3.1 Antidiabetic plants may have rich sources of FABP ligands
All FABP ligands react similarly with FABPs and have common structural features: a carboxylic group at one end and a hydrophobic tail at the other end. Thus, the high affinity of drugs, such as the peroxisome proliferator-activated receptors (PPAR) selective drugs, for FABPs has been attributed to their polar head groups, consisting of carboxylic group or thiazolidinedione ring, which likely mimic the interactions involving the FA carboxyl group shown in figure 1 [86,87].
Unfortunately, diabetic patients usually have several comorbidities and need many specific medicaments and avoid the risk of drug interactions. This is valid for some antidiabetic herbs, such as Ephedra sp., that may interfere with blood glucose control and raise blood pressure in diabetes-controlled patients but not in healthy subjects [88]. Thus, in the field of herbal medicine, the direction towards extraction of specific drugs that affect a metabolic target is more effective. The traditional plants are still having some secrets, making them an attractive source that allows for investigating new antidiabetic drugs or uncovering precise antidiabetic functions of their constituents. The aim of this part is to review some of these plants, their antidiabetic mode of action, and their carboxylic acid constituents that may act as potential FABP ligands. The following plants (Table 2) are alphabetically arranged, independent from their relative weight as antidiabetic, worldwide distribution and utilization, how many FABP potential carboxylic acid ligand candidates have been identified or can be extracted from them, etc.
Boswellia sp. (Burseraceae): The genus Boswellia consists of about 25 species widely cultivated in Arabia, the Northeastern coast of Africa, and India [88,89]. Many species of this traditionally medicinal plants, including B. carterii and B. serrata, are used to treat diabetes [88,89]. The gum resin of these herbs has shown its antihyperglycemic effects in both animal and clinical studies [90-95]. It increased insulin secretion and HDL and decreased LDL, inhibited degenerative changes in pancreatic beta cells, and suppressed apoptosis of peri-insular cells. These effects have been attributed to phenyl propanoid, terpenoids, phenolic compounds, and flavonoid components, and especially to ursane, oleanane, and lupine oils α-thujene, α-pinene, myrcene, and p-cymene [96-98].
More than 12 different pentacyclic triterpene boswellic acids have been identified in the gum resin of Boswellia, which have been widely reported to produce anti-inflammatory activity in several models of human disease. In diabetes, 11-Keto-beta-boswellic acid was reported to decrease cytokine burst, lymphocytes infiltration into pancreatic islets, insulitis and blood glucose [99,100].
Cleome sp. (Capparidaceae): The genus Cleome has a sub-cosmopolitan distribution throughout tropical and warm regions of the world such as Arabia, Egypt, India, Pakistan, and Australia. Many Cleome species, including C. rutidosperma, C. gynandra, C. droserifolia, C. amblyocarpa and C. arabica [88,101-106] are traditionally and still used in Sinai, north Africa and other world regions as antihyperglycemic, although the effective phytochemical ingredients responsible for this antidiabetic effect have not yet been determined.
Many carboxylic acids were identified in Cleomes, including the cembranoid diterpene cleomaldic acid ((1E,5E,11E)-11-formyl-5-methyl-8-(prop-1-en-2-yl)cyclotetradeca-1,5,11-trienecarboxylic acid) and paradoxenoic acid ((4Z,10E)-2,14-dihydroxy-5,11-dimethyl-8-(propan-2-ylidene)cyclotetradeca-4,10-dienecarboxylic acid), and the pentacyclic triterpenoid ursolic acid [107]. However, no investigations related to any correlation between these acids with FABPs were found in the literature.
Cyamposis tertragonoloba (Fabaceae): The Cluster Bean is known to have antidiabetic activity due to presence of flavonoids and phenolic compounds. Although this herb was considered for use in the management of type 2 diabetes, its antihyperglycemic effect was significant in alloxan-induced diabetic rats. It could improve insulin release, decrease the amount of HbA1c, and protect beta cells [108-110].
Many polyphenolic carboxylic acids were identified in this plant, including gallic acid and its derivatives, chlorogenic, ellagic, caffeic, gentisic, p-coumaric and p-coumarylquinic acids [111].
Ephedra sinica (Ephedraceae): Ephedra sinica has been established for thousands of years in traditional uses in Korea and China. It was reported to decrease the risks of glucose intolerance and obesity including reducing body weight, weight gain and epididymal fat accumulation, improving glucose intolerance on the OGTT, decreasing triglycerides and increasing high-density lipoprotein cholesterol, decreasing fasting glucose levels and insulin levels in healthy overweight and healthy obese populations [112-115].
Although people with diabetes cannot use Ephedra because this herb interferes with blood sugar control, and could raise high blood pressure and increase circulation problems, yet many carboxylic acids including quinoline-2-carboxylic acid, 4-hydroxy-6-methoxyquinoline-2-carboxylic acid (6-methoxy-kynurenic acid), Kynurenic and 6-hydroxykynurenic acids have been isolated from Ephedra sp. [88]. Quinoline-2-carboxylic acid was reported to bind FABP3 with high affinity [69] and showed inhibitory effects against α-glucosidase and α-amylase [116].
Euphorbia hirta Linn. (Euphorbiaceae): This plant is found in pantropic and sub-tropic areas worldwide, and was used as a traditional medicine in the treatment of diabetes long time ago. Different extracts and many compounds have been isolated from this plant, but the remarkable antidiabetic action was mostly attributed to polyphenolic compounds that were reported to have an inhibitory action against a-amylase and a-glucosidase activities [117-121]
Many carboxylic acids were identified in this plant, including 5-O-caffeoyl quinic acid, 3,4–di-o-galloyl quinic acid, syringic, gallic, ellagic, and shikimic acids [18,122,123].
Gymnema sylvestre (Apocynaceae): This tropical plant from forests of The Southern and Central India and Sri Lanka has been widely used in several countries around the world to treat diabetes [18]. The major antidiabetic active ingredient of G. sylvestre is the triterpene saponin Gymnemic acid, which was reported to stimulate pancreatic cell regeneration, increase insulin secretion and sensitivity, glucose uptake by muscle and adipose tissue, inhibit intestinal glucose absorption and hepatic gluconeogenesis [124-127]. A recent study [128] reported that GiA-7, a purified compound from Gymnema, significantly suppressed fabp4 expression, indicating an early stage of adipogenic differentiation by inhibiting of PPARγ-dependent mechanisms. However, this is the only work in the literature correlating FABP4 with G. sylvestre. Nevertheless, gymnemic acid can be a ligand candidate for FABPs.
Momordica charantia (Cucurbitaceae): Bitter melon is traditionally known antidiabetic plant in many non-connected cultures as in Egypt, China and India, in addition to its general antiinflammatory, antioxidant, antiviral, anticancer, and antibacterial bioactivities [18,129]. Many reports described its antidiabetic actions including: decreasing blood glucose level, enhancement of glucose uptake, stimulating insulin secretion, stimulating intestinal GLP-1 secretion, inhibition of diabetes-related enzymes, such as alpha-glucosidase and alpha-amylase, and activation of PPARs. These effects were obtained after application of different aqueous, alcoholic or acetonic extracts or by extracted constituents including polypeptide P, momordicosides (3β,7β-dihydroxycucurbita-5,23(E)-dien-19-al-25-O-β-d-glucopyranoside), momordin, saponins, conjugated linolenic acid [130-136]. One study [137] reported that ethanolic extract of bitter melon protected pancreatic beta cells in vitro through suppression of cytokine induced activation of MAPK and NF-kB.
Many carboxylic acids can be extracted from bitter melon. These include ferulic, gentisic, rosmarinic, the phenolic brevifolincarboxylic and margarolic acids (α-eleostearic acid (conjugated linolenic acid)). These acids were considered as antioxidants [138].
Panax ginseng (Araliaceae): Ginseng is the most famous traditional plant used in folk medicine in Korea as well as China and many eastern Asian countries. Ginseng was reported to have remarked antidiabetic activities through increasing the glucose uptake in muscle and adipose tissue, decreasing blood glucose level, gluconeogenesis and insulin resistance and enhancing insulin sensitivity. These antidiabetic activities were proven in human and animals and in vivo and in vitro and attributed mostly to the ginseng-specific saponins (so called ginsenosides) [18,139-148].
Ginseng contains many carboxylic acids that may act as FABP ligand candidates. In particular, phenolic acids are more abundant in ginseng fruit, leaves, and roots than the flavonoids and other compounds. Chlorogenic, gentisic, p- and m-coumaric, caffeic, ferulic, vanillic, p-hydroxybenzoic, cinnamic, syringic, 5-O-cumaroylquinic, 4-O-feruloylquinic, 5-O-feruloylquinic, and sinapic acids are abundant in Ginseng [149-154]. Most of them were thought to have antioxidant roles.
Zingiber offcinale Rosc. (Zingiberaceae): Ginger grows in many countries in the tropical and subtropical areas and used widely as a spice and a traditional pharmacy. Ginger has wide therapeutic potential in type 2 diabetes and against diabetic complications. It is known to interact directly with different molecular and cellular pathways that provoke the pathogenesis of type 2 diabetes. Investigations showed that ginger renders its antidiabetic effects through decreasing fasting blood glucose by improving its peripheral utilization. Its phenolic gingerol constituent is the major active compound enhancing glucose uptake. Ginger also inhibits a-amylase and a-glucosidase activities and angiotensin-converting enzyme [155-160]
Similar to other antidiabetic plants, many carboxylic acids were identified in ginger. Pyrogallol p-hydroxybenzoic, ferulic and p-coumaric acids are more abundant than other acids including gallic, caffeic, syringic, and ellagic acids [161].
Table 2. Plants traditionally used in the treatment of diabetes and their carboxylic acids
Plant name
(Common name)
|
Family
|
Distribution
|
Antidiabetic effect
|
Effective antidiabetic ingredients
|
Carboxylic acids
|
Reported action of carboxylic acids
|
References
|
Boswellia sp.1 (Frankincense or olibanum-tree)
|
Burseraceae
|
Arabia, Northeastern Africa, India
|
Antihyperglycemic,
increased insulin secretion,
inhibited beta cells degeneration.
|
phenyl propanoid, terpenoids, phenolic compounds, and flavonoids
|
boswellic family
|
anti-inflammatory
|
[88-100]
|
Cleome sp.
(Spider plants)
|
Capparidaceae
|
Arabia, north Africa, India, Pakistan, and Australia
|
Antihyperglycemic, antioxidant
|
flavonoids (quercetin, kaempferol, artemitin)
|
cleomaldic, paradoxenoic, ursolic
|
antioxidant
|
[102-107]
|
Cyamposis tertragonoloba
(Cluster bean)
|
Fabaceae
|
Tropical areas: India, Pakistan, USA, Africa, Australia
|
improve insulin release,
decrease the amount of HbA1c
protect beta cells
|
flavonoids and phenolic compounds
|
gallic, chlorogenic, ellagic, caffeic, gentisic, p-coumaric, p-coumarylquinic
|
antioxidant
|
[108-110]
|
Ephedra sinica
(Chinese ephedra)
|
Ephedraceae
|
China and Korea
|
reduce body weight and weight gain, fasting glucose levels and insulin levels
improve OGTT,
decrease triglycerides and increase HDL
|
Ephedrine
|
quinoline-2- carboxylic, 6-methoxy-kynurenic, Kynurenic,
6-hydroxykynurenic
|
inhibitory effects against α-glucosidase and α-amylase
|
[112-116]
|
Euphorbia hirta Linn. (garden spurge)
|
Euphorbiaceae
|
worldwide in pantropic and sub-tropic areas
|
inhibit a-amylase and a-glucosidase activities
|
polyphenolic compounds
|
5-O-caffeoyl quinic, ellagic, 3,4–di-o-galloyl quinic, syringic, gallic, shikimic
|
antioxidant
|
[117-123]
|
Gymnema sylvestre
(Australian cowplant)
|
Apocynaceae
|
Southern and Central India and Sri Lanka, several tropical countries
|
increase insulin secretion and sensitivity, glucose uptake by muscle and adipose tissue, inhibit intestinal glucose absorption and hepatic gluconeogenesis
|
the triterpene saponin Gymnemic acid
|
gymnemic acid
|
Antidiabetic, stimulate beta cell regeneration
|
[124-126]
|
Momordica charantia
(Bitter melon)
|
Cucurbitaceae
|
Egypt, China and India
|
decrease blood glucose,
enhance glucose uptake,
stimulate insulin secretion,
stimulate intestinal GLP-1 secretion,
inhibition of alpha-glucosidase and alpha-amylase,
activation of PPARs
|
polypeptide P, momordicosides (3β,7β-dihydroxycucurbita-5,23(E)-dien-19-al-25-O-β-d-glucopyranoside), momordin, saponins, conjugated linolenic acid
|
α-eleostearic, ferulic, gentisic, rosmarinic, brevifolincarboxylic
|
antioxidant
|
[129-138]
|
Panax ginseng (Ginseng)
|
Araliaceae
|
Korea, China, most eastern Asian countries
|
increasing the glucose uptake in muscle and adipose tissue, decreasing blood glucose level, gluconeogenesis and insulin resistance and enhancing insulin sensitivity
|
saponins (ginsenosides)
|
Chlorogenic, gentisic, coumaric, caffeic, ferulic, vanillic, p-hydroxybenzoic, sinapic cinnamic, syringic, 5-O-cumaroylquinic, feruloylquinic
|
antioxidant
|
[139-154]
|
Zingiber offcinale Rosc. (Ginger)
|
Zingiberaceae
|
Worldwide spice, tropical and subtropical
|
decrease fasting blood glucose,
improve glucose peripheral utilization,
inhibits α-amylase and α-glucosidase activities and angiotensin-converting enzyme
|
gingerol
|
Pyrogallol hydroxybenzoic, ferulic
p-coumaric, gallic, caffeic, syringic, ellagic
|
antioxidant
|
[155-161]
|
1. More than 1 species of this genus have antidiabetic actions.
3.2 Most FABP carboxylic ligand candidates from antidiabetic plants are phenolic acids that have a relevance to diabetes
Most of the naturally occurring carboxylic acids mentioned above (Figure 2) are identified in several antidiabetic plants. These acids are also not restricted to antihyperglycemic plants, but dispersed largely in many plant families. The hydrophobic tails of these acids are mostly aromatic and phenolic or polyphenolic in nature. This aromaticity and high conjugation with multiple hydroxyl groups are advantageous, making these phenolic acids good electron or hydrogen atom donors, allowing them to neutralize free radicals and other reactive oxygen species [162]. Therefore, they are always considered as antioxidants and anti-inflammatory [163]. It is also suggested that more consumption of polyphenol as a diet constituent is correlated with a lower risk of developing diabetes [164,165]. Consumption of dietary phenolic acids improved indices of diabetes risk by regulating carbohydrate metabolism and hepatic glucose homeostasis. Polyphenols from different sources were reported to reduce plasma glucose and insulin area under the curve at 30 min [166], and significantly improved insulin sensitivity and insulin secretion after long-term consumption [167-169].
Many of these acids have been reported to have – per se – a relevance to diabetes. For examples, in different diabetes experiments, chlorogenic acid [170], cinnamic acid [171], ferulic acid [172], gallic acid [173], gymnemic acid [174], rosmarinic acid [175], shikimic acid [176], sinapic acid [177], syringic acid [178] have been reported to improve the glycemic state in a dose-dependent manner, decreasing blood glucose level and stimulating insulin secretion. In some instances, association of more than one of these acids like that of chicoric acid and chlorogenic acid renders an antidiabetic effect such as increasing insulin sensitivity [179]. In many cases, the underlying molecular mechanisms of action have been studied for these acids in detail. For example, gallic acid was reported to be a partial agonist of PPARγ, enhancing glucose uptake through activation of GLUT4 and attenuating insulin resistance in type 2 diabetes model [180]. Gymnemic acid was reported to downregulate the expression of endoplasmic reticulum (ER) stress indicator proteins ORP150, p-c-Jun, p-PERK, and p-eIF2α, which regulates the insulin signal transduction proteins, reducing p-IRS-1(ser) levels and increasing p-IRS-1(tyr) in type 2 diabetic model and in vitro [174].