biology

Review Bioactive Compounds in Anti-Diabetic : From to Modern Drug Discovery

Ngan Tran 1, Bao Pham 2 and Ly Le 1,* 1 School of Biotechnology, International University—Vietnam National University, Ho Chi Minh City 721400, Vietnam; [email protected] 2 Information Science Faculty, Saigon University, Ho Chi Minh City 711000, Vietnam; [email protected] * Correspondence: [email protected]

 Received: 21 July 2020; Accepted: 26 August 2020; Published: 28 August 2020 

Abstract: Natural products, including organisms (plants, animals, or microorganisms) have been shown to possess health benefits for animals and humans. According to the estimation of the World Health Organization, in developing countries, 80% of the population has still depended on traditional medicines or folk medicines which are mostly prepared from the for prevention or treatment diseases. Traditional medicine from plant extracts has proved to be more affordable, clinically effective and relatively less adverse effects than modern drugs. Literature shows that the attention on the application of phytochemical constituents of in the pharmaceutical industry has increased significantly. Plant-derived secondary metabolites are small molecules or macromolecules biosynthesized in plants including steroids, alkaloids, phenolic, lignans, carbohydrates and glycosides, etc. that possess a diversity of biological properties beneficial to humans, such as their antiallergic, anticancer, antimicrobial, anti-inflammatory, antidiabetic and antioxidant activities Diabetes mellitus is a chronic disease result of metabolic disorders in pancreas β-cells that have hyperglycemia. Hyperglycemia can be caused by a deficiency of insulin production by pancreatic (Type 1 diabetes mellitus) or insufficiency of insulin production in the face of insulin resistance (Type 2 diabetes mellitus). The current medications of diabetes mellitus focus on controlling and lowering blood glucose levels in the vessel to a normal level. However, most modern drugs have many side effects causing some serious medical problems during a period of treating. Therefore, traditional medicines have been used for a long time and play an important role as alternative medicines. Moreover, during the past few years, some of the new bioactive drugs isolated from plants showed antidiabetic activity with more efficacy than oral hypoglycemic agents used in clinical therapy. Traditional medicine performed a good clinical practice and is showing a bright future in the therapy of diabetes mellitus. World Health Organization has pointed out this prevention of diabetes and its complications is not only a major challenge for the future, but essential if health for all is to be attained. Therefore, this paper briefly reviews active compounds, and pharmacological effects of some popular plants which have been widely used in diabetic treatment. Morphological data from V-herb database of each species was also included for plant identification.

Keywords: diabetes mellitus; medicinal plants; herb; bioactive compound

1. Introduction Diabetes mellitus (DM) is a metabolic disorder of multiple causes characterized by chronic hyperglycemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. The effects of diabetes mellitus include long–term damage, dysfunction, and failure of various organs [1]. Diabetes mellitus is divided into three main types [1–5]. Type 1 diabetes (insulin-dependent diabetes mellitus) is an autoimmune disorder developing when

Biology 2020, 9, 252; doi:10.3390/biology9090252 www.mdpi.com/journal/biology Biology 2020, 9, 252 2 of 31 Biology 2020, 9, x FOR PEER REVIEW 2 of 31 insulin-producingdeveloping when cellsinsulin-producing of the pancreas cells in the of body the pancreas have been in destroyed the body and have the been pancreas destroyed produces and little the orpancreas no insulin. produces A person little whoor no has insulin. type 1A DM person must who take has insulin type 1 daily DM tomust live. take It develops insulin daily most to often live. inIt childrendevelops and most young often adults. in children Type 2and diabetes young has adults. also beenType known 2 diabetes as another has also term been “insulin-independent known as another diabetesterm “insulin-independent mellitus” which accounted diabetes mellitus” for more whic thanh 90%accounted of diagnosed for more cases than of90% DM of indiagnosed adults. Itcases is a diagnosisof DM in adults. in which It theis a pancreasdiagnosis produces in which enough the pancreas insulin produces but the body enough cannot insulin use the but insulin the body effectively, cannot ause condition the insulin called effectively, insulin a resistance. condition called Gestational insulin diabetes resistance. mellitus Gestational (GDM) diabetes is a degree mellitus of glucose(GDM) intoleranceis a degree of with glucose onset intolerance or first recognition with onset in or the first second recognition or third in trimester the second of the or third period trimester of pregnancy. of the GDMperiod is of caused pregnancy. by the GDM hormone is caused of pregnancy by the hormon or a shortagee of pregnancy of insulin. or GDM a shortage is one ofof the insulin. most GDM popular is disordersone of the ofmost metabolism popular disorders during pregnancy. of metabolism during pregnancy. Hyperglycemia causes damage to eyes, kidneys, nerves,nerves, heart and bloodblood vesselsvessels [[6].6]. According to the ninth edition 2019 of the International Diabetes Fede Federationration (IDF) (IDF) Diabetes Diabetes Atla Atlass released released by by the the IDF, IDF, as of 2019, the the total total adult adult population population in inthe the age age grou groupp of 20–79 of 20–79 years years stands stands at 463 at million 463 million who wholive with live withdiabetes, diabetes, which which is set to is setincrease to increase to 578 tomillion 578 million by 2030 by (Figure 2030 (Figure 1) [7]. 1There)[ 7]. is There one patient is one patientwho dies who of diesdiabetes of diabetes mellitus mellitus every 6 s, every this rate 6 s, is this higher rate th isan higher death than rates death from rateshuman from immunodeficiency human immunodeficiency virus (HIV) virus(1.5 million), (HIV) (1.5tuberculosis million), (1.5 tuberculosis million) and (1.5 malaria million) (0.6 and million), malaria combined (0.6 million), [8–10]. combined [8–10].

Figure 1. NumberNumber of of people people with with diabetes diabetes worldwide worldwide and and per per International International Diabetes Diabetes Federation Federation (IDF) (IDF)region. region.

Following thethe Statistics Statistics of Internationalof International Diabetes Diabet Federationes Federation in 2019 in [7 ],2019 the total[7], adultthe total population adult inpopulation the age groupin the ofage 20–79 group years of 20–79 stands years at 463 stands million at 463 live million with diabetes, live with which diabetes, may which increase may to 578increase million to by578 2030. million Among by them,2030. inAmong 2019, 373.9them, million in 2019, adults 373.9 aged million 20–79 adults yearsworldwide, aged 20–79 7.5% years of theworldwide, adult population, 7.5% of the are adult estimated population, to have are impaired estimated glucose to have tolerance. impaired Most glucose adults tolerance. with impaired Most glucoseadults with tolerance impaired are underglucose the tolerance age of 50 are years under (180.0 the million–48.1%). age of 50 years The (180.0 estimated million–48.1%). prevalence The of diabetesestimated in prevalence men aged of 20–79 diabetes years in is men slightly aged higher 20–79 thanyears in is womenslightly (9.6%higher vs than 9.0%). in women The prevalence (9.6% vs of9.0%). diabetes The prevalence is expected of to diabetes increase is in expected both men to increase and women in both from men 2019 and to women 2030 and from 2045 2019 (Figure to 20302). Alland around 2045 (Figure the world, 2). All there around are top the 10 world, countries there that ar havee top numbers10 countries of people that have with numbers diabetes, includingof people China,with diabetes, the USA, including , China, , the Brazil, USA, Indonesia, Mexico, Japan, India, Pakistan, Brazil, Mexico, Thailand, Japan, and Pakistan, Nigeria. AlthoughThailand, theand risksNigeria. of GDM Although with pregnantthe risks of women GDM havewith pregnant been recognized women clearly,have been there recognized is uncertainty clearly, that there the treatmentis uncertainty reduces that and the controls treatment blood reduces glucose and level controls of women blood during glucose pregnancy level could of women decrease during those riskspregnancy or not. could Moreover, decrease GDM those extends risks to or increase not. Moreover, the risk for GDM the development extends to ofincrease type 2 DMthe risk after for giving the birth.development Nowadays, of type diabetes 2 DM after mellitus giving has birth. risen Nowadays, along with diabetes rapid cultural mellitus and has social risen changes,along with such rapid as aging,cultural population, and social lesschanges, physical such activities, as aging, dietary, population, and so less on. physical The cost activities, associate dietary, with diabetes and so includes on. The increasingcost associate health with services, diabetes an includes economic increa burden.sing health services, an economic burden. Biology 2020, 9, 252 3 of 31 Biology 2020, 9, x FOR PEER REVIEW 3 of 31

Figure 2. PrevalencePrevalence of men and women (20–79 years) with diabetes in 2019, 2030 and 2045.

2. Management of Diabetes Mellitus 2. Management of Diabetes Mellitus Understanding the pathogenesis of diabetes mellitus is extremely important in treatment. Understanding the pathogenesis of diabetes mellitus is extremely important in treatment. The The American Diabetes Association has recommended that the purpose of glycemic control includes a American Diabetes Association has recommended that the purpose of glycemic control includes a pre-prandial blood glucose level of 80 to 120 mg/dL (4.4 to 6.7 mmol/L), a bedtime blood glucose level pre-prandial blood glucose level of 80 to 120mg/dL (4.4 to 6.7 mmol/L), a bedtime blood glucose level of 100 to 140 mg/dL (5.6 to 7.8 mmol/L), and an HbA1c level of less than 7% [2,11]. Healthy eating, of 100 to 140 mg/dL (5.6 to 7.8 mmol/L), and an HbA1c level of less than 7% [2,11]. Healthy eating, physical activity, and weight control are the center of any therapeutic program for patients in DM [12]. physical activity, and weight control are the center of any therapeutic program for patients in DM These lifestyle modifications not only lower blood glucose levels in the body, but also, they ameliorate [12]. These lifestyle modifications not only lower blood glucose levels in the body, but also, they many risk factors for cardiovascular disease, and help weightloss. However, most patients cannot ameliorate many risk factors for cardiovascular disease, and help weightloss. However, most patients havecannot a goodhave a lifestyle good lifestyle [13], so [13], patients so patients must depend must depend on medications on medications for treatment. for treatment. The present treatment of DM is focused on controlling and lowering blood glucose levels in the vessel toto aa normalnormal levellevel [11[11].]. TheThe mechanisms mechanisms of of both both modern modern medicines medicines and and traditional traditional medicines medicines to lowerto lower blood blood glucose glucose concentration concentration are: are: (1) to(1) stimulate to stimulate beta-cell beta-cell of the of pancreatic the pancreatic islet toislet release to release more insulin;more insulin; (2) inhibit (2) theinhibit action the of action hormones of hormones which increases which bloodincreases glucose blood concentration; glucose concentration; (3) increase the(3) sensitivityincrease the of sensitivity insulin receptor of insulin site; receptor (4) inhibit site; hydrolysis (4) inhibit ofhydrolysis glycogen of in glycogen liver; (5) in enhance liver; (5) the enhance use of glucosethe use of in glucose tissues andin ti organssues and [14– organ16]. [14–16]. Currently, therethere areare sixsix mainmain classes of modern medicinesmedicines used all over the world for controlling blood glucose levels and two classes of injections [12]. The tablets are known as biguanides (metformin), blood glucose levels and two classes of injections [12]. The tablets are known as biguanides sulfonylureas,(metformin), thiazolidinedionessulfonylureas, thiazolidinediones (glitazones), meglitinides (glitazones), (glinides), meglitinides alpha-glucosidase (glinides), inhibitors alpha- and DPP-4glucosidase inhibitors. inhibitors The classes and DPP-4 of medications inhibitors. given The cla bysses injection of medications are incretin given mimetics by injection and insulin are incretin [17–26]. Mechanismsmimetics and of insulin these medications[17–26]. Mech haveanisms been of reported. these medications However, have most been modern reported. drugs haveHowever, many most side emodernffects and drugs adverse have emanyffects, side causing effects some and serious adverse medical effects, problemscausing some during serious medication medical processing. problems Metforminduring medication is one medicine processing. of biguanides Metformin which is one can inhibitmedicine the productionof biguanides of glucose which moleculescan inhibit in the liverproduction of human of glucose and increase molecules insulin in sensitivity. the liver However,of human metforminand increase also insulin causes somesensitivity. main sideHowever, effects suchmetformin as gastrointestinal also causes some on the main initial side state, effects including such as dyspepsia,gastrointestinal nausea on andthe initial diarrhea. state, Metformin including shoulddyspepsia, be avoided nausea and in those diarrhea. with severelyMetformin compromised should be avoided renal function, in those de-compensated with severely compromised heart failure, severerenal function, liver disease de-compensated other serious heart medical failure, problems. severe liver The beneficialdisease other effects serious of thiazolidinediones medical problems. in diabetesThe beneficial treatment effects are toof improvethiazolidinediones the sensitivity in ofdiabetes insulin, treatment decrease insulinare to resistanceimprove the and sensitivity also decrease of cardiovascularinsulin, decrease risks. insulin However, resistance the most and common also decr adverseease ecardiovascularffects of thiazolidinediones risks. However, are weight the most gain andcommon fluid retention,adverse effects leading of to thiazolidinediones peripheral edema andare heartweight failure. gain The and drugs fluid were retention, avoided leading to use forto patientsperipheral in edema similar and situations, heart failure. including The heartdrugs failurewere avoided and severe to use liver for problems. patients in Rosiglitazone similar situations, may haveincluding cardiovascular heart failure risks, and and severe increase liver the problems. risk of a Rosiglitazone heart attack. Pioglitazone may have cardiovascular has not been available risks, and in someincrease countries the risk due of toa concernsheart attack. about Pioglitazone an increased has risk not for been bladder available cancer. in some countries due to concernsAccording about an to increased IDF’s statistics, risk for healthbladder expenditure cancer. has been increased, increasing from USD 232 billionAccording spent to IDF’s worldwide statistics, in heal 2007,th expenditure to USD 760 has billion been inincreased, 2019 for increasing adults aged from 20–79 USD 232 years billion [7]. Thespent economic worldwide impact in 2007, of to diabetes USD 760 has billion been in predicted 2019 for adults to continue aged 20–79 to increase years [7]. regularly. The economic The impact health expenditureof diabetes has can been be predicted predicted to continue to reach to USD increase 825 regularly. billion by The 2030 health and expenditure USD 845 billioncan be predicted by 2045. to reach USD 825 billion by 2030 and USD 845 billion by 2045. Therefore, medication expenditure has become a serious problem for patients with diabetes from developing countries. Biology 2020, 9, 252 4 of 31

BiologyTherefore, 2020, 9 medication, x FOR PEER REVIEW expenditure has become a serious problem for patients with diabetes4 from of 31 developing countries. Besides modern modern medication, medication, tradit traditionalional medicines medicines have have been been used used for for a long a long time time and and play play an importantan important rolerole as alternative as alternative medicines medicines [27–30]. [27 –According30]. According to WHO, to WHO,a plant-based a plant-based traditional traditional system ofsystem medicine of medicine is still the is chief still support the chief of supportabout 75–80% of about of the 75–80% world ofpopulation the world mainly population in developing mainly countriesin developing having countries a diversity having of plants a diversity [31]. Traditional of plants [31 medicines]. Traditional are usually medicines the arefirst usually choice thefor primaryfirst choice healthcare for primary of patients healthcare in developing of patients countries in developing because of countries better cultural because acceptability, of better cultural better compatibilityacceptability, betterwith the compatibility human body with and the lesser human side body effects and lesserthan modern side effects therapies. than modern Recently, therapies. some medicinalRecently, someplants medicinal have been plants reported have beento be reported useful in to diabetes be useful worldwide in diabetes and worldwide have been and used have empiricallybeen used empirically as antidiabetic as antidiabetic and antihyperlipidemic and antihyperlipidemic remedies. remedies. More than More 400 thanplant 400 species plant specieshaving hypoglycemichaving hypoglycemic activity activity have been have beenavailable available in the in theliterature literature [32], [32 ],however, however, investigating investigating new antidiabetic drugs from natural plants has still been been attractive attractive because because they they contain contain phytoconstituents phytoconstituents that demonstratedemonstrate alternative alternative and and safe safe eff ectseffects on theon treatmentthe treatment of diabetes of diabetes mellitus. mellitus. Most plants Most containplants containbioactive bioactive components, components, such as phenolics, such as phenolics, glycosides, glycosides, alkaloids, terpenoids,alkaloids, flavonoids,terpenoids, carotenoids,flavonoids, carotenoids,etc., that have etc., been that improved have been as improved having antidiabetic as having activitiesantidiabetic [33 –activities36]. [33–36].

3. Bioactive Bioactive Compounds Compounds from from Plants Having Type 2 Antidiabetic Activity The hypoglycemic and antidiabetic effects effects of several plants used as traditional antidiabetic remedies have been proved, and th thee mechanisms of hypoglycemic activity of these plants have been studied effectively effectively [35–37]. [35–37]. This This review focuses on the mechanism of traditional herbal and natural medicines from traditional medicinal plants for diabetes treatment.

3.1. Bioactive Bioactive Compou Compoundsnds Act Act as as Insulin

3.1.1. MomordicaMomordica charantia charantia (Bitter(Bitter Melon) Melon)

Momordica charantiacharantia(MC) (MC) is oneis one of the of most the commonmost common vegetables vegetables in the tropical in the region, tropical particularly region, particularlyin Vietnam, in India, Vietnam, China, India, East China, Africa, East South–North Africa, South–North Asia, and Asia, Central and andCentral South and America South America [38,39]. [38,39].It is a member It is a member of the Cucurbitaceae of the Cucurbitaceae family and family is known and is as known bitter melonas bitter or bittermelon gourd or bitter (Figure gourd3). (FigureBesides 3). using Besides MC asusing a vegetable, MC as a vegetable, it is supposed it is tosupposed be a herbal to be medicine, a herbal medicine, used as folk used medicine. as folk medicine.Its bioactivities, Its bioactivities, such as anti-inflammatory such as anti-inflammatory activity, anti-oxidant activity, anti-oxidant activity, anti-viral activity, activity, anti-viral anti-cancer activity, anti-canceractivity, anti-bacterial activity, anti-bacterial activity, etc. activity, and especially etc. and anti-diabetic especially anti-diabetic activity [40]. activity [40].

(a) (b)

Figure 3. Pictures show the morphological characteristics of the Momordica charantia (MC): ( a) whole plant and ( b) unripe fruit.

Phytochemistry There were many investigations publishing active components of bitter melon that support type 2 DM treatment. The important phytochemicals of the plants are steroids, momordicosides (A, B, C, Biology 2020, 9, 252 5 of 31

Phytochemistry Biology 2020, 9, x FOR PEER REVIEW 5 of 31 There were many investigations publishing active components of bitter melon that support type 2 DM treatment. The important phytochemicals of the plants are steroids, momordicosides (A, B, C, D, D, E, G, F1, F2, I, K, L), acyl glucosyl sterols, fatty acids, amino acids, alkaloids, phenolic compounds, E,steroidal G, F1,F saponin,2, I, K, L), vitamins, acyl glucosyl carbohydrates, sterols, fatty and acids,minerals, amino etc. acids,[40–48]. alkaloids, phenolic compounds, steroidal saponin, vitamins, carbohydrates, and minerals, etc. [40–48]. Antidiabetic Activity Antidiabetic Activity The fruits, seeds and callus of Momordica charantia contain some insulin-like proteins [49] which The fruits, seeds and callus of Momordica charantia contain some insulin-like proteins [49] which are homologous to human insulin, and it produced consistent hypoglycemic effect when tested on are homologous to human insulin, and it produced consistent hypoglycemic effect when tested on rats, gerbils, langurs and human beings [50]. In India and China, MC was believed to be a treatment rats, gerbils, langurs and human beings [50]. In India and China, MC was believed to be a treatment for diabetes mellitus for thousands of years. Nowadays, scientists have done many types of research for diabetes mellitus for thousands of years. Nowadays, scientists have done many types of research focusing on its anti-hyperglycemic abilities. Indeed, many research papers have shown that its focusing on its anti-hyperglycemic abilities. Indeed, many research papers have shown that its bioactivities decrease significantly in blood glucose levels (Figure 4). These investigations on bitter bioactivities decrease significantly in blood glucose levels (Figure4). These investigations on bitter melon also demonstrated that it can enhance the glucose tolerance of normal and diabetic mice and melon also demonstrated that it can enhance the glucose tolerance of normal and diabetic mice and also in humans [47–51]. Many studies proved that bioactive constituents for MC have considerable also in humans [47–51]. Many studies proved that bioactive constituents for MC have considerable antidiabetic activities (Table 1). antidiabetic activities (Table1).

Figure 4. The mechanism in decreasing blood glucose levels of M. charantia. Figure 4. The mechanism in decreasing blood glucose levels of M. charantia. Table 1. Bioactive compounds and their effects in Momordica charantia. Table 1. Bioactive compounds and their effects in Momordica charantia. Bioactive Compounds Antidiabetic Effects BioactivePolypeptide-p Compounds Act as Insulin-like Antidiabetic protein, decrease Effects blood glucose level Polypeptide-pMomordicosides Act as Insulin-like Enhance protein, the uptake decrease of glucose blood glucose level MomordicosidesSaponins Stimulate insulin Enhance secretion, the uptake a lower of bloodglucose glucose level Conjugated linolenic acid Release intestinal GLP-1 Saponins Stimulate insulin secretion, a lower blood glucose level Momordin PPAR δ activation 9c,Conjugated 11t, 13t conjugated linolenic linolenic acid acid Release PPAR intestinalα activation GLP-1 Momordin PPAR δ activation 9c, 11t, 13t conjugated linolenic acid PPAR α activation Akhtar N et al. reported that Charantin, vicine and polypeptide-p contained in ethanolic extract of MC fresh green whole fruit acted as insulin-like protein, decrease blood glucose level, Akhtar N et al. reported that Charantin, vicine and polypeptide-p contained in ethanolic extract of stimulated insulin secretion, tissue glucose uptake, decreased hepatic gluconeogenesis, stimulated MC fresh green whole fruit acted as insulin-like protein, decrease blood glucose level, stimulated insulin glucose uptake and utilization, inhibited absorption of glucose in the intestine in alloxan-induced secretion, tissue glucose uptake, decreased hepatic gluconeogenesis, stimulated glucose uptake and diabetic rabbits by 200 mg/kg b.w dose [52]. In vitro insulin secretion assay, Momordicoside U utilization, inhibited absorption of glucose in the intestine in alloxan-induced diabetic rabbits by 200 (3β,7β-Dihydroxycucurbita-5,23(E)-dien-19-al-25-O-β-d-glucopyranoside) showed that this compound mg/kg b.w dose [52]. In vitro insulin secretion assay, Momordicoside U (3β,7β-Dihydroxycucurbita- could enhance the uptake of glucose by evaluation of insulin secretion activity [53]. According to 5,23(E)-dien-19-al-25-O-β-D-glucopyranoside) showed that this compound could enhance the uptake of Singhglucose N by et al.,evaluation alcoholic of extract insulin of secretion the whole activity fruit which [53]. According was orally to administered Singh N et al., in adultalcoholic alloxan-induced extract of the β diabeticwhole fruit albino which rats was can orally recover administered-cells of the in isletsadult of alloxan-induced Langerhans of thediabetic pancreas albino by rats 25 mg,can 50recover mg and β- 75cells mg of dosesthe islets ofthe of Langerhans extract [54]. of In the the pancreas acetone by extract 25 mg, of 50 this mg fruit and power, 75 mg thedoses ability of the of extract recovery [54]. of In beta the cellsacetone of theextract islets of of this Langerhans fruit power, of thethe pancreasability of wasrecovery confirmed of beta when cells appliedof the islets to alloxan of Langerhans diabetic albinoof the ratspancreas by 25 was mg, confirmed 50 mg and when 75 mg applied doses to of alloxan extract diabet in 8ic to albino 30 days rats treatment by 25 mg, [ 5550 ].mg An and investigation 75 mg doses on of theextract antidiabetic in 8 to 30 activitiesdays treatment of MC [55]. fruit An juice investigation in streptozotocin-induced on the antidiabetic diabetic activities rats of showedMC fruit that juice this in streptozotocin-induced diabetic rats showed that this herb possesses the ability to enhance insulin secretion of pancreatic β-cells, elevate of serum insulin level, improve β-cell function, decrease insulin resistance, increase glucose utilization in a dose of 10 mL/kg/day for 14 days [56]. In cells of the pancreas, Momordica charantia can be able to renew or recover the partially destroyed cells and encourage the secretion of insulin. Biology 2020, 9, 252 6 of 31 herb possesses the ability to enhance insulin secretion of pancreatic β-cells, elevate of serum insulin level, improve β-cell function, decrease insulin resistance, increase glucose utilization in a dose of 10Biology mL 2020/kg/,day 9, x FOR for PEER 14 days REVIEW [56]. In cells of the pancreas, Momordica charantia can be able to renew6 of or31 recover the partially destroyed cells and encourage the secretion of insulin. Moreover, aqueous ethanolic extract extract of of MC MC se seedseds exposed exposed the the protection protection of ofpancreatic pancreatic β-cellsβ-cells in invitro vitro experimentexperiment [57]. [57 ].In Inthe the treatment treatment of of type type 1 1diabetes diabetes mellitus, mellitus, MC MC extract extract has has been been proven to possibly definitelydefinitely improve improve beta beta cells cells in in pancreatic pancreatic islets islets in streptozotocin-inducedin streptozotocin-induced type-1 type-1 diabetic diabetic rats. Relatedrats. Related with with type-1 type-1 diabetes, diabetes polypeptide-p, polypeptide-p has shown has shown action action similar similar to human to human insulin insulin in the in body the and,body therefore, and, therefore, may bemay used be asused plant-based as plant-based insulin insulin replacement replacement in patients in patients with with type-1 type-1 diabetes diabetes [58]. Other[58]. Other studies studies also investigated also investigated the inhibition the inhibition of diabetes-related of diabetes-related enzymes, suchenzymes, as alpha-glucosidase such as alpha- andglucosidase alpha-amylase and alpha-amylase from MC extracts from MC [59]. extracts [59].

3.1.2. Panax ginseng C.A Meyer In Korea, Ginseng is the mostmost famousfamous traditional plant used in folk medicine for a longlong timetime (Figure(Figure5 5).). GinsengGinseng belongsbelongs toto thethe genusgenus Panax Panax in in family family Araliaceae Araliaceae [ [60].60]. It distributes typically in a cooler climateclimate regionregion that that can can be be found found in Easternin Eastern Asia Asia such such as Korea, as Korea, Eastern Eastern Siberia, Siberia, Northeast Northeast China andChina North and America.North America.

Figure 5. Panax ginseng C.A Meyer.

Phytochemistry The root of of this this plant plant contains contains many many bioactive bioactive compounds, compounds, including including triterpene triterpene glycosides, glycosides, or orsaponins, saponins, commonly commonly referred referred to as to ginsenosides as ginsenosides (Table (Table 2), 2Panaxans,), Panaxans, vanillic vanillic acid, acid, salicylates. salicylates. All Allparts parts of the of plant the plant also have also some have active some activeconstituent, constituent, such as suchamino as acids, amino alkaloids, acids, alkaloids, phenols, proteins, phenols, proteins,polypeptides, polypeptides, and vitamins and vitaminsB1 and B2 B1 which and B2 have which been have identified been identified [61–63]. [61–63].

Antidiabetic Activity Table 2. Structure of ginsenosides (ginseng-specific saponins). Since diabetes mellitus is characterized by insulin resistance, and β-cell dysfunction, therapeutic medications should be involved in improving insulin resistance, enhancing glucose uptake, decreasing blood glucose concentration, and protecting/regenerating β-cell from pancreatic islets. Many researchers have been investigated the anti-diabetic activities on the root of Panax ginseng in vitro and in vivo experiments [62–64]. The most important group of phytochemicals f Panax ginseng is ginseng-specific saponins called ginsenosides. Among them, Ginsenosied Rb2 was the most effective constituent treated for streptozotocin-induced diabetic rats by decreasing blood glucose level [65]. Moreover, in fermented red ginseng extracts, theA. content Protopanaxadiol of ginsenoside Rg2, Rg3, and Rh2 areB. Protopanaxatriol higher than normal ginseng R2= Ra1, Ra2, Ra3, Rb1, Rb2, Rb3, Rc, Rd, Rg2, Rg3, Rs1, Rs2, etc. R2= Re, Rf, Rg1, Rg2, Rh1, etc.

Antidiabetic Activity Since diabetes mellitus is characterized by insulin resistance, and β-cell dysfunction, therapeutic medications should be involved in improving insulin resistance, enhancing glucose uptake, decreasing blood glucose concentration, and protecting/regenerating β-cell from pancreatic islets. Many researchers BiologyBiology 2020, 9 20, x20 FOR, 9, xPEER FOR REVIEWPEER REVIEW 6 of 316 of 31

Moreover,Moreover, aqueous aqueous ethanolic ethanolic extract extract of MC of seeds MC seeds exposed exposed the protect the protection ofion pancreatic of pancreatic β-cells β- incells in vitro vitroexperiment experiment [57]. [57]In the. In treatment the treatment of type of type1 diabetes 1 diabetes mellitus, mellitus, MC extractMC extract has been has beenproven proven to to possiblypossibly definitely definitely improve improve beta cellsbeta cellsin pancreatic in pancreatic islets isletsin streptozotocin in streptozotocin-induced-induced type -type1 diabetic-1 diabetic rats. Relatedrats. Related with withtype -type1 diabetes,-1 diabetes, polypeptide polypeptide-p has-p shown has shown action action similar similar to human to human insulin insulin in the in the bodybody and, thereforeand, therefore, may, bemay used be usedas plant as plant-based-based insulin insulin replacement replacement in patients in patients with withtype- type1 diabetes-1 diabetes [58]. [58]Other. Other studies studies also alsoinvestigated investigated the inhibition the inhibition of diabetes of diabetes-related-related enzymes, enzymes, such such as alpha as alpha- - glucosidaseglucosidase and alpha and alpha-amylase-amylase from fromMC extracts MC extracts [59]. [59].

3.1.2.3.1.2. Panax Panax ginseng ginseng C.A Meyer C.A Meyer In Korea,In Korea, Ginseng Ginseng is the is most the mostfamous famous traditional traditional plant plant used usedin folk in medicinefolk medicine for a forlong a longtime time (Figure(Figure 5). Ginseng 5). Ginseng belongs belongs to the to genus the genus Panax Panax in family in family Araliaceae Araliaceae [60]. It[60 distributes]. It distributes typically typically in a in a coolercooler climate climate region region that canthat becan found be found in Eastern in Eastern Asia Asiasuch suchas Korea, as Korea, Eastern Eastern Siberia, Siberia, Northeast Northeast ChinaChina and North and North America. America.

Biology 2020, 9, 252 7 of 31 FigureFigure 5. Panax 5. Panax ginseng ginseng C.A Meyer C.A Meyer. .

PhytochemistrysoPhytochemistry that those extracts significantly reduced blood glucose levels and increased plasma insulin levels in streptozotocin-induced diabetic rats by orally-administered 100 or 200 mg/kg extracts dissolved The rTheoot ofroot this of plantthis plant contains contains many many bioactive bioactive compounds, compounds, including including triterpene triterpene glycosides, glycosides, or or in water, at 10 a.m. daily in three weeks [66]. These mechanisms have been displayed in Figure6. saponins,saponins, commonly commonly referred referred to as toginsenosides as ginsenosides (Table (Table 2), Panaxans, 2), Panaxans, vanillic vanillic acid, acid,salicylates. salicylates. All All In general, saponins, which were isolated from ginseng that has been proven significant antidiabetic partsparts of the of plant the plant also have also havesome some active active constituent, constituent, such suchas amino as amino acids, acids, alkaloids, alkaloids, phenols, phenols, proteins, proteins, activity. The mechanism of these components in antidiabetic treatment is to moderate the enzyme polypeptides,polypeptides, and vitamins and vitamins B1 and B1 B2 and which B2 which have havebeen beenidentified identified [61–63 [61]. –63]. activity [50,60] to influence glucose metabolism and control insulin secretion [67–73]. Biology 2020, 9, x FOR PEER REVIEW 7 of 31 TableTable 2. Structure 2. Structure of ginsenosides of ginsenosides (ginseng (ginseng-specific-specific saponins) saponins). . Table 2. Structure of ginsenosides (ginseng-specific saponins). have been investigated the anti-diabetic activities on the root of Panax ginseng in vitro and in vivo experiments [62–64]. The most important group of phytochemicals f Panax ginseng is ginseng-specific saponins called ginsenosides. Among them, Ginsenosied Rb2 was the most effective constituent treated for streptozotocin-induced diabetic rats by decreasing blood glucose level [65]. Moreover, in fermented red ginseng extracts, the content of ginsenoside Rg2, Rg3, and Rh2 are higher than normal ginseng so that those extracts significantly reduced blood glucose levels and increased plasma insulin levels in streptozotocin-induced diabetic rats by orally-administered 100 or 200 mg/kg extracts dissolved in water, at 10 a.m. daily in three weeks [66]. These mechanis ms have been displayed in Figure 6. In general, saponins, which were isolated from ginseng that has been proven significant antidiabetic activity. The A. Protopanaxadiol B. Protopanaxatriol mechanism of these componentsA. ProtopanaxadiolA. Protopanaxadiol in antidiabetic treatment is to moderateB. Protopanaxatriol B.the Protopanaxatriol enzyme activity [50,60] to influenceR2R=2=Ra Ra glucose1R1,,2 Ra=Ra Ra22,, 1 RaRa, metabolismRa33, 2Rb , Ra1,,3 Rb, Rb Rb22, 1,Rb, RbandRb33,2 ,Rc,, Rc,Rbcontrol Rd,3, Rd, Rc, Rg Rg Rd,insulin2,2 Rg, Rg 3,23 Rs,, secretionRg Rs1, 31Rs,, Rs Rs2, 12etc., ,Rs etc.[67–73]. 2, etc. R 2= Re, RR2 2Rf,= Re,Re, Rg Rf, Rf,1, Rg Rg 2,1 1Rh,, Rg Rg1,2 2etc., ,Rh Rh 1,1 etc., etc.

AntidiabeticAntidiabetic Activity Activity

FigureFigure 6. 6. MechanismsMechanisms of of PanaxPanax ginseng ginseng saponinssaponins on on different different or organsgans related to diabetes. 3.2. Bioactive Compounds Increase Insulin Secretion from Beta-Cells of Pancreas 3.2. Bioactive Compounds Increase Insulin Secretion from Beta-Cells of Pancreas 3.2.1. Allium cepa (Allium) 3.2.1. Allium cepa (Allium) Allium cepa Linn. is a member of the family Liliaceae which is commonly called onion. It is a usefulAllium ingredient cepa Linn. in cooking is a member in many of countries, the family especially Liliaceae Vietnam, which is China commonly and Egypt. called This onion. plant It is can a usefulsurvive ingredient under harsh in cooking conditions, in many e.g., winter countries, or dryness, especially so thatVietnam, it can China be stored and for Egypt. a long This time plant without can surviveany changes under in harsh phytonutrients conditions, [ 74e.g.,]. winter or dryness, so that it can be stored for a long time without any changes in phytonutrients [74]. Phytochemistry Phytochemistry Onion has large numbers of biologically active compounds. These phytoconstituents have beenOnion successfully has large isolated numbers and identified,of biologically including active phenolics,compounds. flavonoids, These phytoconstituents thiosulfinates, amino have acids,been successfullyessential oils, isolated and vitamins, and identified, etc. onion extractsincluding exhibited phenolics, various flavonoids, bioactivities, thio suchsulfinates, as anti-inflammatory amino acids, essentialactivity, antioxidantoils, and vitamins, activity, etc. and onion antidiabetic extracts exhi activity,bited etc. various The major bioactivities, biochemical such as constituents anti-inflammatory of onion activity,extraction antioxidant were identified activity, as quercetin,and antidiabetic allicin activity, (S-oxodiallyl etc. The disulfide), major biochemical alliin (S-allyl constituents L-cysteine of S-oxide), onion extractiondiallyl disulfide were identified (allyl disulfide), as quercetin, S-methyl allicin L-cysteine (S-oxodiallyl S-oxide disulfide), (3-(methyl alliin sulfinyl (S-allyl alanine), L-cysteine propanethial S-oxide), diallylS-oxide disulfide (thiopropanal (allyl disulfide), S-oxide) and S-methyl 3-mercapto-2-methypentan-1-ol L-cysteine S-oxide (3-(methyl [75 sulfinyl,76]. alanine), propanethial S-oxide (thiopropanal S-oxide) and 3-mercapto-2-methypentan-1-ol [75,76].

Antidiabetic Activity Hypoglycemic activity of Allium cepa Linn. extracts have been reported [77]. The bulb part contains S-methyl cysteine sulfoxide, S-allyl cysteine sulfoxide has been proven anti-diabetic activity. These compounds can lower blood glucose levels and has a potent antioxidant activity which may account for hypoglycemic potential. S-methylcysteine sulfoxide (Figure 7) exerts antidiabetic action in 3 different ways: (1) stimulate the production of insulin in the body and enhance the secretion of the pancreas; (2) interfere with dietary glucose absorption; and (3) use insulin effectively [78,79]. Biology 2020, 9, 252 8 of 31

Antidiabetic Activity Hypoglycemic activity of Allium cepa Linn. extracts have been reported [77]. The bulb part contains S-methyl cysteine sulfoxide, S-allyl cysteine sulfoxide has been proven anti-diabetic activity. These compounds can lower blood glucose levels and has a potent antioxidant activity which may account for hypoglycemic potential. S-methylcysteine sulfoxide (Figure7) exerts antidiabetic action in 3 different ways: (1) stimulate the production of insulin in the body and enhance the secretion of the pancreas;Biology 2020 (2), 9, x interfere FOR PEER with REVIEW dietary glucose absorption; and (3) use insulin effectively [78,79]. 8 of 31

FigureFigure 7.7. Structure ofof S-methylS-methyl cysteinecysteine sulfoxide.sulfoxide. 3.2.2. Allium sativum (Allium) 3.2.2. Allium sativum (Allium) Allium sativum Linn., is commonly herb which has been known as garlic, belongs to the family Allium sativum Linn., is commonly herb which has been known as garlic, belongs to the family Allium. It could be found in Asia, Africa and Europe. It is originally indigenous to Asia, is now widely Allium. It could be found in Asia, Africa and Europe. It is originally indigenous to Asia, is now widely grown in popularity to produce a condiment, especially in Asian cuisine [80]. grown in popularity to produce a condiment, especially in Asian cuisine [80]. Their functions prove that garlic is a powerful medicinal plant for treating many diseases for Their functions prove that garlic is a powerful medicinal plant for treating many diseases for over more than a thousand years. According to numerous scientific research studies, garlic has been over more than a thousand years. According to numerous scientific research studies, garlic has been discovered as having a wide range of biological functions such as anti-tumor activity, being antibiotics discovered as having a wide range of biological functions such as anti-tumor activity, being with antimicrobial activity and especially anti-hyperglycemic activity [81]. antibiotics with antimicrobial activity and especially anti-hyperglycemic activity [81]. Phytochemistry Phytochemistry Raw garlic contains many active phytochemicals like alkaloids, flavonoids, cardiac glycosides, terpenesRaw and garlic steroids, contains resin. many It alsoactive contains phytochemicals some sulfur like compounds, alkaloids, flavonoids, such as alliin, cardiac allicin, glycosides, ajoene, diallylterpenes sulfide, and steroids, enzymes, resin. B-vitamins, It also contains proteins, some minerals, sulfur compounds, saponins, flavonoids, such as alliin, etc., whichallicin, areajoene, not Sulphur-containingdiallyl sulfide, enzymes, compounds B-vitamins, [81–84 proteins,]. minerals, saponins, flavonoids, etc., which are not Sulphur-containing compounds [81–84]. Antidiabetic Activity Antidiabetic Activity Depending on these scientific studies, garlic’s biological activity in anti-diabetics has been shown that itsDepending mechanism on is these to control scientific the excretion studies, ofgarlic’s insulin biological from β-cells, activity enhance in anti-diabetics glucose tolerance has been and glycogenshown that synthesis its mechanism [85]. For is to example, control the these excretion two bioactive of insulin compounds, from β-cells, whichenhance are glucose extracted tolerance from garlic,and glycogen are allyl synthesis propyldisulfide [85]. For example, and S-methylcysteine these two bioactive sulfoxide compounds, can decrease which blood are extracted glucose level.from Ingarlic, addition, are allyl the propyldisulfide ethanol extract and from S-methylcysteine garlic was also hadsulfoxide antidiabetic can decrease activity blood by restoring glucose delayedlevel. In insulinaddition, response the ethanol [86,87 ].extract from garlic was also had antidiabetic activity by restoring delayed insulin response [86,87]. 3.2.3. Aloe vera L. Burm. (Asphodelaceae) 3.2.3. Aloe vera L. Burm. (Asphodelaceae) Aloe vera is the popularly medicinal plant ever known and the most applied medicinal plant especiallyAloe vera in the is cosmeticthe popularly industry, medicinal and antidiabetic plant ever mediation known and (Figure the most8). This applied traditional medicinal medicinal plant plantespecially belongs in the to the cosmetic family industry, Liliaceae. and It is antidiabet original toic Africa mediation and Mediterranean (Figure 8). This countries. traditional It is medicinal reported toplant be distributedbelongs to widely the family in the Liliaceae. islands of It Cyprus, is origin Malta,al to Sicily,Africa Cape and VerdeMediterranean and India [countries.88]. It is reported to be distributed widely in the islands of Cyprus, Malta, Sicily, Cape Verde and India [88]. Phytochemistry Phytoconstituents in the plant are alkaloids, flavonoids, tannins, phenols, saponins, carbohydrates, vitamins and minerals and several other aromatic compounds [89]. These compounds have been proven for various pharmacological activities, such as antioxidant, antimicrobial, antidiabetic, anti-cancer and so on. That is the result why until now scientists continue to investigate biological activities of this plant to production modern medicine and traditional medicine. Biology 2020, 9, 252 9 of 31 Biology 2020, 9, x FOR PEER REVIEW 9 of 31

Figure 8. Aloe vera L. Burm.

AntidiabeticPhytochemistry Activity ThePhytoconstituents experiment on in diabetic the plant rats treatedare alkaloid with Aloes, flavonoids, vera water extracttannins, orally phenols, led to saponins, reducing significantcarbohydrates, blood vitamins glucose and levels. minerals Statistical and several analysis other of aromatic results found compounds that Aloe [89]. vera Thesewater compounds extract is antidiabetichave been withproven fewer for side various effects pharmacological [90,91]. Moreover activities, less expensive such cost as isantioxidant, also a significant antimicrobial, benefit of Aloeantidiabetic, vera in the anti-cancer production and of so medicine on. That against is the result diabetes why mellitus. until now scientists continue to investigate biological activities of this plant to production modern medicine and traditional medicine. 3.3. Bioactive Compounds Regenerate of Beta-Cells of the Islets of the Pancreas

3.3.1.AntidiabeticPterocarpus Activity marsupium () PterocarpusThe experiment marsupium on diabetic(P. marsupium rats treated) is a large,with Aloe high vera tree thatwater can extract grow uporally from led 15 to to reducing 30 m tall (Figuresignificant9). Itblood belongs glucose to the levels. Fabaceae Statistical family analysis and distributes of results in India,found Nepal, that Aloe and vera Sri Lanka,water extract which isis widelyantidiabetic used with in ‘’ fewer side as effects ‘Rasayana’ [90,91]. for Moreover the management less expensive of various cost metabolic is also a disorders significant including benefit hyperglycemiaof Aloe vera in the [92 production]. of medicine against diabetes mellitus.

Phytochemistry3.3. Bioactive Compounds Regenerate of Beta-Cells of the Islets of the Pancreas

3.3.1.Similar Pterocarpus to most marsupium herbs, (Fabaceae)P. marsupium is a rich source of phenolic and flavonoid compounds. It has been reported that this plant contains alkaloids, steroids, terpenoids, tannins, amino acids, proteins,Pterocarpus etc. The marsupium potential (P. antidiabetic marsupium) constituents is a large, high in this tree plant that havecan grow been up identified from 15 successfully, to 30 m tall including(Figure 9). epicatechin.It belongs to Itthe is Fabaceae also reported family to and be richdistributes in polyphenolic in India, Nepal, compounds and Sri which Lanka, have which been is consideredwidely used major in bioactive‘Ayurveda’ compounds, as ‘Rasayana’ such as for marsupsin, the management pterosupin of and various pterostilbene metabolic and flavonoidsdisorders pteroside,including hyperglycemia pteroisoauroside, [92]. carsupin and marsupol. These compounds have many biological effects, e.g., anti-inflammatory, anti-bacterial, anti-oxidant activity, especially antidiabetic activity [93–96]. Biology 2020, 9, 252 10 of 31 Biology 2020, 9, x FOR PEER REVIEW 10 of 31

(a) (b)

Figure 9. Pterocarpus marsupium ::( (a)) whole whole plant plant and and ( (b) leaves. leaves. Antidiabetic Activity Phytochemistry The extract of P. marsupium was orally administered by diabetes patients and gave a strong Similar to most herbs, P. marsupium is a rich source of phenolic and flavonoid compounds. It has anti-hyperglycemic effect [92,94]. Ethyl acetate’s extract of P. marsupium was tested for five days on been reported that this plant contains alkaloids, steroids, terpenoids, tannins, amino acids, proteins, alloxan-induced diabetic rats to conclude the significant anti-diabetes effect. The ethanolic extract of etc. The potential antidiabetic constituents in this plant have been identified successfully, including P. marsupium showed the blood sugar lowering effect [95]. It was found to be effective in lowering epicatechin. It is also reported to be rich in polyphenolic compounds which have been considered the glucose level. Epicatechin, isolated from P. marsupium, showed the ability of regeneration of the major bioactive compounds, such as marsupsin, pterosupin and pterostilbene and flavonoids β-cells of the pancreas islets [97]. Moreover, the aqueous extract of this plant was reported that it pteroside, pteroisoauroside, carsupin and marsupol. These compounds have many biological effects, could stimulate the secretion of insulin and enhance the glucose uptake, so that it can be considered as e.g., anti-inflammatory, anti-bacterial, anti-oxidant activity, especially antidiabetic activity [93–96]. antidiabetic medicine [94]. Antidiabetic Activity 3.3.2. Tinospora cordifolia (Menispermaceae) The extract of P. marsupium was orally administered by diabetes patients and gave a strong anti- Tinospora cordifolia (T. cordifolia) has been commonly known as “Amrita” or “Guduchi”, belong to hyperglycemic effect [92,94]. Ethyl acetate’s extract of P. marsupium was tested for five days on the Menispermaceae family. It has been one of the important drugs of Indian Systems of Medicine alloxan-induced diabetic rats to conclude the significant anti-diabetes effect. The ethanolic extract of for a long time. Guduchi is native to India and mainly distributed in tropical areas such as Myanmar P. marsupium showed the blood sugar lowering effect [95]. It was found to be effective in lowering and Sri Lanka [98]. In India, this plant has been reported as the main source of treatments for many the glucose level. Epicatechin, isolated from P. marsupium, showed the ability of regeneration of the diseases such as fever, dyspepsia and urinary diseases in folk medicine [99]. β-cells of the pancreas islets [97]. Moreover, the aqueous extract of this plant was reported that it couldPhytochemistry stimulate the secretion of insulin and enhance the glucose uptake, so that it can be considered as antidiabetic medicine [94]. Tinospora cordifolia has been reported to contain numerous constituents belonging to different 3.3.2.chemical Tinospora classes cordifolia of secondary (Menispermaceae) metabolites such as alkaloids, terpenoids, essential oils, glycosides, steroids, phenolic constituents, aliphatic compounds, and polysaccharides. Leaves of this plant are a richTinospora source ofcordifolia proteins, (T. flavonoids, cordifolia) has alkaloids been commonly and glycosides known [ 100as “A,101mrita”]. These or “Guduchi”, active compounds belong tohave the been Menispermaceae exposed to several family. biological It has been activities, one of the including important antiseptic, drugs of anti-inflammatory, Indian Systems of anti-cancer, Medicine forantimicrobial a long time. and Guduchi antidiabetic is native activities. to India and mainly distributed in tropical areas such as Myanmar and Sri Lanka [98]. In India, this plant has been reported as the main source of treatments for many diseasesAntidiabetic such Activity as fever, dyspepsia and urinary diseases in folk medicine [99]. T. cordifolia, containing polysaccharide isolated from this plant exposed the β-cell regenerative Phytochemistry properties which could be pointed to develop antidiabetic medicine with few side effects [102]. OralTinospora administration cordifolia of the has extract been ofreportedT. cordifolia to containroots for numerous two weeks constituents experimented belonging with induced to different type 2 chemicaldiabetic rats classes resulted of secondary in this plant metabolites can promote such insulin as alkaloids, secretion andterpenoids, inhibit glucosgenolysis essential oils, processglycosides, and steroids,therefore phenolic improve constituents, the regulation aliphatic of blood compounds, glucose level and in polysaccharides. the body [103]. In Leaves 2011, Patelof this also plant studied are a richthe hypoglycemicsource of proteins, effects flavonoids, of alkaloidal alkaloids fraction and of T.glycosides cordifolia extract.[100,101]. This These investigation active compounds demonstrated have been exposed to several biological activities, including antiseptic, anti-inflammatory, anti-cancer, antimicrobial and antidiabetic activities. Biology 2020, 9, x FOR PEER REVIEW 11 of 31

Antidiabetic Activity T. cordifolia, containing polysaccharide isolated from this plant exposed the β-cell regenerative properties which could be pointed to develop antidiabetic medicine with few side effects [102]. Oral administration of the extract of T. cordifolia roots for two weeks experimented with induced type 2 Biologydiabetic2020 rats, 9, 252resulted in this plant can promote insulin secretion and inhibit glucosgenolysis process11 of 31 and therefore improve the regulation of blood glucose level in the body [103]. In 2011, Patel also thestudied antidiabetic the hypoglycemic activity of T.effects cordifolia of alkaloidaldue to the fraction promoting of ofT. insulin-releasing,cordifolia extract. improvingThis investigation insulin sensitivitydemonstrated and the inhibiting antidiabetic gluconeogenesis activity of processT. cordifolia [104]. due to the promoting of insulin-releasing, improving insulin sensitivity and inhibiting gluconeogenesis process [104]. 3.3.3. Tinospora crispa (Menispermaceae) 3.3.3. Tinospora crispa (Menispermaceae) Tinospora crispa (T. crispa) is a precious medicinal climbing plant. As a kind of vines, its body is veryTinospora rough, crispa light brown,(T. crispa long) is a to precious 6–7 m or medicinal more (Figure climbing 10). Itplan wildlyt. As growsa kind inof manyvines, Southits body East is Asiavery countriesrough, light such brown, as Laos, long Cambodia, to 6–7 m or Thailand, more (Figure and Philippines,10). It wildly etc., grows particularly in many South common East in Asia the Northerncountries areassuch inas VietnamLaos, Cambodia, [105–107]. Thailand, and Philippines, etc., particularly common in the Northern areas in Vietnam [105–107].

(a) (b)

Figure 10. Tinospora crispa:(: (a) whole plant and ( b) leaves.

Phytochemistry In manymany previous previous investigations, investigations,T. crispaT. crispais a is rich a rich source source of secondary of secondary metabolites, metabolites, divided divided into several into groups,several includinggroups, including alkaloids, flavonoid,alkaloids,terpenoids, flavonoid, lignans, terpenoids, sterols, lignans, etc. [105 sterols,]. Alkaloidal etc. constituents[105]. Alkaloidal have β d beenconstituents isolated have including been isolatedN-formylasimilobine including N-formylasimilobine 2-O- - -glucopyranoside, 2-O-β-D-glucopyranoside,N-formylasimilobine N- 2-O-β-d-glucopyranosyl-(1 2)-β-d-glucopyranoside, (tinoscorside A), N-formylanonaine, formylasimilobine 2-O-β-D-glucopyranosyl-(1→ →2)-β-D-glucopyranoside, (tinoscorside A), N- Nformylanonaine,-formyldehydroanonaine, N-formyldehydroanonaine,N-formylnomuciferine, NN-demethyl--formylnomuciferine,N-formyldehydronornuciferine, N-demethyl-N- magnoflorine,formyldehydronornuciferine, etc. [105–108]. Until magnoflorine, now, there etc are [105–1 several08]. flavones Until now, and flavonethere are glycosides several flavones which have and beenflavone isolated glycosides and identified which have from beenT. crispaisolatedextract, and identified such as apeginin, from T. diosmetin,crispa extract, genkwanin, such as apeginin, luteolin 4diosmetin,0-methyl ethergenkwanin, 7-glucoside, luteolin genkwanin 4′-methyl 7-glucoside, ether 7-glucoside, luteolin genkwanin 40-methyl ether7-glucoside, 30-glucoside luteolin [109 4′].- Moreover,methyl ether many 3′-glucoside researchers [109]. reported Moreover, that many this plant researchers also contains reported a lot that of phytochemicalthis plant also contains bioactive a constituentslot of phytochemical [110]. bioactive constituents [110]. Antidiabetic Activity Antidiabetic Activity The investigation of Noor and Ashcroft [106] indicated that the orally administrated extract of The investigation of Noor and Ashcroft [106] indicated that the orally administrated extract of T. crispa exhibited a potential antidiabetic effect. The mechanisms of these activities were predicted so T. crispa exhibited a potential antidiabetic effect. The mechanisms of these activities were predicted that this plant could stimulate insulin secretion through the modulation of β-cell Ca2+ concentration. so that this plant could stimulate insulin secretion through the modulation of β-cell Ca2+ In Noipha’s experiment, T. crispa extracts improved the glucose transport activity of L6 myotubes concentration. In Noipha’s experiment, T. crispa extracts improved the glucose transport activity of by increasing GLUT1 transporter [110]. Thus, it can be further used as an antidiabetic agent for the L6 myotubes by increasing GLUT1 transporter [110]. Thus, it can be further used as an antidiabetic treatment of type II diabetes [110,111]. agent for the treatment of type II diabetes [110,111]. 3.3.4. Gymnema sylvestre (Apocynaceae) 3.3.4. Gymnema sylvestre (Apocynaceae) Gymnema sylvestre (G. sylvestre) belonging to the Apocynaceae family, originated from tropical forests of The Southern and Central India and Sri Lanka [112]. In Vietnam, G. sylvestre has been classified as vines and found in many Northern and Central provinces. So far, this plant has been widely used in several countries around the world in treating diabetes. Biology 2020, 9, x FOR PEER REVIEW 12 of 31

Gymnema sylvestre (G. sylvestre) belonging to the Apocynaceae family, originated from tropical forests of The Southern and Central India and Sri Lanka [112]. In Vietnam, G. sylvestre has been classified as vines and found in many Northern and Central provinces. So far, this plant has been widely used in several countries around the world in treating diabetes.

BiologyPhytochemistry2020, 9, 252 12 of 31 The phytoconstituents of G. sylvestre consist of many groups containing bioactive compounds thatPhytochemistry are listed in the below table (Table 3) [112,113]. The phytoconstituents of G. sylvestre consist of many groups containing bioactive compounds that Table 3. Classification of phytoconstituents of Gymnema sylvestre. are listed in the below table (Table3)[112,113]. Phytoconstituents Classification TableGymnemic 3. Classification acids-acylated of phytoconstituents (tiglolyl, ofmethylbutyroyl)Gymnema sylvestre derivatives. of

TriterpenePhytoconstituents saponins deacylgymnemic acid (DAGA) Classification which is a 3-O-β-glucouronide of gymnemagenin (3β, 16β, 21β, 22α, 23, 28-hexahydroxy-olean-12-ene) Gymnemic acids-acylated (tiglolyl, methylbutyroyl) derivatives of deacylgymnemic acid OleananeTriterpene saponinssaponins (DAGA) Gymnemic which is acids a 3-O- andβ-glucouronide gymnemasaponins of gymnemagenin (3β, 16β, 21β, 22α, 23, Dammarene 28-hexahydroxy-olean-12-ene) Gymnemosides A, B, C, D, E, and F saponinsOleanane saponins Gymnemic acids and gymnemasaponins GurmarinDammarene saponins Gymnemosides A novel 35-amino-acid A, B, C, D, E, and peptide F with a 4209 molecular weight TriterpenoidsaponinsGurmarin A novel 35-amino-acid peptide with a 4209 molecular weight 3-O [β-D-glucopyranosyl (1-3)-β-D-glucopyranosyl]-22-O-tiglyol GymnemasinsTriterpenoidsaponins A Gymnemasins A 3-Ogymnemanol [β-d-glucopyranosyl (1-3)-β-d-glucopyranosyl]-22-O-tiglyol gymnemanol GymnemasinsGymnemasins B B 3-O-[ 3-O-[β-d-glucopyranosyl-(1-3)-β-D-glucopyranosyl-(1-3)-β-d-glucuro-nopyranosyl]-gymnemanolβ-D-glucuro-nopyranosyl]-gymnemanol GymnemasinsGymnemasins C C glucuronopyranosyl-22-O-tigloyl-gymnemanol glucuronopyranosyl-22-O-tigloyl-gymnemanol Gymnemasins D 3-O-β-D-glucopyranosyl-gymnemanol Gymnemasins D 3-O-β-d-glucopyranosyl-gymnemanol Gymnemanol 3,β-16,β-22, α-23-28-pentahydroxyolean-12-ene Gymnemanol 3,β-16,β-22, α-23-28-pentahydroxyolean-12-ene Gymmestrogenin Pentahydroxytriterpene Gymmestrogenin Pentahydroxytriterpene Kaempferol 3-O-β-D-glucopyranosyl-(1-4)-α-L-rhamnopyranosyl-(1-6)- FlavonolFlavonol glycoside glycoside Kaempferol 3-O-β-d-glucopyranosyl-(1-4)-α-l-rhamnopyranosyl-(1-6)- β-d-galactopyranoside β-D-galactopyranoside SterolsSterols StigmasterolStigmasterol

Antidiabetic Activity The major biological active ingredient of G. sylvestre is Gymnemic Gymnemic acids—a acids—a group group of triterpenoid triterpenoid saponins isolated and identified identified successfully (Figure 1111).). Several studies have reported that the main biological activity of this plant is antidiabetic activity [[113].113].

Figure 11. BasicBasic molecular structure of Gymnemic acid.

In thethe investigation investigation of S.of Sathya S. Sathya et al., theet al., aqueous the aqueous extract of extractG. sylvestre of leafG. sylvestre informed leaf hypoglycemic informed hypoglycemicactivity in normal activity and in alloxan-induced normal and alloxan-induced diabetic rats [114diabetic] by reducingrats [114] glucoseby reducing concentration. glucose concentration.Other research Other on G. research sylvestre onextracts G. sylvestre suggested extracts that suggested this extract that this could extract stimulate couldthe stimulate release the of insulin in vitro by permeabilizing the β-cell [115]. Several mechanisms have been proposed to explain the antidiabetic activity of G. sylvestre (Figure 12)[113,116,117]. According to these literature, the action of Gymnemic acids in diabetic treatment was reported to be able to stimulate pancreatic cell production, thereby increasing insulin production, increase insulin sensitivity and insulin activity, help to control and stabilize blood glucose concentration in the body. Gymnemic acids were also reported to be able Biology 2020, 9, x FOR PEER REVIEW 13 of 31 release of insulin in vitro by permeabilizing the β-cell [115]. Several mechanisms have been proposed to explain the antidiabetic activity of G. sylvestre (Figure 12) [113,116,117]. According to these literature, the action of Gymnemic acids in diabetic treatment was reported to be able to stimulate pancreaticBiology 2020, 9cell, 252 production, thereby increasing insulin production, increase insulin sensitivity13 and of 31 insulin activity, help to control and stabilize blood glucose concentration in the body. Gymnemic acids were also reported to be able to inhibit the absorption of glucose in the small intestine and to inhibit the absorption of glucose in the small intestine and inhibit the conversion glycogen in live to inhibit the conversion glycogen in live to glucose molecules in blood [118]. glucose molecules in blood [118].

Figure 12. Mechanisms of Gymnema sylvestre in the antidiabetic activity. Figure 12. Mechanisms of Gymnema sylvestre in the antidiabetic activity. 3.4. Bioactive Compounds Reduce the Absorption of Glucose from Gastrointestinal Tract 3.4. Bioactive Compounds Reduce the Absorption of Glucose from Gastrointestinal Tract 3.4.1. Cyamposis tertragonoloba (Fabaceae) 3.4.1. Cyamposis tertragonoloba (Fabaceae) Cyamopsis tetragonoloba L. Taub is commonly known as Cluster or Guar, belongs to the FabaceaeCyamopsis family. tetragonoloba The plant L. is aTaub very is small commonly drought-resistant known as Cl herbuster and Bean widely or Guar, cultivated belongs in to India. the FabaceaeThis plant family. was reported The plant to containsis a very asmall high drought-resistant amount of carbohydrates herb and and widely fiber cultivated [119]. in India. This plant was reported to contains a high amount of carbohydrates and fiber [119]. Phytochemistry PhytochemistryThere are very few phytochemical studies carried out on this plant. Some phytoconstituents in leavesThere were are reported very few to phytochemical contain carbohydrates, studies carried proteins, out fibers, on this galactomannans, plant. Some phytoconstituents ascorbic acid and in leavescondensed were tannins reported together to contain with, carbohydrates, caffic acid, gallic pr acid,oteins, and fibers, gentisic galactomannans, acid, p-coumaric ascorbic acid, astragalin, acid and condensedp-hydroxycinamyl tannins andtogether coniferyl with, alcohol. caffic acid, Its flavonoid gallic acid, content and gentisic includes acid, quercetin, p-coumaric daidizein, acid, astragalin, kaemferol, pand-hydroxycinamyl its 3-arabinosides. and Moreover,coniferyl alcohol. other polyphenolic Its flavonoid compositions content includes of the plantquercetin, were identified,daidizein, kaemferol,including gallotannins,and its 3-arabinosides. gallic acid Moreover, and gallic other acid derivatives,polyphenolic myricetin-7-glucoside-3-glycoside, compositions of the plant were identified,chlorogenic including acid, ellegic gallotannins, acid, 2,4,3-trihydroxy gallic acid and benzoic gallic acid, acid texasin-7-O-glucoside derivatives, myricetin-7-glucoside-3- and p-coumaryl glycoside,quinic acid chlorogenic [119]. acid, ellegic acid, 2,4,3-trihydroxy benzoic acid, texasin-7-O-glucoside and p- coumaryl quinic acid [119]. Antidiabetic Activity AntidiabeticBecause Activity of the presence of flavonoids and other phenolic compounds of the plant, CyamopsisBecause tetragonoloba of the presenceshowed of a flavonoids marginal antihyperglycemic and other phenolic eff compoundsect on blood of glucose the plant, level Cyamopsis in normal tetragonolobafasted rats, however, showed the a bloodmarginal glucose-lowering antihyperglycemic effect waseffect significant on blood in glucose alloxan-induced level in hyperglycemicnormal fasted rats,rats. however, Other studies the blood showed glucose-lowering that this herb could effect improve was significant insulin releasein alloxan-induced and decrease hyperglycemic the amount of rats.HbA1c Other [120 studies,121]. Gopalsamy showed that Rajiv this Gandhi herb could et al. reportedimprove thatinsulin polyphenols release and identified decrease in C.the tetragonoloba amount of β HbA1cbeans showed [120,121]. hypoglycemic Gopalsamy action Rajiv and Gandhi protected et al-cells. reported [122]. Hence that thispolyphenols plant can beidentified considered in forC. tetragonolobause in the management showed of type hypoglycemic 2 diabetes mellitus.action and protected β-cells [122]. Hence this plant can be considered for use in the management of type 2 diabetes mellitus. 3.4.2. Ocimum sanctum L. (Lamiaceae)

3.4.2.Ocimum Ocimum sanctum sanctumL. L. is (Lamiaceae) a small tree, up to 1 m tall, commonly known as ‘Sacred basil’ or ‘Holy basil’ or “Hương Nhu Tía” in Vietnam, is grown as a household plant in many countries for medicinal Ocimum sanctum L. is a small tree, up to 1 m tall, commonly known as ‘Sacred basil’ or ‘Holy purposes like Vietnam and India (Figure 13). It belongs to the Lamiaceae family. The whole plant has a basil’ or “Hương Nhu Tía” in Vietnam, is grown as a household plant in many countries for medicinal pleasant aroma [123,124]. purposes like Vietnam and India (Figure 13). It belongs to the Lamiaceae family. The whole plant has aPhytochemistry pleasant aroma [123,124]. The phytochemistry of Ocimum sanctum is identified in all parts of this plant, containing many nutrients and bioactive constituents. However, the quantity of these constituents depends on many natural factors, including growing, harvesting, storage conditions [125,126]. Biology 2020, 9, 252 14 of 31 Biology 2020, 9, x FOR PEER REVIEW 14 of 31

(a) (b)

Figure 13. Ocimum sanctum L.: ( (aa)) whole whole plant plant and and ( (b)) leaves. leaves.

PhytochemistryIn leaf extract of O. sanctum, volatile oil was extracted and identified chemical compositions, containing many major components like eugenol, methyleugenol, and p-caryophylen. The essential The phytochemistry of Ocimum sanctum is identified in all parts of this plant, containing many oil of this herb contains various bioactive compounds, such as terpenoids, esters, aliphatic aldehydes nutrients and bioactive constituents. However, the quantity of these constituents depends on many and phenolic acids. This herb also consists of a diversity of second metabolites, including phenolics, natural factors, including growing, harvesting, storage conditions [125,126]. flavonoids, terpenoids, lignans, steroids, fatty acids and their derivatives. These components have In leaf extract of O. sanctum, volatile oil was extracted and identified chemical compositions, been mainly studied for therapeutic purposes because of their biological and pharmacological effects, containing many major components like eugenol, methyleugenol, and p-caryophylen. The essential including antioxidant, anti-inflammatory, antimicrobial, anticancer and antidiabetic activity [125]. oil of this herb contains various bioactive compounds, such as terpenoids, esters, aliphatic aldehydes andAntidiabetic phenolic Activityacids. This herb also consists of a diversity of second metabolites, including phenolics, flavonoids, terpenoids, lignans, steroids, fatty acids and their derivatives. These components have In Hannan’s study, there are four fractions of Ocimum sanctum including the ethanol, aqueous, been mainly studied for therapeutic purposes because of their biological and pharmacological effects, butanol, and ethyl acetate fractions prepared to elucidate the mechanism of antihyperglycemic activity including antioxidant, anti-inflammatory, antimicrobial, anticancer and antidiabetic activity [125]. of this plant showed in literature [127]. This result proved that these fractions could stimulate insulin Antidiabeticsecretion. This Activity study also indicates that the ethanol extract could decrease blood glucose concentration and increase insulin secretion, thereby this plant is a potential herb in diabetic treatment. Moreover, by in vivoIn Hannan’sexperiment, study, the O. ther sanctume are fourextract fractions was showed of Ocimum to be sanctum able to including improveoral the glucoseethanol, tolerance,aqueous, butanol,decrease serumand ethyl glucose, acetate increase fractions glycogen prepared synthesis to elucidate in the liver the [ 128mechanism]. of antihyperglycemic activityIt was of this reported plant showed that leaf in power literature extract [127]. lowered This result plasma proved glucose that thes levele byfractions the presence could stimulate of many insulinactive phytochemicals secretion. This includingstudy also eugenol, indicates carvacrol, that the linalool,ethanol caryophylline,extract could decreaseβ-sitosterol blood which glucose have concentrationbeen studied aboutand potentincrease hypoglycemic insulin secretion, effects ther efficiencyeby this [76 ].plant The otheris a potential investigation herb has in reporteddiabetic treatment.the antidiabetic Moreover, and by hypoglycemic in vivo experiment, activities the of O. a sanctum triterpenoid extract (16-hydroxy-4,4,10,13-tetramethyl- was showed to be able to improve 17-(4-methyl-pentyl)-hexadecahydro-cyclopenta[a]phenanthrene-3-one)oral glucose tolerance, decrease serum glucose, increase glycogen synthesis isolated in the from liverOcimum [128].sanctum by inIt vivo wasinvestigation reported that [129 leaf]. power The mechanisms extract lowered of the plasma antidiabetic glucose and level hypoglycemic by the presence potential of ofmany this activecompound phytochemicals were elucidated including to increase eugenol, the carvacrol, pancreatic linalool, secretion caryophylline, of insulin from β-sitosterolβ-cells, and which enhance have beenglucose studied utilization about [ 129potent]. It hypoglycemic was suggested effects that this effi triterpenoidciency [76]. shouldThe other be consideredinvestigation to behas developed reported theas a antidiabetic potential antidiabetic and hypoglycemic medicine. activities This evidences of a triterpenoid support (16-hydroxy-4,4,10,13-tetramethyl-17- that O. sanctum has many benefits in (4-methyl-pentyl)-hexadecahydro-cyclopenta[a]phenanthrene-3-one)the management of diabetes, and this plant should be encouraged isolated to be a potentialfrom Ocimum anti-diabetic sanctum byactivity in vivo [130 investigation]. [129]. The mechanisms of the antidiabetic and hypoglycemic potential of this compound were elucidated to increase the pancreatic secretion of insulin from β-cells, and enhance glucose3.5. Bioactive utilization Compounds [129]. HaveIt was Oxygen suggested Radical that Scavenging this triterpenoid Activity should be considered to be developed as a potential antidiabetic medicine. This evidences support that O. sanctum has many benefits in the As displayed above, the fruit juice of Momordica charantia herb was determined to be an antioxidant management of diabetes, and this plant should be encouraged to be a potential anti-diabetic activity composition because of the radical scavenging effect of the butanol fraction from M. charantia [130]. extract [131]. As the same result, in 2014, Tsai TH et al. demonstrated antioxidant activity and 3.5. Bioactive Compounds Have Oxygen Radical Scavenging Activity Biology 2020,, 9,, xx FORFOR PEERPEER REVIEWREVIEW 15 of 31

BiologyAs2020 displayed, 9, 252 above, the fruit juice of Momordica charantia herb was determined to 15be of an 31 antioxidant composition because of the radical scavenging effect of the butanol fraction from M. charantia extract [131]. As the same result, in 2014, Tsai TH et al. demonstrated antioxidant activity andcell-protective cell-protective activity activity of M. of charantia M. charantiaextract extract because because this herbthis herb extract extract could could scavenge scavenge several several free freeradicals radicals [132 [132].]. The The antidiabetic antidiabetic action action of ofMomordica Momordica charantia charantiahas hasbeen been elucidatedelucidated through this mechanism. The The efficacy efficacy of of some some Indian Indian ayurvedic ayurvedic plant plant extracts, including including MomordicaMomordica charantia, charantia, Eugenia jambolana (Figure 14)14),, Tinospora cordifolia and pruriens (Figure 15)15) was investigatedinvestigated for the prevention of diabeticdiabetic cataractcataract in vivovivo.. The results showed that Momordica charantia and Eugenia jambolana hadhad betterbetter protectiveprotective activity activity in in the the development development of of diabetic diabetic cataract cataract as as compared compared to toTinospora Tinospora cordifolia cordifoliaand andMucuna Mucuna pruriens pruriens[133 [133].].

FigureFigure 14. 14. EugeniaEugenia jambolana jambolana..

FigureFigure 15.15. MucunaMucuna pruriens pruriens..

3.6. Bioactive Bioactive Compounds Compounds Inhibit Inhibit Alpha-Glucosidase Alpha-Glucosidase and Alpha-Amylase Activities Salivary or or pancreatic pancreatic alpha-amylase alpha-amylase is an is anenzyme enzyme that that catalyzes catalyzes to hydrolyze to hydrolyze α-bondsα-bonds of large, of αlarge,-linkedα-linked polysaccharides, polysaccharides, such as suchstarch as in starch plants in and plants glycogen and glycogen in animals in and animals humans, and to humans, create monosaccharideto create monosaccharide as glucose. as α-glucosidase glucose. α-glucosidase is an enzyme is located an enzyme in the small located intestine in the that small hydrolyses intestine that hydrolyses terminal non-reducing→ (1 4)-linked α-glucose residues to release a single α-glucose terminal non-reducing (1 4)-linked α-glucose→ residues to release a single α-glucose molecule. α- amylasemolecule. andα-amylase α-glucosidase and α are-glucosidase important aredigestive important enzyme digestives affecting enzymes blood a glucoseffecting concentration, blood glucose especiallyconcentration, with especially patients within di patientsabetes mellitus. in diabetes The mellitus. action Theof these action enzymes of these enzymesincreases increases glucose concentrationglucose concentration causing causinghyperlycemic hyperlycemic status related status relatedto diabetes to diabetes mellitus. mellitus. So, the So,inhibition the inhibition of the action of the ofaction these of enzymes these enzymes is one of is onethe most of the important most important keys in keys diabetes in diabetes treatment treatment [134–138]. [134– Many138]. Many herbs herbshave beenhave beenreported reported so that so thatvarious various phytoconstituents phytoconstituents isolated isolated from from these these plants plants had had potential potential inhibitory inhibitory activities of two enzymes, thereby focusing on traditional medicine hashas beenbeen noticed.noticed. Biology 2020, 9, 252 16 of 31 Biology 2020, 9, x FOR PEER REVIEW 16 of 31

3.6.1. CostusCostus pictus pictus (Zingiberacea)(Zingiberacea) Costus pictus D. Don, commonly known as ‘insulin plant’ belongs to the Zingiberacea family (Figure 1616).). It It has has been been famous famous for for antidiabetic antidiabetic acti activityvity and is used used as as a a traditional traditional dietary dietary supplement supplement for diabetes treatment in Southern India [[139].139].

Figure 16. Costus pictus D. Don.

Phytochemistry The analysis of phytochemicals of C. pictus has been reported that most parts of insulin plant including stem,stem, leaves,leaves, rhizome rhizome and and flowers are are a diversity a diversity of primary of primary and secondaryand secondary metabolites metabolites [139]. [139].Among Among them, therethem, are there many are groups many of groups secondary of metabolites,secondary metabolites, including alkaloids, including saccharides, alkaloids, saccharides,terpenoids, glycosides,terpenoids, steroids,glycosides, tannins, steroids, saponins, tannins, phenols, saponins, flavonoids, phenols, etc.flavonoids, [140–143 etc.]. Besides [140–143]. the Besidesextract ofthe this extract herb of also this contains herb also trace contains elements trace such elements as K, Ca, such Cr, as Mn, K, Cu,Ca, Cr, and Mn, Zn [Cu,144 ].and Zn [144].

Antidiabetic Activity Until now,now, various various investigations investigations have have been been carried carried on anon insulin an insulin plant toplant determine to determine anti-diabetic anti- diabeticactivity [activity143]. The [143].in vitro Thestudy in vitro was study undertaken was undertaken to investigate to investigate the effects of the the effectsC. pictus of .the The C. result pictus of. Thethat result investigation of that showedinvestigation that theshowed significant that the mechanism significant of antidiabeticmechanism of activity antidiabetic of Costus activity pictus ofis α α Costusthe -amylase pictus is andthe α-amylase-glucosidase and inhibitory α-glucosidase activity. inhibitory In other activity. research, In theother ethanolic research, and the methanolic ethanolic andextracts methanolic of C. pictus extractswhich of have C. pictus been administratedwhich have been orally administrated to streptozotocin orally and to alloxan-induced streptozotocin and rats alloxan-inducedhave shown a significant rats have reduction shown a in significant the blood sugarreduction level, in and the also blood could sugar increase level, insulin and also level could [144]. increaseAlong with insulin the identification level [144]. Along of trace with elements the identification like K, Ca, Cr, of Mn, trace Cu, elements and Zn stimulates like K, Ca, the Cr, antidiabetic Mn, Cu, andproperty. Zn stimulates The other the study antidiabetic also reported property. that antidiabeticThe other study property also reported on streptozotocin-induced that antidiabetic property diabetic onrats streptozotocin-induced and in vitro pancreatic diabetic islet culture rats ofandC. in pictus vitro. Inhibition pancreatic of islet carbohydrates culture of C. hydrolysing pictus. Inhibition enzymes of α α carbohydratesactivity like -amylase hydrolysing and enzymes-glucosidase activity also like gave α-amylase good results and α-glucosidase [145,146]. In also 2009, gave G. Gireeshgood results et al. [145,146].carried out In an 2009,in vivo G. Gireeshexperiment et al. of carriedC. pistus outleaf an to in determine vivo experiment antihyperglycemic of C. pistus activity leaf to anddetermine insulin antihyperglycemicsecretion in diabetic activity rats. Their and resultsinsulin suggested secretion thatin diabetic insulin rats. plant Their could results lower suggested glucose concentration, that insulin plantincrease could insulin lower secretion, glucose andconcentration, also enhance increase glucose insulin utilization secretion, [147]. and Another also enhancein vitro studyglucose in β utilization2010 showed [147]. that AnotherCostus pictusin vitroextracts study in could 2010 stimulate showed that insulin Costus secretion pictus extracts from -cells could of stimulate islets of insulinLangerhans secretion [148 ].from β-cells of islets of Langerhans [148]. 3.6.2. Phaseolus vulgaris (Leguminosae) 3.6.2. Phaseolus vulgaris (Leguminosae) Phaseolus vulgaris L. (P. vulgaris) belongs to the Leguminosae family, commonly known as kidney Phaseolus vulgaris L. (P. vulgaris) belongs to the Leguminosae family, commonly known as kidney bean, which is a food item of mass consumption in Asia and Eastern countries [149]. P. vulgaris is an bean, which is a food item of mass consumption in Asia and Eastern countries [149]. P. vulgaris is an annual, herbaceous plant which its main root grows deeply so that this plant has good tolerance with changes of climate. In Vietnam, its fresh beans have been used as a daily vegetable. Biology 2020, 9, 252 17 of 31 annual, herbaceous plant which its main root grows deeply so that this plant has good tolerance with changes of climate. In Vietnam, its fresh beans have been used as a daily vegetable.

Phytochemistry P. vulgaris has been reported that is an important source of primary and secondary metabolites necessary in a healthy diet of humans. By using the HPLC technique to separate constituents’ efficiency, the phytochemicals of P. vulgaris were identified successfully [149–151]. These compounds could be divided into different groups displayed in Table4.

Table 4. Some major isolated phytoconstituents on P. vulgaris.

Group Phytochemical Compound Hydroxybezoic acid and derivatives flavonoids, anthocyanins, flavonols, flavanols, isoflavones, Phenolic acids flavanones, proanthocyanidins, and tannins Hydroxycinnamic acid and derivatives Orientin, isoerientin, rutin, myricetin, luteolin, quercetin, kaempferol, myricetin-3-rhamnoside, Flavonoids hyperoside, isorhamnetin-3-glucoside, isoquercitirn Proteins Vicilin, phytohenmagglutinin, alpha-amylase inhibitor (α-AI1, α-AI2, and α-AIL)

Antidiabetic Activity Various previous studies have shown that seeds of kidney bean have α-amylase inhibitors inhibiting α-amylase activities in animals and insects, related to control type-2 diabetes mellitus by inhibition of DPP-IV,and a lectin called phytohaemoagglutinin could adjust the activity of glucagon-like peptides GLP-1 (glucagon-like peptide-1) [152–154]. The common bean P. vulgaris have three isoforms of α-amylase inhibitor including α-AI1 (known as phaseolamin), α-AI2, and α-AIL, which has been identified and tested in numerous clinical studies against α-amylase action [152,155]. The mechanism of action of these enzyme inhibitors indicated that they could reduce the carbohydrate absorption by inhibiting the activity of α-amylases of mammals and insects [155,156]. The reduction of the glycemic index may also limit the risks of insulin resistance in diabetes mellitus, thereby control the serious consequences of the disease. Recently, another investigation continues to determine α-amylase inhibition of P. vulgaris extract [157]. The present study also indicated that α-amylase inhibitor inhibited the α-amylase activity significantly, and prolonged treatment with P. vulgaris extract could reduce several problems related to diabetes mellitus.

3.6.3. Euphorbia hirta Linn. (Euphorbiaceae) Euphorbia hirta Linn. (E. hirta) is a common herb that belongs to Euphorbia genus of Euphorbiaceae family. Euphorbia hirta L. is found in pan-tropic, partly sub-tropic areas and worldwide including Australia, Western Australia, Northern Australia, Queensland, New south wales, Central America, Africa, Indonesia, Malaysia, Philippines, China and India [158]. In Vietnam, Euphorbia hirta L. is commonly distributed in many provinces of the southern area (Figure 17). Euphorbia hirta L. was used as a traditional medicine in the treatment of diabetes for a long time ago [158–161]. The strong anti-diabetes activity of Euphorbiaceae family in general and E. hirta, in particular, was reviewed in 2006 [84]. Unambiguously, E. hirta can serve as a potential candidate to develop newline anti-diabetes drugs in the future. Biology 2020, 9, x FOR PEER REVIEW 18 of 31 BiologyBiology2020, 9 20, 25220, 9, x FOR PEER REVIEW 18 of 3118 of 31 BiologyBiology 2020, 9 20, x20 FOR, 9, xPEER FOR REVIEWPEER REVIEW 18 of 3118 of 31

(a) (b) (a) (b) Figure 17. Euphorbia(a) hirta(a) Linn.: (a) fresh whole plant and (b) plant(b) specimen. Figure 17. Euphorbia hirta Linn.: (a) fresh whole plant and (b) plant specimen. FigureFigure 17. Euphorbia 17. Euphorbia hirta Linn Linn.:hirta. :Linn ( (aa)) fresh fresh.: (a) wholefresh whole whole plant plant plantand and ( ( bband)) plant plant (b) plantspecimen. specimen. specimen . Phytochemistry Phytochemistry PhytochemistryPhytochemistryEuphorbia hirta contains various bioactive compounds, including flavonoids, terpenoids, Euphorbia hirta contains various bioactive compounds, including flavonoids, terpenoids, Euphorbiaphenols,Euphorbia essential hirta contains hirta oil andcontains various other compounds bioactivevarious bioactive compounds, (Table 5 compounds,). Some including flavonoids flavonoids, including have been terpenoids, flavonoids, identified phenols, terpenoids, in E. hirta Euphorbiaphenols, essential hirta contains oil and othervarious compounds bioactive (Table compound 5). Somes, flavonoidsincluding haveflavonoids, been identified terpenoids, in E. hirta essentialincludingphenols, oil and essential q otheruercetin, compounds oil and quercitrin, other (Table compounds quercitol5). Some and( flavonoidsTable derivatives 5). Some have .flavonoids been Isolated identified t haveerpenoids been in E. identified hirtain E.including hirta in include E. hirta phenols,including essential quercetin, oil and other quercitrin, compounds quercitol (Table and 5). derivativesSome flavonoids. Isolated have t erpenoidsbeen identified in E. in hirta E. hirta include quercetin,tincludingriterpenoids, quercitrin, quercetin, α- quercitolamyrin, quercitrin, β and-amyrin, derivatives. quercitol friedelin, and Isolated derivativesteraxerol, terpenoids cycloartenol,. Isolated in E. hirtaterpenoids 24include-methylene in triterpenoids, E. - hirtacycloartenol, include includingtriterpenoids, quercetin, α -quercitrin,amyrin, β -quercitoamyrin, l friedelin,and derivatives. teraxerol, Isol cycloartenol,ated terpenoids 24 -methylenein E. hirta- cycloartenol,include α-amyrin,ingenoltriterpenoids,β-amyrin, triacetate α- friedelin,amyrin, β- sitosterol, teraxerol,β-amyrin, campestrol, cycloartenol, friedelin, stigmasterol teraxerol, 24-methylene-cycloartenol, and cycloartenol, so on. Some complex 24-methylene ingenol tannins triacetate-cycloartenol, have been triterpenoids,ingenol triacetate α-amyrin, β- sitosterol,β-amyrin, campestrol, friedelin, teraxerol,stigmasterol cycloa and rtenol,so on. Some24-methylene-cycloartenol, complex tannins have been β-sitosterol,alsoingenol determined campestrol,triacetate in β -E. stigmasterolsitosterol, hirta extract, campestrol, and such so asd on. stigmasterolimeric Some hydrolysable complex and tanninsso on. dehydro Some have complexellagic been also tannins, tannins determined euphorbins have been ingenolalso triacetate determined β- sitosterol, in E. hirta campestrol, extract, such stigmasterol asdimeric hydrolysable and so on. Some dehydro complex ellagic tannins tannins, have euphorbins been in E.A,also hirta B, determined extract, C, E, etc. such interchebin, E. asdimeric hirta extract, the hydrolysable monomeric such asdimeric hydrolysable dehydro hydrolysable ellagic tannins tannins, dehydro geraniin, euphorbins ellagic 2,4,6 tannins,-tri A,-o- B,galloyl euphorbins C, E,-β-D- also determinedA, B, C, E, in etc. E. hirtaterchebin, extract, the such monomeric asdimeric hydrolysablehydrolysable dehydro tannins geraniin,ellagic tannins, 2,4,6-tri euphorbins-o-galloyl- β-D- etc.glucoseA, terchebin, B, C, and E, the etc. 1,2,3,4,6 monomeric terchebin,-penta hydrolysable the-O- galloyl monomeric-β-D tannins-glucose hydrolysable geraniin, and the tannins 2,4,6-tri-o-galloyl- esters geraniin, 5-O-caffeoyl 2,4,6β-d -glucose- quinictri-o-galloyl acid and -β (neo-D- A, B,glucose C, E, etc. and terchebin, 1,2,3,4,6- pentthe amonomeric-O-galloyl- βhy-Ddrolysable-glucose and tannins the estersgeraniin, 5-O 2,4,6-tri-o-galloyl--caffeoyl quinic acidβ-D- (neo 1,2,3,4,6-penta-O-galloyl-chlorogenicglucose and acid), 1,2,3,4,6 3,4β -–d-pentdi-glucose-o-agalloyl-O-galloyl and quinic the-β esters-D acid-glucose 5-O-caand benzyl ff andeoyl thegallate quinic esters acid[159 5, (neo160].-O-caffeoyl chlorogenic quinic acid), acid 3,4 (neo glucosechlorogenic and 1,2,3,4,6-penta-O-galloyl- acid), 3,4 –di-o-galloylβ quinic-D-glucose acid andand benzyl the esters gallate 5-O-caffeoyl [159,160]. quinic acid (neo –di-o-galloylchlorogenicchlorogenic acid), quinic acid), 3,4 acid –di-o-galloyl 3,4 and –di benzyl-o-galloyl quinic gallate quinic acid [159 andacid,160 benzyl ].and benzyl gallate gallate [159,160]. [159, 160]. Table 5. Some major isolated phytoconstituents on Euphorbia hirta L. Table 5. Some major isolated phytoconstituents on Euphorbia hirta L. Table 5. Some major isolated phytoconstituents on Euphorbia hirta L. GroupTable Table 5. Some 5. Somemajor major isolatedCompound isolated phytoconstituents Name phytoconstituents on Euphorbia onStructure Euphorbia hirta L. ofhirta Compound L. Group Compound Name Structure of Compound GroupGroupGroup Compound CompoundCompound Name Name Name StructureStructure of Compound of Compound

Quercetin Quercetin QuercetinQuercetinQuercetin

Flavonols

FlavonolsFlavonols FlavonolsFlavonols

KaempferolKaempferol KaempferolKaempferol Kaempferol

Leucoanthocyanidins Leucocyanidin LeucoanthocyanidinsLeucoanthocyanidins LeucocyanidinLeucocyanidin Leucoanthocyanidins Leucocyanidin Leucoanthocyanidins Leucocyanidin

Biology 2020, 9, 252 19 of 31 Biology 2020, 9, x FOR PEER REVIEW 19 of 31 Biology 2020, 9, x FOR PEER REVIEW 19 of 31 Biology 2020, 9, x FOR PEER REVIEW 19 of 31 Biology 2020, 9, x FOR PEER REVIEW 19 of 31 Biology 2020, 9, x FOR PEER REVIEW Table 5. Cont. 19 of 31 Biology 2020, 9, x FOR PEER REVIEW 19 of 31 Group Compound Name Structure of Compound

Rutin Rutin Rutin Rutin Rutin RutinRutin

Quercitrin Quercitrin Quercitrin Quercitrin QuercitrinQuercitrin Quercitrin

Myricitrin Myricitrin Myricitrin Flavonoid glycosides MyricitrinMyricitrin Flavonoid glycosides Myricitrin Flavonoid glycosides Myricitrin Flavonoid glycosides Flavonoid glycosides Flavonoid glycosides Flavonoid glycosides

Afzelin Afzelin AfzelinAfzelin Afzelin Afzelin Afzelin

Luteolin-7-O-glucoside Luteolin-7-O-glucosideLuteolin-7-O-glucoside Luteolin-7-O-glucoside Luteolin-7-O-glucoside Luteolin-7-O-glucoside Luteolin-7-O-glucoside

IsoquercitrinIsoquercitrin Isoquercitrin Isoquercitrin Isoquercitrin Isoquercitrin Isoquercitrin

Biology 2020, 9, x FOR PEER REVIEW 20 of 31 Biology 2020, 9, x FOR PEER REVIEW 20 of 31 Biology 2020, 9, 252 20 of 31 Biology 2020, 9, x FOR PEER REVIEW 20 of 31 Biology 2020, 9, x FOR PEER REVIEW 20 of 31 Biology 2020, 9, x FOR PEER REVIEW 20 of 31 Biology 2020, 9, x FOR PEER REVIEW Table 5. Cont. 20 of 31 Biology 2020, 9, x FOR PEER REVIEW 20 of 31

Group CompoundSyringic Name acid Structure of Compound Syringic acid Syringic acid Syringic acid Syringic acid Syringic acid SyringicSyringic acid acid

Ellagic acid Ellagic acid Ellagic acid Ellagic acid Ellagic acid

EllagicEllagic acid acid Acids Ellagic acid Acids Acids Acids Acids Acids Acids Gallic acid Acids Gallic acid Gallic acid Gallic acid GallicGallic acid acid Gallic acid

Gallic acid

Shikimic acid Shikimic acid Shikimic acid ShikimicShikimic acid acid Shikimic acid Shikimic acid Shikimic acid

Terpenoids 2β,16α-dihydroxy-ent-kaurane Terpenoids 2β,16α-dihydroxy-ent-kaurane TerpenoidsTerpenoids 2β2β,16α,16α-dihydroxy-ent-kaurane-dihydroxy-ent-kaurane Terpenoids 2β,16α-dihydroxy-ent-kaurane

Terpenoids 2β,16α-dihydroxy-ent-kaurane Terpenoids 2β,16α-dihydroxy-ent-kaurane Terpenoids 2β,16α-dihydroxy-ent-kaurane

β-sitosterol β-sitosterolβ-sitosterol β-sitosterol β-sitosterol β-sitosterol Sterols β-sitosterol Sterols Sterols β-sitosterol Sterols Sterols Sterols Sterols StigmasterolStigmasterol Sterols Stigmasterol Stigmasterol Stigmasterol Stigmasterol Stigmasterol Stigmasterol Anti-Diabetic Activity Anti-Diabetic Activity Anti-Diabetic Activity Anti-Diabetic Activity Anti-Diabetic Activity Anti-Diabetic Activity Anti-Diabetic Activity Biology 2020, 9, 252 21 of 31

Anti-Diabetic Activity The ethanolic extract of Euphorbia hirta was reported to be able to decrease blood glucose level (hypoglycemic effect) on alloxan-induced diabetic rats. From other in vitro experiments, ethanol extract and ethyl acetate fractions inhibit α-glucosidase activity. In vivo tests also had the same result. [158–160]. The presence of various bioactive compounds, especially in chloroform and ethyl acetate extracts demonstrated the ability in the treatment of diabetes by inhibition of enzymes involving in the metabolism of saccharides such as α-amylase [161]. Polyphenolic compounds have popularly reported inhibitory activity against α-amylase in both in vitro and in vivo experiments. Phenolics and flavonoids found in E. hirta such as quercetin, quercitrin, and rutin have been proved to be effective inhibitors of mammalian α-amylase. Although the α-amylase inhibitory activity of E. hirta powder is not strong enough as acarbose—a standard drug in diabetes treatment—it also proved that E. hirta had mild α-amylase inhibition. Until 2010 Sunil Kumar, Rashmi and D. Kumar presented the evaluation of the antidiabetic activity of Euphorbia hirta Linn. in streptozotocin-induced diabetic mice [160]. In 2014, the ethanolic extract of Euphorbia hirta was reported that it can decrease blood glucose level (hypoglycemic effect) on alloxan-induced diabetic rats. From other in vitro experiments, ethanol extract and ethyl acetate fractions inhibited α-glucosidase activity. In vivo tests also had the same result [158]. In 2015 Manjur Ali Sheliya and his partners studied the inhibition of α-glucosidase by new prenylated flavonoids from E. hirta [162] isolated from ethyl acetate fraction of methanolic extract. By using medium pressure liquid chromatography technique, they successfully isolated four active compounds, including quercetrin (1), dimethoxy quercetrin (2), hirtacoumaroflavonoside (7-O-(p-coumaroyl)-5,7,40-trihydroxy-6-(3,3-dimethylallyl)-flavonol-3-O-β-d- glucopyranosyl-(2”-1”0)-O-α-l-rhamnopyranoside) (3) and hirtaflavonoside-B (5,7,30,40-trihydroxy-6- (3,3-dimethylallyl)-8-(iso-butenyl)-flavonol-3-C-β-d-glucopyranoside) (4) respectively. The α-glucosidase inhibitory activity of isolated compounds was evaluated and compared with standard drug acarbose. The result showed that those flavonoids increased α-glucosidase inhibition. That study provides credence to the ethnomedicinal use of E. hirta in the management of diabetes in folk medicine. In 2016 Manjur Ali Sheliya and his group continued to investigate in vitro α-glucosidase and α-amylase inhibition by aqueous, hydroalcoholic, and alcoholic extract of E. hirta [163]. According to their study, the result clearly indicated that the metholic extract of E. hirta had strong inhibitory activity against α-glucosidase and quietly mild inhibitory activity against α-amylase, two proteins involved in diabetes mellitus directly. E. hirta extract can be used for control of postprandial hyperglycemia with lesser side effects, and provide good material for further studies on treatment type 2 diabetes mellitus. An in silico study, In 2013 Dr. Ly Le and her group investigated antidiabetic activities of bioactive compounds in Euphorbia hirta Linn using molecular docking and pharmacophore [164]. This study demonstrated the effect of bioactive compounds isolated in E. hirta on some proteins relating to diabetes type 2, including α-glucosidase and α-amylase by evaluating whether a relationship exists between various bioactive compounds in E. hirta and targeted protein relating diabetes type 2 in human. By calculating the binding energy and pharmacophore modeling, eight promising compounds in E. hirta were obtained, including cyanidi 3,5-O-diglucose, myricitrin, pelargonium-3,5-diglucose, quercitrin, rutin, α-amyrine, β-amyrine, and taraxerol. The results of that investigation showed that those bioactive compounds have the potential in developing medication for type 2 diabetes mellitus. However, the combination of using the molecular dynamic technique is required to determine more accurate binding affinities and the stability of ligand–proteins’ interactions. Thus, the research results in silico and in vitro studies have shown that this plant has the ability to inhibit two enzymes.

3.7. Bioactive Compounds Increase Glucose Utilization Some medicinal plants such as Cyamospsis tetragonolobus (Gowar plant) [165], Grewia asiatica (phalsa) [166] and Zingiber officinale Rosc (ginger) [166], were reported their hypoglycemic activity by moderating glucose utilization in the body [167]. This part only displays about Zingiber officinale Rosc. because this herb has been popular and useful in Vietnam. Biology 2020, 9, 252 22 of 31

3.7.1. Zingiber officinale Rosc (Ginger) It is a traditionally flowering spicy plant in the family Zingiberaceae which was originally native to southern China, and has been grown in many countries in the tropical and subtropical areas, from East Asia to Southeast Asia and South Asia. All parts of this plant, including rhizome, ginger root are widelyBiology 2020 used, 9, x as FOR essential PEER REVIEW food spices or traditional medicine (Figure 18)[168,169]. 22 of 31

FigureFigure 18. 18.Zingiber Zingiber oofficinalefficinale Rosc. Rosc.

Phytochemistry The phytochemicals of ginger are quite different different depending on the origin and the fresh or dry state of parts of this herb. The The phytochemicals phytochemicals of of rhizome rhizome ginger ginger contain contain strong strong free-radical free-radical reducing eefficacy.fficacy. They They include include volatile volatile oils, oils, phenolic phenolic compounds compounds and and others. others. Among Among them, them, volatile volatile oils, also oils, alsoknown known as ginger as ginger essentia essentiall oils, oils, are are a mixture a mixture of of terpenoid terpenoid compounds, compounds, including sesquiterpene hydrocarbons, monoterpene hydrocarbons, carbonyl compounds, alcoholsand esters. Especially, the phenolics in ginger are the most important components.components. The phenolic constituents were divided into two groups: gingerol-, gingeron- and shogaol-relatedshogaol-related groupgroup andand diarylheptanoids.diarylheptanoids. Gingerol which is the the spicy spicy component component of of this this plant plant contains contains a dive a diversityrsity of various of various bioactive bioactive substances. substances. Besides, Besides, this thisplant plant also alsocontains contains a variety a variety of ofamino amino acids, acids, including including glutamate, glutamate, aspartic aspartic acid, acid, serine, serine, glycine, threonine, alanine, etc. Moreover, Moreover, ginger also contains polysaccharides and and organic acids, such as oxalic acid, tartaric acid, etc. [[168–170].168–170].

Antidiabetic Activity Antidiabetic Activity Sharma and Shukla reported that ginger juice can lower blood glucose concentration in normal Sharma and Shukla reported that ginger juice can lower blood glucose concentration in normal fasting animals and in alloxan diabetic animals [171]. The mechanism of lowering the glucose effect fasting animals and in alloxan diabetic animals [171]. The mechanism of lowering the glucose effect was explained because it can increase the viscosity of gastrointestinal contents, slow gastric emptying was explained because it can increase the viscosity of gastrointestinal contents, slow gastric emptying and also acts as a barrier to diffusion. Other studies also demonstrated that folk medicinal plant ginger and also acts as a barrier to diffusion. Other studies also demonstrated that folk medicinal plant can control tissue glycogen content in diabetic rats by improving the peripheral utilization of glucose ginger can control tissue glycogen content in diabetic rats by improving the peripheral utilization of and repairing the impaired liver [172]. glucose and repairing the impaired liver [172]. Moreover, the rhizome of Zingiber officinale Rosc also proved that its bioactive components can Moreover, the rhizome of Zingiber officinale Rosc also proved that its bioactive components can enhance glucose uptake in cultured L6 myotubes [173]. That investigation suggested that the phenolic enhance glucose uptake in cultured L6 myotubes [173]. That investigation suggested that the phenolic gingerol constituents were the major active compounds enhancing glucose uptake. Other investigations gingerol constituents were the major active compounds enhancing glucose uptake. Other showed that the solution of the fresh ginger sample exhibited inhibition against alpha-amylase and investigations showed that the solution of the fresh ginger sample exhibited inhibition against alpha- alpha-glucosidase activities and inhibit angiotensin-converting enzyme [174,175]. amylase and alpha-glucosidase activities and inhibit angiotensin-converting enzyme [174,175]. Furthermore, powder of ginger can decrease the level of glucose and activate inflammatory Furthermore, powder of ginger can decrease the level of glucose and activate inflammatory activity which can lead to the development of insulin resistance [176]. activity which can lead to the development of insulin resistance [176].

4. Conclusions Diabetes mellitus has been considered to be a major cause affecting the economy of patients, their families and society. Furthermore, uncontrolled diabetes leads to serious chronic complications such as blindness, kidney failure, and heart failure. In order to decrease this problem, researches on new antidiabetic agents are concerned. Because of the adverse effects of modern therapies, many traditional medicines have been noticed. Moreover, herbal extracts nowadays can be used with standard drugs for combinatorial therapies. Each herb has its own active ingredients that can lower Biology 2020, 9, 252 23 of 31

4. Conclusions Diabetes mellitus has been considered to be a major cause affecting the economy of patients, their families and society. Furthermore, uncontrolled diabetes leads to serious chronic complications such as blindness, kidney failure, and heart failure. In order to decrease this problem, researches on new antidiabetic agents are concerned. Because of the adverse effects of modern therapies, many traditional medicines have been noticed. Moreover, herbal extracts nowadays can be used with standard drugs for combinatorial therapies. Each herb has its own active ingredients that can lower blood sugar levels as well as control the complications of diabetes. Future research will focus on isolation, purification, and identification of bioactive substances in plants. This review is looking forward to providing the necessary information in the management of diabetes. In our review, we have introduced a complete list of anti-diabetic plants taken from the Vietherb database [177]. Isolation and identification of bioactive phytochemicals from these plants play an important role in improving insights into anti-diabetic functional food [161] and drug development [178].

Author Contributions: Conceptualization, N.T. and L.L.; methodology, N.T. and L.L.; software, L.L. and B.P.; validation, N.T. and L.L.; formal analysis, L.L., and N.T.; investigation, N.T., and L.L.; resources, N.T.; data curation, N.T.; writing—original draft preparation, L.L. and N.T.; writing—review and editing, N.T. and L.L.; visualization, L.L. and N.T.; supervision, L.L. and N.T.; project administration, N.T. and L.L.; funding acquisition, B.P. All authors have read and agreed to the published version of the manuscript. Funding: This work was supported by the Asian Office of Aerospace Research and Development (AOARD) under grand number Grant No. FA2386-19-1-4032 Conflicts of Interest: The authors declare no conflict of interest.

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