Anatase and rutile titanium oxide nanoparticles induce acute kidney injury by coadministration with paraquat, cisplatin or 5-aminosalicylic acid.

Nanoparticles are used in a variety of fields; for example, titanium oxide nanoparticles are used in paints, food additives, cosmetics, and sunscreen materials. Although the use of titanium oxide nanoparticles is regulated, their safety has not been established. Furthermore, the interaction between titanium oxide nanoparticles and various chemical substances and pharmaceuticals is unknown. We co-administered rutile-type titanium oxide nanoparticles (nTR) or anatase-type titanium oxide nanoparticles (nTA) to mice together with paraquat (PQ), cisplatin (CDDP), or anti-5-aminosalicylic acid (5-ASA), and investigated the extent, if any, of liver and kidney injury. As a result, when nTA and nTR were administered alone, no increases were observed in aspartate aminotransferase (AST) and alanine aminotransferase (ALT), which are indicators of liver damage, or urea nitrogen (BUN), which is an indicator of kidney damage. Next, nTA and nTR were co-administered with PQ, CDDP or 5-ASA. Although no increase in ALT or AST was observed, BUN levels increased significantly and acute kidney injury was induced. The findings suggested that titanium oxide nanoparticles induce acute kidney injury through their interaction with chemicals and drugs.

The hepatoprotective effect of lycopene on Con A-induced liver injury in mice.

Lycopene, the main fat-soluble pigment responsible for the red color of ripe tomatoes, is a symmetrical tetraterpene comprising eight isoprene units. In vitro and in vivo studies have shown that lycopene acts as a potent antioxidant; it is 100 times more effective than vitamin E and 125 times more effective than glutathione as an antioxidant. Here, we divided BALB/c male mice into three equal groups: control, Concanavalin A (Con A), and Con A and lycopene. The control group mice received only vehicle by intraperitoneal injection, the Con A group mice were given Con A, and the Con A and lycopene group mice received Con A and lycopene. The results showed that Con A administration increased histopathological damage, and the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), interleukin (IL)-6, interferon (IFN)-γ and tumor necrosis factor (TNF)-α were increased in serum samples whereas the levels of these compounds were significantly decreased in the Con A and lycopene group compared to the Con A group. Furthermore, we observed that lycopene led to an increase in cell viability and cell growth. The results of this study revealed that lycopene might be a useful hepatoprotective agent for reducing increased proinflammatory cytokine levels, and for increasing cell viability and cell growth.

Effects of surface charge and palladium on hepatic and kidney injury induced by polystyrene nanoparticles co-administered to mice with paraquat and cisplatin.

Recently, with the advancement of nanotechnology, various nanoparticles have been developed and used in fields such as electronics, cosmetics, and foods. However, the toxicity of nanoparticles has yet to be fully investigated. In particular, the interactions between nanoparticles and therapeutic drugs require further study. We previously reported that unmodified polystyrene nanoparticles with a particle size of 50 nm (NPP50) co-administered with paraquat (PQ) or cisplatin (CDDP) induce hepatic and kidney injury. Here, we determined if NPP50 modified with the amino group (NPP50-NH2), carboxyl group (NPP50-COOH), or palladium (Pd-NPP50) caused liver or kidney injury when co-administered with PQ or CDDP. The results showed that when NPP50-NH2, NPP50-COOH, or Pd-NPP50 was administered alone via the mouse tail vein, serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and blood urea nitrogen (BUN) did not increase or cause injury. When NPP50, NPP50-NH2, NPP50-COOH, or Pd-NPP50 was co-administered with PQ, serum levels of ALT and AST increased in the NPP50 group but did not increase in the NPP50-NH2, NPP50-COOH, or Pd-NPP50 groups. When NPP50-NH2, NPP50-COOH, or Pd-NPP50 was co-administered with CDDP, ALT, AST, and BUN values did not increase. These data suggest that injury due to the interaction of polystyrene nanoparticles with CDDP or PQ can be suppressed by changes in the surface charge of nanoparticles or by Pd modification.

Long-term clinical impact of serum albumin in coronary artery disease patients with preserved renal function.

BACKGROUND AND AIMS: Low serum albumin level is reportedly associated with worse clinical outcomes in patients with chronic kidney disease (CKD). However, associations between decreased serum albumin level and outcomes in non-CKD patients with coronary artery disease (CAD) remain unclear. Therefore, we aimed to evaluate the prognostic value of serum albumin concentrations in stable CAD patients with preserved renal function. METHODS AND RESULTS: We studied 1316 patients with CAD and preserved renal function (estimated glomerular filtration rate ≥60 mL/min/1.73 m2) who underwent their first PCI between 2000 and 2011 and had data available for pre-procedural serum albumin. Patients were assigned to quartiles based on pre-procedural albumin concentrations. The incidence of major adverse cardiac events (MACE), including all-cause death and non-fatal myocardial infarction, was evaluated. Mean albumin concentration was 4.1 ± 0.4 g/dL. During the median follow-up of 7.5 years, 181 events occurred (13.8%). Kaplan-Meier curves revealed that patients with decreased serum albumin concentrations showed a higher event rate for MACE (log-rank, p < 0.0001). Using the highest tertiles (>4.3 g/dL) as reference, adjusted hazard ratios were 1.97 (95% CI, 1.12-3.55), 1.77 (95% CI, 0.99-3.25), and 1.19 (95% CI, 0.68-2.15) for serum albumin concentrations of <3.9, 3.9-4.0, and 4.1-4.3 g/dL, respectively. Decreased serum albumin concentration was associated with MACE even after adjusting for other independent variables (HR, 2.21 per 1-g/dL decrease; 95% CI, 1.37-3.56, p = 0.001). CONCLUSION: Decreased serum albumin concentration independently predicted worse long-term prognosis in non-CKD patients after PCI. Pre-procedural serum albumin concentration could offer a useful predictor for patients with CAD and preserved renal function.

Hepatotoxicity, nephrotoxicity, and drug/chemical interaction toxicity of platinum nanoparticles in mice.

Nanomaterials are frequently used in microelectronics, cosmetics, and sunscreens. Platinum reagents are commonly used in disease diagnosis, cosmetics, and the food industry. Although research into the development of nanomaterialbased drug delivery systems has yielded promising results, the toxicity of these materials is not fully understood. We investigated the toxicity and drug interactions of 1- and 8-nm diameter platinum nanoparticles (nPt1 and nPt8, respectively) in mice. Acute hepato-renal toxicity of intravenously administered platinum nanoparticles was evaluated biochemically and histologically. Dose-dependent increases in serum markers of hepato-renal function (serum aminotransferases and blood urea nitrogen) were observed following administration of nPt1, whereas nPt8 had no effect, even at 20 mg/kg. Moreover, nPt1 induced interleukin (IL)-6 and IL-1ß production 3 and 6 hours after administration. The effect of nPts on drug-induced toxicity was evaluated in mice injected intraperitoneally with carbon tetrachloride or cisplatin, with or without intravenous administration of platinum nanoparticles. All treatments in the absence of nanoparticles were non-lethal and resulted in moderate toxicity. However, exacerbated toxicity was observed in mice injected with carbon tetrachloride or cisplatin together with nPt1, but not in mice co-injected with nPt8. We found that nPt1 cause hepato-renal damage, and the effect is enhanced by chemical inducers of hepatotoxicity and nephrotoxicity. This is the first report demonstrating that nPt1 not only are hepatotoxic and nephrotoxic but also exacerbate drug toxicity. These findings will be useful for future nanotechnology and nanoscience research.

Effects of washing of the face with a mild facial cleanser formulated with sodium laureth carboxylate and alkyl carboxylates on acne in Japanese adult males.

BACKGROUND/PURPOSE: Washing the face with a mild cleanser is generally recommended for acne care. Occasionally, the general public has the misconception that acne is exacerbated by cleansers and furthermore it has concerns about inducing skin irritation and xerosis by intensive washing. Recently, we developed a new cleanser based on sodium laureth carboxylate and alkyl carboxylates (AEC/soap) that cleans sebum well without penetrating the stratum corneum. METHODS: We designed a controlled clinical trial conducted on adult Japanese males with moderate or less acne. Twenty subjects washed their faces with AEC/soap base cleanser twice a day for 4 weeks. Assessment of the efficacy was conducted prior to the start of the study, and at the end of weeks 2 and 4. RESULTS: Significant improvement of the acne was observed within 2 weeks, and acne lesions were not detectable in 25% of the subjects at week 4. Sebum secretion levels on the skin significantly increased on the forehead, but significantly decreased on the cheek which correlated with the improvement. No complaints of dryness or irritation occurred during the study. CONCLUSION: Washing the face twice a day with facial cleanser based on AEC/soap is an effective care for moderate or less grade facial acne.

Toxicity of 50-nm polystyrene particles co-administered to mice with acetaminophen, 5-aminosalicylic acid or tetracycline.

We investigated whether nano-sized polystyrene particles affect drug-induced toxicity. The particles, which are widely used industrially, had diameters of 50 (NPP50), 200 (NPP200) or 1000 (NPP1000) nm. The toxic chemicals tested were acetaminophen (APAP), 5-aminosalicylic acid (5-ASA), tetracycline (TC), and sodium valproate (VPA). All treatments in the absence of the nanoparticles were non-lethal and did not result in severe toxicity. However, when mice were injected with APAP, 5-ASA or TC together with polystyrene particles, synergistic, enhanced toxicity was observed in mice injected with NPP50. These synergic effects were not observed in mice co-injected with NPP200 or NPP1000. On the other hand, co-administration of VPA and NPP50, NPP200 or NPP1000 did not elevate toxicity. The results show that NPP50 differs in hepatotoxicity depending on the drug co-administered. These findings suggest that further evaluation of the interactions between polystyrene nanoparticles and drugs is a critical prerequisite to the pharmaceutical application of nanotechnology.

A new formula for a mild body cleanser: sodium laureth sulphate supplemented with sodium laureth carboxylate and lauryl glucoside.

OBJECTIVE: Sodium laureth sulphate (SLES) is an anionic detergent, which has been used globally for personal care products because of its mildness and good foaming ability. However, SLES is somewhat invasive and stimulatory to the skin, and many consumers with sensitive skin desire milder detergents for daily use skin cleansers. We enhanced the mildness of SLES by formulating it with sodium laureth carboxylate (AEC) and lauryl glucoside (LG). METHODS: In skin soak tests, 5% detergent solutions were applied to the forearms of 10 Japanese healthy volunteers for 30 min followed by washing with tap water once a day for 4 days. Twenty-four hours after the last treatment, cutaneous capacitance measurements and visual analyses were performed. In a controlled usage study, 16 Japanese healthy volunteers used the test body cleanser for 4 weeks. Assessment of efficacy and mildness was conducted prior to the start of the study and at the end of week 4 by cutaneous conductance, dermoscopic evaluation of the stratum corneum and visual assessment by a dermatologist. RESULTS: In soak tests, cutaneous capacitance was significantly decreased on the soap-treated region and on the SLES-treated region. No significant decrease was identified on the SLES/AEC/LG-treated region with less induction of erythema or dryness. In the controlled usage study, no significant changes in cutaneous conductance or texture or damage of corneocytes on the forearm and lower thigh were found. However, visual assessment revealed a significant decrease in scaling and erythema on the lower thigh after 4 weeks of usage with an improvement of the discomfort of the consumer. The favourability rating of this formulated detergent in several questionnaire items was very good. CONCLUSION: The newly formulated skin cleanser with the combination of anionic surfactants SLES and AEC and the non-ionic surfactant LG provides a mild surfactant with a satisfactory cleansing activity for body washing.

Altered somatosensory barrel cortex refinement in the developing brain of Mecp2-null mice.

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the methyl-CpG binding protein 2 (MeCP2) gene. In previous studies, monoaminergic dysfunctions have been detected in patients with RTT and in a murine model of RTT, the Mecp2-null mouse. Therefore, the pathogenesis of RTT is thought to involve impairments in the monoaminergic systems. However, there have been limited data showing that the impairment of monoamines leads to early symptoms during development. We used histochemistry to study the somatosensory barrel cortex in the B6.129P2(C)-Mecp2(tm1.1Bird) mouse model of RTT. The barrel cortex is widely used to investigate neuronal development and its regulation by various neurotransmitters including 5-HT. 5-HT levels were measured by high performance liquid chromatography with electrochemical detection (HPLC/EC), and serotonin transporter (SERT) and 5-HT1B receptor mRNAs were measured in the somatosensory cortex, thalamus and striatum on postnatal days (P) 10, P20 and P40. Mecp2-null mice (Mecp2-/y) had significantly smaller barrel fields than age-matched wild-type controls (Mecp2+/y) on P10 and P40, but the topographic map was accurately formed. Levels of 5-HT, and SERT and 5-HT1B receptor mRNA expression in the somatosensory cortex did not differ significantly between the Mecp2-null and wild-type mice on P10. However, thalamic 5-HT was reduced in Mecp2-null mice. Our data indicate that a lack of MeCP2 may disturb the refinement of the barrel cortex in the early postnatal period. Our findings suggest that a decrease in thalamic 5-HT might be involved in this phenomenon.

Influence of 50-nm polystyrene particles in inducing cytotoxicity in mice co-injected with carbon tetrachloride, cisplatin, or paraquat.

The toxicity of nanomaterials has yet to be fully investigated. In particular, the interactions between nanomaterials and therapeutic drugs require further study. We investigated whether nano-sized polystyrene particles affect drug-induced toxicity. The particles, which are widely used industrially, had diameters of 50 (NPP50), 200 (NPP200) or 1000 (NPP1000) nm. The toxic chemicals tested were carbon tetrachloride, cisplatin (a popular anti-tumor agent), and a widely used herbicide, paraquat. Mice were treated intraperitoneally with either carbon tetrachloride (0.01 ml/kg), cisplatin (100 micromol/kg) or paraquat (50 mg/kg), with or without intravenous administration of polystyrene particles. All treatments in the absence of the nanoparticles were non-lethal and did not result in severe toxicity. However, when mice were injected with paraquat or cisplatin together with polystyrene particles, synergistic, enhanced toxicity was observed in mice injected with NPP50. These synergic effects were not observed in mice co-injected with NPP200 or NPP1000. These findings suggest that further evaluation of the interactions between polystyrene nano-particles and drugs is a critical prerequisite to the pharmaceutical application of nanotechnology.

Hepatotoxicity of silica nanoparticles with a diameter of 100 nm.

Nanomaterials have potential toxicity that is not found in micromaterials, and it is therefore essential to understand their biological activity and potential toxicity. We focused on silica nanoparticles, since it was previously reported that the intravenous administration of silica nanoparticles with a diameter of 70 nm (SP70) causes hepatic injury. In the present study, we focused on the effects of the particle diameter of silica. We found that silica nanoparticles caused acute liver toxicity at a diameter of 100 nm, and that liver sinusoidal endothelial cells are directly involved in silica nanoparticle-induced liver injury. These findings suggest that the diameter of nanoparticles has great influence on silica nanoparticle-induced liver injury.

A toxicological evaluation of a claudin modulator, the C-terminal fragment of Clostridium perfringens enterotoxin, in mice.

Tight junctions (TJs) maintain cellular polarity between the apical and basolateral region of epithelial cells. Claudin, a tetra-transmembrane protein, plays a pivotal role in the barrier function of TJs. We previously found that a claudin modulator, the C-terminal fragment of Clostridium perfringens enterotoxin (C-CPE), may be a promising candidate for improving the mucosal absorption of drugs. C-CPE is a fragment of enterotoxin, and putative CPE claudin receptors are highly expressed in liver and kidney. The safety and antigenicity of C-CPE must be evaluated for future clinical application. Therefore, we evaluated whether C-CPE administration in mice leads to tissue injury or production of antibodies. Intravenous administration of C-CPE at 5 mg/kg, which is a more than 25-fold higher dose than that used in a murine mucosal absorption model, did not increase biochemical markers of liver and kidney injury even after 11 injections once a week. Nasal C-CPE administration (2 mg/kg) once a week for 11 administrations also did not increase these biochemical markers, but 6 administrations of C-CPE resulted in elevation of C-CPE-specific serum IgG. These results indicate that development of a less antigenic claudin modulator will be essential for future clinical application of a C-CPE-based mucosal absorption enhancer.

Effect of surface charge on nano-sized silica particles-induced liver injury.

Nanomaterials are used frequently in microelectronics, cosmetics and sunscreen, and research for the development of nanomaterial-based drug delivery systems is promising. We previously reported that the intravenous administration of unmodified silica particles with a diameter of 70 nm (SP70) caused hepatic injury. Here, we examined the acute hepatic toxicity of SP70 modified with amino group (SP70-N) or carboxyl group (SP70-C). When administered intravenously into mice, SP70-N and SP70-C dose-dependently increased the serum level of alanine aminotransferase (ALT). However, the toxicity levels of surface charge-modified silica particles were much less weaker than the level of unmodified particles. When SP70 was repeatedly administered at 40 mg/kg twice a week for 4 weeks into mice, the hydroxyproline content of the liver significantly increased. Azan staining of the liver section indicated the extensive fibrosis. To the contrary, the repeated administration of SP70-N or SP70-C at 60 mg/kg twice a week for 4 weeks into mice did not cause the hepatic fibrosis. These findings suggest that the surface charge of nanomaterials could change their toxicity.

Effect of 70-nm silica particles on the toxicity of acetaminophen, tetracycline, trazodone, and 5-aminosalicylic acid in mice.

Exposure to nano-sized particles is increasing because they are used in a wide variety of industrial products, cosmetics, and pharmaceuticals. Some animal studies indicate that such nanomaterials may have some toxicity, but their synergistic actions on the adverse effects of drugs are not well understood. In this study, we investigated whether 70-nm silica particles (nSP70), which are widely used in cosmetics and drug delivery, affect the toxicity of a drug for inflammatory bowel disease (5-aminosalicylic acid), an antibiotic drug (tetracycline), an antidepressant drug (trazodone), and an antipyretic drug (acetaminophen) in mice. Co-administration of nSP70 with trazodone did not increase a biochemical marker of liver injury. In contrast, co-administration increased the hepatotoxicity of the other drugs. Co-administration of nSP70 and tetracycline was lethal. These findings indicate that evaluation of synergistic adverse effects is important for the application of nano-sized materials.

Postnatal changes in serotonergic innervation to the hippocampus of methyl-CpG-binding protein 2-null mice.

Rett syndrome is a progressive neurodevelopmental disorder caused by mutations in the methyl-CpG-binding protein 2 (MeCP2) gene. Previous reports have revealed serotonergic function to be altered in the medullas of patients with Rett syndrome and in an animal model of the disease. However, it has remained unclear whether a genetic loss of MeCP2 disrupts serotonergic innervation to the forebrain. In this study, we measured levels of monoamines by high-performance liquid chromatography with electrochemical detection in selected regions of the forebrains of Mecp2-null mice (Mecp2-/y) and wild-type mice (Mecp2+/y) on postnatal day (P) 14, P28, P42 and P56. The levels of hippocampal serotonin (5-HT) and its main metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were significantly lower in Mecp2-null mice than in age-matched wild-type mice on P28, P42 and P56. Immunohistochemical analysis revealed a loss of 5-HT-immunoreactive fibers in the Mecp2-null hippocampus on P56. By contrast, in the raphe region of Mecp2-null mice, there were significant decreases in 5-HT and noradrenaline levels, but these differences later disappeared and there was no change in the number of 5-HT-immunoreactive neuronal cell bodies. Furthermore, we conducted an experiment comparing HPLC measurements in presymptomatic heterozygous females (Mecp2+/-) and wild-type female littermates (Mecp2+/+) on P56. Significant decreases in hippocampal 5-HT and 5-HIAA contents in Mecp2-heterozygous mice were revealed, and these were not accompanied by changes in 5-HT or noradrenaline contents in the raphe region. Therefore, these results indicated decreases in serotonergic innervation to the hippocampus in Mecp2-null males and Mecp2 heterozygous females. We speculate that disturbances in serotonergic neurotransmission in the hippocampus may be linked to the behavioral abnormalities seen in Rett syndrome, such as increased anxiety-like behaviors and reduced exploratory locomotion. MeCP2 may be required for stable serotonergic homeostasis and serotonergic innervation to the hippocampus during postnatal development.

Influence of 70 nm silica particles in mice with cisplatin or paraquat-induced toxicity.

In the pharmaceutical industry, nano-size materials are designed as drug carriers and diagnosis probes. Interactions between nano-size materials and chemicals need investigating. Here, we investigated whether nano-size materials affect chemical-induced toxicity using silica particles, which have been widely used in cosmetics and drug delivery and have diameters of 70 (SP70), 300 (SP300) and 1000 (SP1000) nm, a popular anti-tumor agent, cisplatin, and a widely used herbicide, paraquat. Mice were treated with either cisplatin (100 micromol/kg, intraperitoneally) or paraquat (50 mg/kg, intraperitoneally), with or without intravenous silica particle administration. All treatments were non-lethal and did not show severe toxicity, except for injection with both cisplatin and SP70, which were lethal. When mice received with paraquat and/or the silica particles, synergistic enhanced toxicity was observed in both paraquat- and SP70-treated mice. These synergic effects were not observed with either Si300 or 1000 treatment. Our findings suggest that further evaluation on the interaction between nano-size materials and chemicals is critical for the pharmaceutical application of nanotechnology.