An Updated Review on the Phytochemistry, Pharmacology, and Clinical Trials of Salacia oblonga.

Salacia oblonga (S. oblonga), a perennial herb, has been used for thousands of years in ayurvedic medicine and is closely associated with prevention, treatment, and cure of various human ailments such as obesity and diabetes. A vast and wide range of chemical compounds such as polyphenols, friedelane-type triterpenes, norfriedelane-type triterpenes, eudesmane-type sesquiterpenes including various glycosides had been isolated from this plant. This review is aimed to survey the literature covering the phytochemistry and pharmacology of S. oblonga and to review the scientific data including active components and their multi-targeted mechanisms of action against various metabolic syndromes. We also included clinical trials related to this plant in this review. The overview would assist researchers to gather scientific information related to S. oblonga in future.

INTRODUCTION

In the search for novel therapeutic molecules, the hybrid approach is to target multi-factorial diseases, especially metabolic syndrome. Natural products have been recognized as one of the major sources of hybrid molecules containing multi-structural units of a different class.[1] Continuous finding is necessary to find out multi-targeted therapeutics, which is helpful for newer drug discovery. To hit them, two strategies are adopted during discovery. Single compound is used to hit multiple targets which is the first approach and the second is to employ two or more active ingredients in a single drug.[2]

Salacia oblonga, commonly known as ''ponkoranti'' (Family: Celastraceae), due to its golden color root bark,[3] has been emerged to act as an active ingredient to hit multiple targets, preferably in case of all diabetic complications such as impaired glucose uptake, insulin resistance, dyslipidemia, cardiac complications, kidney disorder by acting through multiple targets either by the inhibition of α-glucosidase, aldose reductase (AR), pancreatic lipase, or by the activation of glucose transporter-4 (GLUT-4)-mediated glucose uptake, and various peroxisome proliferator-activated receptor (PPAR) subtypes.[45678]

A plethora of research data indicates that numerous bioactive components from S. oblonga are potentially useful in the treatments of obesity, diabetes, and its complications. Several reports have described the hypoglycemic activity of S. oblonga in animals.[910] Furthermore, clinical trial had been performed using S. oblonga herbal preparation.[11121314] Again, no adverse effect was reported with S. oblonga extract (SOE) in rats, which supports a good safety potential in human.[1516]

To date, despite the wealth of information available on the therapeutic importance of S. oblonga in literature, no review summarizes the real update on the molecular basis of biological activities and mechanisms of action of its active compound. Therefore, we surveyed research papers and clinical trials on S. oblonga and reviewed the scientific data, including active components and pharmacology. This review will provide the researchers with the current status of S. oblonga with a special emphasis on the regulation of hybrid approach of multiple molecular targets and their mechanism of action in diabetes, obesity, and their consequent complications, including various toxicological and cytogenetic aspects.

Phytochemistry

The phytoconstituents of S. oblonga are numerous, and they vary depending on the species to species and place of origin.[17] Kotalanol, kotalagenin 16-acetate, and salacinol were found in the root of S. oblonga.[7] S. oblonga hot water extract of root contains 1.4% of mangiferin (MA),[6] which was identified and quantified by high-performance liquid chromatography method. Apart from these unique constituents, the extract of S. oblonga has also been reported to contain neokotalanol,[18] ponkoranol,[19] neosalacinol, neoponkoranol,[18] 26-hydroxy-1,3-friedelanedione, 3 β,22α-dihydroxyolean-12-en-29-oic acid,[20] (-)-4-O-methylepigallocatechin,[21] salasol A,[22] salasol B, salasones A, salasones B, salasones C, salasones D, salasones E, salaquinone A, salaquinone B,[2223] and 25,26-oxidofriedelane-1,3-dione.[24] All the chemical components of S. oblonga with their chemical structures are given in Figure 1.

Figure 1

Important phytochemicals of S. oblonga participating in biological activities

Pharmacological Uses

The extract of S. oblonga has diverse local and traditional uses because of its action on different molecular targets in the human body. Herein, the different chemical constituents of the extract act on the different molecular targets owing to several useful biological activities which are summarized in Table 1.

Table 1

Multi-targeted approach of biological activities

Diabetes

Inhibition of α-glucosidase

Oxidative stress has an important contribution during diabetes propagation.[25] Numerous reports have documented that the reduction of antioxidant defenses is observed during an oral glucose challenge.[2627] Glucose absorption delays during the inhibition of metabolic enzymes which suppresses postprandial hyperglycemia, resulting in improved glycemic control [Figure 2].[12] S. oblonga root (SOR) extract lowered glucose and increased insulin levels in patients with type 2 diabetes after meal.[28] The production of salacinol, kotalanol and kotalagenin-16-acetate maltose, sucrose, or starch was strong in rat plasma.[672930]

Figure 2

Function of intestinal α-glucosidase enzyme (positive circled sign shows activation and negative circled sign shows inhibition)

In another experiment,[6] water extract of SOR containing MA was investigated against type 2 diabetes during cardiac fibrosis using obese Zucker rats, and the researchers demonstrated that SOR extract restored blood glucose level during cardiac fibrosis. It has also been demonstrated that MA showed much weaker effects than that of SOE having salacinol and kotalanol, suggesting that MA is a moderately active constituent for inhibiting α-glucosidase enzyme.[6]

Activation of glucose transporter 4-mediated glucose uptake

S. oblonga produced GLUT-4 activation through the inhibition of intestinal α-glycosidases and augmentation of glucose uptake in muscle and adipose tissues. Mangifrerin is the key constituent of SOE, which enhances 2-deoxy-D-glucose uptake by 50% in both L6-myotubes and 3T3-adipocytes. In addition, the effects are most likely mediated through two individual pathways that are linked to protein kinase and PPAR-γ activation.[4]

Inhibition of aldose reductase

Kotalagenin-16-acetate and MA had a dramatic role in AR inhibition which was observed in rats' lens-derived AR.[78] In another study, MA is reported to possess the onset or progression of diabetic complications including diabetic neuropathy and nephropathy.[31] These results further coined the protective effect of S. oblonga on vascular and other complications of diabetes.

Inhibition of nicotinamide adenine dinucleotide phosphate oxidase enzyme

During specified application,[32] S. oblonga demonstrated beneficial effects on mitochondrial localization in cells and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in glucose-induced rat muscle cell line. In this study, the L6 cells were treated with high glucose in the absence or presence of SOE, and the NADPH oxidase enzyme activity was determined in cell lysates of control and treated groups.[33] NADPH oxidase enzyme activity was measured in terms of percentage of NADPH consumed in comparison to control. The data from this investigation suggested that high glucose concentration increased the oxidative stress in rat skeletal muscle cell line through the production of increasing amount of superoxide radicals by NADPH oxidase enzyme. Altogether, the study proved the antioxidant potential of SOE and indicated the possible involvement of skeletal muscle mitochondria in helping cells survive the stress.[32]

Inhibition of pancreatic lipase

SOE reduced plasma triglyceride level after loading olive oil in Zucker diabetic fatty (ZDF) rats, whereas it had no effect on plasma triglyceride in the fasted rats.[34] These results suggested that S. oblonga inhibited olive oil-induced hypertriglyceridemia by targeting the gastrointestinal system. The hot water extract of S. oblonga suppressed pancreatic lipase activity.[20] Therefore, the inhibition of pancreatic lipase activity in the small intestine was suggested as one of the main mechanisms of improvement of postprandial hyperlipidemia in type 2 diabetes and obesity by Salacia root.

Peroxisome proliferator-activated receptor-γ activator

PPAR-γ is a transcription factor predominantly expressed in adipose tissue, and it activates adipocyte differentiation both in vivo and in vitro.[35] When PPAR-γ is overexpressed, 3T3-L1 preadipocyte induction begins. This suggests that PPAR-γ suppression blocks adipogenesis and lipogenesis.[36] Thus, PPAR-γ agonism leads to the amelioration of lipid abnormalities in dyslipidemic patients. Findings from a number of rodent studies have demonstrated that PPAR-γ agonists can improve insulin resistance, as well as dyslipidemia. Concomitantly, rodent disease models have demonstrated that PPAR-γ agonists prevented increased adiposity and body weight without any reduction in food intake.[37] An experiment showed that MA increases 2-deoxy-D-glucose uptake in both L6-myotubes and 3T3-adipocytes, and the effects are most likely to be mediated via two pathways, related to 5'-AMP-activated protein kinase and PPAR-γ and may be blocked by GW9662, an irreversible PPAR-γ antagonist.[4] Salacia species are also reported to inhibit PPAR-γ-mediated gene expression in 3T3-L1adipocytes.[38]

Activation of insulin-mediated signaling

Type 2 diabetes mellitus is a complex disorder in which the interaction between environmental and genetic factors results in the development of insulin resistance in peripheral tissues and β-cell dysfunction.[3940] Among the various natural compounds, pentacyclic triterpenoids present in S. oblonga are a class of pharmacologically active and structurally rich metabolites with privileged motifs for further modifications, which are reported to act on glucose metabolism. Thus, it has become clear that PTs may exert their glucose-lowering effect through multi-target pathways, and these molecular targets include glycogen protein kinase B, protein tyrosine phosphatase 1B, insulin receptor, glucocorticoid receptor, phosphorylase, and the membrane G protein-coupled receptor (TGR5).[41] Therefore, oleane-, ursane-, and lupane-type triterpenes have been extensively studied.[42434445]

Cardioprotective action

Huang et al. found that SOE-treated ZDF rats showed less cardiac hypertrophy. SOE is used to suppress cardiac overexpression of atrial natriuretic peptide (ANP), brain natriuretic peptide, AT1 mRNAs, and angiotensin-1 (AT1) protein in ZDF rats. While SOE and MA suppressed angiotensin-II-induced ANP mRNA overexpression and protein synthesis in H9c2 cells. Their findings demonstrated that SOE decreases cardiac hypertrophy in ZDF rats, at least in part by inhibiting AT1 overexpression.[46]

Huang et al. suggested that SOE diminished cardiac hypertrophy by decreasing the excessive collagen accumulation and the enlargement of cardiomyocytes. Besides, AT1 also mediates the autocrine and paracrine effects of locally formed angiotensin-II which are believed to play a key role in the development of cardiac hypertrophy.[47] Furthermore, SOE also suppressed angiotensin-II-stimulated hypertrophic response and protein synthesis in heart-derived H9c2 cells and angiotensin-II-accelerated hyperplasia in rat cardiac fibroblasts.[5] Altogether, these findings suggest that at least a part of the anti-hypertrophic and anti-fibrogenic effects of SOE occur via a cardiac angiotensin-II type 1 receptor/AT1 pathway.

Anti-inflammatory activity

SOE had been shown to exhibit anti-inflammatory response by inhibiting the release of mediators of inflammation and or the stabilization of lysosomes. Recent studies demonstrated that an anti-inflammatory characteristic of SOE was observed on carrageenan and cotton plate-induced rat paw edema at the doses of 500, 1000, 1500, and 2000 mg/kg. The extract at 1000 mg/kg decreased the paw edema volume by 74.19% within 1 h after administration, while the standard drug hydrocortisone decreased the paw edema volume by 68.21% with respect to control.[4849]

Anti-microbial activity

SOE was effective against Gram-positive (Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Bacillus subtilis, and Listeria monocytogenes) and Gram-negative bacteria (Klebsiella pneumoniae, Enterobacter aerogenes, Enterobacter cloacae, Pseudomonas aeruginosa, Escherichia coli, and Salmonella typhimurium) and fungus (Aspergillus niger). S. oblonga exhibited the highest activity against K. pneumonia than ethyl acetate extract in acidic media than neutral media. It is also used in the treatment of various bacterial infectious diseases such as gonorrhea, rheumatism, and skin diseases.[50]

Nephroprotective activity

Ethanol extracts of S. oblonga demonstrated protective activity against paracetamol-induced renal injury. The extract increased the level of anti-oxidant enzymes such as superoxide dismutase, catalase, and glutathione peroxidase, and restored glutathione levels than paracetamol control groups.[51]

Anti-mutagenic activity

The hydroalcholic extract of root bark of S. oblonga had anti-mutagenic activity against mitomycin-C-induced testicular toxicity in albino Wistar rats. The measured parameters were sperm shape abnormality, sperm count, catalase, superoxide dismutase, and total protein. The results suggested that sperm shape abnormality and sperm count were restored to normal level at 1 g/kg of dose of extract. The enzyme levels also increased during the experiment, and the total protein level was similar to normal control.[52]

Weight loss

S. oblonga promoted weight loss via increasing the activities of cholecystokinin and glucagon-like peptide-1 at 1000 mg dose for 30 days. It also reduced the absorption of glucose by inhibiting the activity of oligonucleotides.[53]

CLINICAL TRIALS

The effects of SOE on postprandial glycemia and insulinemia were studied recently in 66 patients with type 2 diabetes in a randomized, double-blinded, crossover controlled trial. Each patient was administered with one of the three meals: A standard liquid control meal, a control meal + 240 mg SOE, and a control meal + 480 mg SOE. Both of the doses containing Salacia extract were found to be beneficial to this population for postprandial glucose control.[28]

The presence of SOE tends to lower postprandial glycemia and significantly reduce the postprandial insulin response. This result has been shown through repeated measurements of the effect of different doses of SOE on postprandial glycemic, insulinemic, and breath hydrogen responses in healthy adults through a double-masked, randomized, crossover design in 39 healthy, nondiabetic adults.[12]

Another clinical trial on a proprietary formulation Glucaffect™ was performed on 50 overweight patients in a single-blinded fashion. The rationale of the study was to prolong the satiety of overweight volunteers by providing delayed absorption of carbohydrates. Glucaffect™ provides potent α-glucosidase inhibitors of herbal sources such as French maritime pine bark extract Pycnogenol®, Syzygium cumini Madeglucyl™, and SOE. Consumption of Glucaffect™ enabled patients to lower blood-fasting glucose, body weight, and HbA1c levels as compared to the control group.[59]

In another randomized, double-masked, crossover design, 43 healthy controls were fed with one of the four meals: Control (a study beverage containing carbohydrate, protein, and fat), control + phenylalanine and leucine (AA), control + SOE, and control + SOE and AA. This clinical trial manifested the extract of S. oblonga as a promising nutraceutical ingredient for glycemic control, and supplementation with amino acids had no significant additional effect on glycemia.[11]

CONCLUSION

Prolonged exposure to high glucose concentration promotes the development of microvascular complications associated with diabetes mellitus. Such complications affect the kidneys (nephropathy), eyes (retinopathy), heart (cardiomyopathy), nerves (neuropathy), and blood vessels. Majority of the plants, except S. oblonga, used traditionally to cure diabetes have not been effective for the treatment of all diabetic complications. S. oblonga containing various active metabolites have been found to meet multiple targets to cure diabetes, obesity, and heart disease via inhibiting α-glucosidase, pancreatic lipase and AR, and modulating PPAR-α/γ-mediated lipogenic gene transcription, AT1 signaling, and GLUT-4-mediated glucose uptake. Although the multiple target regulatory activities of this unique ayurvedic medicine have been clearly shown to be of benefit, clinical trials are now crucial to evaluate the effectiveness and safety of S. oblonga in the treatment and prevention of these metabolic diseases in humans. In addition, further mechanistic studies are necessary to allow a better understanding of how the use of S. oblonga may interact with other therapeutic interventions. For the same reason, recently, there has been some excitement over the potential role of SOE.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Priya Singh Kushwaha

ABOUT AUTHORS

Priya Singh Kushwaha, is working as Project Fellow in Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, A Central University, Lucknow, India. She is mainly focused on separation of antidiabetic agents from natural origin.

Ashok K Singh

Ashok K Singh, is pursuing Ph.D in Pharmaceutical Chemistry in Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, A Central University, Lucknow, India. He is concentrated on synthesis of organic compounds for hepatic carcinoma treatment.

Amit K Keshari

Amit K Keshari, is currently working as Ph.D research scholar in Pharmaceutical Chemistry in Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, A Central University, Lucknow, India. His research is based on synthesis organic compounds for hepatic carcinoma treatment.

Siddhartha Maity

Siddhartha Maity, is currently working as Ph.D. student in Department of Pharmaceutical Technology, Jadavpur University, Kolkata. He is working on colon targeted drug delivery.

Sudipta Saha

Sudipta Saha, is currently working as Assistant Professor in Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, A Central University, Lucknow, India. His research work is based on diabetes and hepatic/colon carcinoma both from natural and synthetic origin.