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Accumulation of methylglyoxal (MG) contributes to oxidative stress, apoptosis, and mitochondrial dysfunction, leading to the development of type 2 diabetes and cardiovascular diseases. Inhibition of mitochondrial abnormalities induced by MG in the heart may improve and delay the progression of heart failure. Although glucagon-like peptide-1 receptor (GLP-1R) agonists have been used as anti-diabetic drugs and GLP-1R has been detected in the heart, the cardioprotective effects of GLP-1R agonists on the inhibition of MG-induced oxidative stress and mitochondrial abnormalities have not been elucidated. Stimulation of GLP-1Rs leads to cAMP elevation and subsequently activates PKA-and/or Epac-dependent signaling pathway. However, the signaling pathway involved in the prevention of MG-induced mitochondrial dysfunctions in the heart has not been clarified so far. In the present study, we demonstrated that stimulation of GLP-1Rs with exendin-4 inhibited MG-induced intracellular and mitochondrial reactive oxygen species (ROS) production and apoptosis in H9c2 cardiomyoblasts. GLP-1R stimulation also improved the alterations of mitochondrial membrane potential (MMP) and expressions of genes related to mitochondrial functions and dynamics induced by MG. In addition, stimulation of GLP-1R exhibits antioxidant and antiapoptotic effects as well as the improvement of mitochondrial functions through cAMP/Epac/PI3K/Akt signaling pathway in H9c2 cells. Our study is the first work demonstrating a novel signaling pathway for cardioprotective effects of GLP-1R agonist on inhibition of oxidative stress and prevention of mitochondrial dysfunction. Thus, GLP-1R agonist represents a potential therapeutic target for inhibition of oxidative stress and modulation of mitochondrial functions in the heart.

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Context: Chatuphalatika (CTPT), is a Thai herbal formulation mixture of Phyllanthus emblica Linn. (Euphorbiaceae), Terminalia belerica Linn. (Combretaceae), T. chebula and the fruit of T. arjuna (Roxb.) Wight & Arn. CTPT is considered to exert anti-inflammatory and antihyperuricemic effects, but there have been no reports to demonstrate these pharmacological effects in a quantitative manner. Objectives: To investigate the antioxidative, anti-inflammatory and antihyperuricemic effects of CTPT. Materials and methods: Antioxidant activities of CTPT extracts were measured in vitro by DPPH, ABTS and FRAP assays, and anti-inflammatory effect by measuring inflammatory mediator production induced by lipopolysaccharide (LPS) in RAW264.7 macrophages. The mechanism of the hypouricemic effect was investigated using oxonate-induced hyperuricemic ddY mice treated with oral administrations of CTPT at 250, 500 and 1000 mg/kg. Results: Antioxidant activities of CTPT measured by ABTS and FRAP assays were 1.35 g TEAC/g extract and 10.3 mmol/100 g extract, respectively. IC50 for the inhibition of DPPH radical was 13.8 µg/mL. CTPT (10 µg/mL) significantly downregulated the mRNA expression of TNF-α and iNOS in RAW 264.7 cells. Lineweaver–Burk analysis of the enzyme kinetics showed that CTPT inhibited xanthine oxidase (XOD) activity in a noncompetitive manner with the Ki of 576.9 µg/mL. Oral administration of CTPT (1000 mg/kg) significantly suppressed uric acid production by inhibiting hepatic XOD activity, and decreased plasma uric acid levels in hyperuricemic mice by approximately 40% (p < 0.05). Conclusions: This study demonstrated for the first time the antioxidative, anti-inflammatory and antihyperuricemic effects of CTPT in vivo and in vitro, suggesting a possibility of using CTPT for the treatment of hyperuricemia in gout.

The objectives of the present study were to demonstrate the antihyperuricemic effect of triphala, a formulation of traditional Ayurvedic medicine, in potassium oxonate-induced hyperuricemic mice in vivo, and to examine its inhibitor effects on xanthine oxidase (XOD), inflammatory mediators and DPPH radicals in vitro. The water extract of triphala was determined to contain the total phenolics and total flavonoids of 317.6 ± 9.2 mg GAE/g and 7.73 ± 0.26 mg QE/g, respectively. Oral administrations of triphala significantly reduced the plasma uric acid levels of potassium oxonate-induced hyperuricemic mice at doses of 1,000 and 1,500 mg/kg, as compared with control ( p<0.05). Moreover, both doses of triphala treatments markedly inhibited the formation of uric acid due to inhibition of XOD activity in liver homogenates extracted from the hyperuricemic mice by about 70-80%. Lineweaver-Burk analysis of enzyme-kinetic data showed that triphala exhibited non-competitive inhibition on XOD activity in vitro with an inhibitory constant (Ki) of 590 μg/mL. Furthermore, triphala significantly suppressed the mRNA expressions of COX-II, TNF-α and iNOS in LPS-stimulated RAW 264.7 cells, as compared with control ( p <0.05), and decreased the expression of TGF-β. IC50 values for inhibition of DPPH radical formation was calculated to be 21.9 ± 2.50 μg/mL. Antioxidant activities of triphala were determined to be 0.81 ± 0.07 g TEAC/g and 6.78 ± 0.29 mmol/100g, respectively, as assessed by ABTS and FRAP assays. In conclusion, this study provided in vivo and in vitro mechanistic evidence for the antihyperuricemic, antioxidative and anti-inflammatory effects of triphala for the first time, rationalizing its therapeutic usage for the treatment of hyperuricemia of gout.