Releasing human pharmaceuticals to the environment is an emerging ecotoxicological concern. In this study, we examine the feasibility of evaluating the algal chronic toxicity of human pharmaceuticals using quantitative structure–activity relationship (QSAR) models and a category approach. We constructed an ecotoxicology database of human pharmaceuticals using publicly available information, such as regulatory agency reports and scientific papers. We created an algal chronic toxicity dataset using this database, and predicted the No Observed Effect Concentrations (NOEC) of human pharmaceuticals using ECOlogical Structure-Activity Relationship (ECOSAR) and KAshinhou Tool for Ecotoxicity (KATE) QSAR models. Almost half of query substances were applicable to the QSAR models, and the feasibility was confirmed with high concordant predictions—predicted/measured ratios were in the range of 0.01–100 in 92.9% and 79.1% of applicable substances in ECOSAR and KATE, respectively—and false predictions (predicted/measured ratios > 100) that could lead to significant underestimation of toxicity were rarely observed. Two case studies of diphenhydramine and lamotrigine demonstrated that detailed evaluation of target and reference substances in the corresponding chemical class could increase the reliability and accuracy of prediction results of KATE. Grouping of substances based on pharmacology revealed some category classes with a toxicological concern. Finally, a workflow model to assess algal toxicity of human pharmaceuticals was proposed based on these evaluations including QSAR predictions and category approach.

Two zinc oxide nanoparticles (ZnO NPs) with different physicochemical properties (ZnO(α) and ZnO(Σ)) were examined in THP-1 cells to investigate their effects on cellular immunomodulation and cytotoxicity. THP-1 cells were cultured in the presence of ZnO(α) or ZnO(Σ) for 48 hr, and the expression of proinflammatory cytokines and immune cell surface antigens was examined. ZnO(α) and ZnO(Σ) reduced cell viability in a concentration- and time-dependent manner, with the latter being more potent. ZnO(α) and ZnO(Σ) increased the expression of CD54, IL-8, and TNF-α to the same extent between 24 and 48 hr. While ZnO(Σ) was more potent at effective concentrations, this potency was comparable between ZnO(α) and ZnO(Σ) when normalized to their cytotoxic concentrations (LC₅₀, LC₂₅, or LC₅). It was considered that there was a potency shift that is associated with cytotoxicity and physicochemical properties, in immunomodulatory activities in THP-1 cells between ZnO NPs.

To evaluate the effects of multi-walled carbon nanotubes (MWCNT) on a host immune system, we assayed them using a murine model of respiratory syncytial virus (RSV) infection. MWCNT suspended in solution were intranasally administered to mice on days 1, 3, and 5 before RSV infection. On day 5 post-infection, the levels of representative inflammatory markers (interferon-γ, chemokines CCL3 and CCL5) in bronchoalveolar lavage fluid (BALF) were significantly increased in RSV-infected mice due to MWCNT exposure compared to the control. A histopathological analysis confirmed the exacerbation of the pneumonia. However, significant histopathological changes were not observed in mock-infected mice in this study. Some alveolar macrophages engulfing the MWCNT aggregates were localized in the inflammatory cells in the lung tissues, but RSV-positive cells immunohistopathologically stained with an anti-RSV antibody were observed apart from those cells. Thus, intranasal treatment with MWCNT should affect the pulmonary immune response against RSV, exacerbating RSV infection in mice.

Trans fatty acids (TFAs) are risk factors for cardiovascular diseases and have been suggested to play roles in various metabolic diseases, including non-alcoholic steatohepatitis (NASH). The present study aimed to assess the influence of TFAs on the development of NASH lesions. Male Harlan Sprague Dawley rats were fed a choline-deficient, methionine-lowered, L-amino acid-defined (CDAA) diet with or without TFAs for two, four, and 13 weeks. The CDAA diet caused hepatic steatosis, macrophage infiltration, and fibrosis. Further, it increased serum activities of aspartate and alanine aminotransferase, and upregulated inflammation- and fibrosis-related genes in the liver. TFAs enhanced or tended to enhance the serum ALT activity but did not affect other outcomes. In the present study using the CDAA rat model, NASH lesions were clearly induced; however, the effect of TFAs was minimal. In conclusion, TFAs may be a risk factor for NASH by enhancing hepatocellular injury. With the composition and amount used in the present study, TFAs did not affect hepatic steatosis, chronic inflammation, or fibrosis in rats fed with the CDAA diet. To assess the risk of TFAs for NASH, more comprehensive studies are warranted, using other compositions and/or amounts of TFAs.

Valacyclovir, a prodrug of acyclovir, may cause adverse drug reactions, so called acyclovir encephalopathy. The acyclovir encephalopathy may not be explained simply by acyclovir blood concentrations, because recent reports suggest the involvement of 9-carboxymethoxymethylguanine (CMMG), a major metabolite of acyclovir. The present study demonstrates changes in serum concentrations of acyclovir and CMMG in a patient with suspected acyclovir encephalopathy. A 63-year-old male was prescribed loxoprofen and valacyclovir for herpes zoster. Seven days after the start of medication, he showed signs of confusion. The next morning, he was emergently transported to hospital for a suspected stroke. There was no stroke lesion but evidence of acute kidney injury, so the patient was given emergency dialysis. With daily hemodialysis sessions performed for three days, the serum concentrations of acyclovir and CMMG decreased, and his state of consciousness improved accordingly.The metabolite CMMG, as well as acyclovir, is efficiently removed by hemodialysis and symptoms of acyclovir encephalopathy improved with decreased serum concentrations. Therefore, if other organic diseases can be ruled out in a patient with suspected acyclovir encephalopathy, it is advisable to introduce hemodialysis immediately.

Diabetes mellitus and brain toxicity are closely linked, and oxidative stress, obesity, insulin resistance, and glucose toxicity can affect the brain. Orexin-A, also known as hypocretin-1, through its activated receptor, participates in many physiological processes. Orexin-A has been associated with feeding behavior, obesity, and pathogenesis of Alzheimer's disease. We have recently established that high-dose thiamine in obese diabetic Otsuka Long–Evans Tokushima Fatty (OLETF) rats leads to reduced obesity and metabolic disorders. Additionally, we found that plasma orexin-A levels in OLETF rats can be modulated by thiamine supplementation under conditions of oxidative stress. Here, we focused on orexin-A in obese diabetic OLETF rats, which at 58 weeks of age and as expected, showed an increase in body weight and blood glucose levels. Plasma orexin-A was measured by ELISA and tended to be higher in obese diabetic OLETF rats than in non-obese diabetic control rats. We evaluated hypocretin receptor 1 (Hcrtr1, also orexin-A receptor) gene expression in the brain of diabetic OLETF rats by reverse transcription (RT)- polymerase chain reaction (PCR) and show that, compared to controls, diabetic OLETF rats exhibited greater orexin-A receptor gene expression in the brain. The results presented here are expected to provide a better understanding of the role of orexin-A and its contribution to brain toxicity in obese diabetic rats.

Methylmercury (MeHg) exposure during pregnancy is a concern because of its potential health risks to the fetus. Wheat bran (bran), which is the outer layer of wheat kernel, is used as a functional substance in food for specified health uses in Japan. In the present study, we examined the effect of bran on the accumulation and excretion of Hg in mice to evaluate its potential use for reducing the health risk of MeHg. Female BALB/cByJ mice were administered MeHg chloride (4 mg Hg/kg, p.o.). Immediately after administration, the mice were fed a basal diet supplemented with 0%, 5%, or 15% bran, and urine and feces were collected for 14 days. The bran groups had lower total Hg levels in all tissues including the brain compared with the control group, but the effects were significant only in the blood and brain of mice on the 15% bran diet. Urinary Hg excretion in the bran groups was markedly higher than in the control group, although there was no difference in the excretion between the bran groups. Moreover, fecal Hg excretion in the bran groups was substantially higher than in the control group and was dose-dependent. These results suggest that bran intake after MeHg exposure may enhance Hg excretion both in urine and feces and decrease tissue Hg levels. In conclusion, dietary bran might be useful for reducing Hg burden in humans ingested MeHg in food.

Low-dose ionizing radiation (LDIR) at a dose reported in the radiation hormesis effect and adaptive response enhances antioxidant abilities and DNA repair abilities. In this study, we investigated the effects of radiation at 0.1–3 Gy on apoptosis induced by serum removal. Irradiation of 1 Gy at the timing of apoptosis induction improved cell viability. The inhibitory effect on apoptosis was strongly observed at 1 Gy of radiation rather than 0.1 Gy, which is the dose reported in the radiation hormesis effect and adaptive response. To study the effect of irradiation on cell cycle and DNA damage repair system, we investigated the activation of cyclin A and the phosphorylation of KAP1, and results showed that the irradiation decreased cyclin A and activated KAP1, suggesting cell cycle arrest and the activation of DNA damage repair system after the irradiation. Next, we investigated the increased phosphorylation of p38 and Jun-N-terminal kinase (JNK), stress response factors, that occurs during the progression of apoptosis by serum removal, and results showed that 1 Gy of irradiation increased p38 but decreased JNK. We investigated the effect of the irradiation on the regulation of DUSP1, which is a substrate specificity for MAPK, and results showed that the irradiation maintained the expression level for the transient induction of DUSP1 expression by serum removal. The results suggest that in LDIR at 1 Gy, apoptosis was suppressed by the activation of DNA damage repair signaling and crosstalk signaling between the p38 and JNK pathways mediated by DUSP1 induction.