The role of selected medicinal plants from Iranian traditional medicine for the treatment of fatigue in metabolic syndrome

Akram Alembagheri ,Homa Hajimehdipoor ,Rasool Choopani ,Somayeh Esmaeili*

1Student Research Committee,Department of Traditional Pharmacy,School of Traditional Medicine,Shahid Beheshti University of Medical Sciences,Tehran 1516745811,Iran.2Traditional Medicine and Materia Medica Research Center,Department of Traditional Pharmacy,School of Traditional Medicine,Shahid Beheshti University of Medical Sciences,Tehran 1516745811,Iran.3Department of Traditional Medicine,School of Traditional Medicine,Shahid Beheshti University of Medical Sciences,Tehran 1516745811,Iran.

Abstract Background:Fatigue is a symptom of metabolic disorders such as metabolic syndrome,which is currently increasing in the world.There is no specific medication for fatigue,but in many cases,such as in metabolic disorders,it can be relieved by treating the underlying causes.Oxidative stress and inflammation are associated with fatigue and metabolic syndrome.Other mechanisms in metabolic syndrome are also involved in causing fatigue.Objective: The aim of this study was to investigate the role of selected medicinal plants from Iranian traditional medicine (ITM) in improving fatigue in patients with metabolic syndrome. Methods: ITM is one of the most ancient systems of medicine.In this article,we first explained fatigue,its types,and treatment from the perspective of ITM and then introduced a list of medicinal plants used in ITM to treat fatigue.Next,we reviewed the biological effects of these plants effective in treating the manifestations of the metabolic syndrome based on a search of electronic databases. Results: They have antioxidant,anti-inflammatory,and anti-diabetic activities.Among them, Matricaria chamomilla L.,Laurus nobilis L., Origanum majorana L., Vitex agnus-castus L., Lawsonia inermis L., Anethum graveolens L.,and Pistacia terebinthus L.improve the lipid profile and reduce dyslipidemia.Also,the antihypertensive effects of Matricaria chamomilla, Laurus nobilis,and Origanum majorana have been proven. Conclusion: These plants prevent fatigue and disease progression by countering oxidative stress and inflammation and affecting the properties of the metabolic syndrome.

Keywords: medicinal plants;fatigue;metabolic syndrome;Iranian traditional medicine;Persian medicine

Highlights

This article reviews the medicinal plants for reducing fatigue based on Iranian traditional medicine.There is no specific medication for fatigue,but in many cases,such as in metabolic disorders,it can be relieved by treating the underlying causes.Upon review,we got 10 medicinal plants with have considerable potential for treating fatigue in metabolic syndrome.These plants prevent fatigue and disease progression by countering oxidative stress and inflammation and affecting the properties of the metabolic syndrome.

Background

Fatigue is one of the most common symptoms in clinical medicine.It is defined as difficulty in initiating or maintaining voluntary activities[1].Fatigue affects more than 20% of people worldwide,impacts the individual’s abilities,motivation,memory,concentration,and social performance,and increases their excitability [2,3].Systemic and neurological causes induce fatigue,but its exact cause is not known yet in some patients.It is considered a common complaint in many conditions,such as multiple sclerosis,Parkinson’s disease,some endocrine diseases,chronic heart failure,cancer,and pregnancy.Many metabolic disorders,including metabolic syndrome,are associated with fatigue[4].Due to people’s current sedentary lifestyle,metabolic syndrome is very common in today’s societies,with characteristics such as obesity,hyperglycemia,insulin resistance,hypertension,and dyslipidemia [5].Oxidative stress,decreased antioxidant potential,and inflammation play essential roles in developing metabolic syndrome and its complications [6].

Mitochondrial dysfunction is an early pathophysiological event in obesity and insulin resistance [7].Mitochondria regulate cellular homeostasis and produce energy as adenosine triphosphate (ATP).Most reactive oxygen species (ROS) originate from the mitochondrial respiratory chain.Dysfunction of the respiratory chain increases ROS production,decreases ATP production and antioxidative capacity,and induces apoptosis [6].The normal cellular antioxidants that usually neutralize these free radicals cannot neutralize all of them,and thus damage to cellular components occurs [8].Membrane phospholipids and their unsaturated fatty acids are very sensitive to oxidative damage by ROS and reactive nitrogen species,resulting in the production of lipid peroxides,which are cytotoxic and lead to free-radical damage to other lipids,DNA,and proteins [9].The accumulation of oxidized fatty acids in mitochondria can result in progressive oxidative damage [9].High caloric consumption rises plasma glucose and free fatty acid levels,which are closely correlated with high ROS formation and worsening obesity [6].On the other hand,lessened mitochondrial function caused by ROS/reactive nitrogen species membrane oxidation is linked to fatigue [9].Indeed,moderate to severe fatigue has been correlated to impairment of mitochondrial function and diminished production or leakage of ATP[8,10].The failure in ATP production reduces physical and mental performance [8].In addition to triggering metabolic syndrome,oxidative stress can lead to inflammation,change in vascular function,and vascular disease[5] (Figure 1).

The metabolic syndrome is associated with a state of chronic low-grade inflammation [4,5].One of the underlying causes of this situation is the presence of visceral obesity,which,in addition to causing insulin resistance,increases the production of inflammatory cytokines such as interleukin (IL)-1,IL-6,and tumor necrosis factor-α(TNF-α) [5,11].An increase in the level of inflammatory cytokines such as IL-6 and TNF-α leads to behavioral changes,including fatigue,sleep disturbances,and depressive-like symptoms[4,12,13].TNF-α is effective in producing insulin resistance and down-regulates muscle glucose uptake [14].Muscle cells uptake glucose via insulin-stimulated translocation of glucose transporter (GLUT)-4;the enzyme glucokinase mediates the following phosphorylation of glucose and its incorporation into the glycogen synthesis pathway.Insulin resistance is defined as the inability of insulin to activate glucose transport in adipose tissue and skeletal muscle and insufficient suppression of hepatic glucose production.Therefore,in patients with insulin resistance,impaired insulin-stimulated glucose transport significantly influences reducing the rate of insulin-stimulated muscle glycogen synthesis [14,15].In normal physiological conditions,the energy for muscle contraction is provided mainly by glycogen.Consequently,the muscle which has a poor glycogen reservoir,the rapid exhaustion would be clinically expressed as fatigue and weakness,and finally muscle wastage[14] (Figure 2).

Figure 1 The mitochondrial dysfunction in metabolic syndrome causes fatigue through a variety of mechanisms. ATP,adenosine triphosphate.

Figure 2 The metabolic syndrome is associated with a state of chronic low-grade inflammation,which causes fatigue via a variety of processes

There is an elevated risk for peripheral vascular disease in metabolic syndrome that fail to balance tissue perfusion with local metabolic demand.So the vascular networks can not deliver blood to working tissues in a suitable level and manner to meet the metabolic need effectively.In an increased metabolic amount,tissue and organ function becomes compromised due to an imbalance between perfusion and metabolic demand.This matter can create a compromised situation even at resting metabolic demands and is associated with a progressive decline in tissue perfusion,negatively affecting the skeletal muscle to resist fatigue.So muscle fatigue occurs faster during an increased metabolic demand [16,17].The presence of various factors in metabolic syndrome to cause fatigue can lead to a new approach to treating fatigue as a symptom of metabolic syndrome.There is no specific medication for fatigue [18].Many researchers have shown an interest in medicinal plants and natural substances and their potential for curing fatigue,increasing physical strength,and eliminating fatigue-related metabolites[18,19].Modern pharmaceuticals and ethnopharmacology extensively use medicinal plants;nonetheless,traditional knowledge of medicinal plants in many societies merits further investigation [20].Iranian traditional medicine(ITM),also known as Persian medicine,is rich in knowledge and information about the prevention,diagnosis,symptoms,and treatment of diseases and uses natural resources,including plants,animals,and minerals,to cure ailments and their symptoms [21-23].According to ITM,health and disorder depend mainly on the temperament and balance of the humors.Each humor corresponds to a specific temperament.The humors are classified into four groups:“Dam” or blood (wet and hot temperament),“Balgham” or phlegm(wet and cold temperament),“Safraa” or yellow bile (dry and hot temperament),and “Soda” or black bile (dry and cold temperament).According to ITM,any imbalance in the humors leads to the onset of disease [21].The present study aims to investigate the treatment of fatigue as a symptom of metabolic syndrome from the perspective of ITM.

Material and Methods

To investigate the types of fatigue and its treatment from the perspective of Iranian traditional medicine,three booksAl-Qanoon fi al-Tibb(Avicenna,970-1037 C.E.),Eksir-e-Azam(Azam Khan,1857-1902 C.E.) andZakhire Kharazmshahi(Jorjani,1042-1136 C.E.)were consulted [21-23].Furthermore,to identify medicinal plants that were used for easing or alleviating fatigue,this study used six books,includingAl-Qanoon Fi al-Tibb,theMakhzan-al-Adviah(Aghili Khorasani,12thAH century,1771 C.E.)Al-Havi(Rhazes,865-925 C.E.),Al-Shamel fi Sena’ate Tabiee(Ebn e Nafis Qarashi,1210-1288 C.E.),Al-abniye an-Hagha’egh-al-Adviah(Heravi,5thAH century),andTohfat-al-Mo’menin(Hakim Mo’men,11thAH century) [21 24-28].Keywords such as “E’aya”,“Ta’ab”,“Mandegi” and “Khastegi”,which denote fatigue in Persian and Arabic,were selected.The matching and translation of traditional names into scientific terms were done using the following four books: matching the old medicinal plant names with scientific terminology,comparative description of ancient medicinal plants,encyclopedia of Traditional medicine (medicinal plants),and scientific names of medicinal plants used in traditional medicine [29-32].Scientific names of the medicinal plants were searched in electronic databases,including PubMed,Science Direct,and Google Scholar.Data were collected from 2008 until December 2021.Only English and Persian language articles which have available full text were included.The study in electronic databases for each plant was performed as follow: “scientific name” (title/abstract) or“common name” (title/abstract) and “fatigue” (title/abstract) or“metabolic syndrome” (title/abstract) or “diabetes” (title/abstract) or“hypertension” (title/abstract]) or “antioxidant” (title/abstract) or“anti-inflammation” (title/abstract)or “oxidative stress”(title/abstract) or “hyperlipidemia” (title/abstract).We have considered in vitro,in vivo,and clinical studies.

Results

Fatigue and its treatment from the perspective of Iranian traditional medicine

Fatigue,with the keyword“E’aya”,is expressed as difficulty in moving and doing activities.According to the views of Iranian traditional physicians,fatigue may occur due to excessive physical activity or spontaneously in the absence of external factors [21-23].They emphasized that fatigue caused by physical activity or exercise is less harmful than spontaneously occurring fatigue which can initiate a disease [21-23].They categorized fatigue into four groups: “E’aya Ghoruhi” as ulcerous-sensed fatigue,“E’aya Tamaddodi”,which means tension-sensed fatigue,“E’aya Varami”as inflammation-related fatigue,and “E’aya Ghashafi” which means dry fatigue.The etiology and symptoms are different in each group.In general,the fatigue treatment depends on the type of fatigue and the person’s temperament,but some recommendations apply to all groups.The principles of treatment protocol comprise lifestyle changes,such as diet modification,sleeping regulation,emotional and mental relaxation,excretion of body wastes,and proper physical activity[21-23].Massage with oils is also recommended.Here we give brief descriptions of all types of fatigue and their treatment.

E'aya Ghoruhi.E’aya Ghoruhi is a type of fatigue in which the person’s body feels sore and painful on the surface or inside the skin,especially when the skin is touched.It is difficult for the afflicted person to move,and while moving,they experience a painful sensation resembling stinging.With the increasing pain,fever and chills may also be present.It is believed that excessive hot humors(waste matter) are formed due to too much physical activity,causing fatigue.The cause must be considered in devising the treatment.Physical activities that lead to fatigue should be moderated.To eliminate excess humors,abstaining from food or reducing food intake is recommended.Continued gentle massage with oil such as chamomile oil (Matricaria chamomillaL.) can disperse excess humors that are accumulated near the skin[21-23].

E’aya Tamaddodi.E’aya Tamaddodi is a type of fatigue in which the individual feels as if their body has been pounded and has a feeling of heat and tautness in the body.It is difficult for the person to move.This condition emanates from waste matter trapped in the muscles.Insufficient sleep is one of the causes of this type of fatigue.An important component of the treatment is relaxing the parts of the body that have become hard and rigid.Therefore,gentle massage with warm oil,prolonged bathing in lukewarm water,even two or three times a day,and rubbing oil onto the skin after each bath can help.Reducing food intake is even more important here.Exercise can break up and disperse the waste,resulting in the easing of this type of fatigue.The use of anise (Pimpinella anisumL.),cumin (Cuminum cyminumL.),and caraway (Carum carviL.) can help in its treatment[21-23].

E’aya Varami.E’aya Varami is a type of fatigue in which a person’s body is warmer than normal,and there is swelling on the skin that is irritated by touching and moving.There is also a sensation of tautness.The causes of this type of fatigue are similar to those of E’aya Tamaddodi.The treatment has three goals: relaxing and cooling the stretched and warm tissue and removing the waste.To achieve these goals,liberal use of warm oil,continued gentle massage,and long stays in the lukewarm bath are recommended.Modifying diet and eating less can help reduce waste[21-23].

E’aya Ghashafi.E’aya Ghashafi is a type of fatigue in which the person suffers from excessive dryness of humor,caused by too much activity,dry air,fasting,and low food intake [21-23].

We ranked the selected medicinal plants based on how many times their fatigue-reducing effects have been mentioned in the studied books.Plants mentioned three or more of in the six selected books are listed in Table 1.

Fatigue and its treatment from the perspective of conventional medicine

Fatigue is one of the most common complaints in clinical conditions[1].It referred to a personal experience of physical and mental exhaustion and decreased energy levels [33,34].Studies show that if fatigue is left untreated,it can lead to chronic fatigue and chronic fatigue syndrome [34].Chronic fatigue syndrome is a complex and debilitating condition in which fatigue does not improve with rest and is associated with mental and physical problems.It is strongly associated with immune system changes arising from physical and mental fatigue and lasts for six months or more [35].Decreased antioxidant defense system,disruption of energy metabolism,and increased inflammatory factors are among the causes of chronic fatigue syndrome [36].Obtaining a complete history from the patient is crucial to identify the underlying cause of the problem [1,33].Patient history should include a review of the lifestyle,diet,sleep schedule,daily activities,stress,depression,chronic illnesses,malnutrition,any medications used,and the time of the onset of fatigue [33].Treatment is based on the diagnosis of the underlying cause of fatigue.In many cases,such as endocrine,nutritional,and metabolic disorders,fatigue is quickly relieved by treating the underlying cause.Antidepressants,graded exercise therapy,and cognitive behavioral therapy appear to be effective in treating chronic fatigue syndrome [33].Because inflammatory cytokines,such as interleukin-1β and TNF-α are involved in fatigue,cytokine antagonists may be effective in treating fatigue[1].

Biological effects of selected medicinal plants from Iranian traditional medicine in fatigue treatment

The biological effects of selected medicinal plants related to fatigue and metabolic syndrome,retrieved from electronic databases,are summarized in Supplementary Table 1.

Chamomile (Matricaria chamomilla L.).Chamomile is the plant of the Asteraceae family.It contains various chemical compounds,such as phenolic compounds,flavonoids,sesquiterpenes,polyacetylenes,and coumarins,responsible for different pharmacological effects [37,38].Several studies have demonstrated its antioxidant activities.Chamazulene,a sesquiterpene,presents in essential oil scavenged free radicals [39].The flower is rich in flavonoids and phenolic compounds.The ethanol and aqueous extracts of the flower decreasedoxidative stress and malondialdehyde (MDA) and improved the antioxidant system by increasing antioxidant enzymes such as superoxide dismutase (SOD) and catalase (Supplementary Table 1).The clinical trial results conducted by Zemestani et al.are in line with in vivo studies.The administration of chamomile tea to diabetic patients three times a day for eight weeks enhanced antioxidant status[40].

Table 1 Medicinal plants with beneficial effects in reducing or curing fatigue based on Iranian traditional medicine

There are several in vitro studies on the anti-inflammatory effects of chamomile (Supplementary Table 1).Aqueous extracts of flower and apigenin (a flavonoid) have demonstrated anti-inflammatory effects.They reduced the production of TNF-α and IL-6[41-44].The aqueous extract inhibited cycloxygenase-2 enzyme activity and reduced lipopolysaccharide (LPS)-induced cycloxygenase-2 mRNA and protein expression in the model of LPS-stimulated macrophages.The sulindac,a non-steroidal anti-inflammatory drug,had similar effects in this study [42].Also,short-term consumption of chamomile tea creates beneficial impacts on inflammatory markers,including high sensitive C-reactive protein and TNF-α in type 2 diabetic patients[45].

Moreover,chamomile tea reduced insulin resistance and the serum level of glucose,part of which is related to the reduction of inflammatory factors [45].TNF-α is effective in creating insulin resistance by affecting several factors,including insulin signaling,GLUT-4,and adiponectin [45].Ethanol and aqueous extracts of chamomile have reversed streptozotocin (STZ)-induced hyperglycemia in rats [46-48].The aqueous extract,luteolin,and quercetin inhibited glycogen phosphorylase;furthermore,aqueous extract and quercetin inhibited hepatic glycogen degradation [47].Rajagopalan et al.investigated the antihyperglycemic effects of an aqueous extract of chamomile in alloxan-induced diabetes in rats.The results revealed that administration of the extract at the dose of 300 mg/kg for six weeks reduced the glucose,hemoglobin A1c (HbA1c)level,and amylase activity,an enzyme involved in the release of glucose from food [49].Also,chamomile tea demonstrated hypoglycemic and hypolipidemic effect in diabetic patients [50].Heidary et al.evaluated the effects of the chamomile capsule(370 mg)on lipid profile in patients with the polycystic ovarian syndrome.The administration of chamomile capsule three times a day for 8 weeks did not have a significant effect on triglycerides (TG),low-density lipoprotein (LDL),and high-density lipoprotein (HDL) level [51].

Chamomile beverages decreased systolic and diastolic blood pressures and heart rate in a clinical trial [52].This result was in line with the in vivo study.Three different extracts of chamomile at the dose of 200 mg/kg and two doses of 100 and 200 mg/kg were administrated to the normotensive and hypertensive rats,respectively.The extracts significantly reduced blood pressure and heart rate and improved lipid profile.They also inhibited the angiotensin converting enzyme(ACE) at the concentration of 0.1 mg/mL [52].

Habibzadeh et al.evaluated the effect of foot massage with chamomile oil on the severity of fatigue in Hemodialysis patients.The results showed that foot massage with chamomile oil reduced fatigue and increased the quality of life [53].

Laurel (Laurus nobilis L.).Laurel is a plant that belongs to the Lauraceae family.The leaves contain chemical compounds such as alkaloids,flavonoids,terpenes,sesquiterpenic alcohols,polyphenols,vitamins,and minerals [54,55].Severina Pacific et al.investigated the antioxidant effect of alcohol extract and seven fractions using different in vitro antioxidant tests,including 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) scavenging activity and 2,2’-azino-bis-3-ethylbenzothiazoline-6-sulfonate tests.The results revealed that alcohol extract scavenged free radicals,but it was a weak scavenger of nitric oxide radicals.The aqueous fractions have shown weak scavenging ability than alcohol extract;in contrast,alcohol fractions were more active than parental extract [56].The essential oil from the leaves of laurel is rich in 1,8-cineole,α-terpinyl acetate,sabinene,eugenol,linalool,and methyl eugenol [57,58].It has significant antioxidant activity that is more than butylated hydroxytoluene (BHT).The phenolic compounds in this plant directly correlate with antioxidant effects[57,59].

Laurel also showed anti-inflammatory activity in several studies[60-64].The aqueous extract ofLaurus nobilisshowed potent anti-inflammatory effects via inhibiting Nuclear factor kappa B(NF-κB)-dependent prostaglandin E2 production and cyclooxygenase-2 gene expression.Laurel affects the pathway responsible for transmitting the signals to cause inflammation [62].Magnolialide,a sesquiterpene lactone,was isolated from the leaves of laurel.Magnolialide may be helpful in treating type-I IgE-mediated allergic inflammatory disease via inhibiting the production of IL-4 and suppressing the proliferation of IL-5-dependent Y16 early B cells[64].Lindoldhamine,a bisbenzylisoquinoline alkaloid,was isolated from the leaves of laurel.It was administrated at a dose of 1 mg/kg in an animal model of Freund’s adjuvant-induced inflammation.It decreased the paw edema [63].Also,eucalyptol andLaurus nobilis,extract by affecting NF-κB signaling pathways,can reduce inflammatory cytokines,which ultimately suppress Propionibacterium acnes-induced skin inflammation [61].

The polyphenolic-rich fraction of leaves at half-maximal inhibitory concentration (IC50)=3.21 mg/mL inhibited α-glucosidase enzyme[59].In addition,aqueous extract of leaves at IC50=25 ± 12 μg/mL inhibited human salivary α-amylase [65].Inhibition of these two enzymes helps control blood sugar.Rafaat Mohammed et al.investigated the biological effects of laurel on STZ-induced diabetes in rats.The results confirmed the hypoglycemic effect of ethanol extract from leaves in which several mechanisms were involved,that is,increasing insulin secretion and decreasing the level of glucose.They suggested that the hypoglycemic effect of laurel may be similar to acarbose,a standard antihyperglycemic drug.Also,it reversed the pathological impacts of STZ in rat’s pancreas and liver tissues[66].In a clinical study,type 2 diabetic patients consumed capsules containing different amounts of laurel leaves for 30 days.The serum level of glucose,LDL,total cholesterol (TC),and TG decreased significantly in all three doses [67].There was an increase in HDL in patients who took 1 or 2 g of leaves per day.In a group that consumed 3 g,the increase was not significant.Another clinical study confirms these results.It emphasized that consumption of leaves (2 g/d) for 30 days improves glucose and lipid profile,which ultimately reduces the cardiovascular risk in diabetic patients [68].

The polyphenolic fraction of laurel leaves also inhibited isolated pancreatic lipase [59].As mentioned above,the lipid-lowering effect of this plant has been proven in some clinical studies.Chbili et al.evaluated the daily consumption of laurel tea on lipid profile.Daily consumption of laurel tea(5 g of dried leaves in 100 mL boiled water)for ten days in healthy volunteers significantly increased HDL,but the decreases in LDL and TG were not significant [69].

The polyphenolic fraction of laurel leaves have inhibitory activity against the ACE enzyme,which anti-hypertension effects should be further investigated in clinical trials [59].

Sweet majoram (Origanum majorana L.).TheOriganum majoranaL.commonly known as sweet majoram is a member of the Lamiaceae family.It contains tannic acid,coumarins,quercetin,flavonoids,chlorogenic acid,cinnamic acid,and rutin [70,71].

The antioxidant effects ofOriganum majoranahave been confirmed in several in vitro and in vivo studies[70-77].The methanolic extract of the seed with the maximum percent inhibition equal to 91.89%exhibited the best antioxidant activity in the DPPH test.The total antioxidant capacity and the antioxidant activity of the seed extracts in other tests were in the order: methanol ＞ethanol ＞acetone ＞chloroform [70].Considering the β-carotene/linoleic acid assay,the essential oil of the aerial part showed better antioxidant activity compared to standard BHT,with IC5012.83 ± 1.04 and 75 ± 1 μg/mL,respectively[73].The administration of the essential oil with the dose of 0.16 mL/kg twice daily for four weeks in the animal model of prallethrin induced oxidative damage and nephrotoxicity in the rats,attenuated the oxidative stress,and increased SOD and catalase activities [76].The ethanol extract of the leaves of majoram significantly scavenged free radicals in the DPPH test and had remarkable reducing power.The total phenolic compounds were determined as 254 mg/g[72].The comparison between the methanol,ethanol,diethyl ether,and hexane extracts of the leaves revealed that the methanol extract with half maximal effective concentration 0.0013 ± 0.0001 had the best antioxidant activity,the antioxidant effects of other extracts were in the order: diethyl ether ＞ethanol ＞hexane [75].The study results with Ghosian Moghaddam et al.revealed that adding marjoram leaves to animal food (6.25%) could reduce oxidative stress and glucose in the animal model of STZ-induced diabetes in the rats [77].The methanol and aqueous extracts of the leaves and its essential oil with the dose of 400 mg/kg significantly elevated the SOD enzyme level in the animal model of STZ-nicotinamide induced non-insulin-dependent diabetes mellitus in the rats;also,the methanol extract and essential oil with both doses 200 and 400 mg/kg increased the catalase enzyme level [74].

M.Wahby et al.demonstrated the anti-inflammatory effects of the ethanol extract of the majoram leaves.The administration of 0.5 mg/kg of the ethanol extract for ten days in the animal model of the LPS-induced oxidative inflammation in rats decreased inflammation,peritoneal macrophages,and nitric oxide in the peritoneal fluid and liver.Furthermore,it improved the antioxidant system via increasing glutathion (GSH) and decreasing MDA [71].

Majoram,via several mechanisms,plays an essential role in regulating blood glucose.The essential oil of the majoram leaves,which contains sabinene,linalool,γ-terpinene,and α-terpinene,inhibited α-amylase enzyme [78].Inhibiting the dipeptidyl peptidase IV enzyme helps reduce hyperglycemia and HbA1c levels.Also,reducing the protein tyrosine phosphatase 1B enzyme activity increases insulin sensitivity.The methanol extract of the majoram seed inhibited both dipeptidyl peptidase IV and protein tyrosine phosphatase 1B enzymes [79].The methanol extract and essential oil of the leaves with the doses 100,200,and 400 mg/kg and the aqueous extract with the dose of 400 mg/kg significantly reduced the glucose level in the animal model of STZ-nicotinamide induced non-insulin-dependent diabetes mellitus in the rats.The aqueous extract could not change the level of insulin.In contrast,all doses of essential oil and two doses of the methanol extract (200 and 400 mg/kg) increased the insulin level compared to glibenclamide.Each dose of the methanol extract and essential oil,and aqueous extract with the dose of 400 mg/kg significantly reduced the HbA1c level[74].Pimple et al.demonstrated similar results,but in their study,the methanol,aqueous and essential oil with two doses of 200 and 400 mg/kg significantly reduced the HbA1c level.Furthermore,with these two doses,all extracts significantly improve lipid profile [80].The administration of the ethanol extract of the majoram leaves with the doses 100,200,and 400 mg/kg for three weeks exhibited hypoglycemic and hypolipidemic effects along with increasing HDL in STZ-induced diabetic rats [81,82].The administration of the aqueous extract of majoram leaves with a 20 mg/kg/day dose for two weeks resulted in improving dyslipidemia and hyperglycemia in the animal model of STZ-induced diabetes in rats with the high-fat diet.It up-regulated the gene expression,which is related to lipid and glucose metabolism,including GLUT-2,lipoprotein lipase,and adiponectin;also,it down-regulated the gene expression of leptin [83].The aqueous extract also exhibited the hypoglycemic effect in alloxan-induced diabetic rats;decreasing oxidative stress plays an essential role [84].

The ethanol extract of majoram dose-dependently caused vasodilation which was effective in the anti-hypertensive activity[85].

Dill (Anethum graveolens L.).Dill is a member of the Apiaceae family.It contains various chemical compounds,including monoterpenoids,limonene,alkaloids,flavonoids,anthocyanins,tannins,carvone,and camphor [86-88].

The different extracts of dill exhibited antioxidant activity in the in vitro tests [87,89-97].Treatment of the diabetic rabbits with the ethanol extract of dill with a dose of 700 mg/kg for 45 days produced a significant increase in the GSH levels[86].Furthermore,the ethanol extract inhibited lipid peroxidation in the dexamethasone-induced diabetic rats and enhanced antioxidant activity such as SOD,catalase,and GSH,and showed a hyperglycemic effect [98].The methanol extract of dill restored the activity of antioxidant enzymes in the carbon tetrachloride-induced hepatotoxicity in rats,compared to the standard drug,silymarin [88,99].These results were also seen when using the aqueous extract in the paracetamol-induced hepatotoxicity in rats [100].

The isolated alkaloid from the aerial parts of dill (500 mg/kg)significantly increased total antioxidant capacity in the animal model of cholesterol-induced hypercholesterolemia in rabbits;also,it improved hyperlipidemia and decreased lipid peroxidation [101].Bahramikia and Yazdanparast evaluated various fractions of dill in the animal model of hypercholesterolaemic rats.The results were consistent with previous studies.The diethyl ether,aqueous,and ethyl acetate fractions,in addition to the hypolipidemic effect,decreased lipid peroxidation and oxidative stress and improved the antioxidant system.The diethyl ether had the best activity,and the aqueous fraction was the least[102].

The chemical compounds including carvone,camphor,carveol,perillyl alcohol,and limonene in the dill essential oil have various antioxidant effects;among them,carveol showed the best free radical scavenging activity,while camphor showed the least [87].The nanoemulsion of essential oil of dill at the doses of 0.125,0.250,and 0.500 mg/L of drinking water inhibited the cadmium-induced oxidative stress in mice and down-regulated the iNOS gene that caused the anti-inflammatory activity[103].The anti-inflammatory of the essential oil of dill has been reported previously.The essential oil at the concentration of 45 mg/mL inhibited LPS-induced nitric oxide secretion with an inhibition percentage equal to 82.0 ± 0.0 % [94].

The ethanol extract of dill seed (10-500 mg/kg) exhibited a hypoglycemic effect on glucose tolerance in rabbits [104].Administration of capsules containing hydro alcohol extract of dill in patients with metabolic syndrome for 12 weeks did not have any significant effect on glucose level and blood pressure,but it lowered TG [105].Mobasseri et al.conducted a clinical study that used dill tablets (1.1 g) three times a day for 8 weeks in diabetic patients.The results demonstrated the positive effects of dill in lowering insulin levels and improving lipid profile[106].

Two doses of the hydro alcohol extract of dill,250 and 500 mg/L,were added to drinking water for 30 days in the NMRI mice.The hydro alcohol extract significantly lowered LDL,TG,and cholesterol and increased HDL [107].The administration of hydro alcohol extract at the dose of 100 mg/kg for four weeks improved the lipid profile in the animal model of STZ-induced diabetes in rats.It did not significantly affect HDL level [108].Masoume Mansouri et al.conducted a randomized,double-blind controlled trial to evaluate the effect of dill on metabolic parameters in patients with metabolic syndrome.The capsule containing the hydro alcohol extract of dill for 12 weeks was administrated.The dill capsule did not improve blood pressure and glucose level but significantly reduced TG from the baseline [105].Consuming six dill tablets daily for two months in hyperlipidemic patients resulted in decreased TC and TG.The reduction of TC by dill tablet was more than gemfibrozil [109].Also,administration of dill capsule containing 500 mg of a dill powder in hyperlipidemic patients twice a day for four weeks exhibited similar results and improved lipid profile [110].

Henna (Lawsonia inermis L.).Lawsonia inermisL.,with the common name henna,is the Lythraceae family plant and contains various chemical compounds such as flavonoids,triterpenoids,aliphatic hydrocarbons,coumarin,and gallic acid derivatives.Several studies have proven the antioxidant activities of this plant [111-115].That the ethanol extract of henna showned better free radical scavenging than the aqueous extract,his is due to the more phenolic substances in the ethanol extract [112].The n-butanolic fraction of alcohol extract of henna leaves contains five phenolic glycosides.The n-butanolic fraction and its phenolic glycosides have antioxidant activity in b-carotene and DPPH tests.Among them,three compounds have potent antioxidant activity,and 1,2,4-trihydroxynaphthalene-1-J-b-D-glucopyranoside showed the highest antioxidant effect.It suggested that the antioxidant activity of phenolic compounds depends on the number of hydroxyl groups attached to the aromatic ring [113].Also,the butanolic fraction has a hepatoprotective effect in an animal model of 2-acetylaminofluorene induced hepatic damage in rats that were related to scavenging free radicals and inhibiting lipid peroxidation [111].

7-Hydroxy-3,5-dimethoxy-6,8-dimethylflavon (a flavone derivative)and eudesmane-4β,7α-diol (a eudesmane derivative) along with ten other compounds have been isolated from henna and evaluated anti-inflammatory effects in the LPS-stimulated macrophage.The results revealed that syzalterin,sideroxyline,and isoscopoletin had shown inhibitory effects on LPS-induced nitric oxide production[116].In two animal models of formaldehyde-induced arthritis and Freund's adjuvant-induced arthritis in the rats,the hydro alcohol of henna decreased the inflammation via suppressing inflammatory mediators [117].Daemi et al.evaluated the effect of topical use of an ointment containing 3% and 6% hydro alcohol extract ofLawsonia inermisleaves in rats’ circular excisional wound model.Topical ointment decreased the edema score,inflammatory cell infiltration,and inflammatory phase,which finally improved wound healing.Furthermore,henna up-regulated the GlUT-1 and insulin-like growth factor I expression that increased the glucose uptake,an essential factor in wound healing [115].

The administration of the hydro alcohol extract of henna (400 mg/kg) significantly decreased the glucose in the animal model of alloxan-induced diabetes in rats.This reduction (39.08%) was comparable to metformin (46.30%) and glibenclamide (44.77%).The hydro alcohol extract increased the production of insulin.Also,it reduced the LDL,TG,very low density lipoprotein,and TC levels and increased HDL [118].

Ammoniac gum (Dorema ammoniacum D.Don).Dorema ammoniacumis a plant of the Apiaceae family.Based on ITM,the oleo-gum resin of this plant is called oshagh.The essential oil of the aerial part contains various compounds,including oxygenated non-terpenes,β-chamigrene,diterpenes,hydrocarbon sesquiterpenes,linalool,and α-pinene.The in vitro evaluation of the antioxidant effects of this plant showed that the ethyl acetate extracts of both aerial parts and roots,along with the chloroform extract of roots,were the best free radical scavenger in the DPPH test.In contrast,the essential oil of both parts of the plant showed the least antioxidant effects in the ferric reducing antioxidant power method (FRAP) and DPPH tests.In addition,the ethyl acetate extract of aerial parts and roots showed the highest ferric-reducing power in the FRAP test[119].

The aqueous solution of the gum exhibited dose-dependent anti-inflammatory activity in the animal model of carrageenan-induced edema in rats;the anti-inflammatory effect at a dose of 500 mg/kg was comparable to indomethacin [120].

The phytochemical investigation of the hydromethanol extract ofDorema ammoniacumroot resulted in the isolation of six compounds.Among them,1,5-dicaffeoylquinic acid at a concentration of 750 μM had a considerable inhibitory effect against the α-glucosidase enzyme,which was determined as 76.9% of the acarbose activity[121].

Camel grass (Cymbopogon schoenanthus (L.) Spreng.).Cymbopogon schoenanthus(L.) Spreng.is a member of the Poaceae family.The essential oil contains different chemical compounds such as oxygenated monoterpenes,monoterpene hydrocarbons,piperitone,limonene,and α-terpineol [122,123].Studying the essential oil from aerial parts of camel grass collected from the Illizi indicated weak antioxidant effects due to the low amount of phenolic substances[122].The essential oil of dried and fresh leaves (67.3 ± 17.5% and 73.8 ± 2.1%,respectively) and dried roots (61.0 ± 5.6%) ofCymbopogon schoenanthusexhibited antioxidant activities that were comparable to standards: BHT (100.0 ± 0.0%),verbenone (77.1 ±0.5%) and carvacrol (87.4 ± 1.5%) in DPPH test [124].These results emphasize that the geographical origin and environmental conditions significantly impact the plant extracts’ chemical components and biological activities [122,124].Furthermore,essential oil had significant metal chelating ability in the ferrous chelating test [123].The hydro alcohol extract of the leaves with IC50of 110 μg/mL had a dose-dependent antioxidant activity in the DPPH test,which was related to its flavonoid contents [125].The aqueous extract also showed potent scavenging ability in the 2,2’-azino-bis-3-ethylbenzothiazoline-6-sulfonate test,making it effective like BHT [126].

The essential oil of the leaves inhibited the α-amylase enzyme,while it did not inhibit the α-glucosidase enzyme [1-3,7,8].

Golestaneh Talaei et al.evaluated the anti-inflammatory effect of the essential oil of camel grass.The essential oil at three doses,50,100,and 200 mg/kg,reversed the carrageenan-induced inflammation and reduced the inflammation and pain in the second phase of the formalin test due to the piperitone and other components of the essential oil [127].The ethanol and aqueous extract of the aerial part showed an anti-inflammatory effect in an in vitro test.The inhibitory effect of the aqueous extract was more than the ethanol extract[128].

German Iris (Iris germanica L.).Iris germanicaL.,commonly known as german Iris,belongs to the Iridaceae family.The plant’s phytochemical investigation has resulted in isolating different compounds,including triterpenes,ceramides,sterols,flavonoids,benzoquinones,and vitamins,especially ascorbic acid [129].The antioxidant effects of this plant have been proven in various studies[129-133].The ethanol extract of rhizome and aerial parts ofIris.germanicashowed better antioxidant activity than BHT and ascorbic acid at similar concentrations in the β-carotene-linoleic acid method[132].Sayyed et al.evaluated the antioxidant effects of methanol and dichloromethane extracts from different parts of the plant.The results revealed that the methanol extracts were significantly more potent than the dichloromethane extracts;such that methanol extract of rhizome,flower,and leaves showed the best antioxidant activity with half maximal effective concentration of 192.8,174.4,and 106.8,respectively [130].The isoflavonoids of the root,irilone,irigenin S,irisolidone,iridin,irilone 4’-O-β-D-glucopyranoside,and irigenin,had antioxidant activity in the DPPH test.Iridin A,an isoflavonoid glycoside with IC508.91 μM,showed the best free radical scavenging activity among other compounds [129].Also,8-hydroxyirilone and 8-hydroxyirilone 5-methyl ether,with IC509.23 and 12.92 μM,displayed noticeable antioxidant activities [131].

Iridin A,irigenin,and irisolidone,the isolated isoflavonoids,displayed inhibitory activity against α-amylase enzyme with %inhibition of 70.5,67.5,and 70.8,respectively,compared the acarbose,a standard α-amylase inhibitor [129].A study conducted with Sabrin et al.confirmed that irisolidone,8-hydroxyirilone,8-hydroxyirilone 5-methyl ether,and irilone inhibited α-amylase enzyme with % inhibition 70.1,78.3,66.1,and 67.3,respectively[131].

The mentioned isoflavonoids,irisolidone,irigenin S,irilone,irigenin,iridin,and irilone 4’-O-β-D-glucopyranoside,decreased paw edema and inflammation in an animal model of formalin-induced paw edema in rats.Studying the chemical structure of flavonoids showed that the presence of the C-2,3 double bond,the pyran ring,and a methoxyl group at C-5 and C-7 are effective in causing anti-inflammatory effects [134].

Chaste tree (Vitex agnus-castus L.).Vitex agnus-castusL.is a plant from the Lamiaceae family.The fruit contains several compounds,including sesquiterpenes,flavonoids,iridoids,diterpenoids,phenolic acids,and tannins [135,136].

The aqueous extract of the fruit,rich in polar chemical compounds,exhibited the best antioxidant activities among the other extracts.The study emphasized that the polarity of the extract has an essential effect on antioxidant effects.In the β-carotene/linoleic acid test,the antioxidant activity of the aqueous extract was 94.07% ± 0.02,which is almost equal to BHT (94.68% ± 0.04).The essential oil was the weakest radical scavenger in the DPPH test,but it showed noticeable activity in the β-carotene/linoleic acid test [136].The methanol extract has shown antioxidant activities and a significantly chelating ferrous ion in the ferric chelating antioxidant capacity test [137].At the concentration of 0.5 mg/mL,the methanol extract had a higher scavenging ability of H2O2than both standards,quercetin and rutin[137].Also,casticin,a flavonoid isolated from the fruit of the chaste tree,exhibited antioxidant activity in different tests [135].The administration of ethanol extract (600 mg/kg,twice daily) for one week in the D-galactose-induced aging mouse model significantly attenuated oxidative stress,decreased MDA,and increased SOD and catalase activity as compared to the aging group [138].

Methyl 3,4-dihydroxybenzoate,p-hydroxybenzoic acid,and 3,4-dihydroxybenzoic acid have been isolated from the methanol extract aerial part.These compounds exhibited significant in vitro anti-inflammatory activity compared to both standards,indomethacin,and aspirin.Also,casticin and artemetin significantly inhibited lipoxygenase enzyme with IC5026.0 and 54.6 μM,respectively [139].The other isolated compounds,3,4-dihydroxybenzoic acid,3,3’-dihydroxy-5,6,7,4’-tetramethoxy flavon,methyl 4-hydroxybenzoate,5-hydroxy-2-methoxybenzoic acid,methyl 3,4-dihydroxybenzoate,and penduletin,did not inhibit this enzyme[139].

The hypoglycemic effects of the chaste tree have been confirmed in an animal model of STZ-induced diabetes in rats.The administration of the methanol extract ofVitex agnus-castus(300 mg/kg) for three weeks resulted in a gradually decreasing level of glucose,which represented a 66.52% reduction compared to the initial level.This amount for the glibenclamide-treated group was 72.87%.Furthermore,it improved the lipid profile,significantly decreased LDL and TG,and increased HDL [140].Moreover,the hydro alcohol extract of this plant (600 mg/kg,bid,one week) improved homeostasis model assessment-estimated insulin resistance in the animal model of D-galactose-induced aging in female mice and showed pancreatic protection [141].

Terebinth (Pistacia terebinthus L.).Pistacia terebinthusL.,commonly known as a terebinth is a member of the Anacardiaceae family.There are various chemical substances in this plant which are tannins,γ-tocopherol,quercetin,triterpenes,flavonoids,linoleic acid,α-pinene,sesquiterpene hydrocarbons,and limonene[142-145].

Considering the antioxidant effects,the ethanol and hydro alcohol extracts of the terebinth fruit exhibited better antioxidant activity than the dichloromethane and n-hexane extract in different in vitro antioxidant tests.The trolox equivalent antioxidant capacity,an indicator for antioxidant capacity,for the ethanol extract was equal to 0.985 ± 0.115 mmol/g,which was the best cupric-reducing activity[146].While,the trolox equivalent antioxidant capacity for the crude extract of the leaf was 85.06 mmol/g,which was higher than synthetic antioxidants,BHT and butylated hydroxyanisole,and ascorbic acid[147].The ethyl acetate and methanol extract of terebinth fruit also have shown their free radical scavenging in the DPPH test.In contrast,their N,N-dimethyl-p-phenylenediamine scavenging ability was lower as compared to DPPH.Neither of them could scavenge H2O2radicals[143].O¨ zcan et al.confirmed that pre-sonication could increase the terebinth extract's phenolic compounds and antioxidant capacity 142.Also,roasting the fruit can enhance the terebinth oil’s antioxidant effects and oxidative stability [148].In consistent with in vitro studies,the administration of an aqueous extract of flower (250 mg/kg) in an animal model of hydrogen peroxide-induced oxidative stress in rats reversed lipid peroxidation in the brain,kidney,and lungs;along with an increase in glutathione level and SOD and glutathione peroxidase enzyme activities [149].

Improving the antioxidant system plays an essential role in protecting β cells against oxidative stress.ThePistacia terebinthusoil has shown a hypoglycemic effect in STZ-induced diabetic rats.In addition to reducing MDA level and enhancing the antioxidant system,treatment of the diabetic rats with the terebinth oil with a dose of 2 mL/kg for 28 days resulted in decreasing glucose levels and improving lipid profile compared to the diabetic group without treatment [150].Also,the aqueous extract of leaves and fruits of terebinth showed inhibitory effects against both α-glucosidase and α-amylase enzymes,which can help manage carbohydrate digestion and absorption [144].The aqueous extract of leaves and fruits of terebinth inhibited pancreatic lipase with IC509.0 ± 0.4 and 125.2 ± 12.1 μg/mL,respectively [144,151].

Bahcecioglu et al.administrated terebinth coffee in water for the thioacetamide-induced liver injury in rats for eight weeks.The results demonstrated the protective effect of terebinth against hepatotoxicity.The terebinth coffee significantly reduced inflammation,fibrosis,and necrosis.It inhibited NF-κB activity and decreased TNF-α,IL-6,and transforming growth factor-beta[145].

Discussion

The metabolic syndrome comprises a constellation of metabolic defects such as insulin resistance,hypertension,dyslipidemia,and obesity [4].There are various mechanisms in a metabolic syndrome that are effective in causing fatigue,including oxidative stress and inflammation,which have been recently introduced as underlying causes of metabolic syndrome[5].The mitochondrial dysfunction due to obesity and insulin resistance increases oxidative stress and reduces ATP production,which causes fatigue [7].Oxidative stress results in the accumulation of oxidation products of lipids,sugars,and proteins,which bring about changes in vascular function by causing vascular inflammation and endothelial dysfunction [6].This condition leads to the elevated risk of peripheral vascular disease,which ultimately impaired tissue and organ function due to insufficient blood supply[16,17].On the other hand,inflammatory cytokines induced by visceral obesity,including IL-1,TNF-α,and IL-6,play an essential role in causing fatigue and sleep disturbances [12,13].That TNF-α and IL-6 by causing insulin resistance and,following that,reducing the glucose uptake,impairs insulin-stimulated muscle glycogen synthesis.So,the muscles get tired faster,shown as weakness and fatigue[4,14,15,152].

From the perspective of ITM,the quality and quantity of the humors and the balances between them play an essential role in being healthy.Any changes in the quantity and quality of substances are called“So-e-Mizaj”,which leads to changes in the blood contents,including sugar and fat,resulting in abnormal humor [21-23].Weakness and fatigue are symptoms of the accumulation of abnormal humor in the body,which is also seen in the condition called “Emtela” [21].The accumulation of abnormal humor,especially the dominancy of phlegm and moisture,is effective in causing fatigue[21-23,153].The amount of humor increases during Emtela,affecting the human metabolism [154].Emtela leads to various symptoms and complications,such as high blood pressure,obesity,drowsiness,fatigue,and sluggish movement[21,155].The most common cause of Emtela is concentrated and viscous humor,such as viscous phlegm and significantly abnormal black bile,which are not readily excreted and increase blood viscosity.The increased blood viscosity reduces tissue blood flow and consequently reduces the function of the tissue and causes functional weakness and fatigue[156,157].

Sleep deprivation is another cause of fatigue based on ITM.In other words,lack of sleep alters the function of the organs and changes the humor's quality and quantity,which results in So-e-Mizaj,Emtela,and their consequences [21,158].

The scientific articles demonstrated that sleep deprivation increases the risk of metabolic defects and subsequent metabolic syndrome[159-166].Regular sleep and circadian rhythm are crucial for metabolic and hormonal regulation,which control glucose and lipid metabolism.It is worth noting that circadian rhythm and sleep are the main factors for regulating energy metabolism [163].The circadian rhythm disruption affects insulin and leptin secretion;also,it changes eating behaviors that contribute to obesity,especially abdominal obesity [162-165].Besides,insufficient sleep leads to fatigue by increasing inflammatory cytokines such as IL-6 [167].In general,short-term disruption of the circadian rhythm leads to fatigue,impaired concentration,and unwell being.Still,long-term disruption leads to impaired sugar and fat metabolism,obesity,diabetes,hypertension,dyslipidemia,depression,and mental disorders [163,164].Also,metabolic syndrome due to abdominal obesity is associated with obstructive sleep apnea syndrome,which is an important reason for excessive daytime sleepiness correlated with fatigue[1,4,165].

Mahjoub et al.compared the symptoms of E’aya with fatigue in conventional medicine.The results showed that E'aya has symptoms similar to chronic fatigue syndrome [153].Given that some of the mechanisms that cause fatigue in metabolic syndrome and chronic fatigue syndrome are similar,we can consider the recommendations suggested by ITM for treating E’aya.

The treatment of fatigue from the perspective of ITM and conventional medicine has common recommendations.One of the most important is to consider the underlying causes for planning the treatment.Both treatment systems recommend improving the quality of life,including modifications in diet,sleep pattern,and physical activity,as part of fatigue treatment [1,21-23,33].A high-calorie diet raises blood glucose and lipid levels,leading to increased oxidative stress and obesity [6].Several studies have demonstrated that caloric restriction with different fasting regimens can improve the glucose level as well as lipid profile and decrease blood pressure and body weight in patients with metabolic syndrome [168,169].Furthermore,7-day fasting increased the quality of sleep and enhanced mode,resulting in decreasing fatigue [168].This is in line with ITM suggestion for reducing food to eliminate excessive humor and prevent the Emtela from getting worse [21-23,170].In addition to changing sleep patterns and diet modification along with improving food timing,physical activity is important for enhancing sleep quality,decreasing mental stress,and preventing fatigue and obesity [14,165,171].Overall,lifestyle modification must be designed based on the patient condition [153,165].

Also,ITM has interventions to increase the catabolism of humor and its excretion [21-23,153].Massage with oils helps in this regard.It changes the viscosity of the humor,which accelerates its removal[153].Scientific studies have confirmed that massage can reduce muscle tension,decrease swelling,enhance flexibility,and improve blood circulation and lymph flow.Therefore,massage has a good effect on recovering from exercise fatigue and injury [172,173].Clinical trials have explored the effectiveness of massage in reducing fatigue in various diseases such as cancer,chronic fatigue syndrome,and fibromyalgia [173-178].The results showed that massage not only reduced fatigue but also relieved physical symptoms,depression,pain,and anxiety in patients with chronic fatigue syndrome[177].

Based on our review,11 medicinal plants,frequently referred to in the most authoritative texts of ITM,were employed in fatigue treatment.In particular,their oils have been recommended topically.These plants have various biological activities.While the obvious,reducing oxidative stress,inflammation,and cardiovascular risk factors are important for treating metabolic syndrome and its complications,including fatigue [16].Some biological effects related to the treatment of metabolic syndrome,including antioxidant,anti-inflammatory,anti-diabetic,antihypertensive,and anti-hyperlipidemic effects,have been established in several studies.Based of our knowledge,except forOpopanax chironius,all these plants have the biological effects on various components of metabolic syndrome or its side effects and underlying causes,such as oxidative stress and inflammation (Supplementary Table 1);in a way,they all show antioxidant,anti-inflammatory,and anti-diabetic activities,Their chemical substances,especially their flavonoids and phenolic compounds,have considerable effects in decreasing oxidative stress and increasing antioxidant enzymes such as SOD and catalase(Supplementary Table 1).Their anti-inflammatory effects are mediated through various mechanisms,such as reducing the macrophage numbers and inhibiting the production of pro-inflammatory cytokines such as IL-1 and TNF-α.These anti-inflammatory effects are in line with the therapeutic use of these plants in ITM for treating “Uram”,swellings,some of which show symptoms of inflammation.It is also essential in relieving E'aya Varami,which is characterized by swelling [21-24].Improving the antioxidant system and inhibiting α-glucosidase and α-amylase enzymes are involved in their anti-diabetic effects (Supplementary Table 1).Also,studies suggest that antioxidant administration improves hypertension through altering markers of oxidative stress,including enhancing FRAP,decreasing plasma lipid hydroperoxides and decreasing arterial stiffness,and enhancing brachial artery flow-mediated dilation.Additionally,considering the important role of the ACE in hypertension and metabolic syndrome,it has been shown that chamomile and laurel have inhibitory effects against ACE.Also,chamomile has been demonstrated to decrease systolic and diastolic blood pressures and the heart rate in clinical trials and hypertensive rats;besides,sweet majoram shows antihypertensive effects by vascular relaxation [52,59,85].

Another important feature of the metabolic syndrome is dyslipidemia which improves with the inhibition of pancreatic lipase.The polyphenolic-rich fraction of laurel and aqueous extract of terebinth inhibit this enzyme.In vivo studies have shown that extracts of several other plants,including chamomile,dill,henna,chaste tree,and sweet majoram,can improve dyslipidemia by decreasing TG,LDL,and TC and increasing HDL levels (Supplementary Table 1).

Numerous studies have proven the anti-fatigue effects of plants on physical fatigue and chronic fatigue syndrome [35,36,180-186].Medicinal plants reduce fatigue by accelerating the elimination of metabolites caused by physical fatigue,improving the antioxidant system and inflammatory conditions[35,36,180-186].

Considering the pharmacological effects of the plants used in ITM to treat E’aya,these plants may effectively treat fatigue in patients with metabolic syndrome.Three species among them,chamomile,laurel,and sweet majoram,have remarkable effects on the underlying causes and characteristics of metabolic syndrome,such as diabetes,hypertension,and hyperlipidemia.

In conclusion,medicinal plants have considerable potential that makes them valuable candidates for the treatment of various diseases and complications based on the therapeutic approaches of ITM.The potentialities ofMatricaria chamomilla,Laurus nobilis,andOriganum majoranahave been confirmed through scientific studies.To further explore these plants’ effects on curing fatigue in patients with metabolic syndrome,animal studies,and clinical trials should be performed.