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The objective of this study was to assess the antioxidant ability of C60(OH)10/2-hydroxypropyl-β-cyclodextrin (HP-β-CD) nanoparticles, by comparing their scavenging ability for reactive nitrogen species, their cytoprotective effects under conditions of oxidative stress, and their therapeutic effects against diseases that are induced by oxidative stress. The C60(OH)10/HP-β-CD nanoparticles had a higher scavenging activity against nitric acid and peroxynitrite (ONOO(-)) than the other antioxidants such as ascorbic acid, trolox, and edaravone. The cytoprotective effect of C60(OH)10/HP-β-CD nanoparticles was examined on HeLa and HepG2 cells by monitoring the percentage of cell death induced by H2O2. Treatment with C60(OH)10/HP-β-CD nanoparticles resulted in an increase in cell viability, due to the suppression of the oxidative stress. Furthermore, the nanoparticles had a high cytoprotective effect, compared with other polyhydroxylated C60 (C60(OH)24 and C60(OH)40). The C60(OH)10/HP-β-CD nanoparticles were intravenously administered to mice with a liver injury induced by an over dose of acetaminophen. Levels of alanine transaminase and aspartate transaminase were essentially the same as those of normal mice and the survival rate was also prolonged by the intravenous administration of the C60(OH)10/HP-β-CD nanoparticles. The results indicate that C60(OH)10/HP-β-CD nanoparticles are a promising antioxidant for use in the treatment of diseases caused by oxidative stresses., (Copyright © 2016. Published by Elsevier Inc.)

Objectives: Oxidative stress is known to be involved in the pathogenesis of chronic renal failure (CRF). In this study, the effect of cyclodextrins (CDs) on oxidative stress and CRF was investigated using 5/6 nephrectomized rats as model animals., Methods: CRF model rats were divided into five groups and treated for 8 weeks as follows: control, α-CD, β-CD, γ-CD and 2-hydroxypropyl-β-CD (HP-β-CD). Blood was collected from the rats after 4 and 8 weeks for an analysis of renal function and oxidative stress tests were carried out., Key Findings: An oral administration of HP-β-CD over an 8-week period resulted in a significant decrease in serum indoxyl sulphate, creatinine and urea nitrogen levels, compared with the other CDs. The ingestion of HP-β-CD also resulted in an increase in antioxidant potential, compared with the other CDs. In in vitro studies, the interaction of HP-β-CD with a uremic toxin, indole molecule, was much higher than that for the other CDs, as evidenced by Proton nuclear magnetic resonance ((1) H NMR) measurements., Conclusions: These results suggest that the ingestion of HP-β-CD might result in a significant reduction in the levels of pro-oxidants in the gastrointestinal tract, such as uremic toxins, thereby inhibiting the subsequent development of oxidative stress in the systemic circulation., (© 2015 Royal Pharmaceutical Society.)

Background: The primary cause of death of hemodialysis (HD) patients is cardiovascular disease, and increased oxidative stress has been proposed to be involved in the disease pathogenesis. In this study, we examined the effect of olmesartan on oxidative stress induced by angiotensin II, lipopolysaccharide, indoxyl sulfate, advanced oxidation protein products (AOPP) or hydrogen peroxide (H2O2), which are known to be present at higher concentrations in the blood of HD patients, using human umbilical vein endothelial cells (HUVECs)., Methods: Oxidative stress was evaluated by measuring the mean fluorescence intensity of CM-H2DCFCA, an ROS-sensitive fluorescent dye, in HUVECs. HUVECs were incubated with each of the above compounds in the presence or absence of olmesartan. Moreover, these oxidant-stimulated cells were also treated with the reactive oxygen species (ROS) inhibitor N-acetyl-cysteine (NAC), NADPH oxidase inhibitor diphenylene iodonium (DPI) or PKC inhibitor calphostin C. In addition, we investigated the effects of olmesartan on cytotoxicity and vascular endothelial growth factor (VEGF) secretion, which is involved in vascular inflammation in HUVECs induced by AOPP or H2O2., Results: The treatment of these oxidant-stimulated cells with olmesartan resulted in a significant reduction in intracellular ROS production to an extent that was nearly equivalent to that of NAC, DPI or calphostin C. Furthermore, olmesartan reduced the cytotoxicity and VEGF secretion induced by AOPP or H2O2., Conclusions: These results demonstrated that the antioxidant activity of olmesartan might contribute to both its vasculoprotective and anti-hypertensive effects.

In this study, we examined a possible use of a surface-deacetylated chitin nano-fiber (SDCH-NF) and hyaluronic acid (HA) interpolymer complex (IPC) tablet as a potential antioxidative compound in extended-release matrix tablets. The antioxidant properties of untreated chitin (UCH), SDCH-NF, and HA were examined using N-centered radicals derived from 1,1'-diphenyl-2-picrylhydrazyl (DPPH) and 2,2'-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS). SDCH-NF and HA had acceptable scavenging abilities and were relatively efficient radical scavengers, but UCH was much less effective. The results suggest that SDCH-NF and HA could serve as scavengers of compounds related to the development of oxidative stress. An SDCH-NF/HA IPC tablet was prepared and evaluated as an extended-release tablet matrix using famotidine (FMT) as a model drug. The release of FMT from the IPC tablet (DCF-NF:HA=1:1) was slower than that from a SDCH-NF only tablet. Turbidity measurements and X-ray diffraction (XRD) data also indicated that the optimum complexation ratio for IPC between SDCH-NF/HA is 1/1, resulting in a good relationship between turbidity or XRD of the complex and the release ratio of FMT. These results suggest that an SDCH-NF/HA tablet has the potential for use in an extended-release IPC tablet with a high antioxidant activity.

The preparation of water-soluble chitosans such as polyethylene glycol (PEG)-grafted derivatives is essential for improving the biocompatibility and water solubility of these types of polysaccharides. In this study, chitosans (CS1; 22 kDa, CS2; 38 kDa, CS3; 52 kDa) with different molecular weights were modified with a succinyl ester derivative of monomethoxypolyethylene glycol (mPEG-COONSu; 2 kDa), and the properties of the resulting conjugates (mPEG-CS1, mPEG-CS2, mPEG-CS3) were investigated. The antioxidant properties of these mPEG-CSs were examined using (1) N-centered radicals derived from 1,1'-diphenyl-2-picrylhydrazyl (DPPH), (2) reducing power, based on their ability to reduce Cu2+ and (3) hydroxyl radicals via the use of ESR spectrometry. The order of their effectiveness was mPEG-CS1>mPEG-CS2>mPEG-CS3, i.e. mPEG-CS1 with a low particle size had the highest scavenging activity of the mPEG-CSs tested. In an in vivo study, we examined the effect of mPEG-CS1 on liver injury, caused by injecting mice with Concanavalin A (Con A). The livers of mice that were treated with mPEG-CS1 were protected from Con A-induced injury. Further, pre-treatment with mPEG-CS1 dramatically reduced the mortality associated with Con A-induced mortality. These findings suggest that mPEG-CS1 could be potentially useful in the treatment of immune-mediated liver injury., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Antioxidant activities of 3-oxygenated and 3,4-dioxygenated carbazole alkaloids and their related carbazoles were comprehensively evaluated. In all assay systems, the 3,8-dihydroxycarbazoles carbazomadurin A (2) and B (3), and their synthetic precursors 2a and 3a exhibited higher antioxidant activities than the 3-monohydroxycarbazoles carazostatin (1), and the synthetic precursors 4a and 4b of carquinostatin A (4). In particular, 2a and 3a exhibited strong scavenging activities due to the reducing ability of formyl group at the C-5 position of carbazoles. The results suggest that these compounds could serve as useful clues for designing and developing novel antioxidants., (Copyright © 2014. Published by Elsevier Ltd.)

The effect of chitosan on oxidative stress and chronic renal failure was investigated using 5/6 nephrectomized rats. The ingestion of chitosan over a 4-week period resulted in a significant decrease in total body weight, glucose, serum creatinine and indoxyl sulfate levels (P=0.0011, P=0.0006, P=0.0012, and P=0.0005, respectively), compared with the non-treated nephrectomized group. The ingestion of chitosan also resulted in a lowered ratio of oxidized to reduced albumin (P=0.003) and an increase in biological antioxidant potential (P=0.023). Interestingly, the oxidized albumin ratio was correlated with serum indoxyl sulfate levels in vivo. These results suggest that the ingestion of chitosan results in a significant reduction in the levels of pro-oxidants, such as uremic toxins, in the gastrointestinal tract, thereby inhibiting the subsequent development of oxidative stress in the systemic circulation., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The purpose of this study was to quantitatively evaluate the extent of contribution of cysteine-34 ((34) Cys) on the antioxidant effect of human serum albumin (HSA) and to elucidate the physiological implication in hemodialysis (HD) patients. The ratio of oxidized albumin correlated directly with the thiol content in plasma of the HD patients who received intravenous iron. Moreover, the degree of oxidation of (34) Cys in HSA purified from the HD patients' plasma correlated with the thiol content in plasma. The radical scavenging activity of purified HSA was dependent on the degree of (34) Cys oxidation. A recombinant mutant, C34S, was produced to confirm the role of (34) Cys. The activity of C34S was about half of that of wild-type HSA (WT-HSA). Consistent with this observation, the protective effects of C34S were significantly lower than those of WT-HSA in suppressing cytotoxicity and vascular endothelial growth factor production induced by fenton reaction in a human vascular endothelial cell model. These results indicate that the (34) Cys residue of HSA may account for more than 40% of the antioxidant effect of HSA in vivo, and thus may exert a protective effect on vascular endothelium function via an antioxidative mechanism in chronic renal disease., (Copyright © 2011 Wiley-Liss, Inc.)

The effect of high and low molecular weight chitosans (HMC; 1000 kDa, LMC; 30 kDa) on oxidative stress and hypercholesterolemia was investigated using male 6-week-old Wistar Kyoto rats as a normal model (Normal-rats) and spontaneously hypertensive rat/ND mcr-cp (SHP/ND) as a metabolic syndrome model (MS-rats), respectively. In Normal-rats, the ingestion of both chitosans over a 4 week period resulted in a significant decrease in total body weight (BW), glucose (Gl), triglyceride (TG), low density lipoprotein (LDL) and serum creatinine (Cre) levels. The ingestion of both chitosans also resulted in a lowered ratio of oxidized to reduced albumin and an increase in total plasma antioxidant activity. In addition to similar results in Normal-rats, the ingestion of only HMC over a 4 week period resulted in a significant decrease in total cholesterol levels in MS-rats. Further, the ingestion of LMC resulted in a significantly higher antioxidant activity than was observed for HMC in both rat models. In in vitro studies, LMC caused a significantly higher reduction in the levels of two stable radicals, compared to HMC, and the effect was both dose- and time-dependent. The findings also show that LDL showed strong binding in the case of HMC. These results suggest that LMC has a high antioxidant activity as well as antilipidemic effects, while HMC results in a significant reduction in the levels of pro-oxidants such as LDL in the gastrointestinal tract, thereby inhibiting the subsequent development of oxidative stress in the systemic circulation in metabolic model rats.

Angiotensin II type 1 receptor blockers, which inhibit the rennin-angiotensin system, are used in the treatment of hypertension. In addition to their ability to lower blood pressure, these compounds have also been reported to protect organs, such as kidney and heart. Although the mechanisms of these protective effects are not fully understood, it is generally thought that their antioxidant effects likely play a role. The aim of the present study was to characterize the relationship between the antioxidant activity of olmesartan and its pharmacological actions such as renoprotective or blood pressure lowering effects, using 5/6 nephrectomy rats. In 5/6 nephrectomy rats, the potential antioxidant power, the ratio of oxidized to unoxidized albumin, as a marker of protein oxidation in blood, both systolic and diastolic blood pressure, plasma creatinine concentration, and amounts of protein excreted into the urine were significantly higher than the corresponding values for sham operated rats. However, olmesartan significantly suppressed these parameters within 8 weeks after oral administration in 5/6 nephrectomy rats. The oxidized albumin ratio was significantly decreased 4 weeks after the administration of olmesartan and these lower levels were maintained at 8 weeks. Furthermore, olmesartan improved radical scavenging activity of isolated albumin from rat plasma. Interestingly, a good correlation was found between the oxidized albumin ratios and renal function, whereas no correlation was found in the case of blood pressure. Based on those findings, we conclude that the antioxidant properties of olmesartan may be related to its renoprotective action rather than an antihypertensive effect.

The effect of water-soluble chitosan, a natural polymer derived from chitin, on indices of oxidative stress was investigated in normal volunteers. Treatment with chitosan for 4 weeks produced a significant decrease in levels of plasma glucose, atherogenic index and led to increase in high density lipoprotein cholesterol (HDL). Chitosan treatment also lowered the ratio of oxidized to reduced albumin and increased total plasma antioxidant activity (TPA). There was good correlation between TPA and oxidized albumin ratio. The results indicate that oxidized albumin ratio represents a potentially useful marker of oxidative stress. In in vitro studies, albumin carbonyls and hydroperoxides were significantly decreased in a time-dependent manner in the presence of chitosan, compared with controls (p<0.05). Chitosan also reduced two stable radicals in a dose- and time-dependent manner. The results suggest that chitosan has a direct antioxidant activity in systemic circulation by lowering the indices of oxidative stress in both in vitro and in vivo studies. This may confer benefits additional to the reduction in plasma carbohydrate and increase in HDL levels. It may also inhibit oxidation of serum albumin commonly observed in patients undergoing hemodialysis, resulting in reduction of oxidative stress associated with uremia.

Purpose: The effect of AST-120, an oral adsorbent, on oxidative stress in the systemic circulation in chronic renal failure (CRF) was examined and the potential role of indoxyl sulfate (IS), an uremic toxin adsorbed by AST-120, in inducing the formation of reactive oxygen species (ROS) in the vascular system was studied, in vitro and in vivo., Materials and Methods: The level of oxidized albumin, a marker for oxidative stress in the systemic circulation was determined by HPLC, as previously reported. The mRNA levels of TGF-beta (1) and Oat1 were measured by quantitative RT-PCR. The IS induced ROS generation in cultured human umbilical vein endothelial cells (HUVECs) was estimated using a fluorescence microplate reader., Results: An increase in the ratio of oxidized to unoxidized albumin was determined using 5/6 nephrectomized rats (CRF rats) compared to a control group. The ratio was significantly reduced in the group that received AST-120 of 4 weeks, suggesting that AST-120 inhibits oxidative stress in CRF. An anti-oxidative effect of AST-120 was also observed in CRF rats with a similar renal function. The ratio of oxidized albumin was correlated with serum IS levels in vivo. The same relationship was also observed in CRF rats with the continued administration of IS. In addition, IS dramatically increased the generation of ROS in both a dose- and time- dependent manner in HUVEC, suggesting that accumulated IS may play an important role in enhancing intravascular oxidative stress., Conclusion: We propose that AST-120 reduces IS concentrations in the blood that induces ROS production in endothelial cells, thereby inhibiting the subsequent occurrence of oxidative stress in the systemic circulation in renal failure.