Glycyrrhizic acid, active component from Glycyrrhizae radix, prevents toxicity of graphene oxide by influencing functions of microRNAs in nematode Caenorhabditis elegans.

We investigated effects of pretreatment with Glycyrrhizae radix (GR) or its specific components on toxicity of graphene oxide (GO) in Caenorhabditis elegans. GR pretreatment prevented GO toxicity on function of both primary and secondary targeted organs. Among active components in GR, the beneficial effects of GR were attributable to presence of glycyrrhizic acid. Glycyrrhizic acid pretreatment suppressed translocation of GO into secondary targeted organs through intestinal barrier. Glycyrrhizic acid pretreatment recovered expression patterns of dysregulated microRNAs (miRNAs) induced by GO, and genes required for oxidative stress control acted as targeted genes for some of these miRNAs. Among these miRNAs, mir-360 mutation enhanced beneficial effects of glycyrrhizic acid. We hypothesize that glycyrrhizic acid may prevent GO toxicity and translocation by influencing functions of miRNAs which upstream regulate functions of their targeted genes. Furthermore, glycyrrhizic acid had potential to extend lifespan, and to suppress accelerated aging process induced by GO. FROM THE CLINICAL EDITOR: Exposure to graphene oxide may pose toxic effects to health, as suggested in animal studies. In this article, the authors showed that the use of glycyrrhizae radix (GR) prevented toxicity of graphene oxide in Caenorhabditis elegans. These results may provide novel strategies in the reducing potential side effects of nanoparticles.

[Effects of selective inhibition of reverse mode of Na(+)/Ca(2+) exchanger on rats with contrast-induced acute kidney injury].

OBJECTIVE: Intracellular Ca(2+) overload is a key factor in contrast-induced renal tubular toxicity. Na(+)/Ca(2+) exchanger (NCX) system is one of main pathways of intracellular Ca(2+) overload. We explore the effects of KB-R7943, an inhibitor of reverse mode of NCX, on contrast-induced acute kidney injury (CI-AKI). METHODS: Rats were divided into control, CI-AKI and pre-treatment groups with KB-R7943 (5, 10 mg/kg). CI-AKI was induced by diatrizoate administration in rats with cholesterol-supplemented diet for 8 weeks. Renal function and hemodynamics were determined at Day 1 post-administration. Renal histopathology was observed under light microscope. Renal tubular apoptosis was examined by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). Renal endothelin-1 (ET-1) was measured by radioimmunoassay. The oxidative markers of renal malondialdehyde (MDA) and catalase (CAT) were measured. The expression of NCX was evaluated by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Levels of serum creatinine (Scr, µmol/L ) in CI-AKI rats ((149 ± 35) µmol/L) were significantly higher than those of normal rats ((55 ± 4) µmol/L, P < 0.01). Renal ET-1, MDA and CAT, resistance index (RI) of renal blood vessels increased significantly in CI-AKI rats. The contrast-induced increases in Scr and RI of renal blood vessels were suppressed significantly and dose-dependently by pretreatment with KB-R7943. Histopathological and TUNEL results showed that contrast-induced severe renal tubular necrosis and apoptosis were significantly and dose-dependently attenuated by KB-R7943. KB-R7943 significantly suppressed the contrast-induced increments of ET-1, MDA and CAT. No significant changes in NCX1 mRNA expression were observed following contrast administration. CONCLUSION: Renal oxidative stress and ET-1 overproduction via the activation of reverse mode of NCX play an important role in the pathogenesis of CI-AKI. And inhibition of reverse mode of NCX expressed in renal tubular epithelial cell has protective effects on CI-AKI.

Na+/Ca2+ exchange inhibitor, KB-R7943, attenuates contrast-induced acute kidney injury.

BACKGROUND: Intracellular Ca2+ overload is considered to be a key factor in contrast-induced acute kidney injury (CI-AKI). The Na+/Ca2+ exchanger (NCX) system is one of the main pathways of intracellular Ca2+ overload. We investigated the effects of KB-R7943, an inhibitor of the reverse mode of NCX, on CI-AKI in a rat model. METHOD: Rats were divided into control group, CI-AKI group and pretreatment groups (with KB-R7943 dose of 5 or 10 mg/kg). CI-AKI was induced by diatrizoate administration in rats with cholesterol-supplemented diet for 8 weeks. Renal function and renal hemodynamics were determined 1 day following contrast medium administration. Renal histopathology was observed by light microscope. Renal tubular apoptosis was examined by TUNEL. Renal endothelin-1 (ET-1) was measured by radioimmunoassay. Renal malondialdehyde (MDA) and catalase (CAT) were measured as oxidative markers. RESULTS: Levels of serum creatinine (Scr), renal ET-1, MDA and CAT, and resistance index (RI) of renal blood vessels increased significantly in CI-AKI rats. The increases in Scr and RI of renal blood vessels induced by diatrizoate were suppressed significantly and dose-dependently by pretreatment with KB-R7943. Histopathological and TUNEL results showed that the contrast medium-induced severe renal tubular necrosis and apoptosis were significantly and dose-dependently attenuated by KB-R7943. KB-R7943 significantly suppressed the increment of renal ET-1 content and MDA and CAT level induced by contrast medium administration. CONCLUSION: Activation of the reverse mode of NCX, followed by ET-1 overproduction and increased oxidative stress, seems to play an important role in the pathogenesis of CI-AKI. The inhibitor of the reverse mode of NCX, KB-R7943, has renoprotective effects on CI-AKI.

Dietary hypercholesterolemia aggravates contrast media-induced nephropathy.

BACKGROUND: Contrast media administration can result in severe nephrotoxicity under pathological conditions such as diabetic nephropathy, congestive heart failure, dehydration, et al. The purpose of this study was to evaluate the effects of dietary hypercholesterolemia on contrast media-induced changes in renal function, blood flow, and histopathology. METHODS: Rats were fed either on a normal rodent diet (group N) or a high-cholesterol supplemented diet (group H; 4% cholesterol and 1% cholic acid) for 8 weeks. Half of the animals (n = 6) from each diet group were then given a tail vein injection of 60% diatrizoate (6 ml/kg; group NC and group HC) and the other half were administered saline. Total serum cholesterol, triglyceride, serum creatinine, creatinine clearance rate, fractional excretion of sodium and potassium, and cortical nitric oxide production were determined one day following contrast media administration. Renal blood flow was determined by color Doppler flow imaging and pulsed-mode Doppler. Renal histopathology was observed by light microscopy. RESULTS: Total serum cholesterol and resistance indices of renal blood vessels increased significantly, while creatinine clearance rate and production of nitric oxide in the renal cortex decreased markedly in group HC and group H when compared to group N and group NC. The creatinine clearance rate decreased significantly in group HC compared to group H. Serum creatinine levels and fractional excretion of sodium and potassium in group HC were significantly higher than those in the other three groups. Severe tubular degeneration and necrosis, protein cast accumulation, and medullary congestion were found in group HC. CONCLUSION: Hypercholesterolemia is a risk factor for contrast media-induced nephropathy. Hypercholesterolemia aggravates contrast media-induced nephrotoxicity through the reduced production of nitric oxide.

[Effects of Valeriana officinalis var. latifolia on expression of transforming growth factor beta 1 in hypercholesterolemic rats].

OBJECTIVE: To evaluate the effect of Valeriana officinalis var latifolia(VOL) on expression of transforming growth factor beta 1 (TGF-beta 1) in hypercholesterolemic rats and study its possible mechanisms. METHOD: Dietary-induced hypercholesterolemia was induced in male Wistar rats by given 4% cholesterol and 1% cholic acid diet for 16 weeks. Changes of serum lipid, urinary albumin, renal function and Mesangial matrix index were assessed. Moreover, immunohistochemical stain for TGF-beta 1 and type IV collagen were performed. RESULT: VOL could reduce the serum levels of total cholesterol, low density lipoprotein, urinary albumin and serum creatinine. Light microscopy and immunohistochemical stain revealed that in the same time of lowing serum lipid, Mesangial matrix index was significantly reduced, accompanied by decreased expression of TGF-beta 1 and type IV collagen. CONCLUSION: VOL has the protective effect on lipid-induced nephropathy, and the inhibition of TGF-beta 1 expression might be the mechanism of VOL on renal protection.