Bladder inflammation is associated with several lower urinary tract symptoms that greatly reduce quality of life, yet contributing factors are not completely understood. Environmental chemicals are plausible mediators of inflammatory reactions within the bladder. Here, we examine whether developmental exposure to polychlorinated biphenyls (PCBs) leads to changes in immune cells within the bladder of young mice. Female mice were exposed to an environmentally relevant mixture of PCBs through gestation and lactation, and bladders were collected from offspring at postnatal day (P) 28–31. We identify several dose- and sex-dependent PCB effects in the bladder. The lowest concentration of PCB (0.1 mg/kg/d) increased CD45+ hematolymphoid immune cells in both sexes. While PCBs had no effect on CD79b+ B cells or CD3+ T cells, PCBs (0.1 mg/kg/d) did increase F4/80+ macrophages particularly in female bladder. Collagen density was also examined to determine whether inflammatory events coincide with changes in the stromal extracellular matrix. PCBs (0.1 mg/kg/d) decreased collagen density in female bladder compared to control. PCBs also increased the number of cells undergoing cell division predominantly in male bladder. These results implicate perturbations to the immune system in relation to PCB effects on the bladder. Future study to define the underlying mechanisms could help understand how environmental factors can be risk factors for lower urinary tract symptoms.
The study aims to evaluate the prognostic value of systematic oxidative stress indexes as a predictor of patient outcomes in UTUC after radical nephroureterectomy.METHODS: The clinical data of 483 patients with UTUC who underwent radical nephroureterectomy were analyzed. Patients were categorized according to an optimal value of systematic oxidative stress indexes (SOSI), including fibrinogen (Fib), gammaglutamyl transpeptidase (g-GGT), creatinine (CRE), lactate dehydrogenase (LDH) albumin (ALB). KaplaneMeier analyses were used to investigate associations of SOSI with overall survival (OS) and progression-free survival (PFS). Moreover, the associations between SOSI and OS were assessed with univariate and Multivariate analyses.RESULTS: The KaplaneMeier survival analysis showed a significant discriminatory ability for death and progression risks in the two groups based on the SOSI.Multivariate Cox proportional hazards models manifested that SOSI was an independent prognostic indicator for OS (p[0.006). SOSI and clinical variables were selected to establish the nomogram.The calibration curves of the nomogram showed high consistencies between the predicted and observed survival probability. Decision curve analysis curves showed that the nomogram could better predict the 1-year, 3-year, and 5-year OS.CONCLUSIONS: The SOSI is an independent unfavorable predictor of OS in patients diagnosed with UTUC undergoing RNU.-Therefore, incorporating SOSI into currently available clinical parameters may improve clinical decision-making.
The multi-morbidity of aging limits the value of targeting any single age associated disease. Despite exercise and metformin individually improving physiological hallmarks of aging, we and others have shown that metformin inhibits adaptions to insulin sensitivity, skeletal muscle mitochondrial respiratory capacity, and cardiorespiratory fitness after aerobic exercise training (AET). The mechanisms underlying these antagonistic effects are unknown but highlight an important need to further understand the interaction between two leading health span treatments. Here, we performed an 8-week progressive AET regimen on 8-month-old male C57BL6/J mice with metformin (AET+MET) in the drinking water (~300mg/kg/day), without (AET), and sedentary control (SED) (n=3/group). Using high resolution respirometry with permeabilized muscle fibers, metformin prevented the increase in complex I (CI) linked respiration after AET. Additional analyses of site-specific hydrogen peroxide (H2O2) emissions in isolated muscle mitochondria revealed metformin increased H2O2 emissions at site IF of CI versus AET with no difference at site IQ. In this preliminary data set, we did not detect differences between AET or AET+MET in glucose tolerance, insulin sensitivity, or maximal exercise performance following exercise. To facilitate the development of hypothesis generating questions, we aimed to identify a skeletal muscle gene expression prolife that was associated with the effects of metformin on skeletal muscle mitochondrial bioenergetics. Globally the number of differentially expressed genes was blunted by the addition of metformin to aerobic exercise training. Both the upregulation (AET: 139 genes vs. AET+MET: 45) and down regulation of genes (AET: 138 genes vs. AET+MET: 108) was attenuated by the addition of metformin. We identified Nicotinamide Riboside Kinase 2 (NMRK2) as the greatest differentially expressed gene between AET and AET+MET. NMRK2 has a dual role in NAD+ biosynthesis and integrin signaling. Therefore, metformin may alter the transduction of mechanical stimuli to NAD+ homeostasis via NMRK2. While the current study is limited in sample size, we have an ongoing cohort to validate these initial findings. Collectively, our data suggest metformin inhibits skeletal muscle mitochondrial adaptations of aerobic exercise training, similar to our previous work in humans. Further, we have identified NMRK2 as a potential candidate mechanism that is associated with how metformin mediates mitochondrial adaptations to exercise. Nathan Shock Center, Salk Institute for Biological Sciences This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
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