Active biomolecules of different
1. Introduction
Diabetes mellitus (DM) is a metabolic disorder resulting from defects in insulin secretion or reduced sensitivity of the tissues to insulin action or both [1]. It is characterized by chronic high blood glucose that causes glycation of body proteins which could lead to severe complications. These complications are classified into acute, sub-acute and chronic.
Acute complications include hypoglycemia, diabetic ketoacidosis, hyperosmolar and hyperglycaemic non-ketotic syndrome while sub acute complications are thirst, polyuria, lack of energy, visual blurriness and weight loss. The chronic complications of diabetes mellitus include hypertension, neuropathy, nephropathy, retinopathy and diabetic foot ulcers which could result in amputation [2].
On the basis of aetiology and clinical presentation, diabetes mellitus can be grouped into type 1 known as insulin- dependent diabetes mellitus (IDDM) and type 2 also known as non insulin-dependent diabetes mellitus (NIDDM). The World Health Organization (WHO) recommends that the terms type 1 and type 2 should be reintroduced, because they classify the patients on the basis of the pathogenesis and not on the basis of treatment. Type 1 diabetes mellitus is caused by immunological destruction of pancreatic β cells leading to insulin deficiency [3], whereas type 2 diabetes results from defects in insulin secretion or rather insulin resistance. It is the most common type of diabetes, afflicting 85-95% of all diabetic individuals. It is a prevalent form of the disease and common in individuals over 40 years of age. The increasing number of ageing population, consumption of calorie-rich diet, obesity and sedentary life style have led to a tremendous increase in the number of diabetes mellitus world wide [2]. About 173 million people suffer with this disease. The number of people with diabetes mellitus will be more than double over the next 25 years to reach a total of 366 million by 2030 [4].
The only therapy of type 1 diabetes is the substitution of insulin. Many and diverse therapeutic strategies for the treatment of type 2 diabetes are known. Conventional treatments include the reduction of the demand for insulin, stimulation of endogenous insulin secretion, enhancement of the action of insulin at the target tissues and the inhibition of degradation of oligo- and disaccharides. One group of drugs introduced in the management of type 2 diabetes is represented by the inhibitors of α-glycosidase [4].
In a general manner DM is a group of metabolic disorders characterized by hyperglycemia. These metabolic disorders include alterations in carbohydrate, fat and protein metabolisms associated with absolute and relative deficiencies in insulin secretion and/or insulin action [5]. Insulin is a hormone needed to convert sugar, starch and other food into energy needed for daily life. The cause of diabetes continues to be a mystery, although both genetic and environmental factors such as obesity and lack of exercise appear to play a part [6]. The control of DM normally involves exercise, diet and drug therapy. In the last years there has been an increasing demand for natural products with antidiabetic activity, mainly due to the side effects associated with the use of insulin and oral hypoglycemic agents [7]. The available therapies for diabetes include insulin and oral antidiabetic agents such as sulfonylureas, biguanides and α-glycosidase inhibitors. Many of these oral antiabetic agents have a number of serious adverse effects [8]. Thus, the management of diabetes without any side effects is still a challenge.
Plants have always been an important source of drugs and many of the currently available drugs have been derived directly or indirectly from them. Ethnobotanical reports indicate about 1200 plants in the world with anti-diabetic potential [9], of which more than three hundred have been reported in the literature referring to a large variety of identified chemical substances. The discovery of the widely used hypoglycemic drug, metformin (
In this regard, several medicinal plants among which are those belonging to the genus
Considering the importance of species of the genus
2. Methods
With the objective of contributing to these studies, a literature search on the ethnomedical information and use of natural products (crude plant extracts, semi-purified fractions and chemically defined molecules) from the genus
3. Results and discussion
In this section we present some considerations about the Moraceae family, the main species from the genus
Consultation of various literature sources resulted in the elaboration of a list of some active biomolecules of different
3.1. The family Moraceae and the genus Morus
Moraceae is a family of flowering plants that comprises about 40 genera and over 1000 species [11]. The genus
Species of this genus has also been used in folk medicine (especially in Chinese traditional medicine) as antiphlogistic, hepatoprotective, hypotensive, antipyretic, analgesic, diuretic, expectorant, antidiabetic [14, 15] as well as to treat anemia and arthritis [12]. The leaves of mulberry species are consumed in Korea and Japan as anti-hyperglycemic nutraceutical food for patients with diabetes mellitus because the leaves are rich in alkaloid components, including 1-deoxynojirymicin (1), which is known to be one of the most potent α-glycosidase inhibitors [16] that decreases blood sugar levels.
This genus contains a variety of phenolic compounds including isoprenylated flavonoids, stilbenes, 2-arylbenzopyrans, coumarins, chromones, xanthones and a variety of Diels-Alder adduct compounds [14, 17]. Some of these compounds exhibit interesting biological properties such as antiphlogistic, antiinflammatory, diuretic, hypotensive effects and some are known as phytoalexins [18]. The antioxidant potential of some phenolic compounds of
The production of mulberry fruits in 2005 was 78,000 tonnes in Turkey and its cultivation in Turkey have been known for more than 400 years [20].
3.2. Morus alba L.
The different parts of this plant have been used in the traditional Chinese medicine for many purposes. The white mulberry leaves, an important food for silkworm, are used to treat hypertension, arthritis, and the fruit is a diuretic and a tonic agent. The root bark of the plant is considered as an important medicine to treat cough, inflammation, diabetes, cancer, hepatitis and heart diseases. Previous studies showed that
The root bark also contain an alkaloid, 1-deoxynojirimycin (1) that inhibited glycogenolyses, glycoprotein, processing and saccharide hydrolysis enzymes whereas its derivatives have great therapeutic potential for the treatment of viral infections, diabetes, obesity and cancer [21].
3.3. Morus bombycis
This plant is found in China, Japan, Korea and Southern Sakhaline. Root bark contains quinones named as Kwanons G and H with hypotensive activity, phytoalexins like Moracin A-Z and Albanins A-H with antimicrobial activity. The leaves also contain
3.4. Morus indica L.
Over the years, medicinal plants and their extracts are gaining importance in the treatment of hyperglycemia and diabetes. The extracts of
3.5. Morus insignis
Ethyl acetate and n-butanol-soluble fractions of the leaves of
Kwanon I; Kwanon I hexamethyl ether; Kwanon I octamethyl ether; 2’-Hydroxy-2,4,4’-trimethoxychalcone; 2’-Hydroxy-3’-prenyl-2,4,4’-trimethoxychalcone III; Mulberrofuran T; Kwanon E; Morusin, Mulberrofuran D, G, K; Kwanon G, H; Mulberroside A; | Root, stem, leaves, fruit | Astringent, anti-helmintic, HIV, cough, antiinflammatory, exudative, high blood pressure, diaphoretic, purgative, emollient, diarhoea, | |
Australone A; triterpenoid 3β-[( | Root, leaves, fruits | Astringent, anti-helmintic, purgative, antiplatelet | |
Root, leaves | Hypotensive, antimicrobial, | ||
Citrulline; hydroxyproline; free amino acids | Fruit | Plaster for sores, cools the blood | |
Deoxynojirimycin | Root, leaves, fruits | ||
β-Amyrin acetate; betulinic acid; cerylalcohol; quercetin; morin | Root | ----- | |
Rubraflavones A, B, C, D | Root | Anti-dysenteric, laxative, purgative, vermifuge, urinary problems, weakness | |
Guangsangons A-N; albafuran C; Kwanon J, X, Y; Mulberrofuran G, K, J | Stem | Antiinflammatory, antioxidative | |
Sanggenols F, G, H, I, J, K; cathayanon A, B | Root | Antiinflammatory, hypertension |
3.6. Morus nigra L.
A medium or small sized tree 6-9 m high, native to West Asia. It is also cultivated in Kashmir, Darjeeling, leaves are ovate-cordate, flower dioecious or monoecious, fruits are syncarp, ovoid, purple to black, juicy, edible. The root bark is purgative and vermifuge. Root has and effect on pancreas and glycogenolysis while its juice reduces the blood sugar level in diabetic patient. The root bark extract contains deoxynojirimycin (DNJ), an alkaloid which said to be active against AIDS virus. An infusion of leaves causes a drop in blood sugar, sometimes diuresis and a reduction of arterial pressure [21].
DNJ is a potent source α-glycosidase inhibitor and helpful to establish greater glycemic control in type 2 diabetes. Young mulberry leaves taken from top part of branches in summer contains the highest amount of DNJ. In a human study, DNJ enriched powder of mulberry leaves significantly suppressed elevation of post-prandial glucose. Newly developed DNJ enriched powder can be used as a dietary supplement for preventing diabetes mellitus [21].
Japan (B) | Used for diabetes | Decoction | Oral | Human adult | [42] | |
Japan (C) | Used as an antidiabetic | Bark | Oral | Human adult | [43] | |
Chile (L) | Used to treat diabetes | Infusion | Oral | Human adult | [44] | |
Spain (L) | Used as a hypoglycemic | Hot H2O extract | Oral | Human adult | [45] | |
Turkey (L) | Used for diabetes | Decoction | Oral | Human adult | [46] | |
Yugoslavia (L) | Used for diabetes | Hot H2O extract | Oral | Human adult | [47] | |
Peru (L + S) | Used as an antidiabetic | Hot H2O extract | Oral | Human adult | [48] | |
France (L) | Used for diabetes | Hot H2O extract | Oral | Human adult | [49] | |
Italy (L) | Used as an antidiabetic | Infusion | Oral | Human adult | [50] | |
Canary Islands (FL) | Used as a hypoglycemic | Infusion | Oral | Human adult | [51] | |
Iran (L) | Used in diabetes | Decoction | Oral | Human adult | [52] | |
Yugoslavia (L) | Used for diabetes | Hot H2O extract | Oral | Human adult | [53] | |
Puerto Rico (NS) | Used for diabetes | Hot H2O extract | Oral | Human adult | [54] | |
Iran (RB) | Used in diabetes | Decoction | Oral | Human adult | [52] | |
USSR (L) | Used for diabetes mellitus | Hot H2O extract | Oral | Human adult | [55] |
The leaves of
In Brazil, the cultivation of
Origin (Part used) | ||||||
Iran (B) | Antihyperglycemic | Decoction | 500.0 mg/kg | Inactive | [56] | |
Japan (B) | α-Glycosidase inhibition | Hot H2O extract | 80.0 mg/kg | Active | [57] | |
South Korea (B) | Hypoglycemic activity | MeOH extract | 2.0 mg/kg | Inactive | [58] | |
China (BR) | Antihyperglycemic | Hot H2O extract | 1.25 mg/kg | Active | [59] | |
China (BR) | Hypoglycemic activity | Hot H2O extract | 1.25 mg/kg | Active | [59] | |
China (BR) | Antihyperglycemic | H2O extract | 2.1 mg/kg | Active | [59] | |
Japan (C) | Glucose transport stimulation | MeOH extract | 5.0 mcg/ml | Weak activity | [43] | |
Iran (F) | Antihyperglycemic | Decoction | 500.0 mg/kg | Inactive | [56] | |
Chile (L) | Antihyperglycemic | Infusion | 0.40 g/animal | Active | [44] | |
Chile (L) | Antihyperglycemic | Infusion | 0.40 g/animal | Inactive | [44] | |
China (L) | Antihyperglycemic | Hot H2O extract | 200.0 mg/kg | Active | [60] | |
Egypt (L) | Hypoglycemic activity | EtOH (100%) extract | Dose not stated | Active | [61] | |
Egypt (L) | Antihyperglycemic | EtOH (100%) extract | Dose not stated | Active | [61] | |
Egypt (L) | Antihyperglycemic | Leaf | Dose not stated | Active | [61] | |
Egypt (L) | Antihyperglycemic | EtOH (100%) extract | Dose not stated | Inactive | [61] | |
Iran (L) | Antihyperglycemic | Decoction | 500.0 mg/kg | Inactive | [56] | |
Iran (L) | Hypoglycemic activity | Decoction | 500.0 mg/kg | Inactive | [56] | |
Japan (L) | Antihyperglycemic | Hot H2O extract | 80.0 mg/kg | Active | [57] | |
Japan (L) | Antihyperglycemic | Hot H2O extract | 200.0 mg/kg | Active | [60] | |
Roumania (L) | Antihyperglycemic | Infusion | 150.0 ml/person | Active | [62] | |
South Korea (L) | Antihyperglycemic | Not specified | Dose not stated | Active | [63] | |
Zimbabwe (L) | Hypoglycemic activity | EtOH (80%) extract | 200.0 mg/kg | Active | [64] | |
Zimbabwe (L) | Antihyperglycemic | EtOH (80%) extract | 200.0 mg/kg | Active | [64] | |
Zimbabwe (L) | Insulin level increase | EtOH (80%) extract | 200.0 mg/kg | Inactive | [64] | |
Japan (L) | Antihyperglycemic | EtOH (5%) extract | 200.0 mg/kg | Active | [65] | |
Japan (P) | Antihyperglycemic | Lyophilized extract | 200.0 mg/kg | Active | [65] | |
Iran (R) | Antihyperglycemic | Decoction | 500.0 mg/kg | Inactive | [56] | |
China (RB) | Hypoglycemic activity | EtOH:H2O (1:1) extract | 20.0 mg/kg | Active | [66] | |
Egypt (RB) | Antihyperglycemic | EtOH (70%) extract | 600.0 mg/kg | Active | [67] | |
South Korea (RB) | Antihyperglycemic | H2O extract | 1.0 mg/kg | Strong activity | [68] | |
China (R) | Antihyperglycemic | Hot H2O extract | 200.0 mg/kg | Active | [60] | |
China (NS) | Hypoglycemic activity | EtOH (95%) extract | Dose not stated | Active | [69] | |
India (L) | Antihyperglycemic | H2O extract | 250.0 mg/animal | Active | [70] | |
India (SC) | Antihyperglycemic | H2O extract | 130.0 mg/animal | Active | [70] | |
Argentina (L) | Antihyperglycemic | EtOH (70%) extract | 100.0 mg/kg | Active | [27] | |
Argentina (L) | Hypoglycemic activity | EtOAc extract | 50.0 mg/kg | Active | [27] | |
Argentina (L) | Hypoglycemic activity | BuOH extract | 50.0 mg/kg | Active | [27] | |
Argentina (L) | Hypoglycemic activity | H2O extract | 50.0 mg/kg | Active | [27] | |
Argentina (L) | Antihyperglycemic | EtOAc extract | 100.0 mg/kg | Active | [27] | |
Argentina (L) | Antihyperglycemic | BuOH extract | 100.0 mg/kg | Active | [27] | |
Iran (B) | Antihyperglycemic | Decoction | 500.0 mg/kg | Active | [56] | |
Iran (B) | Antihyperglycemic | Decoction | 500.0 mg/kg | Inactive | [56] | |
France (L) | Hypoglycemic activity | Hot H2O extract | Dose not stated | Active | [49] | |
France (L) | Hypoglycemic activity | Hot H2O extract | Dose not stated | Active | [71] | |
Iran (L) | Hypoglycemic activity | EtOH (95%) extract | 0.25 mg/kg | Inactive | [72] | |
Iran (L) | Hypoglycemic activity | EtOH (95%) extract | 1.0 mg/kg | Inactive | [72] | |
Iran (L) | Antihyperglycemic | EtOH (95%) extract | 0.25 mg/kg | Active | [72] | |
Iran (L) | Antihyperglycemic | EtOH (95%) extract | 0.5 mg/kg | Active | [72] | |
Iran (L) | Antihyperglycemic | Decoction | 500.0 mg/kg | Active | [56] | |
Iran (L) | Hypoglycemic activity | Decoction | 500.0 mg/kg | Inactive | [56] | |
Iran (L) | Antihyperglycemic | Decoction | 500.0 mg/kg | Inactive | [56] | |
Iran (RB) | Antihyperglycemic | Decoction | 500.0 mg/kg | Inactive | [56] | |
India (L) | Antihyperglycemic | EtOH (95%) extract | 0.5 ml/animal | Inactive | [73] | |
India (L) | Hypoglycemic activity | EtOH (95%) extract | 0.5 ml/animal | Equivocal | [73] | |
India (L) | Antihyperglycemic | EtOH (95%) extract | 0.5 ml/animal | Equivocal | [73] | |
USSR (L) | Antihyperglycemic | Tincture | Dose not stated | Active | [55] | |
Japan (L) | Antihyperglycemic | Infusion | 150.0 mg/kg | Active | [74] |
3.7. Methods for evaluation of hypoglycemic activity of medicinal plants
3.7.1. Oral glucose tolerance test
The oral glucose tolerance test is a fast and inexpensive technique and allows you to check the effects of drugs on glucose metabolism. In normoglycemic rats, the increase of post-prandial glucose level, after glucose load, and the consequent standardization to baseline levels after about 2 h, characterizes a normal metabolism of glucose. The oral glucose tolerance test is an acute methodology for evaluating the resistance of the body to absorb glucose and reduce blood glucose levels. Therefore, it’s a method to perform a screening of drugs with potential hypoglycemic action, but with a profile in the absorption of glucose (type 2 DM) and not in the production of insulin (type 1 DM) [37].
In this experiment, normal Wistar rats are fasted overnight. They are divided into three groups containing six animals each.
Control rats (Group I) are given 1 ml distilled water orally. Extracts of plants in different concentrations (mg/kg body weight) are administered orally using a syringe to second and third groups. Glucose (2 g/kg b.wt.) is given orally using a syringe to all groups immediately after the extracts administration. Blood samples are collected from the tail vein just prior to and 30, 60, 120 and 240 min after the glucose loading and serum glucose levels are measured [38].
3.7.2. Alloxan-induced diabetic rats
Alloxan induces “chemical diabetes” in a wide variety of animal species by damaging the insulin secreting pancreatic β-cell, resulting in a decrease in endogenous insulin release [39]. Numerous studies demonstrated that a variety of plant extracts effectively lowered the glucose level in alloxan-induced diabetic animals. Alloxan produces oxygen radicals in the body, which cause pancreatic injury which is responsible for increased blood sugar seen in the animals. However, it is found that action is not specific to pancreas as other organs such as liver, kidney and haemopoietic system are also affected by alloxan administration as seen from the elevation of marker enzymes and reduction of hematological parameters [40].
In this experiment, diabetes is induced in male rats by single intraperitonial injection of 120 mg/kg b.wt. of alloxan monohydrate. Serum glucose level is checked after 72 h. Animals with serum glucose levels >250 mg/dl are considered diabetic and are used for the study. The rats are divided into four groups of six rats each. Both group I control normal rats (no alloxan treatment) and group II diabetic animals are given 1 ml of distilled water. Group III and IV are given the extracts orally in different doses on 3rd day after alloxan treatment. Overnight fasted blood samples are collected from the tail vein on 3rd day of alloxan treatment prior to and at 2, 4, 6 and 8 h intervals after the administration of the extract orally. Serum is separated and glucose levels are estimated as before [38].
3.7.3. Streptozotocin-induced diabetic rats
Streptozotocin (STZ) at low dose for Wistar rats induces light damage to islet cells, leading to glucose intolerance. Previous studies have showed that STZ-induced diabetic rats had low production of insulin and high levels of blood circulating glucose, which were similar to those found in diabetic humans. The precise mechanisms responsible for this defect remain unknown.
Male rats weighing 150-200 g are used in the study and type 2 diabetes is induced. The rats are fed with high fat diet (diet containing 74% carbohydrate, 22% protein and 4% fat, formulated as 60% total energy is derived from fat) for 15 days except normal control rats and then injected with streptozotocin (40 mg/kg). Five days after injection, the rats are fasted and the plasma glucose levels are estimated; rats having plasma glucose levels ≥300 mg/dl are taken for further studies with administration of plant extracts. The rats are fed with high fat diet throughout the experimental period [41].
4. Conclusion
Diabetes mellitus is a public health problem worldwide. Ethnomedical informations and the scientific knowledge of the hypoglycemic activity of species of
Acknowledgement
The authors wish to express their sincere thanks to the College of Pharmacy, The University of Illinois at Chicago, Chicago, Illinois 60612-7231, U.S.A., for helping with the computer-aided NAPRALERT search and Brazilian agencies CNPq and FACEPE for financial support.
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