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.

Loss of stearoyl-CoA desaturase 2 disrupts inflammatory response in macrophages.

Macrophages are innate immune cells that patrol tissues and are the first responders to detect infection. They orchestrate the host immune response in eliminating invading pathogens and the subsequent transition from inflammation to tissue repair. Macrophage dysfunction contributes to age-related pathologies, including low-grade inflammation in advanced age that is termed "inflammaging." Our laboratory has previously identified that macrophage expression of a fatty acid desaturase, stearoyl-CoA desaturase 2 (SCD2), declines with age. Herein, we delineate the precise cellular effects of SCD2 deficiency in murine macrophages. We found that deletion of Scd2 from macrophages dysregulated basal and bacterial lipopolysaccharide (LPS)-stimulated transcription of numerous inflammation-associated genes. Specifically, deletion of Scd2 from macrophages decreased basal and LPS-induced expression of Il1b transcript that corresponded to decreased production of precursor IL1B protein and release of mature IL1B. Furthermore, we identified disruptions in autophagy and depletion of unsaturated cardiolipins in SCD2-deficient macrophages. To assess the functional relevance of SCD2 in the macrophage response to infection, we challenged SCD2-deficient macrophages with uropathogenic Escherichia coli and found that there was impaired clearance of intracellular bacteria. This increased burden of intracellular bacteria was accompanied by increased release of pro-inflammatory cytokines IL6 and TNF but decreased IL1B. Taken together, these results indicate that macrophage expression of Scd2 is necessary for maintaining the macrophage response to inflammatory stimuli. This link between fatty acid metabolism and fundamental macrophage effector functions may potentially be relevant to diverse age-related pathologies. IMPORTANCE Macrophages are immune cells that respond to infection, but their dysfunction is implicated in many age-related diseases. Recent evidence showed that macrophage expression of a fatty acid enzyme, stearoyl-CoA desaturase 2, declines in aged organisms. In this work, we characterize the effects when stearoyl-CoA desaturase 2 is deficient in macrophages. We identify aspects of the macrophage inflammatory response to infection that may be affected when expression of a key fatty acid enzyme is decreased, and these findings may provide cellular insight into how macrophages contribute to age-related diseases.

The Impact of Methenamine Hippurate Treatment on Urothelial Integrity and Bladder Inflammation in Aged Female Mice and Women With Urinary Tract Infections.

IMPORTANCE: Antibiotics are commonly used to treat and prevent urinary tract infection (UTI), but resistance is growing. Nonantibiotic prophylaxis such as methenamine hippurate (MH) shows clinical promise, but its impact on bladder factors influencing recurrent UTIs (rUTIs) is not well described. OBJECTIVE: The aim of the study was to examine the effect of MH on bladder inflammation and barrier function in aged mice and women with rUTI. STUDY DESIGN: This study included urine samples from an experimental study involving aged female mice with and without methenamine treatment as well as women with rUTI who received either no prophylaxis, MH alone, vaginal estrogen therapy and/or d-mannose alone, or MH in addition to vaginal estrogen therapy and/or d-mannose. We performed a comprehensive cytopathological analysis, which included enzyme-linked immunosorbent assay for immunoglobulin A (IgA), interleukin 6 (in human samples), and fluorescein isothiocyanate-conjugated-dextran permeability assay (in mice) to assess for urothelial permeability. RESULTS: In the aged mice model, there was a decreased urothelial permeability (as seen by retention of fluorescein isothiocyanate-conjugated-dextran fluorescence in superficial cells) and increased urinary IgA in mice treated with MH compared with controls. There was no significant difference in urothelial shedding (P > 0.05). In human samples, there was significantly increased urinary IgA in those taking MH alone compared with no prophylaxis (830.1 vs 540.1 ng/mL, P = 0.04), but no significant difference in interleukin 6. CONCLUSIONS: Methenamine hippurate seems to enhance barrier function as evidenced by decreased urothelial permeability and increased urinary IgA levels, without worsening inflammation. This may reflect another beneficial mechanism by which MH helps prevent rUTI.

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.

Reconstrucción nasal con colgajos locales: Manejo según unidades estéticas / Nasal reconstruction with local flaps: Management according to aesthetic units

Introducción: Las lesiones neoplásicas de la nariz necesitan una resolución con resultado estético satisfactorio. El objetivo del presente estudio es realizar una descripción del lugar en donde se ubicaron las lesiones y los tipos de colgajos más utilizados. Métodos: El presente estudio descriptivo fue realizado en pacientes intervenidos en el 2013 por reconstrucción nasal secundaria exéresis tumoral en Solca-Guayaquil. Se describe la localización de la lesión y la técnica. La muestra fue incidental. Para la descripción se dividió la nariz en 3 zonas: proximal (Z1), media (Z2) y distal (Z3). Las lesiones con >1 zona fueron "defectos complejos". Las Z1 y Z2 fueron divididas en subunidades (SU) central y lateral. La Z3 fue dividida en SU: alar, domo alar, de domo, centr al, columelar y de base nasal. Los defectos con >1 SU fueron combinados. Resultados: Ingresaron al estudio 96 casos, 60 mujeres. 14 defectos (14.6 %) en Z1, 16 defectos (16.7%) en Z2, 50 casos (52 %) en Z3 y 16 defectos complejos (16.7 %). El colgajo frontal (CF) 21 casos (21.88 %), el colgajo avance V-Y (AV-Y) 19 casos (19.79 %) y el colgajo nasolabial (CNL) 15 casos (15.63 %). En Z1, la SU- central se utilizaron los colgajos glabelar (CG), AV-Y y colgajo en Mitra (CM); en la SU- lateral se utilizaron el CG y AV-Y con más frecuencia. En la Z2, la SU- central se utilizaron los CM y el cierre directo (CD); en la SU- lateral se utilizaron el CD, CM, AV-Y y CNL. En la Z3 se utilizaron CNL, AV-Y y colgajos bilobulados. El colgajo frontal fue usado en los defectos complejos y combinados. Conclusión: La SU-Alar y la SU del Surco Domal Alar de la Z3, fueron las áreas más prevalentes. Las técnicas quirúrgicas más utilizadas fueron, el colgajo frontal, el AV-Y y el CNL.

Introduction: The neoplastic lesions of the nose need a resolution with a satisfactory aesthetic result. The aim of the present study is to make a description of the place where the injuries were located and the types of flaps most used. Methods: The present descriptive study was performed in patients who underwent surgery in 2013 for secondary nasal reconstruction of tumor exeresis in Solca-Guayaquil. The location of the lesion and the technique are described. The sample was incidental. For the description, the nose was divided into 3 zones: proximal (Z1), middle (Z2) and distal (Z3). Injuries with> 1 zone were "complex defects". The Z1 and Z2 were divided into central and lateral subunits (SU). The Z3 was divided into SU: alar, domo-alar, dome, central, columelar and nasal base. Defects with> 1 SU were combined. Results: 96 cases, 60 women, entered the study. 14 defects (14.6%) in Z1, 16 defects (16.7%) in Z2, 50 cases (52%) in Z3 and 16 complex defects (16.7%). The frontal flap (FF) 21 cases (21.88%), the flap advance V-Y (AV-Y) 19 cases (19.79%) and the nasolabial flap (NLF) 15 cases (15.63%). In Z1, the SU-central glabellar flap (GF), AV-Y and Mitra flap (MF) were used; in the SU-lateral the GF and AV-Y were used more frequently. In the Z2, the central SU were used the MF and the direct closure (DC); in the SU-lateral DC, MF, AV-Y and NLF were used. In Z3, NLF, AV-Y and bi-lobed flaps were used. The frontal flap was used in complex and combined defects. Conclusion: The SU-Alar and the SU of the Domal Alar Groove of the Z3, were the most prevalent areas. The most used surgical techniques were, the frontal flap, the AV-Y and the NLF.