT, without altering blood glucose response, in normal rats. This research suggested stevioside as a potential drug candidate to treat type 2 diabetes. This finding correlates with the capability of stevioside to exert dose-dependent hypoglycemic activity and reduce insulin resistance in diabetic streptozocin (STZ)-induced rats. Regarding the potential mechanisms of action, it is implied that stevioside stimulates insulin secretion and increases insulin sensitivity due to gluconeogenesis retardation caused by a decrease in phosphoenol pyruvate carboxy kinase (PEPCK) gene expression in the rat liver ^[7].

Moreover, rebaudioside A increased insulin production in isolated murine islets of Langerhans depending on extracellular Ca²⁺ concentration ^[8]. Stevioside and rebaudioside A acted as receptor ligands, mimicking the insulin effect. SGs increased the glucose intake in rat fibroblasts ^[9]. Similar to insulin action, an increase in glucose transport activity was triggered by SGs in HL-60 human leukemia and SH-SY5Y human neuroblastoma cells. Moreover, SGs and insulin promoted PI3K and Akt phosphorylation. Thus, it was implied that GLUT translocation is related to PI3K/Akt pathway modulation ^[10]. Evidence shows that stevioside can increase insulin-mediated glucose transport into skeletal muscle and insulin sensitivity in insulin-resistant and insulin-sensitive rats ^[11].

In addition, stevioside and rebaudioside A increased the activity of TRPM5, a Ca²⁺-activated cation channel in pancreatic β-cells. Consequently, the insulin secretion associated with TRPM5 increased and prevented hyperglycemia in high fat diet induced diabetes mice ^[12]. In vivo and ex vivo studies in rats demonstrated that neither dietary supplementation with stevioside nor that with rebaudioside A (500 and 2500 mg/kg) altered blood glucose, insulin, or the insulin resistance index. Nevertheless, SGs normalized lipid metabolism and protected internal organs from damage in this model ^[13].

Potential undesired effects on metabolism are negligible, since SGs appear not to act as glucocorticoid receptor (GR) agonists and therefore do not hamper expression of GR-target genes, GR protein levels, or GRs on peripheral blood mononuclear cells ^[14]. Regarding normal glucose blood levels, an oral administration of 5.5 mg/kg/day of stevioside for 15 days in normal rats caused no effect with stevioside. In contrast, with stevia (20 mg/kg/day), plasma glucose concentration lowered under basal levels due to decreased activity of pyruvate carboxylase and PEPCK ^[15]. Stevioside does not exert an antihyperglycemic effect at normal glucose concentrations, but it does so at high blood glucose levels in diabetic rats. On the other hand, the observed hypoglycemic effect of stevia could be explained with the presence of another constituent in the extract, different from stevioside, without its selectivity. Clinical evidence supports long-term consumption of stevioside (250 mg, three times/day for three months) with no effect on normal glucose concentration levels or blood pressure ^[16].

2.2. Antihypertensive Activity

Around 8.5 million deaths associated with a systolic blood pressure >115 mmHg were reported globally. Nearby 88% of this quantity corresponds to low- and middle-income countries ^[17]. Accordingly, the estimation of hypertension prevalence is higher in low- and middle-income countries (1.04 billion) than in high-income countries (349 million) ^[18]. Among the risk factors for hypertension are obesity, alcohol consumption, poor physical activity, high sodium intake, and unhealthy dietary habits. Uncontrolled hypertension can lead to cardiovascular and kidney disorders. Since treatment of hypertension is long-term, there is a particular interest in the search for effective therapeutic options with minimal or no adverse effects. In this context, there is evidence of stevioside and rebaudioside A inducing vasodilation, diuresis, and natriuresis with a decrease in plasma volume, leading to general reductions in arterial pressure in preclinical and clinical assessments ^[19]^[20]. The hypotensive effect observed in rats after chronic oral administration (30 days) of 2.67 g stevia leaves/day was confirmed in spontaneously hypertensive rats. In that murine model, stevioside (100 mg/kg; i.v.) was able to reduce blood pressure with no change in serum epinephrine, norepinephrine, or dopamine levels ^[21].

These findings coincide with the effects observed in human patients with mild to moderate hypertension. After one year of continued consumption of 750 mg/day of stevioside and after two years of daily ingestion of 1500 mg/day of stevioside, a significant decrease in systolic and diastolic blood pressure was observed without modifications in blood biochemistry values or the left ventricular mass index ^[20]. In addition, intraperitoneal stevioside caused a dose-dependent relaxation of vasopressin-induced vasoconstriction in isolated aortic rings and failed to inhibit it in a Ca²⁺-free medium. This result suggests that stevioside triggers vasorelaxation via inhibition of Ca²⁺ reflux into the blood vessel ^[22].

Noteworthily, the antihypertensive effect of stevioside requires relatively higher doses than the acceptable daily intake (ADI). There is no evidence of a hypotensive effect in humans with normal arterial pressure levels ^[16]. Therefore, stevioside is an attractive candidate for further investigation due to its selective antihypertensive effect.

2.3. Anti-Inflammatory Property

Chronic inflammation is characterized by continual recruitment of monocytes and lymphocytes, as well as tissue damage because of a persistent stimulus. Numerous chronic diseases, comprising autoimmune c onditions, and metabolic disorders, including atherosclerosis, obesity, fibrosis, and cancer, are primarily influenced by chronic inflammation ^[23]. Proinflammatory cytokines play a role in stimulating inflammatory responses and are generated mainly from activated macrophages. Interesting results were observed when the releases of proinflammatory cytokines (TNF-α and IL-1β) and nitric oxide were measured in a human monocytic THP1 cell line. In lipopolysaccharide (LPS)-stimulated THP1 cells, stevioside (1mM) inhibited NF-κB. This transcription factor controls expression of inflammatory cytokines; in non-LPS-stimulated THP1 cells, the same concentration of stevioside promoted their release moderately ^[24]. After a 7-day assessment of the capability of stevioside (10 mg/kg/day) to regenerate muscular tissue following cardiotoxin-induced injury in Wistar rats, stevioside did not boost muscle regeneration but enhanced satellite cell activation through modulation of the NF-κB signaling pathway, increasing the number of myonuclei ^[25].

Moreover, stevioside prevented in vitro upregulation of genes involved in liver inflammation. In silico assays demonstrated its antagonistic action in two proinflammatory receptors: tumor necrosis factor receptor (TNFR)-1 and Toll-like receptor (TLR)-4-MD2. Stevioside appears to also be beneficial for healthy people, as an enhancer of the innate immune system ^[24]. In addition to stevioside, steviol was found responsible for inhibiting TPA-induced inflammation ^[26]. Thus, steviol and stevioside may be helpful as dietary supplementation for supporting muscle recovery and could be suggested as good candidates to be further developed as new drugs to treat inflammation.

2.4. Antioxidant Activity

Increased production of reactive oxygen/nitrogen species overcomes the antioxidative defenses of the body under oxidative stress, which causes tissue damage, accelerated cell death, and oxidative modification of biological macromolecules. Hence, oxidative stress is the pathological state at the root of many diseases ^[27].

Liver injury induced via thioacetamide decreases its antioxidant capability through downregulation of nuclear erythroid factor 2 (Nrf2). Stevioside coadministration (20 mg/kg, twice a day) upregulated Nrf2 levels in murine models, and, accordingly, no elevation of oxidative markers was observed ^[28]. Likewise, a combination of stevioside, rebaudioside A, rebaudioside C, and dulcoside A enhanced the viability of rat cardiac fibroblasts when exposed to hydrogen peroxide, as well as augmenting the concentration and activity of catalase and superoxide dismutase ^[9]. The antioxidant effect of stevioside and rebaudioside A was confirmed in a fish model. Both effectively controlled lipoperoxidation and protein carbonylation ^[29]. Furthermore, stevioside prevented oxidative DNA damage in the livers and kidneys of a type 2 diabetes murine model. The in silico results thereof revealed the stevioside’s potential mechanism of action associated with its ability to inhibit beta-adrenergic and G-protein-coupled receptor kinases ^[30].

In addition, antioxidant properties were evaluated in food applications. SGs (50, 125, and 200 mg/L) decreased degradation rates of antioxidants (ascorbic and dehydroascorbic acid) in a dose-dependent manner. Higher concentrations of acids and sweeteners displayed more potent antioxidant action. Interestingly, no variation in SG concentration was observed ^[31]. Similarly, preservation of fruit beverages with stevia showed improved antioxidant indexes and increased sweetness ^[32].

2.5. Anticancer Action

According to the American Cancer Society, there will be around 19 million cancer survivors in 2024. The three most common types of cancer in men are prostate (43%), colon (9%), and melanoma (8%), and in women, they are breast (41%), uterine (8%), and colon cancer (8%) ^[33]. Lung (1.35 million cases), breast (1.15 million), and colorectal (1 million) cancers are the three most frequently diagnosed types. Lung (1.18 million cases), stomach (700,000 cases), and liver cancers (598,000 deaths) are the three most frequently fatal types ^[34]. Cancer therapy’s primary limitations are toxicity, poor tolerability, and adherence ^[35]. Therefore, novel drug treatments with no minimum adverse effects are urgently required.

An experimental study in vitro showed that stevioside, steviol, and isosteviol could inhibit the carcinogenic effects induced via Epstein–Barr virus early antigen (EBV-EA) activation mediated through 7,12-dimethylbenz[a]anthracene (DMBA) and TPA in mouse skin ^[36]. In vivo studies confirmed this finding. The activity of the well-known tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA), was successfully inhibited with stevioside in a murine skin-cancer model ^[37]. In addition, stevioside reduced mammary adenoma incidence in F344 rats ^[38].

Stevioside and steviol decreased the viability of human colon carcinoma cells. Steviol inhibited DNA synthesis and induced mitochondrial apoptosis ^[39]. In vitro analysis also showed potential activity of steviol glycosides against breast cancer cells ^[40]. Furthermore, steviol inhibited human gastrointestinal cancer cell growth through caspase-3 activation and mitochondrial apoptotic pathway triggering, and it increased the Bax/Bcl-2 ratio and stimulated p21 and p53 expression. Its pharmacological activity was comparable with that of 5-fluorouracil. Noteworthily, the cytotoxicity exerted by steviol against cancer cells was higher than the action displayed in normal cells ^[41]. Regarding mechanism of action, stevioside and steviol were able to inhibit two cancer pharmacotherapy targets: DNA polymerases and human DNA topoisomerase II ^[26]. Altogether, these results suggest stevioside, steviol, and isosteviol as valuable chemotherapy candidates to be further investigated for cancer therapy.

2.6. Antidiarrheal Activity

Bacterial enterotoxins increase intestinal-fluid and chloride-ion hypersecretion, leading to dehydration and electrolyte imbalance. This anion secretion is mediated with the cystic fibrosis transmembrane conductance regulator (CFTR), a critical cAMP-activated chloride channel. Steviol and dyhidrosteviol inhibit the CFTR ^[42]. Moreover, stevioside controls intestinal smooth muscle contraction ^[43].

These properties and the fact that SGs may possess antibacterial and antiviral activity suggest SGs as a potential treatment for diarrhea. SGs have demonstrated antibacterial action on various foodborne pathogenic bacteria, including Escherichia coli, a well-known etiologic agent of severe diarrhea ^[44]. Regarding antiviral properties, SGs seem to impede binding of rotavirus to host cells ^[45]. Rotavirus is commonly associated with pediatric gastroenteritis.

2.7. Effect on Gut Microbiota

About 1014 bacteria colonize the human digestive tract. Evidence supports the critical role of gut microbiota composition in immune-system maturation, neurophysiology, and maintenance of human health. Gut microbiota dysbiosis may cause gastrointestinal problems, allergies, obesity, cardiovascular disorders, and CNS diseases. Therefore, it can be inferred that each condition could possess a unique gut microbiota pattern and potential usefulness of these gut microbiota as potential biological markers and drug targets ^[46].

It has been reported that sweeteners may alter a gut microbiota population. Saccharin and sucralose modify it with no health-related consequences. In addition, acesulfame-K decreases Akkermansia muciniphila and promotes Firmicutes propagation. Since SGs are metabolized through gut microbiota, it has been suggested that they may modify the gut microbial community ^[47]. Nevertheless, in vitro and in vivo studies have shown no influence of SGs on gut microbiota growth ^[48].

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