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Ketamine-associated cystitis is characterized by suburothelial inflammation and urothelial cell death. Norketamine (NK), the main metabolite of ketamine, is abundant in urine following ketamine exposure. NK has been speculated to exert toxic effects in urothelial cells, similarly to ketamine. However, the molecular mechanisms contributing to NK-induced urothelial cytotoxicity are almost unclear. Here, we aimed to investigate the toxic effects of NK and the potential mechanisms underlying NK-induced urothelial cell injury. In this study, NK exposure significantly reduced cell viability and induced apoptosis in human urinary bladder epithelial-derived RT4 cells that NK (0.01–0.5 mM) exhibited greater cytotoxicity than ketamine (0.1–3 mM). Signals of mitochondrial dysfunction, including mitochondrial membrane potential (MMP) loss and cytosolic cytochrome c release, were found to be involved in NK-induced cell apoptosis and death. NK exposure of cells also triggered the expression of endoplasmic reticulum (ER) stress-related proteins including GRP78, CHOP, XBP-1, ATF-4 and -6, caspase-12, PERK, eIF-2α, and IRE-1. Pretreatment with 4-phenylbutyric acid (an ER stress inhibitor) markedly prevented the expression of ER stress-related proteins and apoptotic events in NK-exposed cells. Additionally, NK exposure significantly activated JNK, ERK1/2, and p38 signaling and increased intracellular calcium concentrations ([Ca2+]i). Pretreatment of cells with both PD98059 (an ERK1/2 inhibitor) and BAPTA/AM (a cell-permeable Ca2+ chelator), but not SP600125 (a JNK inhibitor) and SB203580 (a p38 inhibitor), effectively suppressed NK-induced mitochondrial dysfunction, ER stress-related signals, and apoptotic events. The elevation of [Ca2+]i in NK-exposed cells could be obviously inhibited by BAPTA/AM, but not PD98059. Taken together, these findings suggest that NK exposure exerts urothelial cytotoxicity via a [Ca2+]i-regulated ERK1/2 activation, which is involved in downstream mediation of the mitochondria-dependent and ER stress-triggered apoptotic pathway, consequently resulting in urothelial cell death. Our findings suggest that regulating [Ca2+]i/ERK signaling pathways may be a promising strategy for treatment of NK-induced urothelial cystitis. [ABSTRACT FROM AUTHOR]

BACKGROUND: Epidemiological studies have reported that the prevalence of diabetes in women > 40 years of age, especially those in the postmenopausal phase, was higher than in men in areas with high levels of arsenic in drinking water. The detailed effect of arsenic on glucose metabolism/ homeostasis in the postmenopausal condition is still unclear. OBJECTIVES: We investigated the effects of arsenic at doses relevant to human exposure from drinking water on blood glucose regulation in estrogen-deficient female mice. METHODS: Adult female mice who underwent ovariectomy or sham surgery were exposed to drinking water contaminated with arsenic trioxide (0.05 or 0.5 ppm) in the presence or absence of 17β-estradiol supplementation for 2-6 weeks. Assays related to glucose metabolism were performed. RESULTS: Exposure of sham mice to arsenic significantly increased blood glucose, decreased plasma insulin, and impaired glucose tolerance, but did not induce insulin resistance. Blood glucose and insulin were higher, and glucose intolerance, insulin intolerance, and insulin resistance were increased in arsenic-treated ovariectomized mice compared with arsenic-treated sham mice. Furthermore, liver phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression was increased and liver glycogen content was decreased in arsenic-treated ovariectomized mice compared with arsenic-treated sham mice. Glucose-stimulated insulin secretion in islets isolated from arsenic-treated ovariectomized mice was also significantly decreased. Arsenic treatment significantly decreased plasma adiponectin levels in sham and ovariectomized mice. Altered glucose metabolism/ homeostasis in arsenic-treated ovariectomized mice was reversed by 17β-estradiol supplementation. CONCLUSIONS: Our findings suggest that estrogen deficiency plays an important role in arsenicaltered glucose metabolism/homeostasis in females. http://dx.doi.org/10.1289/ehp.1408663, Introduction Arsenic is a naturally occurring toxic metalloid. Levels of naturally occurring arsenic in groundwater above the drinking water standard of 10 µg/L are not uncommon. Several studies in Taiwan [...]

Objectives: Scabies is a common and annoying disorder. Pernicious anemia (PA) is a serious disease which, when untreated, leads to death. Mounting evidence suggests that immune-mediated inflammatory processes play a role in the pathophysiology of both diseases. The relationship between these two diseases has not been investigated. We conducted this study to explore the potential relationship between scabies and PA.Materials and Methods: This nationwide, population-based study was conducted using the National Health Insurance Research Database of Taiwan. In total, 5,407 patients with scabies were identified as a study group and 20,089 matched patients were randomly selected as a control group. We tracked patients in both groups for a 7-year period to identify the incidence of PA. The demographic characteristics and comorbidities of the patients were analyzed, and Cox proportional hazards regression was used to calculate the hazard ratios for PA.Results: Of the 25,496 patients in this study, 183 (0.7%) patients with newly diagnosed PA were identified during the 7-year follow-up period; 71 of 5,407 (1.3%) from the scabies group and 112 of 20,089 (0.6%) from the control group. Patients with scabies had a higher risk of subsequent PA, with a crude hazard ratio of 2.368. After adjusting for covariates, the adjusted hazard ratio was 1.51 (95% confidence interval: 1.09-2.08).Conclusion: This study demonstrated an increased risk of PA (adjusted hazard ratio 1.51) among patients with scabies. Immune-mediated inflammatory processes may contribute to this association. Further studies are warranted to investigate the entire pathological mechanisms between these two diseases. Physicians should pay attention to patients with history of scabies presented with anemia. Further confirmative tests of PA may contribute to correct diagnosis and initiation of vitamin B12 supplement. [ABSTRACT FROM AUTHOR]