Aims/hypothesis Many of the effects of resveratrol are consistent with the activation of AMP-activated protein kinase (AMPK), silent information regulator T1 (SIRT1) and peroxisome proliferator-activated receptor (PPAR)γ co-activator 1α (PGC-1α), which play key roles in the regulation of lipid and glucose homeostasis, and in the control of oxidative stress. We investigated whether resveratrol has protective effects on the kidney in type 2 diabetes. Methods Four groups of male C57BLKS/J db/m and db/db mice were used in this study. Resveratrol was administered via gavage to diabetic and non-diabetic mice, starting at 8 weeks of age, for 12 weeks. Results The db/db mice treated with resveratrol had decreased albuminuria. Resveratrol ameliorated glomerular matrix expansion and inflammation. Resveratrol also lowered the NEFA and triacylglycerol content of the kidney, and this action was related to increases in the phosphorylation of AMPK and the activation of SIRT1-PGC-1α signalling and of the key downstream effectors, the PPARα-oestrogen-related receptor (ERR)-1α-sterol regulatory element-binding protein 1 (SREBP1). Furthermore, resveratrol decreased the activity of phosphatidylinositol-3 kinase (PI3K)-Akt phosphorylation and class O forkhead box (FOXO)3a phosphorylation, which resulted in a decrease in B cell leukaemia/ lymphoma 2 (BCL-2)-associated X protein (BAX) and increases in BCL-2, superoxide dismutase (SOD)1 and SOD2 production. Consequently, resveratrol reversed the increase in renal apoptotic cells and oxidative stress, as reflected by renal 8-hydroxy-deoxyguanosine (8-OH-dG), urinary 8-OH-dG and isoprostane concentrations. Resveratrol prevented high-glucose-induced oxidative stress and apoptosis in cultured mesangial cells through the phosphorylation of AMPK and activation of SIRT1-PGC-1α signalling and the downstream effectors, PPARα-ERR-1α-SREBP1. Conclusions/interpretation The results suggest that resveratrol prevents diabetic nephropathy in db/db mice by the phosphorylation of AMPK and activation of SIRT1-PGC-1α signalling, which appear to prevent lipotoxicity-related apoptosis and oxidative stress in the kidney.

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ABSTRACT. In two previous reports, we have demonstrated that injection of bee venom (BV) into an acupoint produces a significant antinociceptive and anti-inflammatory effect in both a mouse model of visceral nociception and a rat model of chronic arthritis. Th e present study was designed to evaluate the potential antinociceptive effect of BV pretreatment on formalin-induced pain behavior and it associated spinal cord Fos expression in rats. Adult Sprague-Dawley rats were injected with BV directly into the Zusanli (ST36) acupoint or into an arbitrary non-acupoint located on the back. BV pretreatment into the Zusanli acupoint significantly decreased paw-licking time in the late phase of the formalin test. In contrast, BV injected into a non-acupoint in the back region did not suppress the paw-licking time. In addition, BV pretreatment into the Zusanli acupoint markedly inhibited spinal cord Fos expression induced by formalin injection. These findings indicate that BV pretreatment into the Zusanli acupoint has an antinociceptive effect on formalin-induced pain behavior. Bee venom (BV) from the honeybee consists of melittin, phospholipase A 2 , apamin, adolapin, mast cell degranulating peptide and several other bioactive substances [26]. Melittin and phospholipase A 2 , two major components of BV, are generally thought to play an important role in the induction of the irritation and allergic reaction associated with the bee stings. In this regard, intradermal injection of melittin produces a local hyperthermic effect in human [23]. Phospholipase A 2 is a membrane-associated phospholipid converting enzyme that is important in the production of arachidonic acid. Arachidonic acid is further metabolized by one of two enzyme pathways into various prostaglandins (by cyclooxygenase) or leukotrienes (by lipooxygenase). Subcutaneous BV injection into plantar surface of the rat paw produces characteristic pain behaviors including paw licking and flinching [26] while BV administration in cats has been shown to produce prolonged and tonic nociceptive responses associated with changes in the firing of spinal cord neurons [7]. Chen and his colleagues have since published several reports that have elucidated some of the mechanisms underlying BV-induced nociception in rats and cats [7-13, 27, 28, 34, 35].In contrast to this recent focus on BV's nociceptive effects, Kwon and his co-workers have reported that longterm treatment with BV at a dose of 1 mg/kg/day produces a significant antinociceptive and anti-inflammatory effect on the Freund's complete adjuvant-induced arthritis in rats [24]. Although natural BV produces irritation when injected subcutaneously, injection of diluted BV, particularly into an acupoint, can reduce chronic nociception and inflammation. Thus Kwon et al. have shown that BV treatment into an acupoint can significantly reduce arthritisassociated edema and nociceptive responses [24]. In addition, BV injection into the Zhongwan acupoint significantly reduces the number of abdominal stretches induced by intraper...

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