**5.2. Rutin**

Rutin {2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3-[α-Lrhamnopyranosyl-(1→6)-β-D-gluco pyranosyloxy]-4*H*chromen-4-one} is abundantly present in onions, apples, tea and red wine [86]. The name rutin originated from the plant *Ruta graveolens*. Rutin exhibits multiple pharmacological activities including antibacterial, antitumour, antidiabetic, antiinflammato‐ ry, antidiarrhoeal, antiulcer, antimutagenic, myocardial protecting, vasodilator, immunomo‐ dulator and hepatoprotective activities [87]. It is a potent antioxidant and anti-inflammatory agent that has the potential to provide a lot of health benefits [88].

considered to be a vascular-protecting agent used to treat chronic venous insufficiency, hemorrhoids, lymphedema, and varicose veins. Diosmin exhibits anti-inflammatory, antioxi‐ dant, and anti-mutagenic properties [95-97]. Clinical studies have demonstrated that diosmin can be used to treat venous leg ulcers and hemorrhoids [98]. Also, its anti-inflammatory and

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Diosmin was found to be capable of normalizing capillary filtration rate and prevent ische‐ mia in diabetics [100-101]. Diosmin has been shown to improve factors associated with diabetic complications. A decrease in hemoglobin A1c as well as an increase in glutathione peroxidase was observed in type 1 diabetic patients after an intervention with a diosmin-containing flavonoid mixture [102]. Diosmin and hesperidin are known to lower hepatotoxicity induced bycarbontetrachloride(CCl4)andlipopolysaccharides (LPS),minimizeoxidationstress caused by nicotine, reduce blood sugar and cholesterol, and inhibit carcinogenesis of the bladder and colon[31, 103-106].Administrationofdiosminfor 45days significantly loweredplasma glucose level, increased the activities of hepatic key enzymes such as hexokinase and glucose-6 phosphate dehydrogenase in addition to decreasing glucose-6-phosphatase and fructose-1,6 bisphosphatase concentrations in streptozotocin-nicotinamide treated rats exhibiting its antihypeglycemic properties [107]. Diosmin lowered plasma glucose and increased plasma insulinlevels indiabetic rats by ameliorating the oxidative stress inducedby streptozotocinand nicotinamide. Activities of antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, and glutathione s-transferase), vitamin C, vitamin E and reduced glutathione were increased while lipid peroxidation was reduced in liver and kidney of diabetic rats upon treatment with diosmin. Diosmin was also recently reported to possess antihypertensive property by increasing the activities of antioxidant enzymes,,reducing reactive oxygen species and normalizing marker enzymes in serum and tissues (liver, kidney, heart, aorta) when rats

were made hypertensive by deoxycorticosterone acetate (DOCA) salt [108].

Luteolin (3´,4´,5,7-tetrahydroxyflavone) is a flavonoid widely distributed in the plant kingdom including several such as *Reseda luteola L*., *Achillea millefolium L*, *Chamomillae requtita*, *Cynara scolymus*, *Thymus vulgaris*, *Limonium sinuatum* [109]. Luteolin has a variety of pharmacological activities, including anti-mutagenic, anti-tumorigenic [110], anti-inflammatory [111], antihypertensive [112], and anti-oxidative [113] properties. It is thought to play an important role in the human body as an antioxidant, a free radical scavenger, an agent in the prevention of

anti-apoptotic activity has been demonstrated in neuronal cells [99].

**Figure 4.** The chemical structure of diosmin.

**5.4. Luteolin**

**Figure 3.** The chemical structure of rutin.

Rutin by its ability to scavenge free radicals and to inhibit lipid peroxidation, prevents streptozotocin-induced oxidative stress and protects pancreatic beta cells resulting in in‐ creased insulin secretion and decreased blood glucose levels. Rutin effectively reduced the increased levels of thiobarbituric acid reactive substances and hydroperoxides in the diabetic state *in vivo* [89] and *in vitro* [90]. Rutin reduces hyperglycemia and dyslipidemia while inhibiting the progression of liver and heart dysfunction in diabetic rats [91]. It also signifi‐ cantly decreases elevated reactive oxygen species while increasing endogenous antioxidant enzymes in kidney of diabetic rats and may consequently control or prevent the development of diabetic nephropathy [92]. When Rutin supplementation tablets (500mg) was administered simultaneously with their regular medication for 60 days to patients with type 2 diabetes mellitus, the hypertension, total cholesterol and low-density lipoproteins (LDL) were mark‐ edly attenuated. Rutin also decreased the levels of fasting blood glucose, systolic and diastolic blood pressure and improved lipid profiles in the diabetic subjects [93]. Rutin found in *Morus alba* leaves, possesses significant, dose-dependent antidiabetic activity in a type 2 diabetic rat model [94].

#### **5.3. Diosmin**

Diosmin (3',5,7-trihydroxy-4'-methoxyflavone 7-rutinoside) is a naturally occurring flavonoid glycoside that can be isolated from various plant sources or derived by dehydrogenation of the corresponding flavanone glycoside Hesperidin, that is abundant in the pericarp of various citrus fruits [95]. Diosmin was first isolated in 1925 from *Scrophularia nodosa.* Diosmin is considered to be a vascular-protecting agent used to treat chronic venous insufficiency, hemorrhoids, lymphedema, and varicose veins. Diosmin exhibits anti-inflammatory, antioxi‐ dant, and anti-mutagenic properties [95-97]. Clinical studies have demonstrated that diosmin can be used to treat venous leg ulcers and hemorrhoids [98]. Also, its anti-inflammatory and anti-apoptotic activity has been demonstrated in neuronal cells [99].

**Figure 4.** The chemical structure of diosmin.

**5.2. Rutin**

322 Antioxidant-Antidiabetic Agents and Human Health

**Figure 3.** The chemical structure of rutin.

model [94].

**5.3. Diosmin**

Rutin {2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3-[α-Lrhamnopyranosyl-(1→6)-β-D-gluco pyranosyloxy]-4*H*chromen-4-one} is abundantly present in onions, apples, tea and red wine [86]. The name rutin originated from the plant *Ruta graveolens*. Rutin exhibits multiple pharmacological activities including antibacterial, antitumour, antidiabetic, antiinflammato‐ ry, antidiarrhoeal, antiulcer, antimutagenic, myocardial protecting, vasodilator, immunomo‐ dulator and hepatoprotective activities [87]. It is a potent antioxidant and anti-inflammatory

Rutin by its ability to scavenge free radicals and to inhibit lipid peroxidation, prevents streptozotocin-induced oxidative stress and protects pancreatic beta cells resulting in in‐ creased insulin secretion and decreased blood glucose levels. Rutin effectively reduced the increased levels of thiobarbituric acid reactive substances and hydroperoxides in the diabetic state *in vivo* [89] and *in vitro* [90]. Rutin reduces hyperglycemia and dyslipidemia while inhibiting the progression of liver and heart dysfunction in diabetic rats [91]. It also signifi‐ cantly decreases elevated reactive oxygen species while increasing endogenous antioxidant enzymes in kidney of diabetic rats and may consequently control or prevent the development of diabetic nephropathy [92]. When Rutin supplementation tablets (500mg) was administered simultaneously with their regular medication for 60 days to patients with type 2 diabetes mellitus, the hypertension, total cholesterol and low-density lipoproteins (LDL) were mark‐ edly attenuated. Rutin also decreased the levels of fasting blood glucose, systolic and diastolic blood pressure and improved lipid profiles in the diabetic subjects [93]. Rutin found in *Morus alba* leaves, possesses significant, dose-dependent antidiabetic activity in a type 2 diabetic rat

Diosmin (3',5,7-trihydroxy-4'-methoxyflavone 7-rutinoside) is a naturally occurring flavonoid glycoside that can be isolated from various plant sources or derived by dehydrogenation of the corresponding flavanone glycoside Hesperidin, that is abundant in the pericarp of various citrus fruits [95]. Diosmin was first isolated in 1925 from *Scrophularia nodosa.* Diosmin is

agent that has the potential to provide a lot of health benefits [88].

Diosmin was found to be capable of normalizing capillary filtration rate and prevent ische‐ mia in diabetics [100-101]. Diosmin has been shown to improve factors associated with diabetic complications. A decrease in hemoglobin A1c as well as an increase in glutathione peroxidase was observed in type 1 diabetic patients after an intervention with a diosmin-containing flavonoid mixture [102]. Diosmin and hesperidin are known to lower hepatotoxicity induced bycarbontetrachloride(CCl4)andlipopolysaccharides (LPS),minimizeoxidationstress caused by nicotine, reduce blood sugar and cholesterol, and inhibit carcinogenesis of the bladder and colon[31, 103-106].Administrationofdiosminfor 45days significantly loweredplasma glucose level, increased the activities of hepatic key enzymes such as hexokinase and glucose-6 phosphate dehydrogenase in addition to decreasing glucose-6-phosphatase and fructose-1,6 bisphosphatase concentrations in streptozotocin-nicotinamide treated rats exhibiting its antihypeglycemic properties [107]. Diosmin lowered plasma glucose and increased plasma insulinlevels indiabetic rats by ameliorating the oxidative stress inducedby streptozotocinand nicotinamide. Activities of antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, and glutathione s-transferase), vitamin C, vitamin E and reduced glutathione were increased while lipid peroxidation was reduced in liver and kidney of diabetic rats upon treatment with diosmin. Diosmin was also recently reported to possess antihypertensive property by increasing the activities of antioxidant enzymes,,reducing reactive oxygen species and normalizing marker enzymes in serum and tissues (liver, kidney, heart, aorta) when rats were made hypertensive by deoxycorticosterone acetate (DOCA) salt [108].

#### **5.4. Luteolin**

Luteolin (3´,4´,5,7-tetrahydroxyflavone) is a flavonoid widely distributed in the plant kingdom including several such as *Reseda luteola L*., *Achillea millefolium L*, *Chamomillae requtita*, *Cynara scolymus*, *Thymus vulgaris*, *Limonium sinuatum* [109]. Luteolin has a variety of pharmacological activities, including anti-mutagenic, anti-tumorigenic [110], anti-inflammatory [111], antihypertensive [112], and anti-oxidative [113] properties. It is thought to play an important role in the human body as an antioxidant, a free radical scavenger, an agent in the prevention of inflammation, a promoter of carbohydrate metabolism, and an immune system modulator [114]. The antioxidant activity of luteolin and its glycosides has been associated with their capacity to scavenge reactive oxygen and nitrogen species [115-116], to chelate transition metals that may induce oxidative damage through the Fenton reaction [117] to inhibit prooxidant enzymes [118] and to induce antioxidant enzymes [119-120]. The antioxidant activity of luteolin has been investigated *in vitro* and *in vivo* [121-122].

**Figure 6.** The chemical structure of lycopene.

[145].

**5.6. Catechins**

H antiport [165].

Lycopene values in serum were found to be significantly lower in patients suffering from type-2 diabetes and impaired glucose metabolism [142-143]. Also, according to data from phase I of the Third National Health and Nutrition Examination Survey (1988-1991), lycopene was found to be inversely related to fasting serum insulin suggesting a possible role for lycopene in the pathogenesis of insulin resistance and diabetes [144]. Lycopene was also found to be useful in the management of neuropathy, a complication of diabetes mellitus, by attenuating cold allodynia and thermal hyperalgesia in streptozotocin induced diabetic rats

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Tea (*Camellia sinensis* L) is the most widely consumed beverage in the world, next to water [146-147]. Tea contains catechins, polyphenolic compounds belonging to the flavonoid family. The most important catechins in green tea are: epigallocatechin gallate (EGCG), epigallocate‐ chin (EGC), epicatechin gallate (ECG) and epicatechin (EC) [148]. The antioxidant properties of catechins have been well documented [149-155]. The mechanisms of action of catechins may include free radical scavenging [149-150, 152-153], chelating metal ions to form inactive complexes [150, 152, 156-157], transferring electrons rapidly to ROS induced radical sites on DNA [158] and forming stable semi-quinone free radicals [150]. Catechins also increase the body's endogenous antioxidants to reduce oxidative damage and decrease lipid peroxidation biomarkers in several tissues in rats [158]. Apart from their antioxidant properties, catechins are also anti-carcinogenic, anti-tumorigenic, anti-mutagenic, anti-proliferative, anti-inflam‐

In diabetes mellitus, the effects of catechins *in vitro* and *in vivo* studies were investigated [160-163]. In rat models of diabetes, catechins have been demonstrated to have ameliorative effects on biomarkers of oxidative stress on diabetic erythrocytes [164] and on erythrocyte Na/

matory, anti-allergic, anti-hypertensive and chemopreventative [159].

**Figure 5.** The chemical structure of luteolin.

The antidiabetic property of luteolin was reported by Zarzuelo *et al* [123] where a significant decrease in glycemia levels (> 50%), a 2.5-fold increase in insulin blood levels, elevated pancreatic insulin and DNA content were observed. Luteolin is reported to inhibit alphaglucosidase and alpha-amylase suggesting that it can suppress postprandial hyperglycemia in patients with non-insulin dependent diabetes mellitus [124]. Recently, luteolin was found to influence insulin action and production of adipokines/cytokines in adipocytes by activating the PPARγ pathway suggesting its role in preventing insulin resistance and type 2 diabetes mellitus [125].

#### **5.5. Lycopene**

Lycopene is a carotenoid present in tomatoes (*Lycoperisicon esculentum*). It can be found in many fruits and vegetables like water melon, pawpaw and pink grape fruit. Lycopene is a potent antioxidant according to *in vitro* and human studies, inactivating hydrogen peroxide and nitrogen dioxide [126] and reducing the susceptibility of lymphocyte DNA to oxidative damage [127]. The presence of many conjugated double bonds in lycopene may account for its antioxidant properties [128]. Lycopene quenches singlet oxygen and traps peroxyl radicals [129]. The singlet quenching ability has been reported to be twice as high as that of beta carotene and 10 times higher than that of alpha tocopherol and butylated hydroxyl toluene (BHT) [130-132]. Lycopene is also a potent neuroprotective [133], anti-proliferative, anti-cancer [134], anti-inflammatory [135] and hypocholesterolemic agent [136]. The mechanisms of action against reactive species for lycopene has been proposed to be by adduct formation, electron transfer to radicals and allylic hydrogen attraction [137-141].

**Figure 6.** The chemical structure of lycopene.

Lycopene values in serum were found to be significantly lower in patients suffering from type-2 diabetes and impaired glucose metabolism [142-143]. Also, according to data from phase I of the Third National Health and Nutrition Examination Survey (1988-1991), lycopene was found to be inversely related to fasting serum insulin suggesting a possible role for lycopene in the pathogenesis of insulin resistance and diabetes [144]. Lycopene was also found to be useful in the management of neuropathy, a complication of diabetes mellitus, by attenuating cold allodynia and thermal hyperalgesia in streptozotocin induced diabetic rats [145].

#### **5.6. Catechins**

inflammation, a promoter of carbohydrate metabolism, and an immune system modulator [114]. The antioxidant activity of luteolin and its glycosides has been associated with their capacity to scavenge reactive oxygen and nitrogen species [115-116], to chelate transition metals that may induce oxidative damage through the Fenton reaction [117] to inhibit prooxidant enzymes [118] and to induce antioxidant enzymes [119-120]. The antioxidant

The antidiabetic property of luteolin was reported by Zarzuelo *et al* [123] where a significant decrease in glycemia levels (> 50%), a 2.5-fold increase in insulin blood levels, elevated pancreatic insulin and DNA content were observed. Luteolin is reported to inhibit alphaglucosidase and alpha-amylase suggesting that it can suppress postprandial hyperglycemia in patients with non-insulin dependent diabetes mellitus [124]. Recently, luteolin was found to influence insulin action and production of adipokines/cytokines in adipocytes by activating the PPARγ pathway suggesting its role in preventing insulin resistance and type 2 diabetes

Lycopene is a carotenoid present in tomatoes (*Lycoperisicon esculentum*). It can be found in many fruits and vegetables like water melon, pawpaw and pink grape fruit. Lycopene is a potent antioxidant according to *in vitro* and human studies, inactivating hydrogen peroxide and nitrogen dioxide [126] and reducing the susceptibility of lymphocyte DNA to oxidative damage [127]. The presence of many conjugated double bonds in lycopene may account for its antioxidant properties [128]. Lycopene quenches singlet oxygen and traps peroxyl radicals [129]. The singlet quenching ability has been reported to be twice as high as that of beta carotene and 10 times higher than that of alpha tocopherol and butylated hydroxyl toluene (BHT) [130-132]. Lycopene is also a potent neuroprotective [133], anti-proliferative, anti-cancer [134], anti-inflammatory [135] and hypocholesterolemic agent [136]. The mechanisms of action against reactive species for lycopene has been proposed to be by adduct formation, electron

transfer to radicals and allylic hydrogen attraction [137-141].

activity of luteolin has been investigated *in vitro* and *in vivo* [121-122].

**Figure 5.** The chemical structure of luteolin.

324 Antioxidant-Antidiabetic Agents and Human Health

mellitus [125].

**5.5. Lycopene**

Tea (*Camellia sinensis* L) is the most widely consumed beverage in the world, next to water [146-147]. Tea contains catechins, polyphenolic compounds belonging to the flavonoid family. The most important catechins in green tea are: epigallocatechin gallate (EGCG), epigallocate‐ chin (EGC), epicatechin gallate (ECG) and epicatechin (EC) [148]. The antioxidant properties of catechins have been well documented [149-155]. The mechanisms of action of catechins may include free radical scavenging [149-150, 152-153], chelating metal ions to form inactive complexes [150, 152, 156-157], transferring electrons rapidly to ROS induced radical sites on DNA [158] and forming stable semi-quinone free radicals [150]. Catechins also increase the body's endogenous antioxidants to reduce oxidative damage and decrease lipid peroxidation biomarkers in several tissues in rats [158]. Apart from their antioxidant properties, catechins are also anti-carcinogenic, anti-tumorigenic, anti-mutagenic, anti-proliferative, anti-inflam‐ matory, anti-allergic, anti-hypertensive and chemopreventative [159].

In diabetes mellitus, the effects of catechins *in vitro* and *in vivo* studies were investigated [160-163]. In rat models of diabetes, catechins have been demonstrated to have ameliorative effects on biomarkers of oxidative stress on diabetic erythrocytes [164] and on erythrocyte Na/ H antiport [165].

glcolytic enzyme, hexokinase and decrease in the activity of gluconegoenic enzymes, glu‐

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**6. Selected antioxidant-rich natural plants with antidiabetic potentials**

*Sclerocarya birrea* (Family : Anacardiaceae) is a medium-size-to-large deciduous tree widely used for the treatment of proctitis, dysentery, and diarrhea in South Africa and Africa at large and its antimicrobial and antiparasitic properties has been documented [174-175]. *Sclerocarya birrea* is widely used as traditional remedy against diabetes in Africa [176] and has a significant hypoglycemic effect [177]. The methanolic extracts of different parts of the tree such as the leaves, fruit juice, roots and stem-bark has antioxidant properties [61] due to high contents of

*Prosopis glandulosa* (Family: Fabaceae) commonly known as Honey mesquite is a small to medium height tree or shrub that is thorny and branching near the ground found mostly in southern parts of India. The bark and leaves are used by the tribes and native medical practitioners to treat various ailments such as leprosy, dysentery, bronchitis, asthma, leuco‐ derma, piles, and tremors of the muscles, tumors, eye diseases and rheumatism [178]. It is commonly found in the dry, arid regions of the northern and north-western Cape of South Africa. Literature studies have indicated that the plant contains flavan-3-ol dimer, mesquitol [179-180] and catechin [181]. Phytochemical screening of leaves from *Prosopis glandulosa* indicates the presence of alkaloids, glycosides, flavonoids, phenolic compounds, steroids and

cose-6-phosphatase and fructose-1, 6-bisphosphatase [173].

**6.1.** *Sclerocarya birrea*

**Figure 9.** *Sclerocarya birrea* plant

**6.2.** *Prosopis glandulosa*

terpenoids [182].

flavonoids and polyphenolic compounds.

**Figure 7.** The chemical structure of catechins

#### **5.7. Cinnamic acids**

Cinnamon, used extensively since ancient times in food as a herb or spice, has been shown to ameliorate the symptomsofmetabolic syndromes, suchas insulinresistance andelevatedlevels of glucose and lipids [166]. Cinnamon bark contains cinnamic acid, cinnamaldehyde and cinnamic alcohol [167]. Cinnamic acid has been reported to exhibit several pharmacological propertiesincludinghepatoprotective[168],antioxidant[169]andanti-diabeticproperties[170].

**Figure 8.** The chemical structure of cinnamic acid.

Cinnamic acid was recently reported to be capable of preventing advanced glucated endproducts (AGEs)-mediated diabetic complications. It inhibited the formation of AGEs in a bovine serum albumin (BSA)/fructose system, as well as reduced the levels of fructosamine, the formation of N-(carboxymethyl) lysine (CML) and the level of amyloid cross beta-structure [167]. Sinapic acid is a 4-hydroxy-3, 5-dimethoxy cinnamic acid derivative. It is widely distributed in edible plants such as cereals, nuts, oil seeds and berries [171]. Sinapic acid is a potent antioxidant [172]. Sinapic acid possesses potential anti-hyperglycemic effects, through an increase in insulin production associated with a subsequent increase in the activity of glcolytic enzyme, hexokinase and decrease in the activity of gluconegoenic enzymes, glu‐ cose-6-phosphatase and fructose-1, 6-bisphosphatase [173].
