Dietary anethole: a systematic review of its protective effects against metabolic syndrome

Abstract

Background

Metabolic syndrome (MetS) is a cluster of physiological, biochemical, clinical, and metabolic conditions that aggravate the risk of severe diseases such as cardiovascular disease, type 2 diabetes mellitus, and fatty liver. Several dietary molecules have been considered preventive compounds for MetS. Anethole, a natural phenylpropanoid, has been found to protect against MetS and its associated components.

Aim

This systematic review aims to provide an overview of the preclinical evidence supporting the protective effects of dietary anethole against MetS and the associated diseases.

Methods

A literature search was performed using Web of Sciences, PubMed, Scopus, and Google Scholar to identify studies reporting the protective effects of dietary anethole against MetS, without any time restrictions. Review articles, letters to editors, editorials, unpublished results, and non-English papers were excluded from the study.

Results

The results showed that anethole has the potential to effectively protect against the key features of MetS via various mechanisms, including antioxidant and anti-inflammatory effects, stimulating insulin secretion from β-cells, mediating oxidative stress, modulation of the mTOR/PPARγ axis, arterial remodeling, and improvement of vascular relaxation.

Conclusion

Anethole modulates several molecular pathways that are implicated in the pathogenesis of MetS. Future in vitro and animal investigations should be conducted to explore other anti-MetS signaling pathways of anethole. Additionally, well-designed clinical studies are warranted to determine the optimal human dose, bioavailability, and pharmacokinetic characteristics of this dietary compound.

Introduction

Metabolic syndrome (MetS) indicates a group of metabolic abnormalities such as hyperglycemia, dyslipidemia, insulin resistance (IR), and obesity. MetS increases the risk of diabetes and cardiovascular disease (CVD) [1–4]. According to the definition of the National Cholesterol Education Program (NCEP), persons with three or more of the five risk factors (including fasting plasma glucose ≥ 130 mg/dl, abdominal circumference > 94/102 cm, serum triglyceride (TG) ≥ 150 mg/dl, serum high-density lipoprotein (HDL) cholesterol < 40 mg/dl, and blood pressure (BP) ≥ 130/85 mmHg or medication) are regarded as MetS patients [5, 6]. IR is a mediator of MetS that is induced in part via fatty acid surplus resulting from unsuitable lipolysis. When insulin effects are diminished in IR conditions, lipolysis is enhanced, leading to an increase in fatty acid production, which results in glucose and TG circulating in the blood [7] [8, 9]. Skeletal muscle is one of the main tissues affected by IR, reducing its ability to take up and store glucose and TG. IR plays a remarkable pathophysiologic role in the development of T2DM and is correlated with several conditions, such as glucose intolerance, dyslipidemia, obesity, hypertension, and increased inflammation markers [9] [10] [11]. Inflammation has a vital role in the pathobiology of MetS [12]. Inflammation, including interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), has a vital role in the pathobiology of MetS [13, 14]. There is a significant body of evidence indicating that oxidative stress plays a potential role in the development of MetS and its related manifestations, including T2DM, hypertension, and atherosclerosis [15]. Studies have shown that oxidative stress impairs the ability of muscle and fat cells to uptake glucose, and may also reduce pancreatic ß cell function in secreting insulin [16]. Oxidative stress is an early event in the pathogenesis of MetS-related diseases and can induce cardiovascular disease in individuals with MetS through the induction of oxidative stress in adipocytes [17]. Generally, human adipose tissue consists of “white (WAT)” and “brown (BAT)” types. WAT is mainly responsible for energy storage and is an endocrine tissue, which releases cytokines and adipokines [18]. In obesity, WAT promotes inflammatory conditions and oxidative stress causing insulin resistance and ultimately, MetS. On the other hand, BAT regulates energy consumption and increases heat generation through fat burning following exposure to cold environments and, eventually, to protect against obesity [19].

Based on the International Diabetes Federation (IDF) diabetes atlas, 537 million adults have diabetes. Diabetes prevalence is estimated to rise to 643 million by 2030. The World Health Organization reports that the prevalence of obesity is more than 1 billion people worldwide [20].

The inclusion of inflammation biomarkers in the clinical definition of MetS is necessary and could improve the prognostic assessment of the risk of type 2 diabetes mellitus (T2DM) and CVD [21]. There is evidence that indicates the vital role of the inflammatory response in obesity as well as related chronic diseases [21].

In recent years, several lines of evidence have supported the presence of a relationship between lifestyle choices, such as dietary items and nutritional factors, and various diseases [22–24]. On the other hand, bioactive compounds have been considered reliable sources for drug discovery throughout history. Many therapeutic agents with natural origin such as digitoxin, reserpine, paclitaxel, and hyoscine have been developed in recent decades and numerous studies have shown a vast pharmacological potential for different plant-derived products [25–33]. Anethole ([1-methoxy-4-(1-propenyl)-benzene]; C₁₀H₁₂O) is an aromatic compound and the main component of several essential oils (Fig. 1). Anethole causes the distinctive flavors of various edible plants, including anise and fennel (Apiaceae family), anise myrtle (Myrtaceae), licorice (Fabaceae), camphor, and star anise (Illiciaceae). Anethole has both cis and trans-isomers. The Trans isomer is the most abundant. Natural anethole exists in high concentrations in anise oil, star anise oil, and fennel oil [34]. Anethole has a high solubility in ethanol and is therefore used in different alcoholic drinks. The other uses of anethole are in the food industry as a flavoring component and in cosmetics and pharmaceuticals [35].

Fig. 1.

Chemical structure of anethole

Anethole affects MetS components, such as obesity, hypertension, diabetes, and hyperlipidemia. Anethole induces anti-MetS effects by different mechanisms, including the inhibition of oxidative stress [36] and inflammation [37], modulation of various molecules such as the mammalian target of rapamycin (mTOR), and peroxisome proliferator-activated receptor gamma (PPAR-γ) [38, 39], and enhancement of mitochondrial biogenesis [40] (Fig. 2).

Fig. 2.

Anethole as a promising phenylpropanoid targeting metabolic syndrome components

The current systematic review aims to provide an overview of the preclinical evidence regarding the protective and preventive effects of anethole against MetS.

Methods

Search strategy

A comprehensive literature review was conducted to retrieve relevant papers reporting the protective effects of anethole against MetS. Various databases, including Science Direct, PubMed, Scopus, and Web of Science, were searched using the following keywords: anethole, metabolic syndrome, hyperglycemia, T2DM, diabetes, insulin resistance, dyslipidemia, hyperlipidemia, obesity, steatosis, steatohepatitis, nonalcoholic fatty liver disease, and hypertension. All in vitro and in vivo investigations that reported the protective properties of anethole against MetS were selected. Studies performed using a variety of species, age, and sex were applied. Papers that reported comparisons between two or more groups (e.g., anethole-treated, control, diseased, etc.) were included. Review articles, unpublished information, editorials, commentaries, letters to the editor, abstracts, conference proceedings, and duplicate references were excluded. The titles and abstracts of the selected papers were evaluated to exclude irrelevant articles (Fig. 3).

Fig. 3.

The flowchart of the study selection process

PRISMA guidelines were followed while performing the study (http://www.prisma-statement.org/).

Study selection

English language studies with no time limitation were included, and all studies were added to Endnote software and duplicate articles were removed.

Quality assessment

To assess the quality of in vivo animal studies, the Animal Research Reporting In vivo Experiments (ARRIVE) checklist was used, which includes 20 items. [41]. The quality of in vitro studies was evaluated using the Organization for Economic Cooperation and Development (OECD) Guideline on Good in vitro Method Practices (GIVIMP). [42].

Data extraction

Two investigators separately checked the titles and abstracts of each eligible paper. They further discussed how to solve any disagreement. The following data were extracted from each included study: the first author’s name, the study model (in vivo or in vitro), the cell type or animal species used in the study, sample size, dosage, time/days of exposure, the reported effects and mechanisms, and references. Any disagreement cases were resolved through discussion.

Results

Anti-diabetic effects of anethole

Several studies have confirmed the anti-diabetic and hypoglycemic effects of anethole (Table 1). Anethole has been shown to significantly alter the levels of liver glycolytic enzymes, hepatic shunt enzymes, and gluconeogenic enzymes in the liver and kidney of diabetic rats. Furthermore, anethole attenuated the levels of hepatic and muscle glycogen in diabetic rats, and histological evaluations demonstrated an improvement in beta cell function in the pancreas of these rats. Additionally, anethole was found to stimulate insulin secretion from existing beta cells [36, 43].

Table 1.

Summary of the protective effects of anethole against MetS

NO.	Activity	setting	Model	Dose, exposure time	Effect	References
1	Anti-diabetic	In vivo	Rat	20, 40 and 80 mg/kg for 45 days	↓ body and liver weights, food and water intake, and urine sugar, blood glucose, HbA1c levels, the G6P and FBPase activities. ↑ Hb level, the hexokinase and glucose-6-phosphate dehydrogenase activities, glycogen level in liver and muscle tissues. Improvement of histopathological changes	[43]
2	Anti-diabetic and anti-hyperlipidemic	In vivo In vitro	Rat Cells obtained from fresh chicken eyeballs	10 mg/kg fennel seed for 45 days 50 µg TA for 72 h	↓ blood glucose level, ALR2, serum total cholesterol, TGs, and LDL cholesterol ↑ weight gain, HDL level Anti-cataract activity. ↓ ALR2 activity ↑ GSH levels, SOD and CAT activity	[44]
3	Anti-diabetic and anti-hyperlipidemic	In vivo	Rat	200 and 400 mg/kg fennel seed extract 80 mg/kg TA for 35 days	↓ FBS, MDA level, the serum TG, TC, and LDL-c levels and ALT and AST ↑ total thiol content, CAT and SOD enzymes activity, HDL cholesterol levels ↓ FBS, water intake, glycosuria, food intake, MDA level, the serum TG, TC, and LDL-c levels and ALT and AST Inhibition of weight loss. ↑ total thiol content, CAT and SOD enzymes activity, HDL cholesterol levels Improvement of histopathological changes	[36]
4	Anti-hyperlipidemic	In vitro	Human mesenchymal stem cells	50, 100, 150, 200 and 250 µM for 24 h	↓ accumulation of lipid, the phosphorylation of mTOR, p70S6K, and PPARγ, ROS level ↑ the phosphorylation of AMPK	[38]
5	Anti- hyperlipidemic	In vitro	HepG2 cells	100, 200, 300, 400, 500, 1000, 1500, and 2000 µg/mL for 3 days	↑ the expressions of AMPK, ACS, ACADS, LPL, CPT1, CPT2, PLIN1 and HSL. ↑ GLUT4 level, OPN, PEDF ↓ the expressions of ACC1 and GPAT. ↓ the number of stained granules ↑ respiratory metabolism. Lipid metabolism modulation	[45]
6	Anti-hyperlipidemic	In vivo	Hamsters	5,10,20, and 40 mg/kg for 4 weeks	↓ ALT, AST, TBA, SFA (C16:0 and C18:0) and MUFA (C18:1n9), essential EFAs (C18:2n6 and C18:3n3). ↓ACC1, FAS expressions, SCD1 enzyme ↑ FADS1 and FADS2 enzymes ↑ n-3 PUFA (C20:3n6, C20:4n6 and C22:6n3) ↑ CPT1α and Mitofusin1 ↑ FATP2, FATP4, FATP5 and L-FABP expressions. Improvement of histopathological changes	[46]
7	Anti-hyperlipidemic and anti-obesity	In vivo	Broiler	200, 400, 600, and 800 mg /kg for 42 days	↓ serum TG ↑ HDL cholesterol, palmitoleic acid, daturic acid, oleic acid, linoleic acid, a-linolenic acid, eicostrienoic acid, and EPA, MUFA and PUFA, Met, Thr, Asp, Ser, and Glu. Improvement of lipid metabolism and meat quality.	[47]
8	Anti-hyperlipidemic and anti-obesity	In vivo In vitro	Mice Cultured 3t3-l1 white adipocytes	100 ml/kg for 8 weeks 100 µM for 6–8 days	↓ body weight gain ↑ BAT fat mass, the expression levels of key brown adipocyte and beige-specific genes (Ppargc1a, Prdm16, and Ucp1as well as Cd137, Cited1, Tbx1, and Tmen26), expression mitochondrial biogenesis genes, including Cox4, Nrf1, MtDNA, and Tfam. ↓ expression levels of adipogenic and lipogenic markers: C/EBPα, PPARα, and γ, ACC, and FAS ↑ the mitochondrial protein levels of ACOX1 and CPT1 3T3-L1 adipocytes: ↑ expression of BAT signature proteins (PGC-1α, PRDM16, and UCP1) ↑ expression of encoding genes (Ppargc1a, Prdm16, and Ucp 1) ↑ ↑expression of beige-specific genes including Cd137, Cited1, Tbx1, and Trem26. ↓ fat accumulation ↓TG	[40]
9	Anti Hypertensive	In vivo	Rat	0.25-1 µmol/kg 300 nmol/L 10 µmol/ L 3, 10, and 20 µmol/ L for 15 s	↓ systolic BP ↓ diastolic BP ↓ heart rate ↓ pulse BP Inhibit Ca2 + channels Inhibit RyR2 channels ↑ Cl– current	(Tomasova et al., 2015)
10	Anti Hypertensive	In vivo	Mice	62.5, 125, 250, and 500 mg/kg	↓ BP ↓ inflammatory cells count ↓ inflammatory cytokines ↓ LDH activity	[37]
11	Anti Hypertensive	Ex vivo	Rats		↓ Hyperreactivity induced by 5-HT and PGF2α	[50]
12	Anti Hypertensive	In vivo	Rats	62, 125, and 250 mg/kg for 21 days	↓ systolic BP ↓ diastolic BP ↑ vasorelaxation	[48]
13	Anti-Fatty liver	In vivo	Mice	100 mg/kg for 8 weeks, orally	↓ ballooning and steatosis ↓ hepatic steatosis ↓ expressions of IL-1b, IL-6, TNF-a and Ccl2 ↓ a-smooth muscle actin (a-SMA) expression (fibrotic marker) ↓ Col1a1, Col3a1, Acta2, and Timp1 (fibrosis-related genes) ↓ mRNA and protein levels of TGF-b1 ↓ expression of p-Samd2	[52]
14	Cardioprotective	In vivo	Rats	50 mg, 100 mg, and 200 mg 15 min before coronary ligation	↓ LVEDP ↑ cardiac contractility (LV dP/dtmax) ↓ cTnT ↓ CK-MB ↓ area percentage of collagen fibers ↑ The level of cardiac VAV3 mRNA ↑ cardiac rno-miR-1298 ↑ RQ of cardiac JRKL-AS1 ↓ cardiac content of TNF-α	[53]
15	Cardioprotective	In vivo	Rats	Anethole 125 or 250 mg/kg gastric lavage for 30 days	↓ CKMB, CK, cTnT, and cTnI ↓ TLR4 and MYD88 gene and protein expression ↑ mRNA and protein expression levels of Nrf2 and HO-1 ↓ Keap1 level ↑ mitochondrial antioxidant enzyme activities (SOD, CAT, GPx, GSH and GST) ↓ TBARS in the heart mitochondria ↓ TNF-α, IL-1β, IL-6, and NFκB ↓ Bax mRNA expression level and cleaved caspase-3 and − 9 protein levels ↑ Bcl-2 mRNA expression level ↓myocardial necrosis. Reversing ECG changes such as widening in the ST segment and QT interval, and also shortening in the P wave, QRS complex, and P-R and RR intervals	[61]

Sheikh et al. investigated the antidiabetic effect of Trans-anethole (TA) in streptozotocin (STZ)-induced type 2 diabetic rats. The rats were administered TA. TA treatment led to a significant reduction in body and liver weights compared to the control group, as well as a significant decrease in food and water intake and urine sugar levels. All doses of TA significantly suppressed the increase in plasma glucose levels and increased the plasma insulin contents, with the dose of 80 mg/kg being the most effective. Oral glucose tolerance tests indicated that TA significantly inhibited the increase in blood glucose levels. Hemoglobin levels were significantly increased and the hemoglobin A1c (HbA1c) levels significantly decreased following TA administration. A remarkable reduction in hexokinase and glucose-6-phosphate dehydrogenase activities and a significant increase in glucose-6-phosphatase and fructose-1,6-bisphosphatase activities were observed in diabetic rat liver tissues, all of which were reversed by TA administration. Additionally, TA inhibited the reduction of glycogen levels in liver and muscle tissues compared to diabetic control rats. Histopathological examination revealed well-granulated and prominent hyperplasticity of islets in the pancreas tissue of diabetic rats treated with TA, while the disappearance of nuclei, degeneration of sinusoids, and central vein observed in the diabetic group was diminished following TA treatment in the liver tissue of rats. It was suggested that TA administration may have activated insulin secretion from existing ß-cells [43].

Dongare et al. conducted a study to investigate the antidiabetic and aldose reductase (ALR2) suppression effects of the petroleum ether fraction of Foeniculum vulgare essential oil (FVEO) containing 14.403% TA as determined by high-performance liquid chromatography (HPLC) and gas chromatography–mass spectrometry (GC–MS) analysis. The authors observed a significant reduction in blood glucose levels in diabetic rats treated with FVEO. Moreover, the FVEO-treated diabetic rats demonstrated a significant increase in body weight compared to the diabetic control group. The activity of ALR2, which is a key enzyme in the polyol signaling pathway leading to the conversion of glucose to sorbitol, was decreased in eye lens protein following FVEO exposure. It has been reported that ALR2 activity is increased in diabetic patients. Although various bioactive compounds were identified in FVEO, TA was found to be responsible for the inhibition of ALR2 activity. Interestingly, TA exhibited anti-cataract activity by enhancing soluble lens protein and decreasing glucose-induced cataract development in an in vitro model. TA also demonstrated anti-oxidative stress effects by restoring glutathione (GSH) levels and enhancing the activity of CAT and SOD in the same model [44].

In a separate study, Samadi-Noshahr et al. investigated the effects of fennel seed extract and its bioactive agent, TA on diabetes-induced hepatic injury in rats. Both fennel seed extract and TA significantly reduced fasting blood glucose (FBS) levels in diabetic rats. TA also decreased water intake and glycosuria in diabetic rats, while decreasing food intake and inhibiting weight loss. Furthermore, the authors observed a significant reduction in malondialdehyde (MDA) levels in diabetic rats following treatment with fennel seed extract and TA. Exposure to fennel seed extract and TA also increased the total thiol content and improved CAT and SOD enzyme activity, although the changes in SOD activity were not significant. Histopathological evaluations showed that hepatic fibrosis was significantly reduced in the TA and fennel groups compared to the diabetic group. In the liver of diabetic rats treated with TA, the authors observed a nearly normal appearance, while the liver of diabetic rats showed hepatocyte necrosis, enhanced monocyte infiltration, congested and dilated sinusoids, and thickening of the portal vein wall [36].

Anti-hyperlipidemic effects of anethole

Rhee et al. conducted a study to investigate the effects of anethole on adipogenic differentiation in human mesenchymal stem cells. The study found that anethole did not exhibit cytotoxic effects on the cells, but it suppressed lipid accumulation. Western blot analysis was used to evaluate the mTOR, PPARγ axis, and AMPK involved in adipogenic differentiation suppression by anethole. Adipogenic induction increased the phosphorylation of mTOR, p70S6K, and PPARγ, and decreased the phosphorylation of AMPK in human mesenchymal stem cells. However, these changes were reversed by anethole. The study hypothesized that ROS plays a significant role in adipogenic differentiation of human mesenchymal stem cells. The results showed that hydrogen peroxide-induced ROS levels decreased after treatment with anethole. Moreover, ROS was found to be involved in mTOR phosphorylation and AMPK de-phosphorylation, which was inhibited by anethole. Anethole reduced the PPARγ/mTOR-p70S6K signal axis and increased MPK expression in the presence of hydrogen peroxide, indicating that anethole inhibits adipogenic differentiation by regulating mTOR/PPARγ and ROS [38].

In another study, Song et al. investigated the effects of TA on lipid metabolism in HepG2 cells. The study found that TA activated several lipolytic genes and enhanced AMPK levels, an upstream molecule, in a concentration-dependent manner. Furthermore, TA downregulated some lipogenic genes, including acetyl-CoA carboxylase (ACC)1 and glycerol-3-phosphate acyltransferase (GPAT), and reduced stained granules in HepG2 cells, indicating its lipolytic effects. Additionally, TA increased the levels of osteopontin (OPN) and pigment epithelium-derived factor (PEDF), which have crucial roles in immunoactivity, apoptosis, and angiogenesis inhibition, and cellular proliferation, and survival. The study concluded that TA modulates lipid metabolism by activating lipolytic markers and suppressing lipogenic markers in HepG2 cells, and stimulates mitochondrial potential while inhibiting senescence in these cells [45].

Zhao et al. conducted a study on the effects of anethole dithiolethione on liver fatty acid metabolism in hamsters fed a high-fat diet (HFD). The authors observed that different doses of anethole dithiolethione significantly reduced levels of ALT, AST, and total bile acids (TBA) in HFD-fed hamsters. These changes were in agreement with the histopathological analysis, which revealed significant hepatocyte swelling and enhanced lipid droplets in the liver of HFD-fed hamsters, while the liver structure in groups treated with different doses of anethole dithiolethione exhibited a nearly normal appearance. To investigate the molecular mechanisms of anethole dithiolethione, the authors determined levels of mRNA expression of genes related to synthesis, desaturation, β-oxidation, uptake, and transport of fatty acid in the liver. Anethole dithiolethione decreased expressions of ACC1 and fatty acid synthase (FAS) in a dose-dependent manner. The authors also found that anethole dithiolethione reduced stearoyl-CoA desaturase1 (SCD1), a crucial rate-limiting enzyme that desaturates SFAs into MUFAs, and increased expressions of fatty acid desaturase (FADS)-1 and FADS2, key rate-limiting enzymes in the desaturation of PUFAs. Overall, the authors demonstrated that anethole dithiolethione is effective in improving liver fatty acid metabolism and liver disorders induced by HFD [46].

Yu et al. investigated the effects of TA supplementation on the fatty acid and amino acid profiles of breast muscle in broilers. Administration of TA significantly reduced serum TG and HDL cholesterol but increased HDL cholesterol. Furthermore, the levels of MUFA and PUFA were higher in the breast muscle of TA-treated animals, and amino acids were increased in the breast muscle. Overall, these findings suggest that TA can improve lipid metabolism [47].

Kang et al. evaluated the anti-obesity effects of TA by inducing thermogenic activity through beige phenotype induction in cultured 3T3-L1 white adipocytes and activating brown adipocytes in diet-induced obese mice. The results showed that TA significantly increased BAT signature protein expression in a dose-dependent manner. In vivo studies indicated that TA significantly lowered the body weight gain and WAT weight in obese mice and food efficiency while elevating BAT fat mass. Moreover, TA increased mitochondrial biogenesis in inguinal WAT. TA also reduced the expression of main adipogenic and lipogenic markers in inguinal WAT, suggesting a reduction in adipogenesis and an increase in lipolysis-related proteins [40]. Detailed information on the anti-hyperlipidemic effects of anethole is presented in Table 1.

Anti-hypertensive effects

Anethole has the potential to inhibit hypertension due to its ability to suppress arterial remodeling and decrease vascular relaxation. It also induces anti-inflammatory effects that are relevant in the prevention of hypertension and CVDs. Inflammation can trigger several CVDs such as hypertension [37, 48]. Furthermore, anethole influences vascular tissues by suppressing oxidative stress, which enhances platelet-derived growth factors concentration in vascular smooth muscle, leading to hypertension through thrombogenesis activation and peripheral vascular resistance enhancement [48]. Additionally, TA tends to induce vasorelaxation and inhibit hypertension via the enhancement of vascular relaxation. Anethole suppresses excessive sympathetic nervous system activity, thus reducing the risk of hypertension [48, 49].

Roubenne et al. investigated the effects of Anethole Trithione (ATT) on pulmonary hypertension (PH) hallmarks. In rats with PH induction, ATT reduced the contractile hyperreactivity induced by 5-hydroxytryptamine (5-HT) and prostaglandin F2α (PGF2α). In control rats, ATT reduced contraction to 5-HT and phenylephrine (Phe), but not contraction caused by endothelin-1 (ET-1) and PGF2α. Furthermore, acute ATT exposure did not moderate the basal cytosolic calcium signal in control rat Pulmonary Artery Smooth Muscle Cells (PASMC). However, the number of 5-HT responding cells was reduced in the presence of ATT. ATT also reduced 5-HT-induced proliferation in control human PASMC [50].

Seo et al. investigated the potential of TA to lower hypertension induced by chronic exposure to restraint stress and nicotine in rats. The results showed that TA treatment significantly reduced systolic BP in hypertensive rats compared to untreated hypertensive rats. In addition, TA combined with aerobic exercise or nifedipine reduced both systolic and diastolic BP. TA and aerobic exercise induced more vasorelaxation compared to hypertensive rats [48].

Anti-obesity effects

Anethole was found to alleviate high-fat diet-induced obesity in mice by upregulating beige-specific gene expression, regulating lipid metabolism, and promoting lipolysis and fat oxidation. The study also found that anethole induced thermogenic activity by enhancing mitochondrial biogenesis in white adipocytes and activating BAT. Agonistic and antagonistic evaluations indicated that anethole-induced browning of 3T3-L1 adipocytes by activating β3-AR and regulating the AMPK-mediated SIRT1 pathway to regulate PPARα and PGC-1α. Thus, anethole has promising therapeutic implications for treating obesity through its modulatory effects on inducing the browning of WAT, activating brown adipocytes, and triggering lipid catabolism [40, 46].

Anti-fatty liver effect

The liver is the main organ responsible for the metabolism of xenobiotics such as drugs and chemicals and has a crucial role in oxidative detoxification. During the biotransformation of xenobiotics, the liver produces various ROS and thus oxidative stress. Oxidative stress conditions may aggravate lipid peroxidation, which contributes to the development and progression of NAFLD and liver cancer [51]. Dietary compounds with their antioxidant properties can improve these conditions. Zhang et al. investigated the potential of TA in attenuating Nonalcoholic Steatohepatitis (NASH), which is a severe form of NAFLD. The authors found that administration of TA at a dose of 100 mg/kg for 8 weeks significantly reduced hepatic steatosis, proinflammatory cytokines, collagen deposition, hepatic fibrosis, and p-Smad2 expression in NASH mice, indicating suppression of the TGF-β signaling pathway. These results suggest that TA could be a promising therapeutic agent for NASH [52].

Cardiovascular protective effect

Matboli et al. investigated the anti-inflammatory effects of TA against myocardial ischemia-reperfusion injury. The authors found that TA reduced CK-MB and TNF-α levels, decreased the mean area percentage of collagen fibers, and upregulated the expression of the retrieved RNA-based panel (VAV3 mRNA/miR-1298/lncRNA JRKL-AS1) after ischemia-reperfusion. These findings suggest that TA improved cardiac injury by modulating the inflammatory signaling pathway [53].

Younis et al. evaluated the potential of anethole as a cardioprotective agent against myocardial infarction. The authors found that anethole improved cardiac enzymes levels, reduced gene and protein expression of TLR4, MYD88, and Keap1, and increased the expression of Nrf2 and HO-1 at both mRNA and protein levels. Anethole also improved mitochondrial antioxidant enzyme activities and reduced TBARS levels in the heart mitochondria. Furthermore, anethole moderated myocardial apoptosis, decreased myocardial necrosis, diminished edema, and immune cell infiltration, and reversed ECG changes. These results suggest that anethole could be considered a potential cardioprotective agent [54].

Table 1 summarizes the protective effects of anethole against Metabolic Syndrome (MetS).

Discussion

Anethole is a naturally occurring compound found in various plants, including anise, fennel, and licorice. Anethole has been used in traditional medicine for its anti-inflammatory, anti-bacterial, and anti-tumor properties. It is also commonly used as a flavoring agent in food and beverages. This systematic review aims to provide an in-depth understanding of the protective mechanisms of anethole against MetS, including diabetes, dyslipidemia, hyperglycemia, hypertension, and obesity. The anti-diabetic effect of anethole is mediated by stimulating insulin secretion from β-cells, which are located in the pancreas and play a crucial role in glucose metabolism [43]. In addition, anethole inhibits oxidative stress, which is a key contributor to the development of diabetes. The reduction of oxidative stress is demonstrated by the reduction of MDA levels and the enhancement of GSH levels, as well as the enhancement of the activities of antioxidant enzymes such as SOD and CAT [36, 44]. The anti-hyperlipidemic effect of anethole is attributed to the inhibition of the mTOR/PPARγ axis, which is a signaling pathway involved in regulating lipid metabolism [38]. The mTOR/PPARγ axis is an important pathway involved in lipid metabolism. The mTOR is a serine/threonine kinase that modulates many key cellular processes, including lipid metabolism. PPARγ is a nuclear receptor that is highly expressed in adipose tissue and plays a critical role in regulating adipocyte differentiation and lipid metabolism.

Activation of the mTOR pathway has been associated with an increase in lipogenesis and adipogenesis, leading to increased lipid accumulation in adipocytes and other tissues. The mTOR pathway can activate PPARγ through direct phosphorylation, and activation of PPARγ leads to increased expression of genes involved in lipid metabolism and storage, such as adipocyte fatty acid-binding protein (aP2), FAS, and acyl-CoA synthase [55].

Inhibition of the mTOR/PPARγ axis has been shown to reduce lipid accumulation in adipocytes and improve insulin sensitivity, making it a promising target for the treatment of metabolic disorders such as obesity and T2DM [56]. Anethole has been shown to inhibit the mTOR/PPARγ axis, thereby reducing lipid accumulation and improving lipid metabolism, which may contribute to its anti-hyperlipidemic effect. Anethole also inhibits ROS production, which is a major contributor to the development of dyslipidemia [38]. Furthermore, anethole activates lipolytic markers and inhibits lipogenic markers, which further contributes to its anti-hyperlipidemic effect [45]. Anethole’s anti-hypertensive effect is achieved through inhibition of inflammation, and oxidative stress, which are key factors contributing to the development of hypertension. Additionally, anethole reduces arterial remodeling and enhances vascular relaxation, which further contributes to its anti-hypertensive effect. [37, 48]. Its anti-obesity effect is demonstrated through its modulatory functions in inducing white fat browning, activating brown adipocytes, and promoting lipid catabolism [46]. Anethole also has an anti-fatty liver effect, which is partly due to the inhibition of the TGF-β signaling pathway and inflammation. The TGF-β signaling pathway is a complex and multi-step process that involves numerous signaling molecules, receptors, and transcription factors. In general, TGF-β signaling is known to regulate various cellular processes, including proliferation, differentiation, apoptosis, and extracellular matrix production. In the context of fatty liver disease, TGF-β signaling is thought to contribute to the development of liver fibrosis and inflammation. This pathway is activated in response to liver injury, which can be caused by various factors, including excessive alcohol consumption, obesity, and viral infections. Activation of TGF-β receptors leads to the recruitment and phosphorylation of intracellular signaling molecules, such as SMAD proteins. These phosphorylated SMADs then form complexes with other proteins and translocate to the nucleus, where they regulate gene expression. TGF-β signaling has also been implicated in the regulation of immune cell function and inflammation in the liver. In particular, TGF-β signaling has been shown to promote the activation of immune cells, such as macrophages, leading to the production of pro-inflammatory cytokines. This inflammatory response can exacerbate liver injury and contribute to the development of non-alcoholic steatohepatitis (NASH), a more severe form of fatty liver disease. [52].

Furthermore, anethole has a cardio-protective effect by suppressing the inflammatory signaling pathway, reducing myocardial apoptosis and necrosis, improving mitochondrial antioxidant enzyme activities, and stimulating the Nrf2 signaling pathway [52, 52]. In conclusion, anethole has potential therapeutic applications in MetS and can prevent morbidity and mortality due to CVD.

Pharmacokinetics refers to the processes by which a drug or compound is absorbed, distributed, metabolized, and excreted by the body. Based on experimental studies conducted on rodents such as mice and rats, it has been found that anethole is slowly absorbed after oral administration but is eventually completely absorbed. The primary metabolic pathways for anethole include O-demethylation, oxidation of the C3-side chain, and conjugation with glucuronic acid, glycine, sulfate, and glutathione [57]. Cinnamic alcohol, cinnamic acid, 4-methoxy-hippuric acid, 4-methoxy-benzoic acid, 4-hydroxypropenylbenzene, and 4-methoxy derivatives of acetophenone are the main products of anethole metabolism. anethole is eliminated through renal, pulmonary, and fecal excretion within 48–72 h [58]. At higher doses, anethole metabolism involves side-chain oxidation and epoxidation [57]. This information provides additional insight into the metabolic fate of anethole, which can have important implications for its therapeutic applications.

According to various expert panels such as the Flavour and Extract Manufacturers Association and the Food and Drug Administration (FDA), trans-anethole is considered a generally recognized as safe agent (GRAS), and it is regarded as non-genotoxic and non-carcinogenic [59]. The Joint FAO/WHO Expert Committee on Food Additives (JECFA) established an acceptable daily intake (ADI) of 0–2 mg/kg body weight. Even when used for prolonged periods, anethole does not appear to cause specific side effects such as ulcerogenic, hepatotoxicity, nephrotoxicity, etc. [60].

This review has several limitations that may affect its quality. First, it only includes papers published in English, potentially missing reports in other languages. Second, the different investigations use anethole with varying doses, derivatives, sources, and purities, which may negatively impact data replication. Third, no structure-activity relationship study has been performed, highlighting the need for further research in this area. Fourth, human trials evaluating the protective effects of anethole against MetS, its effective and safe concentrations, clinical data on pharmacokinetic characteristics and oral bioavailability of anethole, and its potential to cross the blood-brain barrier are scarce. Future clinical investigations evaluating these factors will be of great importance.

Conclusions

Phytochemicals and dietary bioactive molecules have been reported to confront a variety of disorders including diabetes, dyslipidemia, hypertension, obesity, etc. Hereto, we surveyed the protective effects of anethole against the various components of MetS. The results of this study may have implications for developing new medications for the treatment of MetS and its components. Anethole has been shown to affect several molecular pathways involved in the pathogenesis of MetS. However, future in vitro and animal investigations will shed light on various other anti-MetS signaling pathways of anethole. Moreover, conducting quality human studies is necessary to evaluate its optimum human dose, bioavailability, drug interactions, unwanted reactions, and pharmacokinetic characteristics.

Abbreviations

MetS

Metabolic syndrome

CVD

Cardiovascular disease

IR

Insulin resistance

NCEP

National Cholesterol Education Program

IDF

International Diabetes Federation

TG

Triglyceride

HDL

high-density lipoprotein

BP

Blood pressure

T2DM

Type 2 diabetes Miletus

mTOR

Mammalian target of rapamycin

PPAR-γ

Peroxisome proliferator- activated receptor gamma

WAT

White adipose tissue

BAT

Brown adipose tissue

ARRIVE

The Animal Research Reporting In vivo Experiments

GIVIMP

The Organization for Economic Cooperation and Development Guideline on Good in vitro Method Practices

IL-6

Interleukin-6

TNF-α

Tumor necrosis factor-alpha

NF-κB

Nuclear factor-κB

MAPK

Mitogen-activated protein kinase

IRS-1

Insulin receptor substrate-1

LDL

Low-density lipoprotein

NAFLD

Non-alcoholic fatty liver disease

TA

Trans-anethole

STZ

Streptozotocin

FVEO

Foeniculum vulgare essential oil

GSH

Glutathione

CAT

Catalase

SOD

Superoxide dismutase

MDA

Malondialdehyde

PDX1

Pancreatic and duodenal homeobox factor-1

MafA

v-maf musculoaponeurotic fibrosarcoma oncogene homolog A

FBS

Fasting blood glucose

ACC

acetyl-CoA carboxylase

GPAT

glycerol-3-phosphate acyltransferase

HPLC

High-performance liquid chromatography

GC–MS

gas chromatography–mass spectrometry

HbA1c

Hemoglobin A1c

OPN

Osteopontin

PEDF

Pigment epithelium-derived factor

HFD

High-fat diet

TBA

Total bile acid

FFAs

Free fatty acids

SFAs

Saturated fatty acids

MUFAs

Monounsaturated fatty acids

PUFA

Polyunsaturated fatty acid

EFAs

Essential fatty acids

FAS

Fatty acid synthase

SCD1

Stearoyl-CoA desaturase1

FADS

Fatty acid desaturase

FATP

Fatty acid transport protein

L-FABP

Liver fatty acid binding protein

EPA

Pentosapentanoic acid

HSL

Hormone-sensitive lipase

ATGL

Adipocyte TG lipase

ACOX1

Acyl-coenzyme A oxidase 1

ATT

Anethole Trithione

PH

Pulmonary hypertension

Phe

Phenylephrine

ET-1

Endothelin-1

PASMC

Pulmonary Artery Smooth Muscle Cells

β3-AR

β3-adrenergic receptor

SIRT1

Sirtuin1

NASH

Nonalcoholic Steatohepatitis

BARS

Thiobarbituric acid reactive substance

GRAS

Generally recognized as safe agent

Funding

This study was funded by the Research Council of Mashhad University of Medical Sciences (Grant number: 8989200).

Declarations

Conflict of interest

The authors have no relevant financial or non-financial interests to disclose.

Ethical approval

Not applicable.

Declaration of generative AI and AI-assisted technologies in the writing process

During the preparation of this work, the author(s) used ChatGPT/OpenAI.com to improve English language]. After using this tool/service, the author(s) reviewed and edited the content as needed and take(s) full responsibility for the content of the publication.