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Abstract Background Currently, the pathophysiology of new bone formation in radiographic axial spondyloarthritis (r-axSpA) remains unclear. Cellular elements and their secreted bone turnover markers might be one of the underlying mechanisms that drive the new bone formation. Our study aimed to investigate the role of bone turnover markers in r-axSpA patients with fatty lesions. Methods 73 r-axSpA patients were enrolled in this study. 48 and 25 patients were divided into r-axSpA group with and without fatty lesions. Clinical variables were collected and all patients received comprehensive rheumatologic assessment for disease activity, including Modified Stoke Ankylosing Spondylitis Spine Score (mSASSS), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Axial Spondyloarthritis Disease Activity Score (ASDAS). Fatty lesions in the sacroiliac joints (SIJs) were scored independently by two radiologists. Serum levels of bone turnover markers, including sclerostin, osteoprotegerin (OPG), procollagen I N-terminal propeptide (PINP), cross linked C-telopeptide of type I collagen (CTX-I), osteocalcin (OC), were measured using enzyme-linked immunosorbent assays. Results There were no significant differences between two groups in terms of gender, age, body mass index (BMI), duration, smoking, HLA-B27 positivity rate, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), BASDAI, ASDAS-ESR, ASDAS-CRP, biological disease-modifying anti-rheumatic drugs (bDMARDs) rate. No significant differences were observed in terms of OPG, PINP, CTX-I or OC between two groups. The mSASSS were higher in fatty lesions group than in those without fatty lesions (p

6:2 fluorotelomer carboxylic acid (6:2 FTCA) is a perfluorooctanoic acid (PFOA) substitute, which is supposedly less accumulative and toxic than PFOA. However, 6:2 FTCA is structurally similar to PFOA, and there had already been reports about its toxicities comparable to PFOA. The aim of the current study is to assess potential effects of developmental exposure to 6:2 FTCA on the development of kidney in chicken embryo and to investigate underlying mechanism. Fertile chicken eggs were exposed to 1.25 mg/kg, 2.5 mg/kg or 5 mg/kg doses of 6:2 FTCA, or 2 mg/kg PFOA, then incubated to hatch. Serum and kidney of hatchling chickens were collected. Blood urea nitrogen (BUN) and creatinine (Cre) levels were measured with commercially available kits. Morphology of kidney was assessed with histopathology. To further reveal molecular mechanism of observed endpoints, IGF signaling molecules were assessed in the kidney samples with qRT-PCR, results indicated that IGFBP3 is a potentially crucial molecule. Lentiviruses overexpressing or silencing IGFBP3 were designed and applied to enhance/suppress the expression of IGFBP3 in developing chicken embryo for further verification of its role in the observed effects. Disrupted nephron formation, in the manifestation of decreased glomeruli number/area and increased serum BUN/Cre levels, was observed in the animals developmentally exposed to 6:2 FTCA. Correspondingly, IGF signaling molecules (IGF1, IGF1R and IGFBP3) were affected by 6:2 FTCA exposure. Meanwhile, overexpression of IGFBP3 effectively alleviated such changes, while silencing of IGFBP3 mimicked observed effects. In conclusion, developmental exposure to 6:2 FTCA is associated with disrupted chicken embryo renal development, in which IGFBP3 seems to be a remarkable contributor, suggesting potential health risks for human and other species. Further risk assessments and mechanistic works are necessary.

Objective: The effects of air pollution on metabolism have become a popular research topic, and a large number of studies had confirmed that air pollution exposure could induce insulin resistance (IR) to varying degrees, but the results were inconsistent, especially for the long-term exposures. The aim of the current study was to further investigate the potential effects of air pollution on IR. Methods: A systematic review and meta-analysis of four electronic databases, including PubMed, Embase, Web of Science and Cochrane were conducted, searching for relevant studies published before June 10, 2023, in order to explore the potential relationships between long-term exposure to air pollution and IR. A total of 10 studies were included for data analysis, including seven cohort studies and three cross-sectional studies. Four major components of air pollution, including PM2.5 (particulate matter with an aerodynamic diameter of 2.5 µm or less), PM10 (particulate matter with an aerodynamic diameter of 10 µm or less), NO2, and SO2 were selected, and each analyzed for the potential impacts on insulin resistance, in the form of adjusted percentage changes in the homeostasis assessment model of insulin resistance (HOMA-IR). Results: This systematic review and meta-analysis showed that for every 1 μg/m³ increase in the concentration of selected air pollutants, PM2.5 induced a 0.40% change in HOMA-IR (95%CI: −0.03, 0.84; I2 =67.4%, p = 0.009), while PM10 induced a 1.61% change (95%CI: 0.243, 2.968; I2 =49.1%, p = 0.001). Meanwhile, the change in HOMA-IR due to increased NO2 or SO2 exposure concentration was only 0.09% (95%CI: −0.01, 0.19; I2 =83.2%, p = 0.002) or 0.01% (95%CI: −0.04, 0.06; I2 =0.0%, p = 0.638), respectively. Conclusions: Long-term exposures to PM2.5, PM10, NO2 or SO2 are indeed associated with the odds of IR. Among the analyzed pollutants, inhalable particulate matters appear to exert greater impacts on IR.

BackgroundDue to the limited availability of established research models, very few studies addressed the health effects and underlying mechanisms following exposure to diesel exhaust during the initiation of pulmonary respiration. It is highly demanded to elucidate such health effects and underlying mechanisms, so as to exert protective measures during the early stages of life.ObjectiveTo evaluate the health effects of diesel exhaust very-early-in-life inhalation in hatchling chicken with a novel chicken embryo air cell inhalation exposure model, and to explore the potential roles of aryl hydrocarbon receptor signaling pathways in the observed effects with a specific aryl hydrocarbon receptor inhibitor.MethodsFertilized chicken eggs were assigned into five groups randomly (15 eggs per group): control group, air control group, aryl hydrocarbon receptor inhibitor (PDM2) group, diesel exhaust group, and diesel exhaust + aryl hydrocarbon receptor inhibitor (PDM2) group. Fertilized eggs were incubated with standard procedure. At embryonic day 17 (ED17), aryl hydrocarbon receptor inhibitor was administered to the corresponding animals. During embryonic day 18-19 (ED18-19), chicken embryos were exposed to diesel exhaust via air cell inhalation, then placed back to incubator until hatch. The air control group received clean air infusion during ED18-19, while the control group did not receive any treatment. Within 24 h post-hatch, 26 hatchling chickens were anesthetized with sodium pentobarbital, subjected to electrocardiography, and sacrificed to harvest tissue samples of heart and lung. Cardiopulmonary toxicities were evaluated by histopathology, and potential changes in the protein expression levels of aryl hydrocarbon receptor pathway molecule cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1) and fibrosis-related pathway molecule phosphorylated SMAD family member 2 (pSMAD2) were assessed by Western blotting. The remaining 29 hatchling chickens were reared until two weeks old, and then subjected to identical treatments.ResultsThe inhalation exposure to diesel exhaust at initiation of pulmonary respiration resulted in thickened right ventricular wall (by 220.3% relative to the control group, same hereafter) and elevated heart rate (17.4%) in one-day-old hatchling chickens. Although no remarkable fibrotic lesions were observed at this point, the expression levels of CYP1A1 and phosphorylation levels of SMAD2 in the lung tissues significantly increased (by 81.3% and 71.6%, respectively). Such changes were effectively abolished by the aryl hydrocarbon receptor inhibitor PDM2 pretreatment. In the two-week-old animals, the thickened right ventricular wall (by 339.3%) and elevated heart rate (by 18.9%) persisted, and significant fibrotic lesions were observed in the lung tissue samples under Masson staining. Again, the aryl hydrocarbon receptor inhibitor PDM2 pretreatment effectively abolished such changes. In addition, no statistically significant changes in CYP1A1 expression levels were observed in the two-week-old chicken lung samples, and a remarkable down-regulation of SMAD2 phosphorylation was observed. The aryl hydrocarbon receptor inhibitor PDM2 pretreatment independently decreased the phosphorylation levels of SMAD2 in the two-week-old chicken lung samples.ConclusionInhalation exposure to diesel exhaust at initiation of pulmonary respiration could result in persistent cardiopulmonary injury in hatchling chickens, and the underlying mechanism might be associated with the regulation of pSMAD2 by the aryl hydrocarbon receptor signaling pathway.

BackgroundHypoglycaemia has been linked to an increased risk of cardiac arrhythmias by causing autonomic and metabolic alterations, which may be associated with detrimental outcomes in individuals with diabetes(IWD), such as cardiovascular diseases (CVDs) and mortality, especially in multimorbid or frail people. However, such relationships in this population have not been thoroughly investigated. For this reason, we conducted a systematic review and meta-analysis.MethodsRelevant papers published on PubMed, Embase, Cochrane, Web of Knowledge, Scopus, and CINHAL complete from inception to December 22, 2022 were routinely searched without regard for language. All of the selected articles included odds ratio, hazard ratio, or relative risk statistics, as well as data for estimating the connection of hypoglycaemia with cardiac arrhythmia, CVD-induced death, or total death in IWD. Regardless of the heterogeneity assessed by the I2 statistic, pooled relative risks (RRs) and 95% confidence intervals (CI) were obtained using random-effects models.ResultsAfter deleting duplicates and closely evaluating all screened citations, we chose 60 studies with totally 5,960,224 participants for this analysis. Fourteen studies were included in the arrhythmia risk analysis, and 50 in the analysis of all-cause mortality. Hypoglycaemic patients had significantly higher risks of arrhythmia occurrence (RR 1.42, 95%CI 1.21-1.68), CVD-induced death (RR 1.59, 95% CI 1.24-2.04), and all-cause mortality (RR 1.68, 95% CI 1.49-1.90) compared to euglycaemic patients with significant heterogeneity.ConclusionHypoglycaemic individuals are more susceptible to develop cardiac arrhythmias and die, but evidence of potential causal linkages beyond statistical associations must await proof by additional specifically well planned research that controls for all potential remaining confounding factors.

Hexafluoropropylene oxide tetramer acid (HFPO-TeA) is an emerging environmental contaminant, with environmental presence but limited toxicological information. To investigate its potential developmental toxicities, various doses of HFPO-TeA exposure were achieved in chicken embryos via air cell injection, and the exposed embryos were incubated until hatch. Within 24 h of hatch, the hatchling chickens were assessed with electrocardiography and histopathology for toxicological evaluation. For mechanistic investigation, in ovo silencing of PPARα was achieved via lentivirus microinjection, then the morphological/functional endpoints along with protein expression levels of PPARα-regulated genes were assessed. HFPO-TeA exposure in chicken embryo resulted in developmental cardiotoxicity and hepatotoxicity. Specifically, decreased right ventricular wall thickness, increased heart rate and hepatic steatosis were observed, whereas silencing of PPARα resulted in alleviation of observed toxicities. Western blotting for EHHADH and FABPs suggested that developmental exposure to HFPO-TeA effectively increased the expression levels of both targets in hatchling chicken heart and liver tissue samples, while PPARα silencing prevented such changes, suggesting that PPARα and its downstream genes are playing critical roles in HFPO-TeA induced developmental toxicities.

Abstract Background Rheumatoid arthritis (RA) is a chronic autoimmune disease, which commonly affects women. Accumulating evidence shows that differentially expressed circular RNAs (circRNAs) play crucial roles in the progress of RA. However, the roles of circRNAs in female RA remains unclear. This study explores potential role and diagnostic value of hsa_circ_0140271 from peripheral blood mononuclear cells (PBMC) in female RA. Methods Differential expression of circRNAs was determined by RNA-sequencing in PBMC from 4 healthy controls (HC) and 4 RA patients, and we further measured the level of hsa_circ_0140271 in a validation cohort consisting of 47 RA and 47 HC via RT-qPCR. Besides, correlation studies with clinical variables were also examined. What’s more, we performed bioinformatics analysis to predict the potential role of hsa_circ_0140271. Results PBMC expression of hsa_circ_0140271 of female RA was significantly higher than that of female HC, and it was positively correlated with antistreptolysin (ASO). Furthermore, the receiver operating characteristic (ROC) curve indicated that hsa_circ_0140271 could distinguish female RA from female HC and female patients with ankylosing spondylitis (AS) or osteoarthritis (OA). Besides, the combined diagnosis anti-cyclic citrullinated peptide (Anti-CCP) + hsa_circ_0140271 could improve diagnostic accuracy with an area under the curve (AUC) of 0.818 to compared with Anti-CCP. Furthermore, KEGG pathway enrichment analysis indicated hsa_circ_0140271 may act as microRNA sponge and participate in fatty acid metabolism pathways. Conclusion Hsa_circ_0140271 was likely to be used as a promising diagnostic biomarker for female RA; it may act as microRNA sponge to regulate fatty acid metabolism pathways in RA.

Introduction The existing findings about the association between polyunsaturated fatty acid (PUFA) status (especially long-chain n-3 PUFAs) and the risk of preclinical or clinical type 1 diabetes (T1D) in children are controversial. This review aimed to evaluate the definite association. Material and methods Three databases were systematically viewed until July, 2019 to identify relevant articles, without language restriction. Any observational study or randomized controlled trial reporting the risk estimates of preclinical or clinical T1D for PUFA status in infants and children was enrolled. Regardless of the statistical heterogeneity assessed by the I2 statistic, we pooled the odds ratios (ORs), relative risks (RRs) or hazard ratios (HRs) with 95% confidence intervals (CI) through random-effects models. Results Five observational studies were enrolled in the meta-analysis. The status of n-3 PUFAs was negatively and significantly associated with the risk of preclinical, but not clinical, T1D (pooled RR = 0.85; 95% CI: 0.73–0.99) with substantial heterogeneity (I 2 = 72.2%). However, no such association was found between n-6 PUFA status and the risk of preclinical or clinical T1D. Conclusions The meta-analysis suggests that n-3 PUFA might play a potential protective role in the cause of preclinical T1D, and n-3 PUFA intake may be beneficial, since the n-3 PUFA status was associated with a significant decrease in the risk of preclinical T1D in children. Nevertheless, more well-designed prospective studies are necessary to determine whether dietary or supplemental intake of specific n-3 PUFA alters the risk of preclinical T1D.

The role of farnesoid X receptor (FXR) in cervical cancer and the underlying molecular mechanism remain largely unknown. Therefore, this study aimed to assess the mechanism of FXR in cervical cancer. Western blot, qRT-PCR, and immunohistochemistry demonstrated that FXR was significantly reduced in squamous cell carcinoma tissues, although there were no associations of metastasis and TNM stage with FXR. In Lenti-FXR cells obtained by lentiviral transfection, the overexpression of FXR reduced cell viability and colony formation. Compared with the Lenti-Vector groups, the overexpression of FXR induced early and late apoptosis and promoted G1 arrest. With time, early apoptosis decreased, and late apoptosis increased. In tumor xenograft experiments, overexpression of FXR upregulated small heterodimer partner (SHP), murine double minute-2 (MDM2), and p53 in the nucleus. Co-immunoprecipitation (Co-IP) showed that SHP directly interacted with MDM2, which is important to protect p53 from ubiquitination. Nutlin3a increased MDM2 and p53 amounts in the Lenti-Vector groups, without effects in the Lenti-FXR groups. Silencing SHP reduced MDM2 and p53 levels in the Lenti-FXR groups, and Nutlin3a counteracted these effects. Taken together, these findings suggest that FXR inhibits cervical cancer via upregulation of SHP, MDM2, and p53.

TFIIB‐related factor 1 (Brf1) modulates the transcription of RNA Pol III genes (polymerase‐dependent genes). Upregulation of Pol III genes enhances tRNA and 5S RNA production and increases the translational capacity of cells to promote cell transformation and tumor development. However, the significance of Brf1 overexpression in human breast cancer (HBC) remains to be investigated. Here, we investigate whether Brf1 expression is increased in the samples of HBC, and we explore its molecular mechanism and the significance of Brf1 expression in HBC. Two hundred and eighteen samples of HBC were collected to determine Brf1 expression by cytological and molecular biological approaches. We utilized colocalization, coimmunoprecipitation, and chromatin immunoprecipitation methods to explore the interaction of Brf1 with estrogen receptor alpha (ERα). We determined how Brf1 and ERα modulate Pol III genes. The results indicated that Brf1 is overexpressed in most cases of HBC, which is associated with an ER‐positive status. The survival period of the cases with high Brf1 expression is significantly longer than those with low levels of Brf1 after hormone treatment. ERα mediates Brf1 expression. Brf1 and ERα are colocalized in the nucleus. These results indicate an interaction between Brf1 and ERα, which synergistically regulates the transcription of Pol III genes. Inhibition of ERα by its siRNA or tamoxifen reduces cellular levels of Brf1 and Pol III gene expression and decreases the rate of colony formation of breast cancer cells. Together, these studies demonstrate that Brf1 is a good biomarker for the diagnosis and prognosis of HBC. This interaction of Brf1 with ERα and Brf1 itself are potential therapeutic targets for this disease.

The levels of the products of RNA polymerase III-dependent genes (Pol III genes), including tRNAs and 5S rRNA, are elevated in transformed and tumor cells, which potentiate tumorigenesis. TFIIB-related factor 1 (Brf1) is a key transcription factor and specifically regulates the transcription of Pol III genes. In vivo and in vitro studies have demonstrated that a decrease in Brf1 reduces Pol III gene transcription and is sufficient for inhibiting cell transformation and tumor formation. Emerging evidence indicates that dysregulation of Brf1 and Pol III genes is linked to the development of hepatocellular carcinoma (HCC) in humans and animals. We have reported that Brf1 is overexpressed in human liver cancer patients and that those with high Brf1 levels have shorter survivals. This review summarizes the effects of dysregulation of these genes on HCC and their regulation by signaling pathways and epigenetics. These novel data should help us determine the molecular mechanisms of HCC from a different perspective and guide the development of therapeutic approaches for HCC patients. Keywords: RNA polymerase III (Pol III), TFIIB-related factor 1 (Brf1), Hepatocellular carcinoma (HCC), c-Jun amino-terminal kinase (JNKs), Histone H3

Early growth response-1 (Egr-1), a transcription factor which often underlies the molecular basis of myocardial ischemia/reperfusion (I/R) injury, and oxidative stress, is key to myocardial I/R injury. Silent information regulator of transcription 1(SIRT1) not only interacts with and is inhibited by Egr-1, but also downregulates reactive oxygen species (ROS) via the Forkhead box O1(FOXO1)/manganese superoxide dismutase (Mn-SOD) signaling pathway. N-n-butyl haloperidol iodide (F2), a new patented compound, protects the myocardium against myocardial I/R injury in various animal I/R models in vivo and various heart-derived cell hypoxia/reoxygenation (H/R) models in vitro. In addition, F2 can regulate the abnormal ROS/Egr-1 signaling pathway in cardiac microvascular endothelial cells (CMECs) and H9c2 cells after H/R. We studied whether there is an inverse Egr-1/ROS signaling pathway in H9c2 cells and whether the SIRT1/FOXO1/Mn-SOD signaling pathway mediates this. We verified a ROS/Egr-1 signaling loop in H9c2 cells during H/R and that F2 protects against myocardial H/R injury by affecting SIRT1-related signaling pathways. Knockdown of Egr-1, by siRNA interference, reduced ROS generation, and alleviated oxidative stress injury induced by H/R, as shown by upregulated mitochondrial membrane potential, increased glutathione peroxidase (GSH-px) and total SOD anti-oxidative enzyme activity, and downregulated MDA. Decreases in FOXO1 protein expression and Mn-SOD activity occurred after H/R, but could be blocked by Egr-1 siRNA. F2 treatment attenuated H/R-induced Egr-1 expression, ROS generation and other forms of oxidative stress injury such as MDA, and prevented H/R-induced decreases in FOXO1 and Mn-SOD activity. Nuclear co-localization between Egr-1 and SIRT1 was increased by H/R and decreased by either Egr-1 siRNA or F2. Therefore, our results suggest that Egr-1 inhibits the SIRT1/FOXO1/Mn-SOD antioxidant signaling pathway to increase ROS and perpetuate I/R injury. F2 inhibits induction of Egr-1 by H/R, thereby activating SIRT1/FOXO1/Mn-SOD antioxidant signaling and decreasing H/R-induced ROS, demonstrating an important mechanism by which F2 protects against myocardial H/R injury.

Glycyrrhetic acid (GA)-modified pullulan nanoparticles (GAP NPs) were synthesized as a novel carrier of curcumin (CUR) with a degree of substitution (DS) of GA moieties within the range of 1.2–6.2 groups per hundred glucose units. In the present study, we investigated the physicochemical characteristics, release behavior, in vitro cytotoxicity and cellular uptake of the particles. Self-assembled GAP NPs with spherical shapes could readily improve the water solubility and stability of CUR. The CUR release was sustained and pH-dependent. The cellular uptake of CUR-GAP NPs was confirmed by green fluorescence in the cells. An MTT study showed CUR-GAP NPs with higher cytotoxicity in HepG2 cells than free CUR, but GAP NPs had no significant cytotoxicity. GAP is thus an excellent carrier for the solubilization, stabilization, and controlled delivery of CUR.

Microsomal epoxide hydrolase (mEH) is a bifunctional protein that plays a central role in the metabolism of numerous xenobiotics as well as mediating the sodium-dependent transport of bile acids into hepatocytes. These compounds are involved in cholesterol homeostasis, lipid digestion, excretion of xenobiotics and the regulation of several nuclear receptors and signaling transduction pathways. Previous studies have demonstrated the critical role of GATA-4, a C/EBPα-NF/Y complex and an HNF-4α/CAR/RXR/PSF complex in the transcriptional regulation of the mEH gene (EPHX1). Studies also identified heterozygous mutations in human EPHX1 that resulted in a 95% decrease in mEH expression levels which was associated with a decrease in bile acid transport and severe hypercholanemia. In the present investigation we demonstrate that EPHX1 transcription is significantly inhibited by two heterozygous mutations observed in the Old Order Amish population that present numerous hypercholanemic subjects in the absence of liver damage suggesting a defect in bile acid transport into the hepatocyte. The identity of the regulatory proteins binding to these sites, established using biotinylated oligonucleotides in conjunction with mass spectrometry was shown to be poly(ADP-ribose)polymerase-1 (PARP-1) bound to the EPHX1 proximal promoter and a linker histone complex, H1.2/Aly, bound to a regulatory intron 1 site. These sites exhibited 71% homology and may represent potential nucleosome positioning domains. The high frequency of the H1.2 site polymorphism in the Amish population results in a potential genetic predisposition to hypercholanemia and in conjunction with our previous studies, further supports the critical role of mEH in mediating bile acid transport into hepatocytes.

Ipomoea stolonifera (I. stolonifera) has been used for the treatment of inflammatory diseases including rheumatism and rheumatoid arthritis in Chinese traditional medicine. However, the anti-inflammatory activity of I. stolonifera has not been elucidated. For this reason, the anti-inflammatory activity of n-butanol extract of I. stolonifera (BE-IS) was evaluated in vivo by using acute models (croton oil-induced mouse ear edema, carrageenan-induced rat paw edema, and carrageenan-induced rat pleurisy) and chronic models (cotton pellet-induced rat granuloma, and complete Freund's adjuvant (CFA)-induced rat arthritis). Results indicated that oral administration of BE-IS significantly attenuated croton oil-induced ear edema, decreased carrageenan-induced paw edema, reduced carrageenan-induced exudates and cellular migration, inhibited cotton pellet-induced granuloma formation and improved CFA-induced arthritis. Preliminary mechanism studies demonstrated that BE-IS decreased the levels of myeloperoxidase (MPO) and malondialdehyde (MDA), increased the activity of anti-oxidant enzyme superoxide dismutase (SOD) in vivo, and reduced the production of nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6 in lipopolysaccharide-activated RAW264.7 macrophages in vitro. Results obtained in vivo and in vitro demonstrate that BE-IS has considerable anti-inflammatory potential, which provided experimental evidences for the traditional application of Ipomoea stolonifera in inflammatory diseases.

The present study was designated to evaluate the antioxidant, antibacterial and antischistosomal activities of Grateloupia livida (GL) extracts in vitro. A GL Ethanol extract (EE) was separated into petroleum ether (PE), ethyl acetate (EA), n-butyl alcohol (BuOH) and aqueous (AQ) fractions to fractionate the polar and non-polar compounds in the EE. Extracts antioxidant activities were evaluated in vitro by DPPH radical-scavenging, deoxyribose radical scavenging, and β-carotene bleaching assays, all using butylated hydroxytoluene (BHT) as the reference antioxidant compound. The most effective antioxidant properties were observed in the PE fraction in all three assays. Antimicrobial testing showed that the PE fraction exhibited broad-spectrum antimicrobial activity, with the PE fraction also exhibiting strong activity against the human pathogenic trematode S. japonicum adult worm. In order to investigate the relationships between bioactivity and chemical composition, the chemical composition of the PE fraction was analyzed by gas chromatography-mass spectrometry (GC-MS). In total, 25 components were identified in the PE fraction, most of which have known antioxidant and antimicrobial activities. However, none of the compounds have reported activity against Schistosoma, suggesting that the schistosomicidal activity of the PE fraction may be related to minor constituents present in the extract, or governed by more intricate synergistic or additive relationships. Finally, fractions with the greatest biological activity displayed neither cellular cytotoxicity, at concentrations up to 100 ug/ml, or acute oral toxicity in mice, at doses up to 2000 mg/kg. Based on antioxidant, antimicrobial, antischistosomal activities, and low toxicity, the PE fraction possesses properties useful for food preservation and overall improvement of human health.

Introduction: The existing findings about the association between polyunsaturated fatty acid (PUFA) status (especially long-chain n-3 PUFAs) and the risk of preclinical or clinical type 1 diabetes (T1D) in children are controversial. This review aimed to evaluate the definite association. Material and methods: Three databases were systematically viewed until July, 2019 to identify relevant articles, without language restriction. Any observational study or randomized controlled trial reporting the risk estimates of preclinical or clinical T1D for PUFA status in infants and children was enrolled. Regardless of the statistical heterogeneity assessed by the I² statistic, we pooled the odds ratios (ORs), relative risks (RRs) or hazard ratios (HRs) with 95% confidence intervals (CI) through random-effects models. Results: Five observational studies were enrolled in the meta-analysis. The status of n-3 PUFAs was negatively and significantly associated with the risk of preclinical, but not clinical, T1D (pooled RR = 0.85; 95% CI: 0.73-0.99) with substantial heterogeneity (I² = 72.2%). However, no such association was found between n-6 PUFA status and the risk of preclinical or clinical T1D. Conclusions: The meta-analysis suggests that n-3 PUFA might play a potential protective role in the cause of preclinical T1D, and n-3 PUFA intake may be beneficial, since the n-3 PUFA status was associated with a significant decrease in the risk of preclinical T1D in children. Nevertheless, more well-designed prospective studies are necessary to determine whether dietary or supplemental intake of specific n-3 PUFA alters the risk of preclinical T1D. [ABSTRACT FROM AUTHOR]

Objectives: To identify disease activity scores and biomarkers that reflect magnetic resonance imaging (MRI)-determined sacroiliac joint (SIJ) inflammation in ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA). Methods: Patients who had AS and nr-axSpA were enrolled. All the patients underwent SIJ MRI. SpondyloArthritis Research Consortium of Canada (SPARCC) method was used to score bone marrow edema in the inflammatory lesions on MRI. Radiographic assessment of the spine was performed using modified Stoke Ankylosing Spondylitis Spine Score. Clinical variables, inflammatory markers, serum alkaline phosphatase, osteocalcin (OC), C-terminal telopeptide of type I collagen (CTX-I), and procollagen I N-terminal peptide (PINP) were measured. Correlation analysis between MRI-determined SIJ inflammation scores and disease activity scores and laboratory variables was performed. Results: Thirty-five patients had AS and 36had nr-axSpA. Significant differences were noted between the AS group and the nr-axSpA group in terms of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Ankylosing Spondylitis Disease Activity Score (ASDAS)-ESR, ASDASCRP, PINP, and SPARCC (p < .001, p = .004, p < .001, p < .001, p = .030, p < .001, respectively). MRI-determined SIJ inflammatory scores correlated with Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), OC, CTX-I, and PINP in AS (p = .036, p = .023, p = .002, p = .041, p = .004, respectively) and correlated with ESR, CRP, ASDAS-ESR, ASDAS-CRP, BASDAI, and BASFI in nr-axSpA (p = .003, p = .002, p < .001, p < .001, p = .010, p = .007, respectively). Multivariate analysis showed that PINP exhibited a positive correlation independent of the MRI inflammatory score and that age exhibited a negative correlation independent of the MRI inflammatory score. Conclusions: In AS, PINP and age independently correlated with active inflammation on SIJ MRI. PINP may be useful as a marker of objective inflammation in AS. [ABSTRACT FROM AUTHOR]

Endothelium dysfunction induced by reactive oxygen species (ROS) is an important initial event at the onset of myocardial ischemia/reperfusion in which the Egr-1 transcription factor often serves as a master switch for various damage pathways following reperfusion injury. We hypothesized that an intracellular ROS/MAPK/Egr-1 signaling pathway is activated in cardiac microvascular endothelial cells (CMECs) following hypoxia/reoxygenation (H/R). ROS generation, by either H/R or the ROS donor xanthine oxidase-hypoxanthine (XO/HX) activated all three MAPKs (ERK1/2, JNK, p38), and induced Egr-1 expression and Egr-1 DNA-binding activity in CMECs, whereas ROS scavengers (EDA and NAC) had the opposite effect following H/R. Inhibitors of all three MAPKs individually inhibited induction of Egr-1 expression by H/R in CMECs. Moreover, N-n-butyl haloperidol (F2), previously shown to protect cardiomyocytes subjected to I/R, dose-dependently downregulated H/R-induced ROS generation, MAPK activation, and Egr-1 expression and activity in CMECs, whereas XO/HX and MAPK activators (EGF, anisomycin) antagonized the effects of F2. Inhibition of the ROS/MAPK/Egr-1 signaling pathway, by either F2, NAC, or inhibition of MAPK, increased CMEC viability and the GSH/GSSG ratio, and decreased Egr-1 nuclear translocation. These results show that the ROS/MAPK/Egr-1 signaling pathway mediates H/R injury in CMECs, and F2 blocks this pathway to protect against H/R injury and further alleviate myocardial I/R injury. [ABSTRACT FROM AUTHOR]

Proinflammatory M1 activation of hepatic macrophages (HM) is critical in pathogenesis of hepatitis, but its mechanisms are still elusive. Our earlier work demonstrates the role of ferrous iron (Fe2+) as a pathogen-associated molecular patternindependent agonist for activation of IκB kinase (IKK) and NF-κB in HM via activation and interaction of p21ras, transforming growth factor β-activated kinase-1 (TAK1), and phosphatidylinositol 3-kinase (PI3K) in caveosomes. However, ironinduced signaling upstream of these kinases is not known. Here we show that Fe2+ induces generation of superoxide anion (O…2) in endosomes, reduces protein-tyrosine phosphatase (PTP) activity, and activates Src at 2∼10 min of Fe2+ addition to rat primary HM culture. Superoxide dismutase (SOD) blocks O…2 generation, PTP inhibition, and Src activation. Fe2+-induced p21ras activity is abrogated with the Src inhibitor PP2 and SOD. Fe2+ stimulates Lys63-linked polyubiquitination (polyUb) of TRAF6in caveosomes, and a dominant negative K63R mutant of ubiquitin or SOD prevents iron-induced TRAF6 polyUb and TAK1 activation. These results demonstrate that Fe2+-generatedO…2 mediates p21ras and TAK1 activation via PTP inhibition and Lys63-polyUb ofTRAF6in caveosomes for proinflammatory M1 activation in HM. [ABSTRACT FROM AUTHOR]

Chronic alcohol consumption is associated with steatohepatitis and cirrhosis, enhancing the risk for hepatocellular carcinoma. RNA polymerase (pol) III transcribes a variety of small, untranslated RNAs, including tRNAs and 5S rRNAs, which determine the biosynthetic capacity of cells. Increased RNA pol III-dependent transcription, observed in transformed cells and human tumors, is required for oncogenic transformation. Given that alcohol consumption increases risk for liver cancer, we examined whether alcohol regulates this class of genes. Ethanol induces RNA pol III-dependent transcription in both HepG2 cells and primary mouse hepatocytes in a manner that requires ethanol metabolism and the activation of JNK1. This regulatory event is mediated, at least in part, through the ability of ethanol to induce expression of the TFIIIB components, Brf1, and the TATA-binding protein (TBP). Induction of TBP, Brf1, and RNA pol III-dependent gene expression is driven by enhanced c-Jun expression. Ethanol promotes a marked increase in the direct recruitment of c-Jun to TBP, Brf1, and tRNA gene promoters. Chronic alcohol administration in mice leads to enhanced expression of TBP, Brf1, tRNA, and 5S rRNA gene transcription in the liver. These alcohol-dependent increases are more pronounced in transgenic animals that express the HCV NS5A protein that display increased incidence of liver tumors. Together, these results identify a new class of genes that are regulated by alcohol through the co-regulation of TFIIIB components and define a central role for c-Jun in this process. [ABSTRACT FROM AUTHOR]

RNA polymerase (pol) III-dependent transcription is subject to stringent regulation by tumor suppressors and oncogenic proteins and enhanced RNA pol III transcription is essential for cellular transformation and tumorigenesis. Since the c-Jun N-terminal kinases (JNKs) display both oncogenic and tumor suppressor properties, the roles of these proteins in regulating RNA pol III transcription were examined. In both mouse and human cells, loss or reduction in JNK1 expression represses RNA pol III transcription. In contrast, loss or reduction in JNK2 expression induces transcription. The JNKs coordinately regulate expression of all 3 TFIIIB subunits. While JNK1 positively regulates TBP expression, the RNA pol III-specific factors, Brf1 and Bdp1, JNK2 negatively regulates their expression. Brf1 is coregulated with TBP through the JNK target. Elk-1. Reducing Elk-1 expression decreases Brf1 expression. Decreasing JNK1 expression reduces Elk-1 occupancy at the Brf1 promoter, while decreasing JNK2 expression enhances recruitment of Elk-1 to the Brf1 promoter. In contrast, regulation of Bdp1 occurs through JNK-mediated alterations in TBP expression. Altered TBP expression mimics the effect of reduced JNK1 or JNK2 levels on Bdp1 expression. Decreasing JNK1 expression reduces the occupancy of TBP at the Bdp1 promoter, while decreasing JNK2 expression enhances recruitment of TBP to the Bdp1 promoter. Together, these results provide a molecular mechanism for regulating RNA pol III transcription through the coordinate control of TFIIIB subunit expression and elucidate opposing functions for the JNKs in regulating a large class of genes that dictate the biosynthetic capacity of cells. [ABSTRACT FROM AUTHOR]

Background: PNRC transcriptionally regulates a wide range of RNA polymerase (pol) IItranscribed genes by functioning as a nuclear receptor coactivator. To search for additional PNRCinteracting proteins other than nuclear receptors, a PNRC fragment was used as bait in a yeast twohybrid screening of a human mammary gland cDNA expression library. Results: RNA pol III/RPC39 fragments were repeatedly identified as PNRC-interacting partners in two independent screenings. The interaction between these RPC39 fragments and PNRC was further confirmed in the independent yeast two-hybrid assays. The association of endogenous PNRC and RPC39 in MCF7 cells was demonstrated by co-immunoprecipitation. Furthermore, ChIP analysis detected co-recruitment of PNRC and RPC39 to tRNA and U6 RNA promoters. The biological consequence of the interaction between PNRC and RPC39 was further studied. Overexpression of PNRC, either by transient or stable transfection, increased RNA pol IIIdependent transcription in MCF7 cells, while a decrease in transcription in MCF7 cells treated with PNRC/siRNA was observed. Conclusion: Here, we demonstrate that human PNRC stimulates RNA pol III transcription through its interaction with the subunit RPC39 of RNA pol III. PNRC is a unique coactivator that has profound effects on many aspects of cellular function by directly influencing both RNA pol II- and RNA pol III-dependent transcription. [ABSTRACT FROM AUTHOR]

TATA binding protein (TBP) is a central transcription factor used by all three cellular RNA polymerases. Changes in the levels of TBP have been shown to have selective effects on gene activity. Overexpression of TBP has been recently shown to contribute to cellular transformation, and elevated levels of TBP occur in a clinically significant proportion of human colon tumors relative to matched normal tissue. To understand the mechanisms by which TBP is regulated, we have analyzed whether activation of the epidermal growth factor receptor (EGFR), a membrane-bound tyrosine receptor kinase that is activated in a large number of human cancers, can serve to regulate cellular TBP. We show that treatment of mouse epidermal cells with EGF produces an increase in TBP levels, which can be blocked with an EGFR-specific inhibitor. In contrast, TBP levels remain unchanged after EGF treatment of EGFR null cells. EGF-mediated increases in TBP are regulated at the transcriptional level, as transient expression of the human TBP promoter is induced with EGF. This regulatory event is dependent upon the downstream activation of Ras and requires the activation of p38, JNK, and ERK mitogen-activated protein kinases. The consequence of elevated TBP on gene expression was further determined. Transcription by RNA polymerase (Pol) I and III was induced by EGF. Directly overexpressing TBP also stimulated transcription from these promoters. Thus, we have identified a new and important target of EGFR signaling, TBP, that contributes to EGF-mediated stimulation of RNA Pol I- and III-dependent gene activity. Since the cellular levels of the products of these genes, tRNAs and rRNAs, determine the translational capacity of cells, this event may be an important contributor to the transforming function of EGF. [ABSTRACT FROM AUTHOR]

An abstract of the article " PTEN Represses RNA Polymerase III-Dependent Transcription by Targeting the TFIIIB Complex," by Annette Woiwede and colleagues is presented.

Emerging evidence supports the idea that the c-Jun N-terminal kinases (JNKs) possess overlapping but distinct functions. The potential roles of the ubiquitously expressed JNK1 and JNK2 in regulating expression of the central transcription initiation factor, TATA-binding protein (TBP), were examined. Relative to wild-type fibroblasts, TBP was decreased in Jnk1-/- cells and increased in Jnk2-/- cells. Similarly, reduction of JNK1 in human hepatoma cells decreased TBP expression, whereas reduction of JNK2 enhanced it. JNK-mediated regulation of TBP expression occurs at the transcriptional level through their ability to target Elk-1, which directly regulates the TBP promoter in response to epidermal growth factor stimulation. JNK1 increases, whereas JNK2 decreases, the phosphorylation state of Elk-1, which differentially affects Elk-1 occupancy at a defined site within the TBP promoter. These JNK-mediated alterations in TBP expression, alone, serve to regulate c-Jun expression and fibroblast proliferation rates. These studies uncovered several new molecular events that distinguish the functions of JNK1 and JNK2 that are critical for their regulation of cellular proliferation. [ABSTRACT FROM AUTHOR]