D-Mannose reduces cellular senescence and NLRP3/GasderminD/IL-1ß-driven pyroptotic uroepithelial cell shedding in the murine bladder.

Aging is a risk factor for disease via increased susceptibility to infection, decreased ability to maintain homeostasis, inefficiency in combating stress, and decreased regenerative capacity. Multiple diseases, including urinary tract infection (UTI), are more prevalent with age; however, the mechanisms underlying the impact of aging on the urinary tract mucosa and the correlation between aging and disease remain poorly understood. Here, we show that, relative to young (8-12 weeks) mice, the urothelium of aged (18-24 months) female mice accumulates large lysosomes with reduced acid phosphatase activity and decreased overall autophagic flux in the aged urothelium, indicative of compromised cellular homeostasis. Aged bladders also exhibit basal accumulation of reactive oxygen species (ROS) and a dampened redox response, implying heightened oxidative stress. Furthermore, we identify a canonical senescence-associated secretory phenotype (SASP) in the aged urothelium, along with continuous NLRP3-inflammasome- and Gasdermin-D-dependent pyroptotic cell death. Consequently, aged mice chronically exfoliate urothelial cells, further exacerbating age-related urothelial dysfunction. Upon infection with uropathogenic E. coli, aged mice harbor increased bacterial reservoirs and are more prone to spontaneous recurrent UTI. Finally, we discover that treatment with D-mannose, a natural bioactive monosaccharide, rescues autophagy flux, reverses the SASP, and mitigates ROS and NLRP3/Gasdermin/interleukin (IL)-1ß-driven pyroptotic epithelial cell shedding in aged mice. Collectively, our results demonstrate that normal aging affects bladder physiology, with aging alone increasing baseline cellular stress and susceptibility to infection, and suggest that mannose supplementation could serve as a senotherapeutic to counter age-associated urothelial dysfunction.

NRF2 promotes urothelial cell response to bacterial infection by regulating reactive oxygen species and RAB27B expression.

Uropathogenic Escherichia coli (UPEC) cause urinary tract infections (UTIs) by invading urothelial cells. In response, the host mounts an inflammatory response to expel bacteria. Here, we show that the NF-E2-related factor 2 (NRF2) pathway is activated in response to UPEC-triggered reactive oxygen species (ROS) production. We demonstrate the molecular sequence of events wherein NRF2 activation in urothelial cells reduces ROS production, inflammation, and cell death, promotes UPEC expulsion, and reduces the bacterial load. In contrast, loss of NRF2 leads to increased ROS production, bacterial burden, and inflammation, both in vitro and in vivo. NRF2 promotes UPEC expulsion by regulating transcription of the RAB-GTPase RAB27B. Finally, dimethyl fumarate, a US Food and Administration-approved NRF2 inducer, reduces the inflammatory response, increases RAB27B expression, and lowers bacterial burden in urothelial cells and in a mouse UTI model. Our findings elucidate mechanisms underlying the host response to UPEC and provide a potential strategy to combat UTIs.

Translation and cross-cultural adaptation of the Brazilian Portuguese version of the Emotional Memory Scale.

Background Emotional memory is an important type of memory that is triggered by positive and negative emotions. It is characterized by an enhanced memory for emotional stimuli which is usually coupled with a decrease in memory of neutral preceding events. Emotional memory is strongly associated with amygdala function and therefore could be disrupted in neuropsychiatric disorders. To our knowledge, there is no translated and culturally adapted instrument for the Brazilian Portuguese speaking population to assess emotional memory. Objective To report the translation and cross-cultural adaptation of a Brazilian Portuguese version of the Emotional Memory Scale, originally published by Strange et al. in 2003. Methods The author of the original scale provided 36 lists with 16 words each. Translation was performed by three independent bilingual translators. Healthy subjects assessed how semantically related each word was within the list (0 to 10) and what the emotional valence of each word was (-6 to +6). Lists without negative words were excluded (negative selection), most positive and most unrelated words were excluded (positive and semantic selection, respectively), and lists with low semantic relationship were excluded (semantic assessment). Results Five lists were excluded during negative selection, four words from each list were excluded in positive and semantic selection, and 11 lists were excluded during semantic assessment. Finally, we reached 20 lists of semantically related words; each list had one negative word and 11 neutral words. Conclusion A scale is now available to evaluate emotional memory in the Brazilian population and requires further validation on its psychometrics properties.

Translation and cross-cultural adaptation of the Brazilian Portuguese version of the Emotional Memory Scale / Tradução e adaptação transcultural da versão brasileira da Escala de Memória Emocional

Abstract Background Emotional memory is an important type of memory that is triggered by positive and negative emotions. It is characterized by an enhanced memory for emotional stimuli which is usually coupled with a decrease in memory of neutral preceding events. Emotional memory is strongly associated with amygdala function and therefore could be disrupted in neuropsychiatric disorders. To our knowledge, there is no translated and culturally adapted instrument for the Brazilian Portuguese speaking population to assess emotional memory. Objective To report the translation and cross-cultural adaptation of a Brazilian Portuguese version of the Emotional Memory Scale, originally published by Strange et al. in 2003. Methods The author of the original scale provided 36 lists with 16 words each. Translation was performed by three independent bilingual translators. Healthy subjects assessed how semantically related each word was within the list (0 to 10) and what the emotional valence of each word was (-6 to +6). Lists without negative words were excluded (negative selection), most positive and most unrelated words were excluded (positive and semantic selection, respectively), and lists with low semantic relationship were excluded (semantic assessment). Results Five lists were excluded during negative selection, four words from each list were excluded in positive and semantic selection, and 11 lists were excluded during semantic assessment. Finally, we reached 20 lists of semantically related words; each list had one negative word and 11 neutral words. Conclusion A scale is now available to evaluate emotional memory in the Brazilian population and requires further validation on its psychometrics properties.

Resumo Introdução Memória emocional é um tipo importante de memória que é acionado por emoções positivas e negativas. Ela é caracterizada por um aumento de memória para estímulos emocionais que normalmente está associado a um prejuízo de memória para eventos neutros que os precedem. Memória emocional é fortemente relacionada à função da amígdala e, portanto, pode estar alterada em transtornos neuropsiquiátricos. Pelo nosso conhecimento, não existe instrumento traduzido e adaptado culturalmente para a população falante de português brasileiro para avaliar memória emocional. Objetivo Descrever a tradução e adaptação transcultural para o português brasileiro da Escala de Memória Emocional, originalmente publicada por Strange et al. em 2003. Métodos O autor da escala original forneceu 36 listas com 16 palavras cada. A tradução foi feita por três tradutores bilíngues e independentes. Sujeitos saudáveis foram selecionados para avaliar o quanto cada palavra era semanticamente relacionada dentro da lista (0 a 10) e qual era a valência emocional de cada palavra (-6 a +6). Listas sem palavras negativas foram excluídas (seleção negativa), palavras mais positivas e menos relacionadas de cada lista foram excluídas (seleções positiva e semântica, respectivamente) e listas com relação semântica fraca foram excluídas (avaliação semântica). Resultados Cinco listas foram excluídas durante a seleção negativa, quatro palavras de cada lista foram excluídas nas seleções positiva e semântica, e 11 listas foram excluídas na avaliação semântica. Por fim, chegamos em 20 listas de palavras semanticamente relacionadas; cada lista com uma palavra negativa e 11 palavras neutras. Conclusão Uma escala está disponível para avaliar memória emocional na população brasileira e requer posterior validação de suas propriedades psicométricas.

Testicular cells exhibit similar molecular responses to cigarette smoke condensate ex vivo and in vivo.

Male exposure to cigarette smoke is associated with seminal defects and with congenital anomalies and childhood cancers in offspring. In mice, paternal exposure to cigarette smoke condensate (CSC) causes molecular defects in germ cells and phenotypic effects in their offspring. Here we used an ex vivo testicular explant model and in vivo exposure to determine the concentration at which CSC impairs spermatogenesis and offspring development. We explanted testis tissue at postnatal day (P)5.5 and cultured it until P11.5. Assessment of growth parameters by analyzing expression of cell-specific markers revealed that the explant system maintained structural and functional integrity. We exposed the P5.5 to -11.5 explants to various concentrations (40-160 µg/ml) of CSC and confirmed that nicotine in the CSC was metabolized to cotinine. We assessed various growth and differentiation parameters, as well as testosterone production, and observed that many spermatogenesis features were impaired at 160 µg/ml CSC. The same parameters were impaired by a similar CSC concentration in vivo Finally, females mated to males that were exposed to 160 µg/ml CSC neonatally had increased rates of pup resorption. We conclude that male exposure to CSC impairs offspring development and that the concentration at which CSC impairs spermatogenesis is similar in vivo and ex vivo. Given that the concentrations of CSC we used contained similar doses of nicotine as human smokers are exposed to, we argue that our model mimics human male reproductive effects of smoking.-Esakky, P., Hansen, D. A., Drury, A. M., Felder, P., Cusumano, A., Moley, K. H. Testicular cells exhibit similar molecular responses to cigarette smoke condensate ex vivo and in vivo.

Paternal exposure to cigarette smoke condensate leads to reproductive sequelae and developmental abnormalities in the offspring of mice.

Paternal smoking is associated with infertility, birth defects and childhood cancers. Our earlier studies using cigarette smoke condensate (CSC) demonstrated several deleterious changes in male germ cells. Here, we hypothesize that chronic paternal exposure to CSC causes molecular and phenotypic changes in the sire and the offspring, respectively. In this mouse study, CSC caused DNA damage and cytotoxicity in testes via accumulation of benzo(a)pyrene (B[a]P) and cotinine. Decreased expression of growth arrest and DNA damage inducible alpha (Gadd45a), aryl hydrocarbon receptor (Ahr), and cyclin-dependent kinase inhibitor 1A (P21) was seen in CSC exposed testes. Apoptotic germ cell death was detected by induction of Fas, FasL, and activated caspase-3. The CSC-exposed males displayed reduction in sperm motility and fertilizing ability and sired pups with reduced body weight and crown-rump length, and smaller litter size with higher numbers of resorption. This model of CSC exposure demonstrates testicular toxicity and developmental defects in the offspring.