The metabolic and molecular mechanisms of α‑mangostin in cardiometabolic disorders (Review)

Abstract

α‑mangostin is a xanthone predominantly encountered in Garcinia mangostana. Extensive research has been carried out concerning the effects of this compound on various diseases, including obesity, cancer and metabolic disorders. The present review suggests that α‑mangostin exerts promising anti‑obesity, hepatoprotective, antidiabetic, cardioprotective, antioxidant and anti‑inflammatory effects on various pathways in cardiometabolic diseases. The anti‑obesity effects of α‑mangostin include the reduction of body weight and adipose tissue size, the increase in fatty acid oxidation, the activation of hepatic AMP‑activated protein kinase and Sirtuin‑1, and the reduction of peroxisome proliferator‑activated receptor γ expression. Hepatoprotective effects have been revealed, due to reduced fibrosis through transforming growth factor‑β 1 pathways, reduced apoptosis and steatosis through reduced sterol regulatory‑element binding proteins expression. The antidiabetic effects include decreased fasting blood glucose levels, improved insulin sensitivity and the increased expression of GLUT transporters in various tissues. Cardioprotection is exhibited through the restoration of cardiac functions and structure, improved mitochondrial functions, the promotion of M2 macrophage populations, reduced endothelial and cardiomyocyte apoptosis and fibrosis, and reduced acid sphingomyelinase activity and ceramide depositions. The antioxidant effects of α‑mangostin are mainly related to the modulation of antioxidant enzymes, the reduction of oxidative stress markers, the reduction of oxidative damage through a reduction in Sirtuin 3 expression mediated by phosphoinositide 3‑kinase/protein kinase B/peroxisome proliferator‑activated receptor‑γ coactivator‑1α signaling pathways, and to the increase in Nuclear factor‑erythroid factor 2‑related factor 2 and heme oxygenase‑1 expression levels. The anti‑inflammatory effects of α‑mangostin include its modulation of nuclear factor‑κB related pathways, the suppression of mitogen‑activated protein kinase activation, increased macrophage polarization to M2, reduced inflammasome occurrence, increased Sirtuin 1 and 3 expression, the reduced expression of inducible nitric oxide synthase, the production of nitric oxide and prostaglandin E2, the reduced expression of Toll‑like receptors and reduced proinflammatory cytokine levels. These effects demonstrate that α‑mangostin may possess the properties required for a suitable candidate compound for the management of cardiometabolic diseases.

Keywords: Garcinia mangostana; metabolic syndrome; metabolism; obesity; xanthone; α-mangostin.

Figure 1

Chemical structure of α-mangostin.

Figure 2

Anti-obesity and antidiabetic effects of α-mangostin. The anti-obesity effects of α-mangostin are mediated via the modulation of adipose tissue biology, reduction in visceral fat accumulation and inhibition of fatty acid synthase. Its antidiabetic effects are mediated through an improvement in insulin sensitivity and glucose tolerance, increased pancreatic lipase activity, increased glucose transporter activity, the increased stimulation of insulin receptor and the increased phosphorylation of the PI3K, AKT and ERK signaling cascades. PPARγ, peroxisome proliferator-activated receptor γ; GLUT4, glucose transporter 4; HOMA-IR, homeostatic model assessment for insulin resistance; Pdx1, pancreatic and duodenal homeobox 1; LDL, low-density lipoprotein; VLDL, very low-density lipoprotein; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase.

Figure 3

Anti-steatotic and hepatoprotective effects of α-mangostin. The improvement in hepatic structure and function by α-mangostin is mediated through decreased collagen deposition and fibrosis, affecting related genes/proteins (TGF-β1, Smad3, TIMP-3, TIMP-1, PAI1, COL1A1, miRNA-155-5p and α-SMA). α-mangostin also prevents the apoptosis of hepatic tissues, regulates hepatic lipid and carbohydrate homeostasis via AMPK, PPARγ, SIRT1 and RXRα, reduces steatosis, improves liver function, prevents inflammation and oxidative stress and upregulates hepatic autophagy. TIMP, tissue inhibitor of metalloproteinases; PAI1, plasminogen activator inhibitor-1; COL1A1, collagen type I alpha 1 chain; α-SMA, α-smooth muscle actin; TG, triglyceride; TBARS, thiobarbituric acid reactive substances; SOD, superoxide dismutase; GSH, glutathione; GPx, glutathione peroxidase; GRd, glutathione reductase; CAT, catalase; AST, aspartate aminotransferase; ALT, alanine aminotransferase; MDA, malondialdehyde; GLUT, glucose transporter; PPARγ, peroxisome proliferator-activated receptor γ; SIRT1, sirtuin 1; RXRα, retinoid-X-receptor α; SREBP, sterol regulatory element-binding transcription factor; LPL, lipoprotein lipase; SCD1, stearoyl-CoA desaturase-1; HMG-CoA, β-hydroxy β-methylglutaryl-CoA.

Figure 4

Cardioprotective and anti-atherogenic effects of α-mangostin. α-mangostin protects the heart and blood vessels against several stressors, including reactive oxygen species, drug-induced stressors, lipids, aSMase activity, hyperglycemia and various potentially harmful signaling pathways. It lowers the levels of inflammatory cytokines and proapoptotic proteins, such as Bax and caspase-3 and-9, leading to tissue death, lactate accumulation and aSMase/ceramide signaling. α-mangostin increases the levels of anti-apoptotic proteins (p53) and antioxidant enzymes. It restores the heart and blood vessel morphology by reducing creatine kinase-MB and lactate dehydrogenase, reducing aortic perivascular adipose tissue deposition and reducing VCAM-1 expression, tunica intima-media thickening. aSMase, acid sphingomyelinase; VCAM-1, vascular cell adhesion molecule 1; GLUT, glucose transporter; SIRT1, sirtuin 1.

Figure 5

Antioxidant mechanisms of α-mangostin. α-mangostin exhibits antioxidant activity via three main mechanisms as demonstrated in the present review. It stabilizes Nrf2, which is a transcription factor that leads to the production of antioxidant proteins. It inhibits aSMase activity and modulates various signaling pathways. These actions in turn increase production of SOD, GPx, CAT and GSH in various tissues, leading to a decrease in ROS and MDA levels. aSMase, acid sphingomyelinase; ROS, reactive oxygen species; SOD, superoxide dismutase; GSH, glutathione; GPx, glutathione peroxidase; CAT, catalase; MDA, malondialdehyde; NO, nitric oxide; Nrf2, nuclear factor-erythroid 2-related factor 2; HO-1, heme oxygenase 1; eNOS, endothelial nitrix oxide synthase.

Figure 6

Anti-inflammatory effects of α-mangostin. Prolonged inflammatory responses lead to tissue damage. α-mangostin exerts anti-inflammatory effects and the effects are observed throughout the body. It modulates signaling pathways (JAK-STAT, TGF-β1, TLR4 and SIRT1 pathways) that terminate with NF-κB translocating into the nucleus. NF-κB activates inflammatory cytokines, such as TNF-α, IL-6 and IL-1β, which are released mainly through white blood cells. α-mangostin also reduces COX-2 signaling, suppresses MAPK activation, increases macrophage polarization to anti-inflammatory M2, reduces proinflammatory cytokine levels, reduces NLRP3 inflammasome levels, reduces chemokine expression (MIP-1α, MIP-1β, CXCL10, CCL11, CX3CL1, CCL5, RANTES, IP-10), increases SIRT3 and SIRT2 expression, reduces iNOS expression, reduces NO and PGE2 production, reduces the expression of TLR-2 and TLR-4 genes and increases anti-inflammatory cytokine levels (IL-10). TLR, Toll-like receptor; SIRT1, sirtuin 1; COX-2, cyclooxygenase 2; MIP, macrophage inflammatory protein; RANTES, regulated on activation, normal t cell expressed and secreted; IP-10, interferon gamma-induced protein 10; NO, nitric oxide; PGE2, prostaglandin 2; iNOS, intracellular nitric oxide synthase; CRP, C-reactive protein; TSPO, translocator protein.