Syzygium cumini (Myrtaceae) is a worldwide medicinal plant traditionally used in herbal medicines due to its vaunted properties against cardiometabolic disorders, which include: antihyperglycemic, hypolipemiant, antiinflammatory, cardioprotective, and antioxidant activities. These properties have been attributed to the presence of bioactive compounds such as phenols, flavonoids, and tannins in different parts of the plant, albeit the knowledge on their mechanisms of action is scarce. This mini-review highlights the cardiometabolic properties of S. cumini by correlating its already identified phytochemicals with their described mechanisms of action. Data herein compiled show that some compounds target multiple metabolic pathways; thereby, becoming potential pharmacological tools. Moreover, the lack of clinical trials on S. cumini usage makes it a fruitful field of interest for both scientific community and pharmaceutical industry.

Background: Flavonoids have been characterized as a prominent class of compounds to treat thrombotic diseases through the inhibition of thiol isomerases. Syzygium cumini is a flavonoid-rich medicinal plant that contains myricetin and gallic acid. Little is known about the potential antiplatelet properties of S. cumini and its constituent flavonoids.Objective: To evaluate the antiplatelet effects and mechanism of action of a polyphenolrich extract (PESc) from S. cumini leaf and its most prevalent polyphenols, myricetin and gallic acid.Methods: PESc, myricetin, and gallic acid were incubated with platelet-rich plasma and washed platelets to assess platelet aggregation and activation. In vitro platelet adhesion and thrombus formation as well as in vivo bleeding time were performed. Finally, myricetin was incubated with recombinant thiol isomerases to assess its potential to bind and inhibit these, while molecular docking studies predicted possible binding sites.Results: PESc decreased platelet activation and aggregation induced by different agonists. Myricetin exerted potent antiplatelet effects, whereas gallic acid did not. Myricetin reduced the ability of platelets to spread on collagen, form thrombi in vitro without affecting hemostasis in vivo. Fluorescence quenching studies suggested myricetin binds to different thiol isomerases with similar affinity, despite inhibiting only protein disulfide isomerase (PDI) and ERp5 reductase activities. Finally, molecular docking studies suggested myricetin formed non-covalent bonds with PDI and ERp5.Conclusions: PESc and its most abundant flavonoid myricetin strongly inhibit platelet function. Additionally, myricetin is a novel inhibitor of ERp5 and PDI, unveiling a new therapeutic perspective for the treatment of thrombotic disorders.

Syzygium cumini (L.) Skeels (Myrtaceae) has been traditionally used to treat a number of illnesses. Ethnopharmacological studies have particularly addressed antidiabetic and metabolic-related effects of extracts prepared from its different parts, especially seed, and pulp-fruit, however. there is a lack of studies on phytochemical profile and biological properties of its leaf. As there is considerable interest in bioactive compounds to treat metabolic syndrome and its clustered risk factors, we sought to characterize the metabolic effects of hydroethanolic extract of S. cumini leaf (HESc) on lean and monosodium L-glutamate (MSG)-induced obese rats. HPLC-MS/MS characterization of the HESc polyphenolic profile, at 254 nm, identified 15 compounds pertaining to hydrolysable tannin and flavanol subclasses. At 60 days of age, both groups were randomly assigned to receive HESc (500 mg/kg) or vehicle for 30 days. At the end of treatment, obese+HESc exhibited significantly lower body weight gain, body mass index, and white adipose tissue mass, compared to obese rats receiving vehicle. Obese rats treated with HESc showed a twofold increase in lipolytic activity in the periepididymal fat pad, as well as, brought triglyceride levels in serum, liver and skeletal muscle back to levels close those found in lean animals. Furthermore, HESc also improved hyperinsulinemia and insulin resistance in obese+HESc rats, which resulted in partial reversal of glucose intolerance, as compared to obese rats. HESc had no effect in lean rats. Assessment of ex vivo glucose-stimulated insulin secretion showed HESc potentiated pancreatic function in islets isolated from both lean and obese rats treated with HESc. In addition, HESc (10-1000 µg/mL) increased glucose stimulated insulin Syzygium cumini Dual Effect in MSG-Obese Rats secretion from both isolated rat islets and INS-1E β-cells. These data demonstrate that S. cumini leaf improved peripheral insulin sensitivity via stimulating/modulating β-cell insulin release, which was associated with improvements in metabolic outcomes in MSG-induced obese rats.

Syzygium cumini (L.) Skeels has been reported to exert anti-inflammatory and cardiometabolic activities due to its high content of polyphenols. We characterized the chemical composition and assessed the antidiabetic effects of a novel polyphenol-rich extract (PESc) obtained from S. cumini leaf. Rats were injected with alloxan (150 mg/kg, ip, ALX group) and followed up for 7 days. Some were orally treated with PESc (50 mg/kg/day) for 7 days before and after diabetes induction (ALX-PP) or only for 7 days after alloxan injection (ALX-P). ALX-P and ALX-PP decreased fasting glycemia in 37 and 43%, respectively, as compared to ALX. Triglycerides and total cholesterol serum levels were also significantly reduced in comparison to ALX. PESc presented high polyphenol concentration (71.78 ± 8.57 GAE/100 g), with flavonoid content of 8.21 ± 0.42 QE/100 g. Upon HPLC-MS/MS and MS/MS studies, five main polyphenols—gallic acid, quercetin, myricetin, and its derivatives—were identified. Myricetin was predominant (192.70 ± 16.50 μg/mg PESc), followed by measurable amounts of gallic acid (11.15 ± 0.90 μg/mg PESc) and quercetin (4.72 ± 0.06 μg/mg PESc). Kinetic assessment of total antioxidant capacity revealed PESc high potency, since maximum response was reached within 5 min reaction time in a concentration-dependent manner. Specific antioxidant activity of PESc was assessed against both DPPH• and ABTS•+, showing strong activity (IC50: 3.88 ± 1.09 and 5.98 ± 1.19 μg/mL, resp.). PESc also inhibited lipoxygenase activity (IC50: 27.63 ± 8.47), confirming its antioxidant activity also on biologically relevant radicals. Finally, PESc induced insulin secretion by directly stimulating INS-1E β cells in the absence of any cytotoxic effect. Overall, our results support that PESc is a potent antioxidant phytocomplex with potential pharmacological use as a preventive antidiabetic natural product.

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