Association between Perceived Stress and Motoric Cognitive Risk Syndrome in an Elderly Population: Rugao Longevity and Aging Study.

INTRODUCTION: Previous studies have indicated a correlation between perceived stress and cognitive decline. However, it remains unknown whether high levels of perceived stress can result in motoric cognitive risk (MCR) syndrome. This study investigated the relationship between perceived stress and MCR in a community-based population. METHODS: The study cohort comprised 852 elderly individuals from the Rugao Longitudinal Aging Cohort. Perceived stress was assessed using the 10-item Perceived Stress Scale (PSS-10), while MCR was defined as the coexistence of subjective memory complaints (SMCs) and slow gait speed. RESULTS: The average age of the study participants is 79.84 ± 4.34 years. The mean score of PSS-10 among participants is 10.32 (range = 0-33; [SD] = 5.71), with a median score of 10.00 (6.00, 14.00). The prevalence of MCR is 9.3%. In the logistic regression analysis, for each 1-SD (5.71) increase in the global PSS-10 score, the risk of MCR increased by 40% (95% CI 1.09-1.80). Additionally, in the aspect of two components of MCR, with a 1-SD increase (5.71) in the global PSS-10 score, there was a 50% (95% CI 1.29-1.75) increase in the risk of SMCs and a 27% (95% CI 1.04-1.55) increase in the risk of slow gait speed. In terms of specific walking speed, there was a reverse correlation between the global PSS-10 score and walking speed (r = -0.14, p < 0.001). CONCLUSIONS: This study provided preliminary evidence that high levels of perceived stress were associated with the risk of MCR in a community-dwelling population.

Forsythiaside A suppresses renal fibrosis and partial epithelial-mesenchymal transition by targeting THBS1 through the PI3K/AKT signaling pathway.

Renal fibrosis is a key feature of chronic kidney disease (CKD) progression, whereas no proven effective anti-fibrotic treatments. Forsythiaside A (FTA), derived from Forsythia suspense, has been found to possess nephroprotective properties. However, there is limited research on its anti-fibrotic effects, and its mechanism of action remains unknown. This study aimed to investigate the suppressive effects of FTA on renal fibrosis and explore the underlying mechanisms. In vitro, we established a HK2 cell model induced by transforming growth factor ß1 (TGF-ß1), and in vivo, we used a mice model induced by unilateral ureteral obstruction (UUO). CCK-8 assay, qRT-PCR, Western blotting, immunofluorescence, flow cytometry, histological staining, immunohistochemistry, TUNEL assay, RNA transcriptome sequencing, and molecular docking were performed. The results showed that FTA (40 µM or 80 µM) treatment improved cell viability and suppressed TGF-ß1-induced fibrotic changes and partial epithelial-mesenchymal transition (EMT). Furthermore, FTA treatment reversed the activation of the PI3K/AKT signaling pathway, and THBS1 was identified as the target gene. We found that THBS1 knockdown suppressed the activation of the PI3K/AKT signaling pathway and reduced the fibrosis and partial EMT-related protein level. Conversely, THBS1 overexpression activated the PI3K/AKT signaling pathway and exacerbated renal fibrosis and partial EMT. In vivo, mice were administered FTA (30 or 60 mg/kg) for 2 weeks, and the results demonstrated that FTA administration significantly mitigated tubular injury, tubulointerstitial fibrosis, partial EMT, and apoptosis. In conclusion, FTA inhibited renal fibrosis and partial EMT by targeting THBS1 and inhibiting activation of the PI3K/AKT pathway.

UCHL5 Promotes Proliferation and Migration of Bladder Cancer Cells by Activating c-Myc via AKT/mTOR Signaling.

Ubiquitin C-terminal hydrolase L5 (UCHL5) is a deubiquitinating enzyme (DUB) that removes ubiquitin from its substrates. Associations between UCHL5 and cancer have been reported in various tissues, but the effect of UCHL5 on bladder cancer has not been thoroughly investigated. This study investigates the expression and function of UCHL5 in bladder cancer. UCHL5 was shown to be abnormally expressed using IHC of tissue microarray and Western blotting. Several procedures were performed to assess the effect of UCHL5 overexpression or knockdown on bladder cancer, such as cell proliferation, colony formation, wound-healing, and Transwell assays. In addition, RNA-Seq and Western blotting experiments were used to verify the status of downstream signaling pathways. Finally, bladder cancers with knockdown or overexpression of UCHL5 were treated with either SC79 or LY294002 to examine the participation of the AKT/mTOR signaling pathway and the expression of downstream targets c-Myc, SLC25A19, and ICAM5. In contrast to adjacent tissue samples, we discovered that UCHL5 was substantially expressed in bladder cancer samples. We also found that UCHL5 downregulation significantly suppressed both tumor growth in vivo and cell proliferation and migration in vitro. According to RNA-Seq analyses and Western blotting experiments, the expression of c-Myc, SLC25A19, and ICAM5 was modified as a result of UCHL5 activating AKT/mTOR signaling in bladder cancer cells. All things considered, our findings show that increased UCHL5 expression stimulates AKT/mTOR signaling, subsequently triggering the expression of c-Myc, SLC25A19, and ICAM5, which in turn promotes carcinogenesis in bladder cancer. UCHL5 is therefore a potential target for therapy in bladder cancer patients.

A novel model of urosepsis in rats developed by injection of Escherichia coli into the renal pelvis.

Despite extensive research, urosepsis remains a life-threatening, high-mortality disease. Currently, animal models of urosepsis widely accepted by investigators are very scarce. This study aimed to establish a standardized and reproducible model of urosepsis in rats. Forty adult Wistar rats were randomly divided into four groups according to the concentration of injected E. coli suspensions: Sham, Sep 3×, Sep 6×, and Sep 12×. Because the ureter is so thin and fragile, no conventional needle can be inserted into the ureter, which is probably why rats are rarely used to develop models of urosepsis. To solve this problem, the left ureter was ligated in the first procedure. After 24 hours, the left ureter above the ligation was significantly dilated, then saline or different concentrations of E. coli at 3 ml/kg were injected into the left renal pelvis using a 30G needle. The left ureter was subsequently ligated again at a distance of 1 cm from the renal hilum to maintain high pressure in the renal pelvis. Following injection of E. coli or saline for 24 h, three rats from each group were sacrificed and their organs (lung, liver, and right kidney) were collected. In contrast, the remaining seven rats continued to be observed for survival. At 10 days after E. coli injection, rats in the sep12× group had a higher mortality rate (100%) compared to the sep3× group (28.6%) or the sep6× group (71.4%). The significant changes in peripheral blood WBC count, serum IL-6 and TNF-α levels were also in the sep12× group. In addition, rats in the sepsis group showed multi-organ dysfunction, including damage to the lungs, liver, and kidneys. The establishment of a standardized rat model of urosepsis may be of great value for studying the pathophysiological of urosepsis.

Systematic Pan-Cancer Analysis of KIF23 and a Prediction Model Based on KIF23 in Clear Cell Renal Cell Carcinoma (ccRCC).

PURPOSE: This study aims to carry out a pan-cancer analysis of kinesin family member 23 (KIF23) and construct a predictive model for the prognosis of clear cell renal cell carcinoma (ccRCC) patients. METHODS: We evaluated the differential expression of KIF23 in pan-cancer by The Cancer Genome Atlas (TCGA) and Oncomine database. Then, the correlation between KIF23 with prognosis, clinical grade, stage, immune subtype, tumor mutation burden (TMB), microsatellite instability (MSI) and immune microenvironment was explored by TCGA, an integrated repository portal for tumor-immune system interactions (TISIDB) and cBioPortal. Subsequently, we screened out ferroptosis-related genes (FRGs) related to KIF23 and constructed a risk score model. Univariate Cox analysis was used to determine independent prognostic factors for ccRCC overall survival (OS), and a nomogram was established. Furthermore, gene set enrichment analysis (GSEA) was applied to study the biological functions and pathways of KIF23. Finally, quantitative real-time polymerase chain reaction (qRT-PCR) was carried out to evaluate the expression of KIF23. RESULTS: KIF23 was highly expressed in most tumors. Further, KIF23 was strongly correlated with prognosis, clinical grade, stage, immune subtype, TMB, MSI and immune microenvironment in different tumors. We found that KIF23 was significantly associated with all aspects of ccRCC. Then, 8 FRGs were identified to construct a risk score model together with KIF23. And a prognostic nomogram prediction model of OS was established. After GSEA analysis, cell cycle, condensed chromosome and other physiological processes were screened out. Finally, qRT-PCR verified the high expression of KIF23 in ccRCC cell lines than normal kidney cell line. CONCLUSION: KIF23 may act as a pivotal part in occurrence and progression of different tumors. In ccRCC, KIF23 can be a great prognostic biomarker, and the nomogram based on KIF23 may contribute to better treatment plans for ccRCC patients.

Ozone pollution in the west China rain zone and its adjacent regions, Southwestern China: Concentrations, ecological risk, and Sources.

Located in the transitional region between the Sichuan Basin (SCB) and Qinghai-Tibetan Plateau (QTP), the West China Rain Zone (WCRZ) is a large-scale ecotone and partially belongs to the Southwest China Mountains, which is one of the world's 34 biodiversity hotspots. Using observation data from national air quality stations and our own monitoring data, we investigated the risk from O3 to vegetation and the major source-region of O3 for two UNESCO (i.e., United Nations Educational, Scientific and Cultural Organization) world heritage properties (Mt. Qingcheng and Mt. Emei) and one city (Ya'an) in the WCRZ. The results show that the annual mean maximum daily 8-h average (MDA8) O3 concentration in Mt. Qingcheng (54 ppb) was higher than that in the adjacent SCB cities (38-48 ppb). The acute and chronic risk levels from O3 to vegetation were also higher in Mt. Qingcheng than at all the other sites. The mean MDA8 O3 concentrations and the O3 risk levels to vegetation in Mt. Emei and Ya'an fell in the range of that at the SCB and QTP cities. However, O3 exposures at all the WCRZ, SCB, and QTP sites exceeded the empirical critical loads for natural ecosystems, forest trees, and highly O3-sensitive plants. The SCB was identified as the largest source-region of O3 for Mt. Qingcheng and Mt. Emei but other Chinese regions and northern India also had considerable contributions. To protect biodiversity and ecosystem services, there is a need to further systematically study O3 and its ecological impacts for the entire WCRZ.

Wet deposition of sulfur and nitrogen at Mt. Emei in the West China Rain Zone, southwestern China: Status, inter-annual changes, and sources.

The West China Rain Zone (WCRZ) is of ecological importance and thus, anthropogenic impacts on its vitality are of concern. To ascertain if China's SO2 and NOx emissions reductions in the recent years are reflected in reduced impacts, sulfur and nitrogen wet deposition at Mt. Emei was observed during 2017-2019. The source contributions to sulfur and nitrogen wet deposition were estimated using the positive matrix factorization (PMF) and the source-oriented Community Multi-scale Air Quality (CMAQ) model. The annual Volume Weighted Mean (VWM) pH of precipitation increased from 4.01 to 4.75 in the 1980s-2000s to 5.39 in 2017-2019. However, 12% of the samples during 2017-2019 had pH < 4.50. The VWM SO42- concentration decreased from 80.9 to 26.0 µeq L-1 from 2007-2009 to 2017-2019. The VWM NO3- concentration (18.3 µeq L-1) in 2017-2019 was close to that measured in 2007-2009. Although the dry deposition fluxes onto forest canopy were under-estimated, the mean annual total wet and dry deposition flux of nitrogen (24.3 kg N ha-1 yr-1) was higher than the critical load (CL: 10.0-15.0 kg N ha-1 yr-1), while the flux of sulfur (12.1 kg S ha-1 yr-1) was lower than the CL (16.0-32.0 kg S ha-1 yr-1). The annual wet deposition fluxes of SO42- and NO3- were mainly from industries (54% and 43%, respectively) and power plants (21% and 25%, respectively), and that of NH4+ was mostly from agriculture (88%). Emissions within and outside the Sichuan Basin (SCB) were both important sources of the wet deposition fluxes of sulfur (45% and 39%, respectively) and nitrogen (68% and 29%, respectively), and other unidentified sources accounted for 16% and 3% of the sulfur and nitrogen fluxes, respectively. This study suggests that to protect Mt. Emei's ecosystems, efforts are needed to further control sulfur and nitrogen deposition through reducing emissions within and outside the SCB.

Air pollution reduction in China: Recent success but great challenge for the future.

China's rapid economic growth has caused severe air pollution, raising serious concerns about the growing evidence of its negative health, environmental, and economic impacts. Consequently, the Chinese government has implemented a number of policies and measures to reduce air pollution. Relying on published information over the last three decades in China, we analyzed trends in air pollutant emissions (SO2 and NOx) and concentrations of particulate matter (PM) and ozone (O3). During the past decade, SO2 and NOx emissions had declined throughout China and concentrations of PM2.5 and PM10 had considerably decreased in most cities, but average reported 90th MDA8 O3, M7, and AOT40 O3 for 31 capital cities showed an increasing trend between 2013 and 2017. Despite progress in air pollution reduction and an increasing number of "clear sky" days, PM concentrations throughout China remain higher than the World Health Organization guidelines, and urban smog and haze remain a major threat to human health and the environment. Thus far, significant emission reductions have occurred largely through robust administrative power, especially when emission reductions were tied to the performance evaluations and promotion of government officials. Similar to most already-industrialized nations, China is now shifting away from SO2-dominated to NOx- and O3-dominated air pollution. Existing technologies and improved operations of existing control equipment appear unlikely to achieve sufficient reductions in NOx and O3 pollution. Considering the complex relationship between O3, NOx, VOCs, weather, and socio-economic changes in China, it is necessary to increase research on impacts of increasing ozone on plants and to adopt novel technologies and implemented to further reduce air pollution to levels that will protect human health and the environment.

Silencing long non-coding RNA NEAT1 enhances the suppression of cell growth, invasion, and apoptosis of bladder cancer cells under cisplatin chemotherapy.

It has been proven that NEAT1 as a long non-coding RNA (lncRNA) is highly expressed in bladder cancer (BC). Nevertheless, the oncogenic roles of NEAT1 in BC remain largely unknown. In the present study, we observed that the RNA level of NEAT1.1, one RNA variant of NEAT1, was reduced in cisplatin-sensitive T24 cells compared to cisplatin-resistant T24 (T24R) cells after both treated with cisplatin modulated through Wnt/ß-catenin signaling pathway using RNA-seq. Furthermore, NEAT1.1 was knocked down within T24R cells and caused a phenotype of the compromised cell growth, invasion and enhanced apoptosis upon cisplatin treatment compared to untreated T24R cells. Finally, c-MYC, OCT4 and p53 were determined to contribute to the transcriptional regulation of NEAT1.1 under cisplatin using ChIP assay. Taken together, our results suggest that NEAT1.1 blocking can promote the effect of cisplatin for BC treatment.

4-HPR impairs bladder cancer cell migration and invasion by interfering with the Wnt5a/JNK and Wnt5a/MMP-2 signaling pathways.

In order to identify the anti-invasive and anti-metastatic effect of the synthetic retinoid N-(4-hydroxyphenyl) retinamide (4-HPR) on the human bladder cancer EJ cell line, and to study its impact on the expression of wingless-type mouse mammary tumor virus integration site family, member 5a (Wnt5a), the phosphorylation of c-Jun N-terminal kinase (JNK), the expression levels of matrix metalloproteinase-2 (MMP-2), and the migration and invasion of EJ cells, migration and Matrigel invasion assays, as well as western blot analyses, were used in the present study. The results of the migration and Matrigel invasion assays indicated that the inhibitor of JNK SP600125 could inhibit the effect of 4-HPR on EJ cells. The expression of Wnt5a and MMP-2, and the phosphorylation of JNK, were analyzed by western blotting. The data revealed that 4-HPR inhibited the migration and invasion of bladder cancer cells through stimulating Wnt5a activation, causing the downregulation of MMP-2 expression and enhancing the phosphorylation of JNK in these cells. However, JNK signaling did not appear to have a direct effect on the expression of MMP-2. The present study demonstrated that 4-HPR may be a potent anti-invasive and anti-metastatic agent that functions via the Wnt5a/JNK and Wnt5a/MMP-2 signaling pathways.

BDNF-ERK1/2 signaling pathway in ketamine-associated lower urinary tract symptoms.

OBJECTIVES: Long-term ketamine abuse can affect the urinary system, resulting in lower urinary tract symptoms (LUTS), but the pathogenesis of this is still unknown. Previous studies have demonstrated that ketamine can change the expression of the brain-derived neurotrophic factor (BDNF) in the serum of ketamine abuse patients. The aim of the present study is to explore the mechanism of the ketamine-mediated BDNF signaling pathway in the bladder of rats on chronic ketamine treatment. METHODS: Rats were randomly assigned to a control (normal saline) or ketamine (30 mg/kg) group, with five rats in each group. The experimental group was given ketamine via intraperitoneal injection daily, while the control group was treated with saline. After 12 weeks of treatment, bladders were excised and samples from the control and ketamine group were examined with transmission electron microscopy (TEM). Phosphoprotein and non-phosphoprotein purification, histopathology, immunohistochemistry, and western blot were carried out in all groups. RESULTS: Histological study showed hyperplastic epithelium and inflammatory cell infiltration in ketamine-treated rat bladders. TEM showed that chronic ketamine treatment results in structural damage to organelles. Immunohistochemical staining and western blot showed that the expression of BDNF was significantly lower in the ketamine group. However, the expression of phosphorylated extracellular signal-regulated kinases ½ (ERK1/2) in the ketamine group was higher, whereas the total ERK1/2 was similar to the control group. CONCLUSIONS: Long-term ketamine abuse reduces expression of BDNF, while inducing phosphorylation of ERK1/2 in the bladder wall. This may play an important role in the pathogenesis of ketamine-associated LUTS.