Protective Effects of Broussonetia kazinoki Siebold Fruit Extract against Palmitate-Induced Lipotoxicity in Mesangial Cells

Abstract

Diabetic nephropathy is one of the most serious complications of diabetes. Lipotoxicity in glomerular mesangial cells is associated with the progression of diabetic nephropathy. Paper mulberry, Broussonetia kazinoki Siebold (BK), has been used in oriental medicine for human health problems. However, to date, the beneficial effect of BK fruit has not been studied. In this study, we investigated the protective effect of an ethanolic extract of BK fruit (BKFE) against palmitate- (PA-) induced toxicity in mesangial cells. BKFE significantly increased the viability of PA-treated SV40 MES13 cells. BKFE significantly inhibited PA-induced apoptosis and decreased the expression of apoptotic genes, cleaved caspase-3, and cleaved PARP. Moreover, BKFE inhibited the expression of endoplasmic reticulum (ER) stress-related genes, such as BiP, phosphorylated eIF2α, cleaved ATF6, and spliced XBP-1, in PA-treated SV40 MES13 cells. BKFE decreased PA-induced ROS production. In addition, BKFE activated the transcription factor Nrf2 and increased the expression of antioxidant enzymes. However, knockdown of Nrf2 using siRNA suppressed this BKFE-induced increase in antioxidant enzyme expression. Furthermore, the protective effect of BKFE on PA-induced apoptosis was significantly reduced by Nrf2 knockdown. In conclusion, BKFE induced the expression of antioxidant enzymes via activation of Nrf2 and protected against PA-induced lipotoxicity in mesangial cells.

Dose- and Time-Dependent Effects of Oleate on Mitochondrial Fusion/Fission Proteins and Cell Viability in HepG2 Cells: Comparison with Palmitate Effects

“…The combination of oleic and palmitic acid at a mole ratio of 1:1 (200 µM palmitic acid: 200 µM oleic acid) rescued the INS-1E cells from cell damage. These findings confirmed that saturated fatty acids are lipotoxic, whereas unsaturated fatty acids could be less toxic or even reduce apoptosis promoted by saturated fatty acids [ 35 , 37 ]. However, there are controversial data in the literature regarding oleic acid cytotoxicity in Hepg2 cells.…”

“…In neuronal cells, palmitic acid (400 µM) also induced dramatic cell apoptosis by increasing caspase 3 and caspase 8 activities, whereas 200 µM oleic acid did not induce increase in apoptosis makers, and its coincubation with palmitic acid blunted the apoptotic process [ 36 ]. Moreover, Kim et al [ 37 ] observed a dose-dependent decrease in mesangial cells viability with palmitic acid doses ranging from 12.5 µM to 400 µM. They also showed an increase in cleaved caspase 3 content in cells treated with 100 µM of palmitic acid.…”

Prevention of Oxidative Stress-Induced Pancreatic Beta Cell Damage by Broussonetia kazinoki Siebold Fruit Extract via the ERK-Nox4 Pathway

“…Furthermore, various reports have detailed the anti-inflammatory, anti-diabetic, and anti-cancer effects of the leaves, twigs, root, and stem barks of BK [23][24][25][26], but very little is known about beneficial effects of BK fruits in diabetes, especially on beta cells. Recently, we reported that an ethanol extract of BK fruit (BKFE) reduced mesangial cell apoptosis induced by palmitate, and this was due to activation of Nrf2 and upregulation of antioxidant genes [27], suggesting that BKFE may have anti-apoptotic effects on beta cells. Moreover, it was reported that stem bark and root bark of BK have anti-apoptotic effects on beta cells [28,29].…”

Cudrania tricuspidata Root Extract Prevents Methylglyoxal‐Induced Inflammation and Oxidative Stress via Regulation of the PKC‐NOX4 Pathway in Human Kidney Cells

“…To examine time- and dose-dependent effects of MGO on ROS production, HK-2 cells (1.5 × 10 5 cells/well) were seeded in 6-well plates and cultured for 24 h. Then, cells were treated with 0.5 mM MGO for different periods (0.5–12 h) or with different concentrations of MGO (0.125–1.0 mM) for 2 h. To determine the inhibitory effect of CTRE on MGO-induced ROS production, cells were incubated with vehicle (DMSO) or 20 μ g/mL CTRE for 1 h and then further incubated for 2 h, with or without 0.5 mM MGO. Intracellular ROS levels were measured through flow cytometry using 2,7-dichlorodihydrofluorescein diacetate (DCFH-DA, Invitrogen, San Diego, CA, USA), as described in our previous report [ 19 ].…”