The history of methylmercury (MeHg) toxicity research goes back to Minamata disease. In Japan, histopathological examination of patients afflicted with Minamata disease, alongside meticulous investigations at both in vitro and in vivo, were robustly undertaken to elucidate the deleterious effects of MeHg. It is not an overstatement to assert that Japanese investigations on MeHg toxicity have spearheaded global advancements in this field. Nevertheless, more than half a century has passed since the onset of Minamata disease, yet the intricacies of MeHg toxicity remains enigmatic. Moreover, environmental pollution of mercury and toxic metals is a global problem that needs to be solved. Therefore, our research has focused on, "toxicology of MeHg" and "remediation of mercury and other toxic metals". This review discusses the molecular mechanisms underlying roles of autophagy in MeHg responses of mammalian cells, identification of an anti-MeHg natural product, analysis of bacterial mercury-resistant gene, and plant biotechnology using bacterial transporters for phytoremediation.
Although co-administration of amenamevir (a helicase–primase inhibitor) reportedly decreases exposure to midazolam, a CYP3A4 substrate, it remains unclear whether amenamevir induces the metabolism of calcineurin inhibitors (tacrolimus and cyclosporine) metabolized by CYP3A4. Herein, we illustrated two cases of induction of metabolism for calcineurin inhibitors by amenamevir. The concentration/dose normalized by body weight was defined as exposure to calcineurin inhibitors. The first case is a 63-year-old female (CYP3A5*3/*3 in both the recipient and donor) who received sustained-release tacrolimus 1.0 mg × 1 after living-donor liver transplantation. Although she temporarily withdrew tacrolimus on days 1 and 2 (from the initiation of combination), the same dosage was restarted from day 3. There was no significant difference in the C/D ratio regardless of co-administration of amenamevir 400 mg × 1 for 4 days (day -16: 4.5 ng/mL, 277.2 ng/mL/mg/kg vs. day 5: 3.6 ng/mL, 221.8 ng/mL/mg/kg). The second case is a 71-year-old female who received an induction therapy of microemulsion cyclosporine 50 mg × 2 from day -2 for nephrotic syndrome. The genotype of CYP3A5 was unknown. Blood cyclosporine concentrations at 2 h post-dose were 153.5 ng/mL (80.6 ng/mL/mg/kg) on day 2 and 166.8 ng/mL (87.6 ng/mL/mg/kg) on day 4 when administered amenamevir 400 mg × 1 for 5 days from day 0. After the discontinuation of amenamevir, blood cyclosporine concentration at 2 h post-dose on day 19 remained unchanged (170.4 ng/mL, 89.5 ng/mL/mg/kg). In conclusion, amenamevir co-administered for ≤5 days had less impact on the pharmacokinetics of tacrolimus and cyclosporine at low concentrations.
It is well known that administration of non-selective cyclooxygenase (COX) non-steroidal anti-inflammatory drugs (NSAIDs) increases the risk of developing gastric and duodenal ulcers. Previously, we reported that administration of indomethacin, one of these COX non-selective drugs, results in acute inflammation of the small intestine and that the subsequent increased release of cytokines, such as interleukin-6 and tumor necrosis factor-α, and histamines can lead to the development of dry skin. However, the effect of indomethacin administration in aging mice remains unknown. We aimed to investigate the effect of indomethacin administration on the small intestine of 40-week-old adult mice. As a result, both macroscopic and histologic abnormalities were observed in their small intestines. Expression of diamine oxidase, a histamine-degrading enzyme in the jejunum, was also decreased. In addition, expressions of mucin-2 and zonula occludens-1, both of which regulate the intestinal barrier function, were also decreased. Therefore, it was suggested that administration of indomethacin to aging mice may cause the release of histamines, which consequently increase in concentration in the small intestine, infiltrate into the blood, and circulate throughout the body as the intestinal barrier function declines.
Semi-synthetic antibiotic, azithromycin (AZM) does not show significant bactericidal activity against Pseudomonas aeruginosa (P. aeruginosa). We focused on potential for AZM as a multi targeting drug against P. aeruginosa and found combination of AZM and Polymyxin B nonapeptide (PMBN) to increase the permeability of the outer membrane. This combination is effective for P. aeruginosa including multidrug-resistance clinical isolates and shows 32-512-fold potentiation of the anti-P. aeruginosa activity of AZM. We found a great opportunity to create new anti-P. aeruginosa drug candidates based on AZM and PMBN.
Parkinson's disease (PD) is a neurodegenerative disorder marked by progressive motor dysfunction. Dopaminergic neurons in the substantia nigra are likely the main cause of PD onset. The Hippo signaling pathway regulates organ size and tumor suppression. The Yes-associated protein (YAP) is a nuclear effector of the Hippo signaling pathway, and activation of YAP may be beneficial in several neurodegenerative diseases. In this study, we examined the effects of compound A [N-(tert-butyl)-2-(pyridin-4-yl)-1,7-naphthyridin-4-amine], a large tumor suppressor kinase (LATS) inhibitor, on 6-hydroxydopamine (6-OHDA)-induced cell damage in vitro and in vivo. In human neuroblastoma SH-SY5Y cells, compound A showed a protective effect against 6-OHDA-induced cell death without exhibiting any cytotoxicity. In order to investigate the effects of compound A on dopaminergic neurons, compound A was orally administrated to mice twice a day for 21 d. Next, mouse brains were harvested to assess the expression of (1) a dopaminergic neuron marker and (2) a YAP transcriptional target. Treatment of mice with 6-OHDA suppressed the expression of tyrosine hydroxylase (TH), a dopaminergic neuron marker, and compound A (3 mg/kg, per os) administration ameliorated the TH expression levels. In addition, compound A upregulated the mRNA expression levels of connective tissue growth factor (CTGF), a YAP transcriptional target. These results suggest that activation of the Hippo signaling pathway by LATS inhibition may be used as a novel therapeutic target for treating PD.
Enterobacter cloacae are thought to exhibit resistance to third-generation cephalosporins (3GCs) despite their sensitivity to these drugs; therefore, broad-spectrum antibiotics such as carbapenems are primarily used against them. Reports elucidating the treatment outcomes of 3GCs against E. cloacae are limited; therefore, we aimed to accumulate further evidence in this regard. Patients with isolated E. cloacae infections who were treated with antibiotics between April 2008 and April 2021 at Hokkaido University Hospital were included in the study. The primary endpoint was the difference in treatment efficacy between patients treated with the 3GCs after the detection of E. cloacae and those treated with other drugs. As a secondary endpoint, we compared the differences in treatment efficacy rates according to specimen type, severity, and type of antibiotics. Furthermore, multivariate analysis was performed to identify the factors influencing treatment failure. Among the 146 cases analyzed, 25 and 121 were categorized into the 3GCs and others groups, respectively. The treatment efficacy rate did not significantly differ between the two groups (3GC vs. others: 80.0% vs. 84.3%; P = 0.564). Only one patient in the 3GCs group developed resistance. The treatment efficacy rate did not differ according to the specimen type, severity, or antibiotic class between the groups. Multivariate analysis confirmed that the use of 3GCs did not affect treatment failure. 3GCs may be considered a potential therapeutic option for E. cloacae infections.