Background
Dendrophthoe pentandra is a hemiparasitic woody shrub that belongs to the Loranthaceae family of mistletoes and is commonly found on tropical trees [
1]. This plant has been extensively used in folklore medicine despite being commonly considered as an unwanted plant due to its parasitic nature. It is widely distributed in China, Cambodia, India, Indonesia, Laos, Malaysia, Myanmar, Philippines, Thailand, and Vietnam [
2]. In Indonesia, the leaves of
D. pentandra has been reported used in the traditional medicine to treat wounds and skin infection; while whole part of the plant is used to cure hypertension and cough [
3]. It is also used for its antidiuretic activity in Indonesian traditional medicine [
1]. In Sulawesi Island, this plant has been used as medicine to cure cancer [
3]. Previous investigations on this species have demonstrated that the
D. pentandra leaf extract stimulated the proliferation of mice splenocytes and thymocytes in a time- and dose-dependent manner [
4]. Artanti et al. reported the antioxidant activity of this plant on the basis of DPPH free radical scavenging ability and later confirmed the exact chemical identity of the active antioxidant to be quercetin-3-O-rhamnoside, a flavonol glycoside on the basis of isolation and multiple spectrophotometric techniques [
2]. Consequent phytochemical analysis revealed that flavonoids are the main active fraction of the leaf extracts of
D. pentandra. The existence of other plant secondary metabolites including: saponins and tannins being present in extracts of solvents of varying polarity [
1,
2].
There has been a worldwide upsurge in the incidence of diabetes mellitus. It is projected to rise from 171 million in 2000 to 366 million in 2030 [
5]. Diabetes mellitus is a metabolic disorder of multiple etiologies in which chronic hyperglycemia results from absent or inadequate pancreatic insulin secretion, with or without concurrent impairment of insulin action [
6]. Long-term complications associated with hyperglycemia, such as retinopathy, neuropathy and angiopathy, result in significant disability and mortality [
7]. Standard treatments to tackle diabetes include recombinant insulin and oral antidiabetic drugs, but these are faced with challenges such as ensuring adequate production of insulin to meet the soaring demands and difficult patient compliance due to the recurrent side effects of antidiabetic drugs [
8,
9]. Hepatic diseases refer to aberrations of the structure or changes in the biochemical activity of liver cells. They occur in almost every age group and account for a global mortality of one million in 2010 [
10]. Despite the immense advancements in the field of modern medicine, the absence of potent and effective hepatoprotective agents has remained a constant issue [
11].
A large number of medicinal preparations based on plants are recommended for the treatment of hyperglycemia and for their hepatoprotective effect [
12,
13]. The World Health Organization (WHO) expert committee on diabetes has listed as one of its recommendations that traditional methods of treatment for diabetes should be further investigated [
14]. On the other hand, natural products are also an invaluable pool of molecular scaffolds to discover new drug leads and most currently marketed drugs derive directly or indirectly from plant constituents [
15]. As a part of our ongoing research of pharmacological screening of the Bangladeshi medicinal plants, the methanolic extract of
D. pentandra had been chosen for the present study. In this study, we have investigated the hepatopotective, antihyperglycemic and antidiabetic potential of
D. pentandra leaf extracts in rats for the first time. We concluded for further study for the identification of key active compounds responsible for the observed effects.
Discussion
Medicinal plants have remained integral components of traditional systems of medicine in many countries worldwide and are still relied upon today for various healthcare and medicinal needs [
23]. Many plant-derived substances can serve as leads or precursors for the synthesis of modern drugs and have been reported to alleviate a range of ailments including diabetes and hepatic injuries [
24,
25]. Hyperglycemia is the result of either insulin deficiency or insulin resistance that confers a reduced ability of liver and muscle cells to store glucose [
26]. Though oral antihyperglycemic agents are widely used in practice, they present some disadvantages owing to their poor pharmacokinetic attributes and accompanying side effects [
27].
Several biological activities of the extracts of
D. pentandra have been already reported in a number of previous literatures. According to Endharti et al., the
D. pentandra methanolic leaf extract containing quercetin has therapeutic potential to ameliorate TNBS (2,4,6-trinitrobenzene sulfonic acid) induced colitis syndrome in mice. It was also reported that the same extract can inhibit the differentiation of Th17 cells by inhibiting IL-17 production. These findings suggest that the extract of this plant has the important role in inhibiting intestinal inflammation [
1]. Extracts of
D. pentandra have also been reported to effectively inhibit inflammation, proliferation and induce p53 expression on mice models of colitis-associated colon cancer [
28].Analysis of cytotoxicity revealed that the extracts of
D. pentandra had cytotoxic effects on K562 and MCM-B2 cell lines thus suggestive of a potential anticancer activity of this plant [
29]. Methanolic extracts of
D. pentandra leaves have been also found to exert potent anti-proliferative effects on BCR/ABL-Positive and Imatinib Resistant Leukemia Cell lines [
30]. On the other hand, Artanti et al. observed significant antioxidant activities for the methanolic extracts and identified an active flavonol glycoside, quercetin-3-O-rhamnoside as antioxidant where as anti-diabetic activity had been exhibited by both the methanolic and aqueous extracts [
3].
In our OGTT, which measures the body’s ability to metabolise glucose and clear it out of the bloodstream [
17],
D. pentandra methanolic leaf extracts showed prominent activity. Extracts also exhibited some potential for controlling diabetes via significant antihyperglycemic activity at a concentration of 400 mg/kg in comparison to the standard drug MET, an oral antihyperglycemic agent used in addition to regulation in diet and exercise for the management of type 2 (non-insulin dependent) diabetes mellitus [
31]. It has been already discussed that the main active bioactive components in the
D. pentandra leaf extract are flavonoids. Presence of flavonoids in the
D. pentandra extract explains its different biological and pharmacological activities [
1,
2]. According to Fitrilia et al., different extracts of
D. pentandra was found out to be rich in flavonoids, tannins and saponins [
32]. Most recently, Yee et al. in [
33] also reported the presence various phytochemicals including alkaloids, flavonoids, saponins, and tannins in the ethyl acetate leaf extract of this plant. Other extracts of plants indigenous to the Indian sub-continent such as,
Allium cepa, Allium sativum, Cajanus cajan, Coccinia indica, have been attributed some anti-hyperglycemic activity and it has been suggested that the presence of phytochemicals such as flavonoids, alkaloids and other phenolics may contribute to the activity [
34]. Indeed, the role of flavonoids has already been reported in the stimulation of peripheral glucose uptake, enhancement of lipogenesis and facilitation of insulin release and conversion from pro-insulin to insulin [
35]. Considering all these studies, it can be concluded that the antidiabetic and antihyperglycemic activities of the methanolic leaf extract of
D. pentandra is mostly associated with its flavonoids content. These studies also suggest that
D. pentandra methanolic leaf extracts could either stimulate the pancreatic insulin secreting cells or improve the receptor responsiveness of tissues to insulin for an increased glucose uptake. Alloxan is a chemical that confers its toxicological effects by the selective necrosis of pancreatic islet cells, leading to a 3 to 4 times increase in blood glucose levels compared to the untreated animals [
36,
37]. It is possible that the administration of
D. pentandra methanolic leaf extracts to alloxan-induced diabetic animals leads to elevated insulin secretion from regenerated or remnant beta cells or augmented stimulation of glucose uptake by peripheral tissues [
38,
39].
The liver plays a vital role in the detoxification of a wide range of xenobotics [
40]. Liver damage mediated by the excessive exposure to drugs (e.g. high doses of paracetamol) and environmental pollutants leads to cellular necrosis, plasma membrane damage, depletion in glutathione (GSH) levels accompanied with elevated levels of serum markers of liver damage such as ALT, AST and alkaline phosphatase (ALP) [
41]. The rise in total cholesterol, total bilirubin and hypoproteinemia are also key features of liver damage in PCM-intoxicated rats [
42,
43]. Several indigenous medicinal plants from the Indian sub-continent including,
Bixa orellana, Cajanus cajan, Glycosmis pentaphylla and
Casuarina equisetifolia are known to possess some hepatoprotective activity [
44]. In our study, PCM-treated rats showed a significant rise in the levels of their liver function parameters (AST, ALT, total cholesterol, and total protein) while the levels were significantly lowered following administration of
D. pentandra methanolic leaf extracts. This hepatoprotective effect was comparable to the one observed for rats treated with silymarin, a popular hepatoprotective herbal remedy prepared from
Silybum marianum (milk thistle) [
45,
46]. Various secondary metabolites have been identified in the leaf extract of
D. pentandra including flavonoids, alkaloids, saponins and tannins. Flavonol glycosides i.e., quercetin-3-O-rhamnoside was also isolated from this plant extract [
2,
32,
33]. These secondary metabolites have been reported to be associated with the hepatoprotective effects of different medicinal plants [
47,
48]. The observed hepatoprotective effect of
D. pentandra extract might be associated with the presence of these flavonol as well as other secondary metabolites. It is possible that
D. pentandra extracts help improve the functions of hepatocytes by stabilising cell membranes and/or enhancing the regeneration of parenchymal cells [
11]. Overall, this suggests that
D. pentandra methanolic leaf extracts can effectively control liver damage and restore liver functions.