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Abstract

Metabolic syndrome, also known as insulin resistance disorder, is the simultaneous manifestation of multiple metabolic disorders in an individual. The present-day complementary and alternative therapies suggest several medicinal herbs that may have the potential to improve one or multiple complications of metabolic syndrome. All of them have their own limitations in efficacy and unwanted effects. Therefore, we reviewed species of Satureja as widespread medicinal herbs and potentially good remedies for metabolic syndrome. We reviewed literature found in PubMed and the ISI Web of Knowledge with the key word Satureja in the title. The influence of any species of Satureja on any disease or syndrome, enzymatic, metabolic, or physiological pathways, in human, animals, or in vitro conditions related to any characteristics of metabolic syndrome were considered. The main outcomes of treatment with Satureja species were categorized, and the possible mechanisms of action are discussed in this article.

Keywords

metabolic syndrome medicinal herb

Introduction

Metabolic syndrome, also known as insulin resistance disorder, is the simultaneous manifestation of multiple metabolic disorders in an individual. It is strongly associated with the incidence of cardiovascular disease and is known as a major global health problem.^1,2

For the first time, Reaven,³ in the year 1988, described the symptoms of this syndrome (known as syndrome X). He mentioned insulin resistance as an underlying factor and proposed a constellation of other abnormalities that included hyperglycemia, dyslipidemia (hypertriglyceridemia, lowered high-density lipoprotein cholesterol), and hypertension. A sedentary lifestyle, an unhealthy diet, and genetics are factors of concern in the etiology of metabolic syndrome.³

In 1998, the American Diabetes Association developed the criteria for metabolic syndrome,⁴ and in 2001 the National Cholesterol Education Program Adult Treatment Panel III created the most common criteria and definition, requiring the presence of at least three of the following 5 characteristics: abdominal obesity (waist circumference ≥102 cm or 40 inches men and ≥88 cm or 35 inches in women), triglycerides ≥150 mg/dL, high-density lipoprotein cholesterol <40 mg/dL in men and <50 mg/dL in women, blood pressure ≥130/85 mm Hg, and fasting blood glucose ≥110 mg/dL.⁵

The Adult Treatment Panel III also identified 6 metabolic syndrome components that are related to cardiovascular disease: abdominal obesity, atherogenic dyslipidemia, increased blood pressure, insulin resistance ± glucose intolerance, pro-inflammatory state, and prothrombotic state. The critical sequelae of metabolic syndrome are type 2 diabetes mellitus, hypertension, dyslipidemia, and atherosclerotic vascular disease, particularly coronary artery diseases.^2,5

The medical therapy for metabolic syndrome consists of lifestyle modification and drug therapy. Lifestyle modification includes diet and exercise.⁶ Dietary approaches include diets such as the Mediterranean diet^7,8 and the DASH or Dietary Approach to Stop Hypertension diet.⁹ Exercise also results in a negative energy balance that contributes to dietary approaches to achieve weight loss and its metabolic benefits.¹⁰

A drug therapy regimen includes administration of 3 groups of drugs. An oral hypoglycemic agent is prescribed to increase sensitivity to insulin, such as metformin¹¹ and thiazolidinediones,¹² statins like simvastatin,^13,14 and atorvastatin¹⁵ are commonly administered to lower a patient’s lipid profile; antihypertensive therapy with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers^16,17 are also recommended.

These drugs, however, have some significant adverse effects. The significant adverse effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are acute renal failure and hypercalemia.^18,19 Diarrhea, headache, abdominal pain, myalgia, and nasopharyngitis for statins²⁰ and diarrhea, nausea/vomiting, headache, and edema for metformin and thiazolidinedions are addressed in several articles.^21–23

Natural products are a potential source of new drugs. Present-day complementary and alternative therapies suggest several medicinal herbs that may have the potential to improve one or multiple complications of metabolic syndrome. As examples, fenugreek (Trigonella foenum-graecum L),²⁴ bitter melon (Momordica charantia L),²⁵ and cinnamon bark (Cinnamomum cassia J Presl)^26–28 were examined for hyperglycemia, and dill (Anethum graveolens L),²⁹ garlic (Allium sativum L),³⁰ roselle (Hibiscus sabdariffa L),³¹ and mulberry (Morus alba L)³² were investigated for their hypotensive and hypolipidemic effects.

Despite attempts to find a comprehensive treatment or control for metabolic syndrome, no remarkable improvement was achieved with any of the current synthetic or natural singular drugs. All of them have their own limitations in efficacy and unwanted effects. Therefore, we reviewed Satureja species as widespread medicinal herbs and good potential remedies for metabolic syndrome.

Among the various species of medicinal herbs, Satureja (S. hortensis, S. khuzestanica, S. montana, S. viminea, S. macrostema, S. thymbra, S. spicigera, and S. obovata) belongs to the Lamiaceae family and the subfamily of Nepetoidae.³³ The dried leaves of Satureja are used as a pleasant spice and food additive as well as an herbal tea. Recent phytochemical studies aiming to find the major and effective components of Satureja’s aerial parts revealed the existence of carvacrol and flavenoids like apigenin, naringenin, aromadendrin, luteolin, diosmetin, eriodictyol, and taxifolin, and phenolic acids like labiatic acid, monoterpene hydrocarbons, and thymol.^34–39

It has been reported that Satureja species extracts and fractions possess various therapeutic effects. They are antioxidants,^40–44 control blood lipids,^42,44,45 attenuate blood glucose,^42,46–48 and inhibit lipid peroxidation.^{42,45,49–51} They are anti-inflammatory,^43,51–54 analgesic,^52,55 and antiproliferative.^56,57 Moreover, they have antidiarrheal,^55,58 vasorelaxant,⁵⁹ antifungal,⁶⁰ antibacterial,^61,62 antinociceptive,⁵² antiviral,⁶³ antispasmodic,⁵⁸ and anticoagulant⁶⁴ effects.

Herein we present a review study aimed at reporting the health benefits of Satureja species in preventing or treating metabolic syndrome. Their possible mechanisms of action are discussed separately, considering the effect of these plants on every characteristic of this syndrome.

Methods

We have reviewed the literature found in PubMed and ISI Web of Knowledge with the key word Satureja in the title from 1999 up to June 20, 2013. In all, 442 articles (101 articles in PubMed and 341 articles in ISI Web of Knowledge) were found. Human, in vivo, and in vitro studies were included in the review; irrelevant articles such as reviews, letters to the editor, brief communications, and articles regarding unrelated in vitro antimicrobial, analytical, morphological, and botanical studies were excluded. Influences of any species of Satureja on any disease or syndrome, enzymatic, metabolic, or physiological pathways, in human, animals, or in vitro conditions related to any characteristics of metabolic syndrome were considered. After filtering using the aforementioned criteria, 27 articles were selected, and the main outcomes of each study are discussed in this review.

Results and Discussion

Efficacy

After reviewing all 27 selected articles (Table 1), the main outcomes of treatment with the Satureja species were categorized as shown in Table 2. Satureja species such as S. hortensis, S. khuzestanica, S. montana, S. viminea, S. macrostema, S. thymbra, S. spicigera, and S. obovata showed insignificant and positive effects in each phase (in vivo, in vitro, and human study).

Table 1.

Main Outcomes of Satureja Species, Summarized in Order of Each Study and Its Properties.

Author/s (Year)	Objectives	Type of Study	Target and Sample Size	Satureja Species Dose/Duration	Main Outcomes
Ramón Sánchez de Rojas et al (1999)⁵⁹	Vasodilator effect of eriodictyol	In vitro	Rat thoracic aorta rings	S. obovata’s eriodictyol 10⁻⁵ and 5 × 10⁻⁵ M	Slightly relaxed noradrenaline and KCl-induced contractions, inhibited sarcoplasmic reticulum release of calcium
Hajhashemi et al (2000)⁵⁸	Ileum contractions induced by acetylcholine and KCl	In vitro and in vivo	18 mice for diarrhea test and female Wistar rats	S. hortensis essential oils 10% emulsion 1 mL/100 g and 9-36 mg/mL in vitro for 4 hours	Inhibited the ileum contractions response to KCl in a concentration dependent manner, attenuated the maximum inducible response of acetylcholine concentration response curve
Hajhashemi et al (2002)⁵²	Analgesic and anti-inflammatory activity	In vivo	Fasted male Swiss mice, male Wistar rats, 21 groups comprising 6 animals	S. hortensis hydroalcoholic extract, essential oils and polyphenolic fraction, 200-2000 mg/kg, single dose	Inhibited the mice acetic acid–induced writhing responses, showed analgesic activity, reduced carrageenan induced edema
Abdollahi et al (2003)⁴²	Antidiabetic, antihyperlipidemic, and antioxidative stress effects, primary acute toxicity, and teratogenicity	In vivo	24 pregnant and 3 groups of 6 + 6 male Sprague–Dawley rats	S. khuzestanica essential oils 500, 1000, and 1500 ppm in water for 15 days	Not lethal up to 2 g/kg, no signs of toxicity, decreased normal lipid peroxidation, blood glucose and triglycerides; increased antioxidant capacity and number of implantation and live fetuses, total cholesterol not affected
Suárez et al (2003)⁵⁵	Biological effects	In vivo	2 female Sprague–Dawley rats for each dosage and 3 groups of 6 albino mice	S. viminea 250-1000 mg/kg	Reduced motor activity and grasping strength, exploratory behavior and curiosity were diminished, analgesic effect and inhibited intestinal transit and gastric emptying, LD50 is 556.8 mg/kg
Cetojević-Simin et al (2004)⁵⁶	Antioxidative effect on free radicals and antiproliferative effect	In vitro	Human tumor cell lines	S. montana concentrations ranging from 0.05 to 1 mg/mL	Antioxidative activity increased dose-dependently n-butanol > methanol > water > ethyl acetate > petroleum ether. Antiproliferative effect on HeLa cell line except for petroleum ether, strong stimulation of HT-29 proliferation
Dorman and Hiltunen (2004)⁴¹	Antioxidant, DPPH., ABTS ^.+ , and hydroxyl radical-scavenging properties	In vitro		S. hortensis dried crude extract	Ethyl acetate soluble fraction was the most effective fraction in a concentration-dependent fashion
Saadat et al (2004)⁷²	Hepatic enzymes activity, phosphoenolpyruvate carboxykinase and glycogen phosphorylase	In vivo	16 adult male Wistar rats, 2 groups, RCT	S. khuzestanica essential oils 1000 ppm dissolved in water for 2 weeks	No change in blood glucose concentration, increased hepatic GP and decreased hepatic PEPCK activity
Amanlou et al (2005)⁵³	Anti-inflammatory and antinociceptive effects	In vivo	Case control, 9 + 9 male albino Wistar rats	S. khuzistanica extract 10-150 mg/kg, single dose	Similar anti-inflammatory activity with indomethacin antinociceptive activity (dose dependently)
Ghazanfari et al (2006)⁵¹	Acetic acid–induced inflammatory bowel disease (IBD)	In vivo	Sprague Dawley rats	S. khuzestanica essential oils 500, 1000, and 1500 ppm	Decreased lipid peroxidation and myeloperoxidase activity, attenuated macroscopic and microscopic characters
Mosaffa et al (2006)¹²⁹	Protection on rat lymphocytes DNA lesions	In vitro	Rat lymphocytes	S. hortensis ethanolic extract and essential oils, 0.05, 0.1, 0.5, 1.0, and 2.5 mg/mL for 30 minutes	Reduced H₂O₂-induced DNA and chromosomal damage, inhibited oxidative DNA damage
Basiri et al (2007)⁴⁸	Protective effects on toxicity of malathion	In vivo	20 adult male Wistar rats, 4 groups	S. khozestanica 225 mg/kg per day for 28 days	Recovered hyperglycemia and AChE inhibition, restored activation of PEPCK and GP
Prieto et al (2007)⁵⁰	Peroxynitrite-induced formation of 3-nitrotyrosine and malondialdehyde	In vitro	Wistar rat livers	S. montana essential oils	Decreased 3-nitrotyrosine and malondialdehyde formation
Yazdanparast and Shahriyary (2008)⁶⁴	Adhesion of the activated platelet to laminin-coated plates, aggregation and protein secretion	In vitro	Human platelets	S. hortensis concentration of 200 μg/mL	Inhibited platelet adhesion to laminin-coated wells, self-aggregation and protein secretion were also affected
Shahsavari et al (2009)⁴⁷	Hepatic PEPCK and GP activities and mRNA levels	In vivo	Male Wistar albino rats, 6 groups comprising 6 animals	S. khuzestanica 50-100 mg/kg per day for 21 days	Decreased plasma glucose concentration and Hepatic PEPCK activity and its mRNA levels, moderately increased hepatic GP activity and its mRNA levels
Rezvanfar et al (2010)⁴³	Protective effects in hemorrhagic cystitis	In vivo	32 adult male Wistar rats, 4 groups	S. khuzestanica essential oils 225 mg/kg for 28 days	Ameliorated urothelial topography, decreased number of mucosal mast cells and inflammatory cells, attenuated lipid peroxidation and total antioxidant capacity
Gutierrez and Navarro (2010)⁴⁵	Antioxidative potential, total phenolic and flavonoid content	In vivo	Male Wistar albino rats, 3 groups comprising 6 animals	S. macrostema extract Single daily dose (200, 400 and 600 mg/kg intraperitoneally) for 4 days	Reduced elevated levels of ALT, AST, ALP, total bilirubin, cholesterol and increased the level of HDL, protected lipid peroxidation, powerful free radical scavenging, not lethal up to 4000 mg/kg after 72 hours
Vosough-Ghanbari et al (2010)⁴⁴	Serum glucose, lipids, and markers of oxidative stress	Human	DB-RCCT hyperlipidemic patients with type 2 diabetes, 11 case + 10 placebo, mean age 50.65 yrs	S. khuzestanica dried leaves 250 mg/d for 60 days	Decreased total cholesterol and LDL, increased HDL and total antioxidant power (TAP), did not altered blood glucose, triglyceride, creatinin and TBARS
Ghalamkari et al (2011)¹³⁰	Carcass characteristics, immune responses and serum biochemical parameters	In vivo	RCT, 240 one-day old mixed sex broiler chicks (Ross 308), 4 groups, 4 replicates with 15 broilers	S. hortensis powder 5 and 10 g/kg per day for 42 days	Improved antibody titers against SRBC, serum biochemical parameters and weight not affected
Masuda et al (2011)¹³¹	Peripheral body temperature	Human	DB- RCCT, 7 females experienced the feeling of cold, 18-22 years old	S. montana essential oils 300 mg, single dose	Elevated recovery rate temperature
Tavafi et al (2011)¹³²	Renal protective effects	In vivo	RCT, 40 male Sprague–Dawley rats, 4 groups	S. khuzestanica essential oils 250 or 500 ppm in drinking water for 8 weeks	Inhibited glomerular hypertrophy, sclerosis and glomerular number loss, attenuated serum urea and ameliorated serum creatinine
Ahmadvand and Tavafi (2012)⁷³	Lipid profile, atherogenic index, and liver enzyme markers	In vivo	Case control, 30 Sprague–Dawley rats 3 groups	S. khuzestanica essential oils 500 ppm in drinking water	Inhibited ALT and ALP activities, decreased FBG, TG, cholesterol, LDL and VLDL, increased HDL
Gohari et al (2012)⁵⁷	Main compounds cytotoxicity	In vitro	Four cancerous cell lines	S. spicigera 5-100 μg/mL, 24- to 48-hour incubation	Only oleanolic acid inhibited T47D (human, breast, ductal carcinoma) growth
Kaeidi et al (2013)⁴⁶	Neuroprotective effects	In vivo and in vitro	PC12 cells and male Wistar rats, several groups comprising 6-8 rats	S. khuzestanica 50 and 200 mg/kg per day for 3 weeks	Ameliorated hyperglycemia, weight loss, hyperalgesia, and motor deficit, inhibited caspase 3 activation, and decreased the Bax/Bcl-2 ratio
Öztürk (2012)⁴⁹	Antioxidant and anti-cholinesterase activities	In vitro		S. thymbra essential oils and methanolic extract	Inhibited acetylcholinesterase and butyrylcholinesterase (except p-cymene), inhibited lipid peroxidation
Sabzghabaee et al (2012)⁵⁴	Denture stomatitis	Human	DB-RCCT, 80 Palatal lesions patients (T II and III)	S. hortensis essential oils 1% gel applied 2 times daily for 2 weeks	Reduced erythematous lesions and Candida colonies’ count
Bagheri et al (2013)⁶⁵	Antioxidative activities, oxidation of LDL	In vitro		S. khuzestanica essential oils 50 to 200 μg/mL	Inhibited LDL oxidation dose dependently, antioxidant capacity of SKEO was 3.20 ± 0.40 nmol of ascorbic acid equivalents for 1 g SKEO

Abbreviations: ppm, parts per million; DPPH ^. , 2,2-diphenyl-1-picrylhydrazyl; ABTS ^.+ , 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid); RCT, randomized clinical trial; GP, glycogen phosphorylase; PEPCK, phosphoenolpyruvate carboxy kinase; ALT, alanine transaminase; AST, aspartate transaminase; ALP, alkaline phosphatase; HDL, high-density lipoprotein; DB-RCCT, double blind randomized controlled clinical trial; LDL, low-density lipoprotein; TBARS, thiobarbituric acid reactive substances; FBG, fasting blood glucose; TG, triglyceride; VLDL, very low density lipoprotein; SKEO, S. khuzestanica essential oils.

Table 2.

Satureja Efficacy, Summarized in Objective, Species, Type of Study, Dosage Form, and Results.

Objective	Satureja Species	Type of Study	Dosage Form	Results	Reference
Antioxidant power and lipid peroxidation	S. hortensis	In vitro	Crude extract	Sig. Inc. antioxidative activity	41
	S. khuzestanica	In vivo	PO	Sig. Inc. antioxidant capacity, Dec. lipid peroxidation	42
	S. khuzestanica	In vivo	EO PO	Sig. Inc. antioxidant capacity	43
	S. khuzestanica	Human	Dried leaves PO	Sig. Inc. antioxidant capacity, Insig. lipid peroxidation	44
	S. macrostema	In vivo	ME IP	Sig. Inc. antioxidant capacity, Dec. lipid peroxidation	45
	S. thymbra	In vitro	Different extract	Sig. Dec. lipid peroxidation	49
	S. montana	In vitro	EO	Sig. Dec. oxidative stress	50
	S. khuzestanica	In vivo	EO PO	Sig. Dec. lipid peroxidation	51
	S. montana	In vitro	Different extract	Sig. Inc. antioxidative activity	56
	S. khuzestanica	In vitro	EO	Sig. Inc. antioxidant capacity, Inh. LDL oxidation	65
	S. hortensis	In vitro	EO and EE	Sig. Dec. DNA oxidative damage	129
Blood glucose	S. khuzestanica	In vivo	PO	Sig. Dec. blood glucose	42
	S. khuzestanica	Human	Dried leaves PO	Insig. Change in blood glucose	44
	S. khuzestanica	In vivo	EO PO	Sig. Dec. blood glucose	46
	S. khuzestanica	In vivo	EO PO	Sig. Dec. blood glucose	47
	S. khuzestanica	In vivo	EO PO	Sig. Dec. blood glucose	48
	S. khuzestanica	In vivo	EO PO	Insig. change in blood glucose	72
	S. khuzestanica	In vivo	EO PO	Sig. Dec. blood glucose	73
	S. hortensis	In vivo	Powder PO	Insig. change in blood glucose	130
Blood lipids	S. khuzestanica	In vivo	PO	Sig. Dec. TG, Insig. chang in T chol	42
	S. khuzestanica	Human	Dried leaves PO	Sig. Dec. T chol and LDL, Inc. HDL, Insig. change in TG	44
	S. macrostema	In vivo	ME IP	Sig. Dec. T chol, Inc. HDL	45
	S. khuzestanica	In vivo	EO PO	Sig. Dec. T chol LDL TG VLDL, Inc. HDL	73
	S. hortensis	In vivo	Powder PO	Insig. change in T chol LDL HDL TG	130
Anti-inflammatory effect	S. khuzestanica	In vivo	EO PO	Sig. Dec. inflammation	43
	S. hortensis	In vivo	PF PO	Sig. Dec. inflammation	52
	S. khuzistanica	In vivo	HAE IP	Sig. Dec. inflammation	53
	S. hortensis	Human	EO topical	Sig. Dec. erythematous lesions	54
Vasorelaxant	S. obovata	In vitro	Eriodictyol	Sig. vasodilatory effect	59
Enzymes regulation	S. khuzestanica	In vivo	EO PO	Sig. Inc. h.GP, Dec. h.PEPCK	47
	S. khuzestanica	In vivo	EO PO	Sig. Dec. h.GP, Dec. h.PEPCK	48
	S. khuzestanica	In vivo	EO PO	Sig. Inc. h.GP, Dec. h.PEPCK	72
Gastrointestinal transition time	S. viminea	In vivo	EO and AE PO	Inh. gastric emptying	55
Gastrointestinal transition time	S. hortensis	In vitro	EO emulsion	Inh. ileum contraction	58
Platelet adhesion and aggregation	S. hortensis	In vitro	ME	Inh. platelet adhesion and aggregation	64

Abbreviations: PO, per os (taken orally); IP, intraperitoneal; EO, essential oils; EE, ethanolic extract; ME, methanolic extract; PF, polyphenolic fraction; HAE, hydroalcoholic extract; AE, aqueous extract; Sig, significantly; Insig, insignificantly; Inc, increased; Dec, decreased; Inh, inhibited; T chol, total cholesterol; LDL, low-density lipoprotein; HDL, high-density lipoprotein; TG, triglyceride; VLDL, very low density lipoprotein; h.PEPCK, hepatic phosphoenolpyruvate carboxy kinase; h.GP, hepatic glycogen phosphorylase.

The most cited pharmacological effects of Satureja species on different metabolic syndrome characteristics are discussed below.

Antioxidant

Satureja as an antioxidant agent was investigated by researchers in nine studies comprising 5 in vitro, 3 in vivo, and 1 human study.

In an in vitro study, Bagheri et al⁶⁵ investigated the antioxidative activities and oxidation of low-density lipoprotein effects of S. khuzestanica essential oil. The results showed that S. khuzestanica essential oil inhibited low-density lipoprotein oxidation dose-dependently, and the antioxidant capacity of S. khuzestanica essential oil was 3.20 ± 0.40 nmol of ascorbic acid equivalents/g of S. khuzestanica essential oil. The triterpenoid, carvacrol, tannin, steroid, and flavonoid components of Satureja may contribute to its remarkable antioxidative activity.⁶⁵

In another in vitro study, Dorman and Hiltunen⁴¹ investigated the antioxidant, 2,2-diphenyl-1-picrylhydrazyl, 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid), and hydroxyl radical–scavenging properties of S. hortensis dried crude extract. Ethyl acetate soluble fraction was the most effective fraction in a concentration-dependent fashion. The mechanism of scavenging free radical reactive species is suggested as being caused by the action of electron-hydrogen donation.⁴¹

Cetojević-Simin et al⁵⁶ conducted an in vitro study in which they investigated the antioxidative effect of 6 S. montana extracts on free radicals. Antioxidative activity increased dose-dependently. The highest amount of antioxidative activity was shown by n-butanol extract followed by methanol, water, ethyl acetate, and petroleum ether extracts, respectively.

Gutierrez and Navarro⁴⁵ evaluated the antioxidative potential of the methanol extract of S. macrostema in an in vivo study. A single daily dose (200, 400, 600 mg/kg intraperitoneally) given to male Wistar albino rats for 4 days induced powerful free radical scavenging activity. Two antioxidation mechanisms for OH ^. scavenging activities are suggested: First, binding with metal ions and suppressing OH ^. generation, and second, transferring single electrons directly to the generated radical.⁴⁵

The NO ^. scavenging activity of the Satureja species could be effective in preventing nitrosamine-mediated carcinogenesis. It can inhibit nitrate reactions with amines and amides in the digestive tract, which generates carcinogenic nitrosamines and nitrosamides.⁶⁶

Antihyperglycemic

In 8 studies (1 human study, 7 in vivo studies), Satureja species were observed to lower blood glucose levels in 5 in vivo studies, but other studies showed no significant change after treatment.

The Satureja species inhibited phosphoenolpyruvate carboxy kinase (PEPCK) in 3 studies and glycogen phosphorylase in 2 studies, but activated glycogen phosphorylase in 1 study.

Shahsavari et al⁴⁷ performed an in vitro study in which they evaluated the effects of S. khuzestanica essential oil on hepatic glycogen phosphorylase and PEPCK activities and gene expression in rats. Their results indicated a reduction in plasma glucose concentrations and hepatic PEPCK and its mRNA levels, while hepatic glycogen phosphorylase activity and its mRNA levels increased moderately.

The rate-limiting enzyme of gluconeogenesis is PEPCK, which is expressed in the liver. Studies have revealed the role of reactive oxygen intermediates in the regulation of glucose production in the liver.⁶⁷ Hyperglycemia results in elevated oxidative stress by generating reactive oxygen species.⁶⁸ Reactive oxygen species lead to the upregulation of PEPCK gene expression via stress-activated signaling pathways.^47,69

In their in vivo study, Basiri et al⁴⁸ investigated improvement affected by S. khuzestanica essential oil in the malathion-induced alteration of hepatic mitochondrial glycogen phosphorylase and PEPCK activities in rats. S. khuzestanica essential oil facilitated recovery from hyperglycemia and helped restore PEPCK and glycogen phosphorylase activity. Flavonoids cause the repression of glucose production and PEPCK gene expression.⁷⁰ Recent studies have revealed that antioxidants need glucose to oppose free radicals in the form of glucose-6-phosphate, provided by stimulating hepatic glycogenolysis and gluconeogenesis. This mechanism involves the pentose phosphate pathway in reducing NADP to NADPH, which intervenes in the reduction of oxidized glutathione, the end product of the antioxidative process.^48,71 One possible mechanism that comes to mind is the antioxidant property of flavonoids which consumes hepatic glucose through the pentose phosphate pathway, thereby depleting hepatic glycogen stores.

Therefore, the plasma glucose lowering action of Satureja may be related to its excessive inhibition of hepatic PEPCK, which is more than its inhibition of hepatic glycogen phosphorylase, which leads to decreased gluconeogenesis. On the other hand, the uptake of blood glucose for hepatic glycogenesis is enhanced when the gluconeogenesis pathway is blocked.⁷²

Antihyperlipidemic

Three out of 5 studies showed that Satureja lowered total cholesterol. Three studies were done on low-density lipoprotein cholesterol, and 2 of them exhibited a lowering effect. For high-density lipoprotein cholesterol, 3 out of 4 studies exhibited an increasing effect. For triglycerides, however, only 2 studies out of 4 revealed lower levels after treatment with Satureja.

In 2 different in vivo studies, both Gutierrez and Navarro⁴⁵ and Ahmadvand et al⁷³ revealed that S. macrostema extract and S. khuzestanica essential oils decreased total cholesterol and increased HDL cholesterol. Isopropanoids, carvacrol, and thymol, 3 main components of the Lamiaceae family, suppress cholesterol synthesis by increasing microsomal geranyl pyrophosphate pyrophosphatase activity and regulating the 3-hydroxy-3-methylglutaryl coenzyme A reductase,⁷⁴ a key enzyme in cholesterol synthesis. Enhancing one’s antioxidant supply may help prevent the evolution of hyperlipidemia, since oxidative stress has been found to be an early event in increasing concentrations of total cholesterol, low-density lipoprotein cholesterol, and triglycerides.⁷⁵

A double-blind randomized controlled trial by Vosough-Ghanbari et al.⁴⁴ investigated the effect of S. khuzestanica supplements on serum lipids in hyperlipidemic patients with type 2 diabetes mellitus. Results showed decreased total cholesterol and low-density lipoprotein cholesterol levels as well as increased high-density lipoprotein cholesterol levels. Isoprenols from herbs and fruits are capable of activating peroxisome proliferator-activated receptors (PPARs), like PPARγ and PPARα.⁷⁶ PPARγ is related to adipogenesis⁷⁷ and the regulation of insulin resistance in adipose tissue. PPARγ activation promotes adipocyte differentiation which could improvement insulin resistance.^78,79

PPARγ is related to lipid catabolism by regulating the expression of genes involved in the process.⁸⁰ PPARα activation results in the clearance of circulating or cellular lipids.⁸¹ Consequently, the reduction in lipids stimulates fat degradation in skeletal muscle and peripheral tissue where PPARα expression is high.⁸² It may be concluded that using isoprenols to activate PPARα and PPARγ in the liver and adipocytes may contribute to the improvement of hyperlipidemia.

Lipid peroxidation inhibitor

Six studies, comprising 2 in vitro, 3 in vivo, and 1 human study, showed lipid peroxidation inhibition, and 1 study showed no significant alteration after treatment with Satureja species.

Prieto et al⁵⁰ investigated the peroxynitrite-induced formation of 3-nitrotyrosine and malondialdehyde in isolated rat livers in an in vitro study. Their results indicated that S. montana essential oils reduced the formation of 3-nitrotyrosine and malondialdehyde. Carvacrol, c-terpinene, and thymol inhibited lipid peroxidation^83,84 and oxidation of low-density lipoprotein efficiently.⁸⁵ Thymol has been reported to reduce the oxidation induced by Fenton’s reagent⁸⁶ and to act directly as a peroxynitrite scavenger.⁸⁷ Peroxynitrite is responsible for oxidative damage to many organs⁸⁸ via 2 toxic compounds, 3-nitrotyrosine and malondialdehyde, which are considered biomarkers of pathological stress.^89,90 Reactive oxygen species, through lipid peroxidation, could induce cell and tissue injury and activate the nuclear factor-κB.⁹¹ Increased activation of nuclear factor-κB has been reported to be involved in the upregulation of the inflammation response of the immune system, which can lead to atherosclerosis.⁹²

On the other hand, the antiphosphodiesterase activity of flavonoids could raise intracellular cyclic adenosine monophosphate and cyclic guanosine monophosphate levels.⁹³ The elevation of these levels is involved in reducing oxidative stress,^72,94–99 suppressing secretion of tumor necrosis factor-α, and inhibiting production of superoxide anions.^100,101 Tumor necrosis factor-α is an adipokine related to inflammation induction and is a key mechanism of disease.¹⁰² Polyphenols are known to be powerful heavy metal chelators. As a result, iron-chelating capacity reduces catalyzing transition metals needed in Fenton reaction for the peroxidation of lipids.⁴⁵

Anti-inflammatory

Three in vivo studies and one human study showed Satureja species to have anti-inflammatory effects. A case control in vivo study conducted by Amanlou et al⁵³ evaluated the anti-inflammatory and antinociceptive effects of S. khuzistanica on rats using the carrageenan-induced rat paw edema and formalin tests. Results revealed that the hydroalcoholic extract of S. khuzistanica possesses anti-inflammatory activity similar to that of indomethacin in a dose-dependent manner. This property may originate from the presence of flavonoids, steroids, and tannin that exert anti-inflammatory and analgesic effects.^103–105 Another reason may be the attribution of humoral reactions related to the antioxidative effect during inflammation when the production of reactive free radicals is high.⁵³ Moreover, flavonoids can inhibit the release of histamine and the expression of proinflammatory cytokines in the mast cells.^106,107

A recent study revealed that carvacrol could be a potent suppressor of cyclooxygenase-2 expression,¹⁰⁸ a key enzyme for initiation of the inflammation cascade.

Vasorelaxant

Vasorelaxant effects for Satureja species was revealed in one prior study. Ramón Sánchez de Rojas et al⁵⁹ investigated the vasodilator effect of eriodictyol isolated from S. obovata in rat thoracic aorta rings. Eriodictyol slightly relaxed noradrenaline and KCl-induced contractions and also inhibited the sarcoplasmic reticulum release of calcium. Rosmarinic acid, a polyphenol commonly found in the Laminaceae family, exhibited in vitro endothelium-dependent vasodilation activated by NO ^. agent.¹⁰⁹ In the smooth muscle, guanylate cyclase activation by NO ^. raises the level of the intracellular second messenger cyclic guanosine monophosphate, which causes smooth muscle relaxation by decreasing the intracellular Ca²⁺ concentration.^110,111

Flavonoids have also been shown to be acutely effective in improving coronary circulation when administered orally to healthy adult men.¹¹²

Gastric Emptying Inhibitor

The gastric emptying inhibition property was revealed in 2 in vivo studies. Hajhashemi et al⁵⁸ demonstrated that S. hortensis essential oils 10% emulsion attenuated the maximum inducible response of the acetylcholine ileum concentration response curve. Suárez et al⁵⁵ investigated S. viminea essential oils and revealed their intestinal transit and gastric emptying inhibition property. The noncompetitive antagonism effect of Satureja components on muscarinic receptors in gastrointestinal smooth muscle attenuates the maximum acetylcholine concentration response which results in ileum relaxation.⁵⁸

The essential oil of Satureja can delay gastric emptying and intestinal transit time. The possible mechanism can be explained by directly effecting gastrointestinal smooth muscle fibers by inhibiting parasympathetic autonomous nervous system excitability.⁵⁵

Anticoagulant

In their in vitro study on human platelets, Yazdanparast and Shahriyary⁶⁴ revealed that S. hortensis inhibited platelet adhesion to laminin coated wells. It also affected self-aggregation and protein secretion of the treated platelets. Several studies have shown that coumarins, polyphenols, and flavonoids in the Satureja species^113,114 could inhibit platelet adhesion, aggregation, and secretion.^115–117 Suggested mechanisms are prostaglandin synthesis, scavenging reactive oxygen species, and inhibiting cyclic nucleotide phosphodiestrases.¹¹⁸ Polyphenols can activate NO ^. agent, which raises the level of intracellular cyclic guanosine monophosphate that causes platelet aggregation inhibition.^110,119

Safety

Articles have shown that Satureja species are safe in rats. In one study, the essential oil of S. khuzestanica was found to be not lethal in doses up to 2 g/kg of a rat’s body weight, and no signs of toxicity were seen.⁴⁷ Another study suggested that S. macrostema extract was not lethal in doses up to 4000 mg/kg of a rat’s body weight after 72 hours of observation.⁴⁵ The LD50 of S. viminea essential oil is suggested to be 556.8 mg/kg of body weight.⁵⁵

Conclusion

Several studies were recently conducted to investigate the diminishing chemical drug use and the shift to herbal products and remedies.¹²⁰ It is commonly believed that they can be more efficient in some cases where chemical synthetic drugs have not shown sufficient success. Furthermore, natural products may have fewer unwanted side effects.¹²¹ Of course, their possible disadvantages and interactions with other drugs should be considered. It is a fact that natural products are good potential materials for finding new drugs provided their indications and contraindications can be investigated impartially and without bias.^122,123

Reports have substantiated the involvement of free radical oxidation, lipid peroxidation, and inflammation in the pathogenesis of metabolic syndrome main concomitant disorders, such as type 2 diabetes mellitus, dyslipidemia, and hypertension.^124–127 As previously discussed in this article, Satureja species exert anti-oxidant, lipid peroxidation inhibitory, and anti-inflammatory activities. Therefore, consuming Satureja species in order to improve any of the aforementioned metabolic syndrome complications could be helpful.

Satureja can delay gastric emptying time, which could result in a prolonged digestion process and reduced feelings of hunger,¹²⁸ which, in turn, may contribute to better weight management. Furthermore, Satureja species can be effective in the treatment or prevention of metabolic syndrome symptoms, like glucose intolerance, atherogenic dyslipidemia, increased blood pressure, and a prothrombotic state through different mechanisms of action suggested in the present discussion.

Satureja species are used as herbal medicines or consumed daily by people all over the world. They have no known remarkable adverse effects on human health. Moreover, it seems Satureja species may be recommended for the prevention, improvement, or treatment of chronic metabolic diseases such as type 2 diabetes mellitus, cardiovascular disease, hypertension, and metabolic syndrome.

Footnotes

Acknowledgments

This research is part of an MS thesis in the Faculty of Nutrition using Grant No. 92-6707 from the Vice-Chancellery of Research and Technology, Shiraz University of Medical Sciences.

Author Contributions

FN wrote the preliminary draft and contributed in data gathering and first idea of starting this project. AZ rewrote the draft and contributed in data gathering and writing the final version of the article. The other coauthors contributed toward the guidance, revision, and correction of the article.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Ethical Approval

Ethical approval is not required for this study as no human subjects were involved.

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A Review of the Benefits of Satureja Species on Metabolic Syndrome and Their Possible Mechanisms of Action

Abstract

Keywords

Introduction

Methods

Results and Discussion

Efficacy

Antioxidant

Antihyperglycemic

Antihyperlipidemic

Lipid peroxidation inhibitor

Anti-inflammatory

Vasorelaxant

Gastric Emptying Inhibitor

Anticoagulant

Safety

Conclusion

Footnotes

Acknowledgments

Author Contributions

Declaration of Conflicting Interests

Funding

Ethical Approval

References