Oxidized low-density lipoprotein (OxLDL) is thought to be involved in the early development of atherosclerosis through foam cell formation. It has been more than 20 years since the importance of OxLDL in atherogenesis was pointed out. During the last decade a couple of groups including ours have successfully detected OxLDL present in human circulating blood, and showed close relationship between the OxLDL levels and cardiovascular diseases. However, the actual nature of OxLDL found in vivo remained obscure until recently. In this article, a basis of the so-called “OxLDL hypothesis” on atherosclerosis will be summarized briefly, and the important issues to be solved in the near future are also discussed.
Antioxidant responsive element (ARE) mediated gene expression is a pivotal cellular defense mechanism against the toxicity of electrophiles and reactive oxygen species (ROS). Nrf2 belongs to the Cap-N-Collar family of basic region-leucine zipper transcription factors and has emerged as an essential signal transducer that responds to electrophiles and ROS by regulating transcription via the ARE. The ARE-regulated gene battery consists of detoxification enzymes and antioxidant genes and confers protection against oxidative insults such as hyperoxic lung injury and benzo[a]pyrene-induced tumorigenesis in the forestomach. Recent investigations indicated that the ARE gene battery also plays significant roles in the regulation of inflammation. Indeed, many natural or synthetic substances activating the ARE-mediated transcription pathway inhibit pro-inflammatory gene expression. On the other hand, cyclooxygenase-2 (COX-2) exerts anti-inflammatory roles in the protection against inflammation by certain stimuli. Downstream effectors of the COX-2 pathway include cyclopentenone prostaglandins (cyPGs) such as 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2). We recently demonstrated that the Nrf2 pathway is activated by endogenous 15d-PGJ2 during carrageenin-induced inflammation. Thus, cyPGs may act as physiological regulators of Nrf2.
The present study was aimed to clarify whether bone uncoupling occurs in early (3-5 years) natural menopause. Plasma bone specific alkaline phosphatase (bALP) and osteocalcin (OC), as markers of bone formation, urinary free deoxypyridinoline (Dpd) and type I collagen helical peptide, as markers of bone resorption, in addition to circulating insulin-like growth factor-1 (IGF-1) and L2-L4 spine bone mineral density (BMD), were measured concomitantly to serum calcium and phosphate minerals. Vertebral BMD of postmenopausal women (n = 30) was significantly lower than that of premenopausal controls (n = 30). All markers of bone turnover, except for bALP, and serum minerals were markedly greater in the postmenopausal group whereas circulating IGF-1 level was lower (p < 0.01). Bone uncoupling in early menopause was confirmed by a negative uncoupling status index (USI) value, indicating an excess of resorption over formation. The difference between groups was more pronounced for type I collagen helical peptide (+49.4%) than Dpd (+35.9). This new marker of bone resorption correlated better with bone formation (as assessed by OC) and with serum minerals. The study demonstrated that bone formation and resorption increased but did not balance in early untreated postmenopausal women. Helical peptide discriminated better than Dpd early postmenopausal women from control premenopausal women. It was postulated that an alteration in the quality of bone collagen matrix might be involved in postmenopausal bone mineral loss.
The aim of the present study was to determine whether imidapril, an angiotensin-converting enzyme inhibitor, prevents diabetic nephropathy and to determine the effect of imidapril on oxidative damage in the diabetic glomeruli in mice. We used female BKS.cg-m+Leprdb/+Leprdb (db/db) mice, a rodent model of type 2 diabetes, and their non-diabetic db/m littermates. The mice were divided into the following four groups: non-diabetic db/m, diabetic db/db, and diabetic db/db treated with imidapril at doses of 1 mg/kg and 5 mg/kg. Blood glucose level, body weight, urinary albumin, and urinary 8-hydroxydeoxyguanosine (8-OHdG) were measured during the experiments. Histological and 8-OHdG immunohistochemical studies were performed for 12 weeks from the beginning of treatment. After 12 weeks of treatment, the levels of blood glucose and the body weight were not significantly different between the imidapril-treated group and the non-treated db/db group. The systolic blood pressure was significantly increased in db/db mice compared with db/m mice. The increased blood pressure was significantly reduced by the treatment with imidapril at a dose of 5 mg/kg. The relative mesangial area calculated by the mesangial area/total glomerular area ratio was significantly ameliorated in the imidapril-treated group compared with the non-treated db/db group. The increases in urinary albumin and 8-OHdG at 12 weeks of treatment were significantly inhibited by chronic treatment with imidapril in a dose-dependent manner. The 8-OHdG immunoreactive cells in the glomeruli of non-treated db/db mice were more numerous than in the imidapril-treated db/db mice. In conclusion, imidapril prevented the progression of diabetic nephropathy in mice, not only by decreasing the glomerular pressure but also by decreasing the oxidative stress in glomerular cells.