Particulate Matter-Induced Neurotoxicity: Unveiling the Role of NOX4-Mediated ROS Production and Mitochondrial Dysfunction in Neuronal Apoptosis.

Urban air pollution, a significant environmental hazard, is linked to adverse health outcomes and increased mortality across various diseases. This study investigates the neurotoxic effects of particulate matter (PM), specifically PM2.5 and PM10, by examining their role in inducing oxidative stress and subsequent neuronal cell death. We highlight the novel finding that PM increases mitochondrial ROS production via stimulating NOX4 activity, not through its expression level in Neuro-2A cells. Additionally, PMs provoke ROS production via increasing the expression and activity of NOX2 in SH-SY5Y human neuroblastoma cells, implying differential regulation of NOX proteins. This increase in mitochondrial ROS triggers the opening of the mitochondrial permeability transition pore (mPTP), leading to apoptosis through key mediators, including caspase3, BAX, and Bcl2. Notably, the voltage-dependent anion-selective channel 1 (VDAC1) increases at 1 µg/mL of PM2.5, while PM10 triggers an increase from 10 µg/mL. At the same concentration (100 µg/mL), PM2.5 causes 1.4 times higher ROS production and 2.4 times higher NOX4 activity than PM10. The cytotoxic effects induced by PMs were alleviated by NOX inhibitors GKT137831 and Apocynin. In SH-SY5Y cells, both PM types increase ROS and NOX2 levels, leading to cell death, which Apocynin rescues. Variability in NADPH oxidase sources underscores the complexity of PM-induced neurotoxicity. Our findings highlight NOX4-driven ROS and mitochondrial dysfunction, suggesting a potential therapeutic approach for mitigating PM-induced neurotoxicity.

Continuous TNF-α exposure in mammary epithelial cells promotes cancer phenotype acquisition via EGFR/TNFR2 activation.

Tumor necrosis factor alpha (TNF-α), an abundant inflammatory cytokine in the tumor microenvironment (TME), is linked to breast cancer growth and metastasis. In this study, we established MCF10A cell lines incubated with TNF-α to investigate the effects of continuous TNF-α exposure on the phenotypic change of normal mammary epithelial cells. The established MCF10A-LE cell line, through long-term exposure to TNF-α, displayed cancer-like features, including increased proliferation, migration, and sustained survival signaling even in the absence of TNF-α stimulation. Unlike the short-term exposed cell line MCF10A-SE, MCF10A-LE exhibited elevated levels of epidermal growth factor receptor (EGFR) and subsequent TNF receptor 2 (TNFR2), and silencing of EGFR or TNFR2 suppressed the cancer-like phenotype of MCF10A-LE. Notably, we demonstrated that the elevated levels of NAD(P)H oxidase 4 (NOX4) and the resulting increase in reactive oxygen species (ROS) were associated with EGFR/TNFR2 elevation in MCF10A-LE. Furthermore, mammosphere-forming capacity and the expression of cancer stem cell (CSC) markers increased in MCF10A-LE. Silencing of EGFR reversed these effects, indicating the acquisition of CSC-like properties via EGFR signaling. In conclusion, our results reveal that continuous TNF-α exposure activates the EGFR/TNFR2 signaling pathway via the NOX4/ROS axis, promoting neoplastic changes in mammary epithelial cells within the inflammatory TME.

Augmented interpretation of HER2, ER, and PR in breast cancer by artificial intelligence analyzer: enhancing interobserver agreement through a reader study of 201 cases.

BACKGROUND: Accurate classification of breast cancer molecular subtypes is crucial in determining treatment strategies and predicting clinical outcomes. This classification largely depends on the assessment of human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), and progesterone receptor (PR) status. However, variability in interpretation among pathologists pose challenges to the accuracy of this classification. This study evaluates the role of artificial intelligence (AI) in enhancing the consistency of these evaluations. METHODS: AI-powered HER2 and ER/PR analyzers, consisting of cell and tissue models, were developed using 1,259 HER2, 744 ER, and 466 PR-stained immunohistochemistry (IHC) whole-slide images of breast cancer. External validation cohort comprising HER2, ER, and PR IHCs of 201 breast cancer cases were analyzed with these AI-powered analyzers. Three board-certified pathologists independently assessed these cases without AI annotation. Then, cases with differing interpretations between pathologists and the AI analyzer were revisited with AI assistance, focusing on evaluating the influence of AI assistance on the concordance among pathologists during the revised evaluation compared to the initial assessment. RESULTS: Reevaluation was required in 61 (30.3%), 42 (20.9%), and 80 (39.8%) of HER2, in 15 (7.5%), 17 (8.5%), and 11 (5.5%) of ER, and in 26 (12.9%), 24 (11.9%), and 28 (13.9%) of PR evaluations by the pathologists, respectively. Compared to initial interpretations, the assistance of AI led to a notable increase in the agreement among three pathologists on the status of HER2 (from 49.3 to 74.1%, p < 0.001), ER (from 93.0 to 96.5%, p = 0.096), and PR (from 84.6 to 91.5%, p = 0.006). This improvement was especially evident in cases of HER2 2+ and 1+, where the concordance significantly increased from 46.2 to 68.4% and from 26.5 to 70.7%, respectively. Consequently, a refinement in the classification of breast cancer molecular subtypes (from 58.2 to 78.6%, p < 0.001) was achieved with AI assistance. CONCLUSIONS: This study underscores the significant role of AI analyzers in improving pathologists' concordance in the classification of breast cancer molecular subtypes.

Cancer risk according to fasting blood glucose trajectories: a population-based cohort study.

INTRODUCTION: Diabetes mellitus is known to increase the risk of cancer. Fasting blood glucose (FBG) levels can be changed over time. However, the association between FBG trajectory and cancer risk has been insufficiently studied. This research aims to examine the relationship between FBG trajectories and cancer risk in the Korean population. RESEARCH DESIGN AND METHODS: We analyzed data from the National Health Insurance Service-National Health Screening Cohort collected between 2002 and 2015. Group-based trajectory modeling was performed on 256,271 Koreans aged 40-79 years who had participated in health examinations at least three times from 2002 to 2007. After excluding patients with cancer history before 2008, we constructed a cancer-free cohort. The Cox proportional hazards model was applied to examine the association between FBG trajectories and cancer incidence by cancer type, after adjustments for covariates. Cancer case was defined as a person who was an outpatient thrice or was hospitalized once or more with a cancer diagnosis code within the first year of the claim. RESULTS: During the follow-up time (2008-2015), 18,991 cancer cases were identified. Four glucose trajectories were found: low-stable (mean of FBG at each wave <100 mg/dL), elevated-stable (113-124 mg/dL), elevated-high (104-166 mg/dL), and high-stable (>177 mg/dL). The high-stable group had a higher risk of multiple myeloma, liver cancer and gastrointestinal cancer than the low-stable group, with HR 4.09 (95% CI 1.40 to 11.95), HR 1.68 (95% CI 1.25 to 2.26) and HR 1.27 (95% CI 1.11 to 1.45), respectively. In elevated-stable trajectory, the risk increased for all cancer (HR 1.08, 95% CI 1.02 to 1.16) and stomach cancer (HR 1.24, 95% CI 1.07 to 1.43). Significant associations were also found in the elevated-high group with oral (HR 2.13, 95% CI 1.01 to 4.47), liver (HR 1.50, 95% CI 1.08 to 2.08) and pancreatic cancer (HR 1.99, 95% CI 1.20 to 3.30). CONCLUSIONS: Our study highlights that the uncontrolled high glucose level for many years may increase the risk of cancer.

Determinants of unhealthy living by gender, age group, and chronic health conditions across districts in Korea using the 2010-2017 Community Health Surveys.

OBJECTIVES: We investigated the prevalence and determinants of unhealthy living by gender, age, and comorbidities across Korean districts. METHODS: For 806,246 men and 923,260 women from 245 districts who participated in the 2010-2017 Korean Community Health Surveys, risk scores were calculated based on obesity, physical inactivity, smoking, and high-risk alcohol consumption, each scored from 0 (lowest risk) to 2 (highest risk). A risk score ≥4 was defined as indicating unhealthy living, and weighted proportions were calculated for each district. Using multivariate regression, an ecological model including community socioeconomic, interpersonal, and neighborhood factors was examined by gender, age, and comorbidities. RESULTS: The mean age-standardized rate of unhealthy living was 24.05% for men and 4.91% for women (coefficients of variation, 13.94% and 29.51%, respectively). Individuals with chronic diseases more frequently exhibited unhealthy lifestyles. Unhealthy lifestyles were associated with educational attainment (ß-coefficients: men, -0.21; women, -0.15), high household income (ß=0.08 and 0.03, respectively), pub density (ß=0.52 and 0.22, respectively), and fast-food outlet density (ß=2.81 and 1.63, respectively). Negative associations were observed with manual labor, social activity participation, and hospital bed density. Unhealthy living was positively associated with living alone among women and with being unemployed among middle-aged men. Access to parks was negatively associated with unhealthy living among young men and women. The ecological model explained 32% of regional variation in men and 41% in women. CONCLUSIONS: Improving the neighborhood built and socioeconomic environment may reduce regional disparities in lifestyle behaviors; however, the impacts may vary according to socio-demographic traits and comorbidities.

A MEK inhibitor arrests the cell cycle of human conjunctival fibroblasts and improves the outcome of glaucoma filtration surgery.

Better agents are needed to improve glaucoma filtration surgery outcomes compared to current ones. The purpose of this study is to determine whether mitogen-activated protein kinase kinase (MEK) inhibitors can effectively arrest the cell cycle of human conjunctival fibroblasts (HCFs) and inhibit the formation of fibrosis and scarring following glaucoma filtration surgery. A cell counting kit­8 assay revealed that the MEK inhibitor PD0325901 exhibited concentration-dependent growth inhibition of HCFs. Quantitative PCR, immunocytochemistry, and western blotting demonstrated decreased expression of proliferating cell nuclear antigen (PCNA) and cyclin D1 and increased expression of p27 in HCFs treated with PD0325901. Flow cytometry indicated that PD0325901 arrested the cell cycle of HCFs in the G0/1 phase. The cell-migration assay showed that HCF migration rate was significantly suppressed by PD0325901 exposure. Rabbits were divided into PD0325901-treatment and control groups, and glaucoma filtration surgery was performed. Although intraocular pressure did not differ between PD0325901-treatment and control groups, bleb height was greater in the treatment group. Histopathological evaluation revealed that fibrotic changes were significantly attenuated in the PD0325901-treatment group compared to the control group. In conclusion, the MEK inhibitor impedes HCF proliferation via cell-cycle arrest and may be beneficial for glaucoma filtration surgery by reducing bleb scarring.

Low Molecular Weight Collagen Peptide (LMWCP) Promotes Hair Growth by Activating the Wnt/GSK-3ß/ß-Catenin Signaling Pathway.

Low molecular weight collagen peptide (LMWCP) is a collagen hydrolysate derived from fish. We investigated the effects of LMWCP on hair growth using human dermal papilla cells (hDPCs), human hair follicles (hHFs), patch assay, and telogenic C57BL/6 mice, while also examining the underlying mechanisms of its action. LMWCP promoted proliferation and mitochondrial potential, and the secretion of hair growth-related factors, such as EGF, HB-EGF, FGF-4, and FGF-6 in hDPCs. Patch assay showed that LMWCP increased the neogeneration of new HFs in a dose-dependent manner. This result correlated with an increase in the expression of dermal papilla (DP) signature genes such as, ALPL, SHH, FGF7, and BMP-2. LMWCP upregulated phosphorylation of glycogen synthase kinase-3ß (GSK-3ß) and ß-catenin, and nuclear translocation of ß-catenin, and it increased the expression of Wnt3a, LEF1, VEGF, ALP, and ß-catenin. LMWCP promoted the growth of hHFs and increased the expression of ß-catenin and VEGF. Oral administration of LMWCP to mice significantly stimulated hair growth. The expression of Wnt3a, ß-catenin, PCNA, Cyclin D1, and VEGF was also elevated in the back skin of the mice. Furthermore, LMWCP increased the expression of cytokeratin and Keratin Type I and II. Collectively, these findings demonstrate that LMWCP has the potential to increase hair growth via activating the Wnt/ß-catenin signaling pathway.

In Vitro and In Vivo Bone-Forming Effect of a Low-Molecular-Weight Collagen Peptide.

This study reveals that low-molecular-weight collagen peptide (LMWCP) can stimulate the differentiation and the mineralization of MC3T3-E1 cells in vitro and attenuate the bone remodeling process in ovariectomized (OVX) Sprague-Dawley rats in vivo. Moreover, the assessed LMWCP increased the activity of alkaline phosphatase (ALP), synthesis of collagen, and mineralization in MC3T3-E1 cells. Additionally, mRNA levels of bone metabolism-related factors such as the collagen type I alpha 1 chain, osteocalcin (OCN), osterix, bone sialoprotein, and the Runt family-associated transcription factor 2 were increased in cells treated with 1,000 µg/ml of LMWCP. Furthermore, we demonstrated that critical bone morphometric parameters exhibited significant differences between the LMWCP (400 mg/kg)-receiving and vehicle-treated rat groups. Moreover, the expression of type I collagen and the activity of ALP were found to be higher in both the femur and lumbar vertebrae of OVX rats treated with LMWCP. Finally, the administration of LMWCP managed to alleviate osteogenic parameters such as the ALP activity and the levels of the bone alkaline phosphatase, the OCN, and the procollagen type 1 N-terminal propeptide in OVX rats. Thus, our findings suggest that LMWCP is a promising candidate for the development of food-based prevention strategies against osteoporosis.

Real flue gas CO2 hydrogenation to formate by an enzymatic reactor using O2- and CO-tolerant hydrogenase and formate dehydrogenase.

It is challenging to capture carbon dioxide (CO2), a major greenhouse gas in the atmosphere, due to its high chemical stability. One potential practical solution to eliminate CO2 is to convert CO2 into formate using hydrogen (H2) (CO2 hydrogenation), which can be accomplished with inexpensive hydrogen from sustainable sources. While industrial flue gas could provide an adequate source of hydrogen, a suitable catalyst is needed that can tolerate other gas components, such as carbon monoxide (CO) and oxygen (O2), potential inhibitors. Our proposed CO2 hydrogenation system uses the hydrogenase derived from Ralstonia eutropha H16 (ReSH) and formate dehydrogenase derived from Methylobacterium extorquens AM1 (MeFDH1). Both enzymes are tolerant to CO and O2, which are typical inhibitors of metalloenzymes found in flue gas. We have successfully demonstrated that combining ReSH- and MeFDH1-immobilized resins can convert H2 and CO2 in real flue gas to formate via a nicotinamide adenine dinucleotide-dependent cascade reaction. We anticipated that this enzyme system would enable the utilization of diverse H2 and CO2 sources, including waste gases, biomass, and gasified plastics.

Most patients with COPD are unaware of their health threats and are not diagnosed: a national-level study using pulmonary function test.

This study aimed to investigate national-level prevalence of COPD, proportion of patients diagnosed with and without COPD. We performed pulmonary function test (PFT) in 24,454 adults aged > 40 years for 8 years (2010-2017). The annual COPD prevalence increased from 13.1% in 2010 to 14.6% in 2012, followed by 13.3% in 2017. However, patients diagnosed with COPD ranged between 0.5 and 1.0% in the last 8 years, which means that only 5% of all COPD patients were diagnosed with COPD by doctors. We defined potential high-risk individuals as those with a FEV1/FVC ratio of < 0.70, who have not been diagnosed with COPD and other respiratory diseases tuberculosis, asthma, lung cancer. The proportion of this group was 80.8% in 2010 and 78.1% in 2017. The older age group, women, low-educated group, and current smokers who have been smoking for a long time are more likely to be in the high-risk group having a higher possibility to develop COPD but are not diagnosed with COPD appropriately. Although COPD prevalence was high in the ever, current, and heavy smokers, only the diagnosis rate of COPD in ever smokers was 2.38 times higher than never smokers, indicating that a system is needed to screen and intervention for these groups.

Association of NRF2 with HIF-2α-induced cancer stem cell phenotypes in chronic hypoxic condition.

The acquisition of the cancer stem cell (CSC) properties is often mediated by the surrounding microenvironment, and tumor hypoxia is considered an important factor for CSC phenotype development. High levels of NRF2 (Nuclear Factor Erythroid 2-Like 2; NFE2L2), a transcription factor that maintains cellular redox balance, have been associated with facilitated tumor growth and therapy resistance. In this study, we investigated the role of NRF2 in hypoxia-induced CSC phenotypes in colorectal cancer cells. Chronic hypoxia for 72 h resulted in CSC phenotypes, including elevation of krupple-like factor 4 (KLF4) and octamer-binding transcription factor 4 (OCT4), and an increase in cancer migration and spheroid growth with concomitant hypoxia-inducible factor 2α (HIF-2α) accumulation. All these chronic hypoxia-induced CSC properties were attenuated following HIF-2α-specific silencing. In this chronic hypoxia model, NRF2 inhibition by shRNA-based silencing or brusatol treatment blocked HIF-2α accumulation, which consequently resulted in decreased CSC marker expression and inhibition of CSC properties such as spheroid growth. In contrast, NRF2 overactivation by genetic or chemical approach enhanced the chronic hypoxia-induced HIF-2α accumulation and cancer migration. As a molecular mechanism of the NRF2-inhibition-mediated HIF-2α dysregulation, we demonstrated that miR-181a-2-3p, whose expression is elevated in NRF2-silenced cells, targeted the HIF-2α 3'UTR and subsequently suppressed the chronic hypoxia-induced HIF-2α and CSC phenotypes. The miR-181a-2-3p inhibitor treatment in NRF2-silenced cells could restore the levels of HIF-2α and CSC markers, and increased cancer migration and sphere formation under chronic hypoxia. In line with this, the miR-181a-2-3p inhibitor transfection could increase tumorigenicity of NRF2-silenced colorectal cancer cells. Collectively, our study suggests the involvement of NRF2/miR181a-2-3p signaling in the development of HIF-2α-mediated CSC phenotypes in sustained hypoxic environments.

Impact of data extraction errors in meta-analyses on the association between depression and peripheral inflammatory biomarkers: an umbrella review.

BACKGROUND: Accumulating evidence suggests that alterations in inflammatory biomarkers are important in depression. However, previous meta-analyses disagree on these associations, and errors in data extraction may account for these discrepancies. METHODS: PubMed/MEDLINE, Embase, PsycINFO, and the Cochrane Library were searched from database inception to 14 January 2020. Meta-analyses of observational studies examining the association between depression and levels of tumor necrosis factor-α (TNF-α), interleukin 1-ß (IL-1ß), interleukin-6 (IL-6), and C-reactive protein (CRP) were eligible. Errors were classified as follows: incorrect sample sizes, incorrectly used standard deviation, incorrect participant inclusion, calculation error, or analysis with insufficient data. We determined their impact on the results after correction thereof. RESULTS: Errors were noted in 14 of the 15 meta-analyses included. Across 521 primary studies, 118 (22.6%) showed the following errors: incorrect sample sizes (20 studies, 16.9%), incorrect use of standard deviation (35 studies, 29.7%), incorrect participant inclusion (7 studies, 5.9%), calculation errors (33 studies, 28.0%), and analysis with insufficient data (23 studies, 19.5%). After correcting these errors, 11 (29.7%) out of 37 pooled effect sizes changed by a magnitude of more than 0.1, ranging from 0.11 to 1.15. The updated meta-analyses showed that elevated levels of TNF- α, IL-6, CRP, but not IL-1ß, are associated with depression. CONCLUSIONS: These findings show that data extraction errors in meta-analyses can impact findings. Efforts to reduce such errors are important in studies of the association between depression and peripheral inflammatory biomarkers, for which high heterogeneity and conflicting results have been continuously reported.

Influence of implantation of diffractive trifocal intraocular lenses on standard automated perimetry.

BACKGROUND: This prospective comparative study aimed to investigate the influence of diffractive trifocal intraocular lenses (IOLs) implantation on standard automated perimetry. METHODS: Patients with no diseases affecting the visual field had undergone cataract surgery following the implantation of trifocal or monofocal IOLs from July 2019 to August 2020 were recruited. The normality of the anterior and posterior segments and absence of glaucomatous optic nerve cupping were confirmed preoperatively by slit-lamp examination. Standard automated perimetry was performed using Humphrey Visual Field 10-2 testing, 2-3 months after cataract surgery in only one eye per patient. The mean deviation (MD) and foveal sensitivity were compared between IOLs in eyes with acceptable reliability indices and best-corrected visual acuity of 20/25 or better. RESULTS: Among the 83 eyes of the 83 patients included, 39 and 29 eyes eligible for perimetry analysis had trifocal and monofocal IOLs, respectively. The mean MD and foveal sensitivity in eyes with trifocal IOLs were significantly lower than those in eyes with monofocal IOLs (P < 0.021), with mean differences of 0.77 and 1.01 dB, respectively. CONCLUSION: The comparison in nonglaucomatous eyes demonstrated that the influence of trifocal IOLs on standard automated perimetry was greater than that of monofocal IOLs.

Association between lifestyle factors and metabolic syndrome in general populations with depressive symptoms in cross-setional based cohort study of Ansung-Ansan.

BACKGROUND: Metabolic syndrome (MetS) is caused by both genetic and environmental factors, such as daily calorie intake, smoking, and alcohol consumption. Lifestyle factors, such as alcohol consumption, are considered to be related to the prevalence of MetS and plays an essential role in the pathogenesis and prognosis of depression. METHODS: We investigated the bidirectional association between lifestyle factors and MetS among Korean adults with depressive symptoms in third wave of a community-based cohort study. A total of 1,578 individuals, aged 39-72 years, who had MetS at baseline were recruited. Participants were divided into two groups according to depressive symptoms. Logistic regression models were used to estimate the risk of MetS. RESULTS: The percentage of heavy drinkers was lower in men with depressive symptoms compared to those who did not (7.0% vs. 7.1%), while the percentage of current smokers were higher in participants who had depressive symptoms (40.2% vs. 30.0%). After adjusting for age, education, monthly income, body mass index (BMI), sleep duration, and volume of drinking and smoking status, logistic regression analysis demonstrated that male heavy drinkers with depressive symptoms were 2.75 times more likely to have MetS than those without depressive symptom. Conversely, depressive women with a high BMI were 3.70 times more likely to have MetS than in those with lower BMI. Limitations The cross-sectional nature of the study, and the study population ethnicity and ages were limitations. CONCLUSIONS: Lifestyle factors, such as alcohol consumption, may be associated with the risk of MetS in adults with depressive symptoms.

A case of adult-onset Wolfram syndrome with compound heterozygous mutations of the WFS1 gene.

PURPOSE: Wolfram syndrome is a rare genetic disorder characterized by juvenile onset of diabetes mellitus with bilateral optic atrophy. We report a case of adult onset Wolfram syndrome with diabetes mellitus at age 22 and optic atrophy after age 40. The WFS1 gene sequence was analyzed in the patient and her father. OBSERVATIONS: A 46-year-old woman presented with bilateral vision loss. She had developed diabetes mellitus at age 22 and underwent bilateral cataract surgery at age 37. Visual acuity was 20/50 in the right eye and 20/200 in the left eye. The pupillary light reflex was sluggish in both eyes. Fundus examination showed bilateral optic atrophy, but there was no diabetic retinopathy. Cecocentral scotoma of both eyes was observed in Goldmann perimetry. There were no intracranial lesions on magnetic resonance imaging. Audiometry demonstrated high-frequency sensorineural hearing loss. Sequence analysis of the WFS1 gene revealed compound heterozygous mutation: c.908T>C p.L303P and c.1232_1233del, p.S411Cfs*131 in the patient and heterozygous mutation c. 908 T>C, p. L303P in her father. CONCLUSIONS AND IMPORTANCE: The patient was diagnosed with adult-onset Wolfram syndrome with compound heterozygous mutations of the WFS1 alleles. Wolfram syndrome must be ruled out even in adult-onset diabetic patients with optic atrophy.

Genetic deficiency of nuclear factor of activated T cells 5 attenuates the development of osteoarthritis in mice.

OBJECTIVES: This study is aimed to investigate the role of nuclear factor of activated T cells 5 (NFAT5), originally known as the osmosensitive mammalian transcription factor, in the pathogenesis of osteoarthritis (OA) in mice. METHODS: OA was induced in male C57BL/6 (wild-type) and NFAT5 haplo-insufficient (NFAT5+/-) mice via destabilization of the medial meniscus (DMM) surgery. OA severity and synovial inflammation were histologically assessed. Expression of CCL2, inflammatory cytokines, cartilage degrading enzymes was determined in the knee joints and cultured chondrocytes from wild-type and NFAT5+/- mice. RESULTS: NFAT5 expression was significantly upregulated in the knee joint of a mouse after DMM surgery. NFAT5 deficiency decreased the severity of synovial inflammation and osteoarthritic changes in cartilage and subchondral bone. Moreover, NFAT5 deficiency also decreased the expression of CCL2, IL-1ß, MMP-13, ADMATS-5, and macrophage infiltration in the joint. In cultured chondrocytes, hyperosmolar or IL-1ß stimulation significantly enhanced the expression of NFAT5, CCL2, IL-1ß, IL-6, and MMP-13, and this effect was abolished in chondrocytes from NFAT5+/- mice. Hyperosmolarity or IL-1ß-induced NFAT5 and CCL2 downregulated by inhibiting p38 MAPK, JNK, and ERK pathways. CONCLUSIONS: Our results indicate that NFAT5 is a crucial regulator of OA pathogenesis by upregulating CCL2 expression and macrophage recruitment. In chondrocyte, NFAT5 plays an important role in the response to hyperosmolar or IL-1ß stimulation. Thus, NFAT5 could be an attractive therapeutic target for OA treatment.

Positive fecal immunochemical test results are associated with non-colorectal cancer mortality.

BACKGROUND/AIMS: Studies have reported an association between fecal occult blood and increased all-cause, non-colorectal cancer (CRC) as well as CRC mortality. This study aimed to determine whether positive fecal immunochemistry test (FIT) results are associated with death from various causes in the South Korean population. METHODS: Using the Korean National Cancer Screening Program database, we collected data on patients who underwent FIT between 2009 and 2011. RESULTS: Of the 5,932,544 participants, 380,789 (6.4%) had positive FIT results. FIT-positive participants had a higher mortality rate than FIT-negative participants from CRC (1.33 and 0.21 per 1,000 person-years, p < 0.001, respectively) and non-CRC causes (10.40 and 7.50 per 1,000 person-years, p < 0.001, respectively). Despite adjusting for age, sex, smoking status, alcohol consumption habits, body mass index, comorbidity, and aspirin use, FIT positivity was associated with an increased risk of dying from all non-CRC causes (adjusted hazard ratio [aHR], 1.17; 95% confidence interval [CI], 1.15 to 1.18) and CRC (aHR, 5.61; 95% CI, 5.40 to 5.84). Additionally, FIT positivity was significantly associated with increased mortality from circulatory disease (aHR, 1.14; 95% CI, 1.11 to 1.17), respiratory disease (aHR, 1.14; 95% CI, 1.09 to 1.19), digestive disease (aHR, 1.57; 95% CI, 1.48 to 1.66), neuropsychological disease (aHR, 1.08; 95% CI, 1.01 to 1.16), blood and endocrine diseases (aHR, 1.10; 95% CI, 1.04 to 1.17), and external factors (aHR, 1.16; 95% CI, 1.11 to 1.20). CONCLUSION: Positive FIT results are associated with an increased risk of mortality from CRC and various other chronic diseases, suggesting that it could be a predictor of mortality independent of its association with CRC.

Synthesis of Arylene Ether-Type Hyperbranched Poly(triphenylamine) for Lithium Battery Cathodes.

We synthesized a new poly(triphenylamine), having a hyperbranched structure, and employed it in lithium-ion batteries as an organic cathode material. Two types of monomers were prepared with hydroxyl groups and nitro leaving groups, activated by a trifluoromethyl substituent, and then polymerized via the nucleophilic aromatic substitution reaction. The reactivity of the monomers differed depending on the number of hydroxyl groups and the A2B type monomer with one hydroxyl group successfully produced poly(triphenylamine). Based on thermal, optical, and electrochemical analyses, a composite poly(triphenylamine) electrode was made. The electrochemical performance investigations confirmed that the lithium-ion batteries, fabricated with the poly(triphenylamine)-based cathodes, had reasonable specific capacity values and stable cycling performance, suggesting the potential of this hyperbranched polymer in cathode materials for lithium-ion batteries.

Discovery proteomics defines androgen-regulated glycoprotein networks in prostate cancer cells, as well as putative biomarkers of prostatic diseases.

Supraphysiologic androgen (SPA) inhibits cell proliferation in prostate cancer (PCa) cells by transcriptional repression of DNA replication and cell-cycle genes. In this study, quantitative glycoprotein profiling identified androgen-regulated glycoprotein networks associated with SPA-mediated inhibition of PCa cell proliferation, and androgen-regulated glycoproteins in clinical prostate tissues. SPA-regulated glycoprotein networks were enriched for translation factors and ribosomal proteins, proteins that are known to be O-GlcNAcylated in response to various cellular stresses. Thus, androgen-regulated glycoproteins are likely to be targeted for O-GlcNAcylation. Comparative analysis of glycosylated proteins in PCa cells and clinical prostate tissue identified androgen-regulated glycoproteins that are differentially expressed prostate tissues at various stages of cancer. Notably, the enzyme ectonucleoside triphosphate diphosphohydrolase 5 was found to be an androgen-regulated glycoprotein in PCa cells, with higher expression in cancerous versus non-cancerous prostate tissue. Our glycoproteomics study provides an experimental framework for characterizing androgen-regulated proteins and glycoprotein networks, toward better understanding how this subproteome leads to physiologic and supraphysiologic proliferation responses in PCa cells, and their potential use as druggable biomarkers of dysregulated AR-dependent signaling in PCa cells.