INTRODUCTION:

Anethum graveolens L. (AG) is a famous herb as medicine and aromatic herb used in management of diabetes mellitus (DM) commonly called as “dill seed” found in Mediterranean region, Europe and Central and South Asia [1]. Anethum graveolens is an annual herb belong to Apiaceae family [4]. It is most common herb used for the treatment of different diseases and spices in food [3].

The herbal origin medicines get the more interest due to less cost, less side effects and more useful properties [2]. A. graveolens have many therapeutic effects and used in Iranian folk medicine as an anti-hypercholesterolaemic plant. In gastrointestinal complications such as flatulence, indigestion, stomachache colic and intestinal gas A. graveolens is used. Different compounds have been obtained from the parts of seed, leaves and also the inflorescence of this herb. Anethoferon, Carvone and Limonene known as monoterpenes that are present as the important components of dill oil from fruits. á-Phellandrene, dill ether and myristicin compounds form the odor of dill herb. Flavonoids, phenolic compounds and essential oil components in seeds of A.graveolens make an essential component used for the formation of gripe water. A.graveolens contain different pharmacological effects like anti-cancer, anti-gastric irritation, anti-inflammatory, anti-oxidant, anti-microbial, anti-spasmodic, anti-secretary and mucosal protective effects [1,4]. It is also used to cure digestive disorders, bad breath, lactation motivation and considered as hypolipidemic agent. A.graveolens (dill tablet)is used as hypolipidemic agent that consist of important constituents such as Anethum graveolens (68%), Cichorium intybus (5%), Fumaria parviflora (5%), and Citrus aurantifolia sp (4%) [2,12]. Usage of A.graveolens in animals, diabetic patients, hyperlipidemic patients and patients of metabolic disorder reduce the blood glucose, total cholesterol, triglyceride, very-low-density lipoprotein cholesterol, low-density lipoprotein cholesterol and increased the high density lipoprotein cholesterol levels [2]. Leaves of A. graveolens are the richest source of minerals, proteins and fibers. The oil of A. graveolens have the anti-oxidant, anti-microbial and anti-spasmodic effets [3]. It is used in the improvements of some upper respiratory system diseases and also contain galactogogue and anti-inflammatory properties [4]. AG caused dieresis and increased sodium, calcium excretion in dogs by using the dried ethanol extract of AG fruits, essential oil. AG caused hypotension, increased respiratory volume in cats by using the AG seed oil [15]. Diabetes mellitus (DM) is one the most fatal and chronic metabolic disorder that is identified by decreasing insulin lead to hyperglycemia, underutilization of blood glucose and deficiency of metabolism of major components such as protein, carbohydrates and fats [2,8]. Diabetes also cause many complications like microvascular damage, kidney failure, heart disease, nerve damage and blindness. The most important way to trigger the diabetes mellitus (DM) is the increase of blood glucose that forms advanced glycation end products (AGEs). Protein glycation cause multiple complications such as diabetic nephropathy, retinopathy, neuropathy and heart disease [2]. It is a most common health problem and one of the most important challenging disease facing the health care professionals today [4,3]. According to World Health Organization (WHO) there was 194 million adults (between 29-79 years old) affected from diabetes in 2003 worldwide and it is assuming that 333 million people will affect from diabetes in 2030. In 2008, 7.9% cases of diabetic patients were recorded [4]. Due to failure of pancreatic beta-cells the deficiency of insulin is produced that causes Type 1 diabetes. That’s why exogenous insulin injections provide to patients to fulfill this insulin deficiency. The patients suffer from Type 2 diabetes are called as Insulin independent, don’t show the response to insulin [8]. Improper diet is the main cause of type 2 diabetes [4]. Type 2 diabetes show 93% cases of diabetes worldwide. Besides the cancer disease and heart disease, diabetes mellitus is the third hazardous disease that has high mortality rate in the world [8]. Type 2 diabetes is related with decrease in high density lipoprotein (HDL) of plasma due to catabolism increase in HDL constituents. The decrease of lipoprotein lipase enzyme and increase of hepatic lipase in diabetic patients is related with increase of HDL catabolism more than LDL-c. Recent studies show that LDL-c catabolism in diabetic persons is 31% less than healthy persons [7]. Hyperglycemia, abnormal thirst, repeated urination, weight loss, extreme hunger, nausea, vomiting, mood changes process, extreme weakness and tiredness are the symptoms of type 1 and type 2 diabetes [8].

RESULTS AND DISCUSSION:

Levels of Blood Sugar and Lipid in Diabetic Patients.:

The utilization of A. graveolens through extravascularly (orally) for the time period of 15 days cause the significant decrease in blood glucose level. For haematological aspect, it was noted that A. graveolens had useful effects on haemopoeitic system of mus musculus. It also increased the RBC, HCT. The increase in RBC reflects that A. graveolens and carvone have the ability to provoke erythropoietic release from kidney whose function is the hormonal regulation for RBC formation. The increase haemotocrit is a signal of rise of haemo concentration. The use of Anethum graveolens and its major component carvone in appropriate dose significantly increased the hemoglobin level that will provide the help in increasing oxygen carrying capacity of blood. RBC (or white blood cells) and hemoglobin play a significant role in the transport of respiratory gaseous system. A. graveolens and carvone also increases WBC that act as major booster dose for immune system. Several studies supported that A. graveolens don’t have undesirable side effects on the bone marrow, kidney and haemoglobin metabolism since, the value for RBC is not soo much affected [1]. Blood sugar level raised in diabetic patients as compared to non-diabetic patients. The administration of A. graveolens in suitable amount decreased blood sugar levels. The production of Advanced glycation end products (AGE’s) increased in diabetic persons [2]. A. graveolens supplementation increased the serum levels of high density lipoprotein cholesterol (HDL). It was also observed that serum level of low density lipoprotein cholesterol (LDL-c) was decreased [3]. The uptake of A. graveolens caused a significant decreased in serum total cholesterol and LDL-c concentration, further, no changes were observed in serum triglyceride and HDL level. Several objections were noted through the human analysis and experimental evidences about the effects of A. graveolens on lipid biomarkers. Hajhashemi and Abbasi, reported that 16 hypercholesterolemic wistar male rats with the amount of 10% A. graveolens powder for the time duration of 14 days caused the decreased in TC, LDL-c and TG but increased the HDL levels. In Madani et al, survey, A. graveolens extract were given to male rats for 2 days. The control group got the physiological serum, diabetic control group (DCG), diabetes was introduced by using Alloxan monohydrate and they were also treated with the suitable amount of hydroalcoholic A. graveolens extract. Experimental analysis showed the significant decreased in glucose, total cholesterol, triglyceride, LDL-c and V-LDL levels in these effected rats. The HDL level was raised due to use of A. graveolens extracts. The useful mechanism through which A. graveolens can reflects its lipid lowering activities is not fully determined. Therefore, many advantageous mechanisms have been determined: a) phenolic constituents most importantly flavonoids that determine the LDL/HDL contents in A. graveolens, b) increasing behavior of LDL receptor and uptake of LDL-c and inhibition of the activity of acetyl-CoA carboxylase, c) decline in cholesterol absorption from intestine binding to bile acids, d) reduction in HMG-CoA reductase activity, suppression cholesterol and fatty acids formation [4]. The utilization of hydroalcholic extracts of A. graveolens, swimming excercises and their combination has significantly decreased the LDL-c, V-LDL, TG and cholesterol of diabetic rats but increased the HDL level [5]. Final analysis concluded that after 4-weeks aerobic training, the amount of glucose of plasma declined but the HDL to LDL ratio was increased. Obesity is the main effect in resistance development to insulin, decreasing amount of fat weight improve the sensitivity of insulin. Aerobic training caused the oxidative capacity of skeletal muscle to increase through increasing the fat acid of plasma and also increased protein carrier of fatty acids. The oxidation of lipids decreased and glucose homeostasis increased when fat weight is reduced. The reduction of fat weight and liver glucose, insulin secretion is increased from pancreas and also increased the sensitivity to insulin that control blood sugar level. The oxidation of fat is increased but the amount of triglyceride is decreased due to aerobic training [7]. Blood lipid peroxidation is increased in diabetic patients due to vascular injury that is enhanced by hyperglycemia and free radicals. HDL and hypertriglyceridemia are decreased but oxidative stress is increased. Diabetes also causes the heart diseases. Cardiovascular diseases (CVD’s) are caused due to uncontrollable hyperlipidemia. CVD’s is the most severe condition in diabetes mellitus (DM), that is the major reason for high mortality rate in diabetic patients. Dyslipidemia and hyperlipidemia should be control to prevent CVD’s. Excess amount of glucose attached to free amino groups in tissues or blood proteins and body fluids and caused the inappropriate functions. Due to non enzymatic effects advanced glycation end products are obtained. Glycation reactions change the function and chemical structure of proteins. The AGE’s synthesis is a major element in diabetic condition [8].

Reactive Free Radicals in Case of Diabetes Mellitus:

A. graveolens has the most powerful (O₂−) and hydrogen peroxide (H₂O₂) scavenging activity rather than butylated hydroxytoluene (BHT) and ascorbic acid. A. graveolens cause most significant superoxide anion (O₂−) and hydrogen peroxide (H₂O₂) scavenging activity with IC₅₀. It shows the most powerful activity e.g, 96% than butylated hydroytoluene (BHT) with 93.5% activity [2].More chemically reactive compounds are present in form of free radicals in diabetic patients like hydroxyl radical (∙OH), hydrogen peroxide (H₂O₂), lipid peroxyl radical (LOO∙), superoxide anion (O₂∙−), and peroxyl radicals (ROO∙). These free radicals are formed during the earliest stages of diabetes. The chemical reaction between free radicals and polyunsaturated fatty acids lipid peroxidation is a factor caused by the chemical reaction between free radicals and polyunsaturated fatty acids that showed the cardiovascular disease. Enzymatic antioxidant phenomenon play a significant role in the deletion of free radicals. Superoxide dismutase (SOD) is the endogenous enzyme that removes O₂− and form H₂O₂ which is further treated with water by the activity of catalase (CAT) and glutathione peroxidase (GPx). SOD provide protection against O₂∙− and prevent the formation of these free radicals. CAT is the enzyme that causes the detoxification of the hydrogen peroxide to water and oxygen Glutathione peroxidase (GPx) prevent the destruction of free radicals by controlling the formation of the lipid peroxides and organic hydroperoxides. Glutathione S-transferase (GST) make a balance in cellular redox conditions. The hydroxyl radical (∙OH) and hydrogen peroxide (H₂O₂) attack the polyunsaturated fatty acids and lipid peroxidation is caused. The combination of Iron ion and hydrogen peroxide is called as Fenton reaction that cause the synthesis of hydroxyl radical (∙OH) that is a oxidative specie. Extravascular usage of herbal medicines increase the activities of SOD, CAT, GSH, GST and GPx in diabetic patients [8].

Preventions of Diabetes Mellitus.:

There are different parameters that are associated with prevention of diabetes mellitus (DM) such as use of insulin or hypoglycemic drugs, regular diet, continuous exercise. Carvone is the key component of A. graveolens that is used for the treatment of diabetes and anemia [1]. Cinnamon and Cortidis Rhizoma are the herbs that are recognized for insulin secretagogues properties [4]. Chemical drugs are too much expensive have low efficiency, high toxicity so that some patients can’t bear this long time hazardous treatment and take the high doses of these drugs. As compared to herbal medicines, that are most effective have low cost and don’t have toxicity [8].

Advantages and Disadvantages.:

A. graveolens increase the weight of kidney, liver and spleen. Increase in the body weight and organs is a major symptom of important property that is inflammation but decrease is an identification of cell constriction. This increase in weight of testis, epididymis and other organs is due to inflammation [1]. A. graveolens has different types of coumarins with phototoxic effects that can increase the oxidative stress and destruction of β-cells [4]. Limonene and Carvone are the most important constituents of A. graveolens that suppress the cyclooxygenase 1 and 2 pathways and prevent the release of inflammatory mediators. It is suggested that A. graveolens should add to dietary plan of diabetic patients as vegetable because it reduces the release of inflammatory biomarkers [6]. Patients use a variety of medicines like sulfonylureas (glimepiride, glipizide and glyburide), biguanides (met formin), thiazolidinediones (pioglitazone), alpha-glucosidase inhibitors (acarbose), meglitinides (nateglinide) and dipeptidyl peptidase 4 inhibitors (janvvia, onglyza) to prevent the hyperglycemic condition. Due to harmful effects in all diabetic drugs, diabetic patients stop the medication process and the ratio of these diabetic patients is larger than 10 to 20%. Few amount of diabetes drugs cause the hypoglycemic condition which is lethal to human health. Weight gain, more risks of fractures in women and gastrointestinal complications such as abdominal pain, gassiness, vomiting, nausea, diarrhea and bloating. Edema and increase level of low density lipoprotein cholesterol (LDL-c) see in some diabetic patients. Chemically reactive diabetic medicines also cause congestive heart failure, allergic reactions and anemia that is the reaction from confiscation of RBC in the spleen, that cause the production of red blood cells and improper functions of bone marrow [1,8]. Dill reduces sexual potency, spermatogenesis in males. High doses of seed of aqueous and ethanolic extract lead to increase the time duration of estrous cycle, diestrus phase and progesterone concentration level [14].

Importance of Herbal Medicine in Diabetes Mellitus.:

Herbal medicines are the drugs that have high activity and efficiency but low toxicity. Anethum graveolens reduces the blood glucose level. Carvone which is important compound of A. graveolens, that is famous for treating the diabetes and anemia [1]. Herbal originated drugs are going to be very useful due to low cost, less toxicity and more beneficial properties such as antihyperglycemic, antihyperlipidemic and antioxidant effects. A. graveolens (dill) is used as a traditional medicine for the treatment of different diseases like digestive disorders, bad breath, lactation motivation and also as hypolipidemic agent. A. graveolens also contain flavonoids (30.2%), phenols (6.6%), terpenes (17.3%), saponins (9.4%), tannins (4.7%), alkaloids (5.2%), polysaccharides (3.2%), miscellaneous compounds (18%) and glycosides that are useful for many medical purposes [2,8]. A. graveolens is used for some gastrointestinal problems like indigestion and flatulence [3,13]. All parts of the plant of A. graveolens such as stem, leaves, seed and fruit are used as food spices and also important with respect to biological roles [4]. Leaves of A. graveolens are the richest source of minerals, proteins and fiber. Anethoferon, carvone and limonene are the key components of Anethum oil with the biological activity. Myristicin, anethole and umbelliferone are the important chemical components of A. graveolens [6]. Researchers also suggest that A. graveolens protect the mucosa of gastric due to presence of flavonoids such as Isorhamnetin and Quercetin. Isorhamnetin and Quercetin reduce the level of total glyceride [7]. Now a days, doctors prescribe the diabetic patients to take the insulin, thiazolidinediones, sulphonyl ureas, α-glucosidase inhibitors to control the diabetes. Due to unknown mechanism, some of the plants are used for the treatment of diabetes. According to World Health Organization (WHO), 80% of the people around the world introduce the use of herbs for curing the different diseases. Although, some plants have been recommended for curing the diabetes due to their antidiabetic activity, in this review article, we will provide a new route towards the applications of A. graveolens and its multi key components for the treatment of diabetes mellitus (DM) [8]. Dill tablet cantain important constituents such as A. graveolens, Cichorium intybus, Fumaria parviflora, Citrus aurantifolia sp [12].

Table 1: Antidiabetic properties of AG in different Experiments

References	Preparation	Analysis and time interval	Pharmacological efffects
[1]	Aqueous extract of AG seeds	Alloxan monohydrate induced diabetic mice, 48 h	(i) Hyperglycemia
[1]	Aqueous extract of AG seeds	Alloxan monohydrate induced diabetic mice, 5 h	(i) Hypoglycemia
[1]	Aqueous extract of AG plant	Alloxan monohydrate induced diabetic mice	(i)Increased in RBC (ii)Decreased in platelets, (iii)Increased in weight of liver, kidney and spleen
[1]	Ethanolic extract of AG	Alloxan monohydrate induced diabetic mice	(i)Increased in HGB, WBC (ii)Decreased in platelets
[2]	AG tablet	Streptozotocin induced male rats, 2 months	(i) Hypoglycemia (ii) AGE’s formation decreased
[2]	Dill tablet	Diabetic patients, hyperlipidemic patients, patients with metabolic syndrome	(i)Hypoglycemia (ii)Triglyceride, V-LDL, LDL-c reduced (iii)HDL increased
[2]	AG tablet	In vivo, hyperlipidemic patients	(i)Antioxidant activity and antiradical activity (ii) Total cholesterol, triglyceride reduced
[2]	Aqueous extract of AG tablet	Streptozotocin induced male rats, 2 months	(i)Hypoglycemia
[3]	Powder of AG tablet	Type 2 DM patients, 6 weeks	(i)AG powder reduced the serum level of insulin, HOMA-IR, LDL-c, MDA, HDL, TAC, but didn’t improve TG
[3]	AG extract along with aerobic training	Diabetic women, 4 weeks	(i)AG increased HDL but decreased LDL-c to HDL ratio
[3]	AG tablet twice daily	Hyperlipidemia patients, 6 weeks	(i)AG increased serum level of TG but didn’t improved TC, LDL-c level
[3]	Aqueous extract of AG seed	Type 2 diabetic patients	(i)Hypoglycemia (ii)Hypolipidemia (iii) Antioxidant activity
[3]	Powder of AG leaves	Hyperlipidemic patients, 4 weeks	(i)AG decreased levels of TC, TG, LDL-c, V-LDL
[3]	Dill (AG) power	Normal rats	(i)AG decreased serum levels of hs-CRP, IL-6, TNF-α
[4]	AG powder	Hypercholesterolemic male rats, 2 weeks	(i)AG decreased TC, TG LDL-c, but increased HDL
[4]	Hydroalcoholic extract of AG	Alloxan monohydrate induced diabetic male rats	(i)Hypoglycemia, (ii)AG decreased total cholesterol, triglyceride, LDL-c, V-LDL
[4]	AG extract	Male rats of high fat diet, 1 month	(i)AG decreased TC, TG, LDL-c but increased HDL
[4]	AG tablet	Hyperlipidemia patients, 6 weeks	(i)AG decreased LDL-c, TC but increased HDL, triglycerides
[4]	AG extract	High fat diet induced diabetic male rats, 3 weeks	(i)AG increased plasma blood glucose level
[4]	Hydroalcoholic extract of AG	Male diabetic rats, 10 days	(i) Hypoglycemia
[5]	Hydroalcoholic extract of AG	Sprague dawley male rats	(i)LDL-c, V-LDL, TG, cholesterol reduced (ii)HDL increased (iii)AG improved lipid profile
[7]	AG along with aerobic training	Type 2 diabetic patients, 4 weeks	(i)Hypogylemic effects (ii)Hypolipidemic effects
[9]	Methanolic extract of AG leaves	Hepatotoxicity induced by carbon tetrachloride in rats, 21 days	(i)Antioxidant activity, hepatoprotective activity, normalized the level of blood glucose (ii)AG improved lipid profile
[11]	Hydroalcoholic extract of AG	Cardiovascular obese male rats, 12 weeks	(i)AG increased levels of TC,TG, LDL-c, V-LDL, TC/HDL-C, ratio of LDL-c to HDL the hydroalcoholic (ii)strong antilipolytic activity
[12]	Dill tablet	Hepatotoxicity induced by carbon tetrachloride in rats, 10days	(i)AG reduced liver enzymes lactate dehydrogenase, alkaline phosphate, aspartate transaminase, alanine transaminase, γ-glutamyl transferase, total bilirubin, direct bilirubin, liver cholesterol, triglyceride (ii)AG increased protein, albumin, total antioxidant capacity, catalase activity (iii) Significant hepatoprotective activity
[13]	AG tablet	Normal rats, 2 weeks	(i)AG decreased total cholesterol, triglyceride, LDL-c (ii)AG increased HDL (iii)Antioxidant activity
[15]	Crude extract of AG	Rats with high fat	(i)Anti-hypercholesterolaemic, anti-hyperlipidemic activities
[15]	Ethanolic extract of AG	Hyperlipidemic rats	(i)AG increased HMG-CoA/mevalonate (ii) Hypolipidemia
[15]	Dill power, dill oils	Rats	(ii) Hypolipidemia
[15]	Dried ethanol extract of AG fruits, essential oil	Dogs	(i)AG caused dieresis (ii) Increased sodium, calcium excretion
[15]	AG seed oil	Cats	(i ) AG caused hypotension, increased respiratory volume

Botanical Status and Taxonomic Version of AG.:

The generic name of ‘’Anethum’’ comes from the Greek word ‘’anethone’’ and the demotic name of dill herb comes from Old Norse word ‘’dilla’’ that means ‘’to soothe’’. A. graveolens is the rare species of genus Anethum that is classified by the several other botanists relate to Peucedanum genus as Peucedanum graveolens (L.). It is the annual herb that has the stem size of 50-150 cm of Apiaceae family. The color of fruits of AG are brown but flat, long ansd oval in texture. This herb grow in Mediterranean regions, Europe, Central and South Asia. Anethum graveolens consist of 36.8% carbohydrates, 15.99% proteins, 14.91% fiber, 10.1% ash and 8.91% moisture and also essential oils, fatty oil, minerals and vitamins [8,15].

Benefits of Anethum Graveolens.:

A. graveolens is used as a herbal drug to cure the digestive complications, bad breath, lactation motivation, stomachache, insomnia, gastrointestinal complications, flatulence, intestinal spasms [1,2,4,9,12,13,14,18]. A. graveolens (Dill tablet) is used as Iranian folk medicine consist of Anethum graveolens (68%), Cichorium intybus (5%), Fumaria parviflora (5%) and lime (citrus aurantifolia) (4%). Dill herb reduces the metabolic disorders such blood glucose level, total cholesterol, triglyceride, very low density lipoprotein cholesterol (V-LDL), low density lipoprotein cholesterol (LDL-c) and increase the high density lipoprotein cholesterol (HDL) [2]. Anethum Graveolens have the different pharmacological effects such as antimicrobial, antispasmodic, antisecretary, anticancer, antigastric irritation, anti-inflammatory, antioxidant and mucosal protective effects [1,2,4,10,15,19]. Major components of fruits of Anethum Graveolens consisted of essential oil, carvone, limonene, α-phellandrene, pinene, diterpene, dihydrocarvone, cineole, myrcene, paramyrcene, dillapiole, isomyristicin, myristicin, myristin, apiol, dillapiol [15].

Hypolipidemic and Hypoglycemic Potentials of Anethum Graveolens.:

The utilization of different extractions of A. graveolens seeds, leaves and the essential oils in the diabetic patients decreased blood glucose level, total cholesterol, triglyceride, very low density lipoprotein cholesterol (V-LDL), low density lipoprotein cholesterol (LDL-c) but increase the high density lipoprotein cholesterol (HDL) [2]. Experimental analysis revealed that A. graveolens consist of hypoglycemic and antioxidant activity. Its antioxidant property is due to phenolic proanthocyanidins and flavonoids components. Recent studies showed that the extract of A. graveolens flowers contain more antioxidant activity than their seed or leaf parts. Time duration to study the antidiabetic characteristics of dill herb is different in different experiments; for example in some experiments single dose for one hour, while the treatment period was about 12 weeks in other experiment. All these experiments show that one month is convenient to study the antidiabetic characteristics of dill herb. To see their antidiabetic properties of Anethum Graveolens, usually rats were used. Few important mechanisms have been considered to investigate the hypolipidemic factors of A. graveolens. Due to inhibition of absorption of intestinal cholesterol connect with bile acids in intestine then fecal excretion and production of bile acids are increased that associates with antidiabetic functions of A. graveolens. Experiments also showed that carvone, limonene and alpha-phellandrene constituents of A. graveolens cause hypolipidemia and also reduce the acyl-CoA carboxylase or 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase that are important enzymes in fatty acids and cholesterol mechanism of action. These Anethum graveolens constituents slightly increase the liver LDL receptors, reduce the fatty acids production and lipoprotein homoestatis by improving the functions of lipoprotein metabolism. The antioxidant characteristics of Anethum graveolens improves lipid profile. It has observed that use of 100 and 200mg/kg of AG tablet and hydroalcoholic extract of AG in hypercholesterolemic condition decreased the HMG-CoA reductase function and also in RNA. Lipid profile is normalized by reducing the HMG-CoA reductase in hypercholesterolemic condition and rats affected with type 2 diabetes. A. graveolens increase the LDL-c receptor in liver that clear the cholesterol from blood stream. The other analysis concluded that Anethum graveolens increased the cholesterol-7-alpha hydroxylase function that is rate limiting enzyme in bile acid formation. The another important constituents of Anethum graveolens e.g, rutin and quercetin decreased the serum cholesterol, LDL-c and liver cholesterol. Several studies indicated that quercetin decreased the action of HMG-CoA reductase. Histopathological data reported that the treatment of diabetes affected rats with varying amounts of Anethum graveolens normalized lipid that deposited in liver, pancreas and heart. HPLC study represented high amount of quercetin in Anethum graveolens that suppress HMG-CoA reductase action. Flavonoids, terpenoids, alkaloids, tannins and phytosterols are the chemical constituents of A. graveolens that cause the hypoglycemia. We also examined that varying amounts of A. graveolens decreased the antiglycation end products bio-synthesis. It was also noted that decreased in fasting blood glucose level with 300 mg/kg hydroalcoholic extract of Anethum graveolens. The amount of A. graveolens upto 2g/kg can’t cause death in animals and its amount upto 1000 mg/kg can’t cause undesirable side effects (toxicity). Minimum amount of dose is 1g/kg/day in 45 days but 300mg/kg is the effective dose to study metaboilic effects in animals. A variety of studies reported that both high and low doses of A. graveolens have hypolipidemic and hupoglycemic properties. Dose less than 50mg/kg can’t cause side effects in animals. Therefore, 3 weeks utilization of Anethum extract with the dose of 50, 100 and 200mg/kg only normalized the blood lipid but the change in blood glucose level was not soo much. The dose of 650mg/kg is the enough dose for human studies. Different amounts of A. graveolens in concentrations of 0.034, 0.067,0.126, 0.26, 0.6 and 1 mg/ml decreased the antiglycation end product biosynthesis; fructosamine level and carbonyl groups, also, increased thiol groups in animals affected with type 2 diabetes. The major constituents of A. graveolens affect the antiglycation characteristics. Oxidation of carbonyl and thiol groups is decreased on blood proteins by Anethum graveolens. Proteins glycation is performed by the non-enzymatic reaction in persons affected with diabetes cause AGEs synthesis that occur in diabetic pathogenesis and ageing. Few drugs are classified as inhibitors of AGEs biosynthesis. Intracellular glycation by fructose found in increased rate as compared to glucose. That’s why fructose and its metabolites are considered as major precursors for the synthesis of AGEs in the body. Fructose is used for the glycation of BSA. At the initial stages of protein glycation, schiff’s base is changed into fructosamine (Amadori product). This metabolite is clinically very important which is used for the study of hyperglycemia. Reduced levels of fructosamine are useful for declining of vascular problems. Anethum Graveolens decreased AGEs biosynthesis and fructosamine [2]. A. graveolens is the richest source of antioxidant components; so, antioxidant and flavonoids constituents of A. graveolens repair the damaged β-cells and insulin secretion. Antioxidant activity of A. graveolens increased the insulin formation. Anethum Graveolens decreased the blood glucose level by increasing insulin secretion. Colorimetric and HPLC data reported that it was the richest source of quercetin, phenol, flavonoids, tannins, saponins and alkaloids. These components have the hypolipidemic, hypoglycemic and metabolic effects. It was also reported that A. graveolens has a major component carvone that is responsible for antidiabetic effects. Carvone decreased the plasma glycoprotein constituents and increased the insulin secretion. The ethanolic extracts of A. graveolens prepared in India have very low antidiabetic effects [6]. Ethanolic extracts of A.graveolens prepared in Pakistan decreased blood glucose level by 38%. The aqueous extract of A. graveolens don’t have deleterious effects on bone marrow, kidney, hemoglobin metabolism and RBC values are not soo much increased. The ethanolic extract of Anethum graveolens don’t cause any change in RBCs but haemoglobin was 12.16g/dL and 13.59g/dL was reported in affected mice. Ethanolic extract showed a little bit increase in WBC value but no increased observed in RBC value. Platelets amount also decreased. This showed that the ethanolic extract of A.graveolens don’t cause anaemia during 15 days of administration. HPLC, NMR and IR data of Anethum graveolens showed the presence of higher amount of carvone in aqueous extracts of seeds [1]. In our present study, the scavenging activity of H₂O₂ was 96.06% due to 1 mg/ml of AG water extract, whereas ethanolic extract of AG showed 27.30% radical scavenging activity. It was also reported that A. graveolens cause Fe²⁺ chelation that perform as defence mechanism against oxidative damage by reducing the free radical formation via Fenton reaction. Iron (II) is oxidized by H₂O₂ to form hydroxyl radical in this reaction mechanism. It is also known for best nitric oxide scavenging activity. This activity is similar to activity of radical scavengers, ascorbic acid and butylated hydroxyl toluene (BHT). It was reported that a 1 mg/ml solution of A. graveolens water extract consisted of 90.51%. NO scavenging activity that was higher than 78.62% for ethanolic extract of A. graveolens. Best antioxidant activity of A. graveolens water extract was noted than methanolic extract. Finally, with help of this review article, we can observe that different forms such as hexane, ethanol, water and hydroalcoholic extracts of seed and leaves have been utilized in different experimental analysis but hydroalcoholic extract represented the greater antidiabetic properties as compared to other extracts [8]. AG reduced liver enzymes lactate dehydrogenase, alkaline phosphate, aspartate transaminase, alanine transaminase, γ-glutamyl transferase, total bilirubin, direct bilirubin, liver cholesterol, triglyceride but it increased protein, albumin, total antioxidant capacity, catalase activity and possess significant hepatoprotective activity [12].

Chemical Formation.:

A. graveolens L. grown in Mediterranean region, Europe and Central and South Asia consisted of carvone, limonene called as monoterpenes that are occurred as main components of dill oil from fruits. The major constituents of A. graveolens are the á-Phellandrene, dill ether and myristicin that make the special odor of dill herb. It is also the richest source of flavonoids, phenolic compounds and essential oils in seeds of dill herb used for the formation of gripe water [1]. Dill is also consisted of terpenes, saponins, tannins, cardiac glycosides, flavonoids and phenolic compounds that are beneficial for the useful effects [2]. The leaves of Anethum graveolens are full of minerals, protein and fiber, flavonoids, phenolic compounds, essential oil, fatty oil, moisture, proteins, carbohydrates, fibre, ash, mineral elements such as calcium, potassium, magnesium, phosphorous, sodium, vitamin A, and niacin [4,6,13]. Anethoferone, carvone and limonene are the major constituents of Anethum oil that are important according to biological aspects [4,6]. Anethum graveolens is the richest source of antioxidants such as vitamin C, polyphenols and carotenoids [4]. The other beneficial chemical components of Anethum Graveolens are myristicin, anethole and umbelliferone [6]. Quercetin and Isorhamnetin are key components of Anethum Graveolens [7]. Fatty oil, carbohydrates, proteins, moisture, fibers, ash, vitamins (A and niacin) and minerals (calcium, potassium, magnesium, phosphorus and sodium) are also present in a dill herb. The seeds and leaves of Anethum Graveolens contain some important constituents that have therapeutic effects. Carvone, dill apiole, limonene, trans- and cis-dihydrocarvone and linalool are the other chemical compounds of A. graveolens. A variety of components of Anethum graveolens have been showed in different literature survey that are listed in Table 2 [8]. The seed of Anethum Graveolens contain D-carone, D-limonene, flavonoids, quercetin, isorhamnetin, anethole, dillapiole [11]. Volatile oil of A. graveolens contain the some basic components like Carvone, limonene, dillapiole, linalool, linoleic acid, trans-anethole, 2-propanone, 1-(4-methoxyphenyl), carvone, p-anisaldehyde, myristicin [16].

Deleterious Effects.:

It has been observed that the use of Anethum Graveolens is not soo harmful but it can cause hypoglycemia which is lethal, weight gain, more risk of fractures in women, flatulence, indigestion and gastrointestinal disorders such as abdominal pain, gassiness, vomiting, diarrhea, nausea, bloating [1,8]. It can also lead to allergic reactions, oral pruritus, urticaria tongue and throat swelling. It is not recommended to pregnant women [8]. Other clinical and experimenat analysis did not report the deleterious effects of Anethum Graveolens [2,3,4,5,6,7].

Table 2: Multiple Key components of AG in different Experiments

References	Preparation	Components
[1]	Dill oil	Carvone, limonene, α-Phellandrene, dill ether, myristicin
[1]	AG seed oil	Flavonoids, phenolic compounds, essential oil
[2]	Dill tablet	Anethum graveolens, cichorium intybus, fumaria parviflora, citrus aurantifolia sp, flavonoids, phenolic, terpenes, saponins, tannins, cardiac glycosides, flavonols, alkaloids, anthocyanins
[2]	Dill seed	Alkaloids, flavonoids, tannins, saponins
[2]	Dried dill	Phenol content, flavonoids
[4]	AG oil	Anethoferone, carvone, limonene
[4]	AG leaves	Minerals, proteins, fibers, coumarins
[6]	AG leaves	Fibers, minerals, proteins
[6]	AG oil	Anethoferone, carvone, limonene
[6]	AG herb	Myristicin, anethole, umbelliferone, vitamin-C, polyphenols, carotenoids
[7]	AG herb	Isorhamnetin, quercetin
[8]	AG herb	Carbohydrates, proteins, fibers, ash, moisture, essential oil, fatty oil, minerals, vitamins, flavonoids, phenolic compounds, saponins, cardiac glycosides, terpenes
[8]	Dill oil	Carvone, 𝛼-phellandrene, limonene, fatty oil, proteins, carbohydrates, moisture, fibers, ash, vitamins (A and niacin), mineral elements (calcium, potassium, magnesium, phosphorus, sodium)
[8]	AG seed	Carvone, limonene, 𝛼-phellandrene, myristicin, dill ether
[8]	Dill oil	𝛼-phellandrene, limonene, carvone, dill apiole, trans- and cis-dihydrocarvone, linalool
[11]	AG seed	D-caron, D-limonene (ketone), fatty content, flavonoids, quercetin, isorhamnetin, anethole, dillapiole
[12]	Dill tablet	A. graveolens, Cichorium intybus, Fumaria parviflora, Citrus aurantifolia sp
[13]	AG leaves	Flavonoids, phenolic compounds, essential oil, fatty oil, moisture, proteins, carbohydrates, fibre, ash, mineral elements such as calcium, potassium, magnesium, phosphorous, sodium, vitamin A, and niacin
[13]	Fruits of dill	Carvone, limonene, alpha-phellandrene, pinene, diterpene, dihydrocarvone, cineole, myrcene, Paramyrcene, dillapiole, isomyristicin, myristicin, myristin, apiol and dillapiol
[13]	Dill essential oil	Furanocoumarin, 5-(4”-hydroxy-3”methyl-2”butenyloxy)-6,7-furocoumarin, oxypeucedanin, oxypeucedanin hydrate, falcarindiol
[15]	AG	Essential oils, fatty oil, moisture, proteins, carbohydrates, fiber, ash, mineral elements such as calcium, potassium, magnesium, phosphorous, sodium, vitamin A and niacin
[15]	Fruits of AG	Essential oil, carvone, limonene, α-phellandrene, pinene, diterpene, dihydrocarvone, cineole, myrcene, paramyrcene, dillapiole, isomyristicin, myristicin, myristin, apiol, dillapiol
[16]	AG seeds, stem	α-phellandrene, limonene, terpinene, phellandral, β-phellandrene, dill ether , myristicin
[16]	AG leaves, flowers	α-phellandrene, β-phellandrene, dill ether, myristicin, limonene
[16]	AG fruits	Cis-carvone, limonene
[16]	AG seed oil	Carvone
[16]	Volatile oil of AG	Carvone, limonene, dillapiole, linalool, linoleic acid, trans-anethole, 2-propanone, 1-(4-methoxyphenyl), carvone, p-anisaldehyde, myristicin
[17]	Dill seed	Carvone,a-phellandrene, limonene, dill ether, myristicin, coumarins, flavonoids, phenolic acids, steroids
[17]	Dill herb	α-phellandrene, limonene, dill ether, myristicin
[18]	Dill leaves	Phosphorus, potassium, magnesium minerals
[19]	Dill herb	Essential oil, fatty oil, proteins, carbohydrates, fiber, mineral elements (potassium, calcium, magnesium, phosphorous, sodium), vitamin A, niacin
[19]	Dill seed	Carvone, limonene, α-phellandrene, α-pinene, α-terpinene, apiole, dill apiole, 1,8-cineole, dihydrocarvone, p-cymene
[19]	Dill seed oil	Carvone, limonene, cis-dihydrocarvone, trans-dihydrocarvone, cis-carveol, trans-carveol
[20]	AG seed	Flavonols, alkaloids, antocianin, tannins, saponins

CONCLUSION:

Herbal medicines consist of important compounds such as flavonoids, terpenoids, saponins, polyphenols, tannins, alkaloids and polysaccharides that have their clinical and biological importance [8]. Medicinal plant especially Anethum Graveolens contain the different pharmacological effects like antimicrobial, antispasmodic, antisecretary, anticancer, antigastric irritation, anti-inflammatory, antioxidant and mucosal protective effects [1,2,4]. A. graveolens has a variety of coumarins with phytotoxicity that increases the oxidative stress and destruction of β-cells [4]. The utilization of A. graveolens along with aerobic training is an effective method for the reduction of lipid disorders and also the reduction of glucose in diabetic patients [7]. Recent studies showed that A. graveolens possess the excellent antidiabetic activity in both humans and animals. Due to antidiabetic activity of dill herb, it can be used for the prevention of diabetes mellitus. However, its preparation mode, its dose, time interval of A. graveolens consumption and link with other drugs should be normalized. All the essential compounds of Anethum Graveolens possess antioxidant, hypolipidemic and hypoglycemic effects, these compounds are present in lesser amount in A. graveolens and have harmonious effects. A. graveolens is used as traditional herbal medicine for the treatment of digestive problems, cardiovascular diseases, bad breath, lactation motivation, and also as hypolipidemic agent [2,8]. It is also reported that it is also used to overcome the gastrointestinal problems such as indigestion and flatulence. All the aerial parts of the plant like stem, leaves, seeds, fruits are used as food ingredients and also important in medical point of view [4]. Moreover, studies suggest that components of Anethum Graveolens suppress the cyclooxygenase 1 and 2 pathways and prevent the release of inflammatory mediators [6].

COMPETING INTERESTS:

The authors have no competing interests to disclose.

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Received on 23.05.2020 Modified on 17.06.2020

Asian J. Res. Pharm. Sci. 2020; 10(4):248-256.

DOI: 10.5958/2231-5659.2020.00045.4