1. Evaluation of oxidative stress in D-serine induced nephrotoxicity
Marisol Orozco-Ibarra, et al. Toxicology. 2007 Jan 5;229(1-2):123-35. doi: 10.1016/j.tox.2006.10.008. Epub 2006 Oct 20.
It has been suggested that oxidative stress is involved in d-serine-induced nephrotoxicity. The purpose of this study was to assess if oxidative stress is involved in this experimental model using several approaches including (a) the determination of several markers of oxidative stress and the activity of some antioxidant enzymes in kidney and (b) the use of compounds with antioxidant or prooxidant effects. Rats were sacrificed at several periods of time (from 3 to 24h) after a single i.p. injection of d-serine (400mg/kg). Control rats were injected with l-serine (400mg/kg) and sacrificed 24h after. The following markers were used to assess the temporal aspects of renal damage: (a) urea nitrogen (BUN) and creatinine in blood serum, (b) kidney injury molecule (KIM-1) mRNA levels, and (c) tubular necrotic damage. In addition, creatinine clearance, proteinuria, and urinary excretion of N-acetyl-beta-d-glucosaminidase (NAG) were measured 24h after d-serine injection. Protein carbonyl content, malondialdehyde (MDA), 4-hydroxy-2-nonenal (4-HNE), fluorescent products of lipid peroxidation, reactive oxygen species (ROS), glutathione (GSH) content, and heme oxygenase-1 (HO-1) expression were measured as markers of oxidative stress in the kidney. Additional experiments were performed using the following compounds with antioxidant or pro-oxidant effects before d-serine injection: (a) alpha-phenyl-tert-butyl-nitrone (PBN), a spin trapping agent; (b) 5,10,15,20-tetrakis (4-sulfonatophenyl) porphyrinato iron(III) (FeTPPS), a soluble complex able to metabolize peroxynitrite; (c) aminotriazole (ATZ), a catalase (CAT) inhibitor; (d) stannous chloride (SnCl(2)), an HO-1 inductor; (e) tin mesoporphyrin (SnMP), an HO inhibitor. In the time-course study, serum creatinine and BUN increased significantly on 15-24 and 20-24h, respectively, and KIM-1 mRNA levels increased significantly on 6-24h. Histological analyses revealed tubular necrosis at 12h. The activity of antioxidant enzymes catalase, superoxide dismutase, glutathione peroxidase, and glutathione reductase remained unchanged at all times studied. Protein carbonyl content, MDA, 4-HNE, and ROS remained unchanged at all time-points studied. GSH content decreased transiently on 9 and 12h. Interestingly, fluorescent products of lipid peroxidation decreased significantly on 3-24h. HO-1 expression was undetectable by Western blot and the immunohistochemistry studies revealed that the intensity of HO-1 staining was weak. The administration of PBN, FeTPPS, ATZ, SnCl(2), and SnMP did not prevent or enhance renal damage induced by d-serine. Our data taken as a whole suggest that oxidative stress is not involved in the early phase of the nephrotoxicity induced by d-serine.
2. The disposition of tert-butyl-D-serine in the rat
S Knott, A Warrander, P J Phillips, J R Harding Xenobiotica. 1990 Jan;20(1):1-5. doi: 10.3109/00498259009046807.
1. Following intravenous administration of 14C-tert-butyl-D-serine to rats, radioactivity was eliminated rapidly via the kidneys. 2. One metabolite was detected in urine and was identified as the N-acetyl derivative of tert-butyl-serine. 3. Elimination was more rapid in female than male rats.
3. Honokiol protects hepatocytes from oxidative injury through mitochondrial deacetylase SIRT3
Jing-Xin Liu, Sheng-Nan Shen, Qiang Tong, Yi-Tao Wang, Li-Gen Lin Eur J Pharmacol. 2018 Sep 5;834:176-187. doi: 10.1016/j.ejphar.2018.07.036. Epub 2018 Jul 20.
Oxidative stress contributes to the initiation and progression of liver damage. SIRT3 is a member of nicotinamide adenine dinucleotide-dependent deacetylases that plays a key role in anti-oxidative defense and mitochondrial function in the liver. Honokiol is a natural lignan from the plants of Magnolia genus that exhibits potent anti-oxidative property. This study aims to evaluate the hepatoprotective potential of honokiol against oxidative injury in tert-butyl hydroperoxide (t-BHP)-injured AML12 hepatocytes in vitro and carbon tetrachloride (CCl4)-stimulated liver damaged mice in vivo and to determine whether or not this effect occurs by activating SIRT3. The results showed honokiol protects t-BHP-injured AML12 hepatocytes and CCl4-stimulated liver damage in mice by activating SIRT3. Honokiol reduces the acetylation level of superoxide dismutase 2 to enhance its anti-oxidative capacity, which decreases reactive oxygen species accumulation in AML12 cells. Honokiol increases the deacetylated peroxisome proliferator-activated receptor γ coactivator 1-α level to promote mitochondrial biogenesis. Moreover, honokiol attenuates t-BHP induced mitochondrial fragmentation through Ku70-dynamin-related protein 1 axis. These results suggest that honokiol can ameliorate oxidative damage in hepatocytes by activating SIRT3, which might be a potential therapeutic agent for liver oxidative injury.
