benzofurans and Diabetic-Nephropathies

The rhizome of Ligusticum chuanxiong Hort. has been widely used for the therapy of diabetic nephropathy (DN) in traditional Chinese medicine (TCM). The nuclear transcription factor erythroid 2-related factor (Nrf2) is a potential target for treating DN. The purpose of this research was to study the chemical constituents from the rhizome of L. chuanxiong, evaluate their Nrf2 inducing activity, and find the molecules with potential therapeutic effect against DN. In this study, two new phthalides (1-2) along with twenty-seven known constituents were obtained from the rhizome of L. chuanxiong. Their structures were elucidated through various spectroscopic methods. Twelve constituents, including eight phthalides (2, 5, 6,10-13, 14) and four other compounds (17, 18, 20,28), stimulated NAD(P)H: quinone reductase (QR) activity, suggesting that these bioactive constituents were potential Nrf2 activators. Among the isolated compounds, phthalide levistolide A (LA, 14) upregulated the protein levels of Nrf2, NQO1, and γ-GCS in a dose-dependent manner. Our results implied that the clinical application of the rhizome of L. chuanxiong as an anti-DN drug in TCM might be attributed to the Nrf2 inducing effect of phthalides. Thus, phthalides is a group of promising leading molecules for discovering anti-DN agents.

Topics: Benzofurans; Diabetic Nephropathies; Humans; Hypoglycemic Agents; Ligusticum; Molecular Structure; NF-E2-Related Factor 2; Rhizome

Nephropathy related with renin can be alleviated with ACE-inhibitors or AT1R blockers, whereas they might be ineffective after long-term administration because of a feedback production of enhanced renin. Therefore, it is urgent to develop a new category of anti-nephropathy medicine directly targeting renin. Riligustilide (C20), originally isolated from the Chinese herb Ligusticumporteri, a rhizome, was confirmed effective against many diseases.. The therapeutic effect of C20 on renal injury and its underlying mechanism were investigated in three different nephrotic models, which were spontaneously hypertension rats (SHR) model, diabetic nephropathy in BTBR ob/ob mice model and 5/6-nephrectomized (5/6NX) rats model.. The intensity of kidney fibrosis was extensively decreased in the C20-treated rats compared to the vehicle animals. C20 significantly alleviated renal injury much more in 5/6 NX rats than in vehicle group. The rats in 5/6 NX without administrated C20 developed albuminuria earlier with more severe symptoms. Additionally, our findings showed that C20 down-regulated the renin expression and relocation of CREB-CBP complex in vivo and in vitro.. C20 plays importantly reno-protective roles most likely through the relocation of CREB-CBP complex.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Benzofurans; Cell Line; CREB-Binding Protein; Diabetic Nephropathies; Disease Models, Animal; Down-Regulation; Kidney; Male; Medicine, Chinese Traditional; Membrane Proteins; Mice; Mice, Knockout; Mice, Obese; Molecular Docking Simulation; Nephrectomy; Phosphoproteins; Rats; Rats, Inbred SHR; Renin

Lithospermic acid B (LAB), an active component isolated from Salvia miltiorrhizae, has been reported to have renoprotective effects in type 1 diabetic animal models. In the present study we investigated the effects of LAB on the prevention of diabetic nephropathy in type 2 diabetic Otsuka Long-Evans-Tokushima Fatty (OLETF) rats. LAB (20 mg/kg) was given orally once daily to 10-week-old male OLETF rats for 28 weeks. Treatment of OLETF rats with LAB had little effects on body weight and blood glucose levels. Treatment with LAB resulted in significant reduction in blood pressure. LAB markedly attenuated albuminuria and significantly lowered levels of lipid peroxidation, monocyte chemoattractant protein-1 (MCP-1), and transforming growth factor-beta (TGF-beta1) expression in renal tissues of OLETF rats. In addition, LAB inhibited the progression of glomerular hypertrophy, mesangial expansion, and expansion of the extracellular matrix in the renal cortex. Collectively, these results suggest that LAB has beneficial effects on the diabetic nephropathy in OLETF rats by decreasing blood pressure, oxidative stress, and MCP-1 expression. Our results suggest that LAB might be a new therapeutic agent for the prevention of nephropathy in type 2 diabetes.

Topics: Administration, Oral; Aldehyde Reductase; Animals; Benzofurans; Blood Glucose; Blood Pressure; Chemokine CCL2; Depsides; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Gene Expression Regulation; Male; Oxidative Stress; Rats; Rats, Inbred OLETF; Rats, Long-Evans; Salvia miltiorrhiza

Topics: Albuminuria; Animals; Benzofurans; beta 2-Microglobulin; Cyclosporine; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Enzyme Inhibitors; Immunosuppressive Agents; Kidney; Organ Size; Pancreas Transplantation; Pyrazines; Rats; Rats, Wistar; Thromboxane A2; Thromboxane-A Synthase; Transplantation, Isogeneic