Acid-sensitive ROS-triggered dextran-based drug delivery system for advanced chemo-photodynamic synergistic therapy.

In order to improve the treatment efficacy and reduce the side effects, the synergistic therapy has been effectively exploited in cancer treatment. Herein, we fabricated a kind of acid-sensitive ROS-triggered dextran-based drug delivery system (DHTD/Zn-TPP) for synergistic therapy, in which chemotherapeutics doxorubicin was conjugated to the dextran backbone via ROS cleavable thioketal conjugates while photosensitizer porphyrin (Zn-TPP) was encapsulated via acid-responsive metallic coordinated interaction. The structure and acid-responsive self-assemble behavior of DHTD/Zn-TPP were measured by 1 H NMR, Fourier transform infrared, dynamic laser scattering, and transmission electron microscopy. Further, the in vivo ROS-triggered DOX release and anticancer efficiency were evaluated toward HeLa cells and MCF-7 cells. All the data obtained verified that DHTD/Zn-TPP had a significantly improved cell growth inhibitory effect with light irritation due to the combined application of photodynamic-chemotherapy.

Analysis of postpartum reversible cerebral vasoconstriction syndrome in China: A case report and literature review.

Reversible cerebral vasoconstriction syndrome (RCVS) is a rare clinical syndrome accompanying with severe headache as its main symptom. Postpartum reversible cerebral vasoconstriction syndrome (PPRCVS) refers to RCVS occurring in the puerperium, in which it has a low incidence, and that is easily missed diagnosed and misdiagnosed in clinical practice.By searching in CNKI and Wanfang databases, 9 published articles reported PPRCVS were found, totally including 12 cases with PPRCVS. The clinical data of these 12 cases were accordingly analyzed and summarized. The characteristics of these cases were compared with those reported in other countries, and eventually the clinical characteristics of Chinese PPRCVS patients were summarized.The clinical characteristics of Chinese PPRCVS patients were basically as same as those found in other countries, while the onset age was earlier, PPRCVS often occurred earlier after delivery, with higher proportions of concomitant symptoms and abnormal laboratory and imaging examinations; moreover, and fewer patients were diagnosed by digital subtraction angiography (DSA).

A single-nucleotide polymorphism induced alternative splicing in Tacr3 involves in hypoxic-ischemic brain damage.

Single-nucleotide polymorphism (SNP) and Alternative splicing (AS) were found to be implicated in certain diseases, nevertheless, the contributions of mRNA SNPs and AS to pathogenesis in developing rat brains with hypoxic-ischemic encephalopathy (HIE) remained largely vague. Additionally, the disease associated with Tacr3 was normosmic congenital hypogonadotropic hypogonadism, while the relationship between HIE and Tacr3 remained largely elusive. The current study was designed to investigate the differentially expressed mRNAs and related SNPs as well as AS in neonatal rats subjected to HIE to identify if the exhibition of AS was associated with SNPs under pathological condition. Firstly, we used postnatal day 7 Sprague-Dawley rats to construct neonatal HIE model, and analyzed the expression profiles of SNP mRNA in hypoxic-ischemic (HI) and sham brains by using RNA sequencing. Then four genes, including Mdfic, Lpp, Bag3 and Tacr3, connecting with HIE and exhibiting SNPs and AS were identified by bioinformatics analysis. Moreover, combined with exonic splicing enhancer (ESE) and alternative splice site predictor (ASSP) analysis, we found that Tacr3 is associated specifically with HIE through 258547789 G > A SNP in inside the Alt First Exon and 258548573 G > A SNP in outside the Alt First Exon. Taken together, our study provides new evidence to understand the role of Tacr3 in HIE and it is possibly a potential target for the treatment of HIE in future clinic trial.

In Situ Growth of NiO@SnO2 Hierarchical Nanostructures for High Performance H2S Sensing.

Heterostructured metal oxides with large specific surface area are crucial for constructing gas sensors with high performance. However, using slurry-coating and screen-printing methods to fabricate gas sensors cannot result in high uniformity and reproducibility of the sensors. Here, NiO nanowalls decorated by SnO2 nanoneedles (NiO@SnO2) were in situ grown on ceramic microchips via a chemical bath deposition method to detect H2S instead of print-coating and slurry-coating methods. The morphologies and compositions of the NiO@SnO2 hierarchical nanostructures (HNSs) were well tuned by varying the growth time of the NiO@SnO2 HNSs to optimize the sensing performance. The response of the NiO@SnO2 HNSs (2 h) to 1 ppm of H2S was over 23-fold higher than that of the pure NiO nanowalls and 17-fold higher than that of the pure SnO2 nanosheets. This dramatic enhancement is attributed to the large surface area of the NiO@SnO2 HNSs and the p-n heterojunction at the heterointerface of SnO2 and NiO. The variation in the depletion layers (WSnO2 and WNiO) at the heterointerface of SnO2 and NiO greatly depends on the properties of the target gases (e.g., electron-withdrawing property (NO2) or electron-donating property (H2S)).

Metformin Is Associated With Reduced Odds for Colorectal Cancer Among Persons With Diabetes.

INTRODUCTION: Metformin may be associated with reduced colorectal cancer (CRC) risk, but findings from previous studies have been inconsistent and had insufficient sample sizes to examine whether the association differs by anatomic site. This study examined whether metformin was associated with reduced CRC risk, both overall and stratified by anatomic site, in a large sample of persons with diabetes who underwent colonoscopy. METHODS: We performed a case-control study of US Veterans with prevalent diabetes who underwent colonoscopy between 1999 and 2014 using Department of Veterans Affairs electronic health record data. Cases were defined by presence of CRC at colonoscopy, while controls had normal colonoscopy. The primary exposure was metformin use at time of colonoscopy (yes/no). Association of metformin exposure with CRC (further stratified by proximal, distal, or rectal subsite) was examined using multivariable and multinomial logistic regression and summarized by odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: We included 6,650 CRC patients and 454,507 normal colonoscopy patients. CRC cases were older and had lower metformin exposure. Metformin was associated with 8% relative reduction in CRC odds (OR: 0.92, 95% CI: 0.87-0.96). By subsite, metformin was associated with a 14% statistically significant reduced rectal cancer odds (OR: 0.86, 95% CI: 0.78-0.94) but no reduced distal or proximal cancer odds. DISCUSSION: Metformin was associated with reduced CRC odds-particularly rectal cancer-in a large sample of persons with diabetes undergoing colonoscopy.

VEGF-transfected BMSC Improve the Recovery of Motor and Sensory Functions of Rats With Spinal Cord Injury.

STUDY DESIGN: Basic science. OBJECTIVE: The aim of this study was to examine the effect of vascular endothelial growth factor (VEGF)-transfected bone marrow mesenchymal stem cells (BMSCs) on the recovery of motor and sensory functions of rats with spinal cord injury (SCI). SUMMARY OF BACKGROUND DATA: There is no effective treatment to protect against SCI. BMSCs have been widely applied to the treatment of nervous system damage due to the function of prompt neurite growth and inhibition of demyelination following injury. METHODS: VEGF-transfected BMSCs were injected to rats with SCI and the recovery of motor and sensory functions was observed. The Basso, Beattie, and Bresnahan, mechanical withdrawal threshold and thermal withdraw latency grading was conducted to assess the recovery status of motor and sensory functions of the SCI rats. The expression of VEGF, CD31, and NF200 was detected by immunofluorescence. RESULTS: The recovery of the rat motor and sensory functions in the VEGF-transfected BMSC (BMSC-VEGF) group was higher than those of the other groups with the exception of the Sham group (P < 0.05). The expression of the CD31 and NF200 proteins in the rat SCI regions was the highest in the BMSC-VEGF group, whereas the survival of BMSC in the BMSC-VEGF group was increased compared with that in the BMSC-Ad group. In addition, the injection of VEGF-transfected BMSCs can improve the angiogenesis of the injured area and retain the survival of injected cells and neurons. CONCLUSION: The injection of BMSC-VEGF improved the recovery of motor function in SCI rats. LEVEL OF EVIDENCE: N/A.

Association of circulating selenium concentration with dyslipidemia: Results from the NHANES.

BACKGROUND: Observational studies have suggested that selenium levels might associate with the risk of cardio-metabolic diseases, but how circulating selenium is related to dyslipidemia remains inconclusive. OBJECTIVES: To investigate the association of circulating selenium levels with lipid profiles and dyslipidemia among US adults. METHODS: Using the data collected from the National Health and Nutrition Examination Survey (NHANES 1999-2006), we performed multivariate logistic regression to examine the association of circulating selenium levels (in quartiles) with total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-HDL-C, and atherogenic index (AI). RESULTS: We included 2903 adults (49.3 % male) (average age: 61.9) for analysis. Circulating selenium had non-linear association with TC, LDL-C, HDL-C, and AI (all p < 0.05). When comparing with the lowest quartile, subjects with the highest quartile of circulating selenium (>147.00 µg/L) had the higher odds of elevated TG (OR: 1.75, 95% CI = 1.14, 2.68), TC (OR: 2.47, 95% CI = 1.62, 3.76), LDL-C (OR: 2.52, 95% CI = 1.60, 3.96), non-HDL-C (OR: 2.17, 95% CI = 1.41, 3.33), AI (OR: 1.20, 95% CI = 0.73, 1.97) and low-HDL-C (OR: 2.10, 95% CI = 1.19, 3.72). Similar patterns were observed in subgroup analysis. CONCLUSIONS: Higher circulating selenium levels had non-linear association with lipid profiles and the increased odds of dyslipidemia.

Salt-free fractionation of complex isomeric mixtures of glycosaminoglycan oligosaccharides compatible with ESI-MS and microarray analysis.

Heparin and heparan sulfate (Hp/HS) are linear complex glycosaminoglycans which are involved in diverse biological processes. The structural complexity brings difficulties in separation, making the study of structure-function relationships challenging. Here we present a separation method for Hp/HS oligosaccharide fractionation with cross-compatible solvent and conditions, combining size exclusion chromatography (SEC), ion-pair reversed phase chromatography (IPRP), and hydrophilic interaction chromatography (HILIC) as three orthogonal separation methods that do not require desalting or extensive sample handling. With this method, the final eluent is suitable for structure-function relationship studies, including tandem mass spectrometry and microarray printing. Our data indicate that high resolution is achieved on both IPRP and HILIC for Hp/HS isomers. In addition, the fractions co-eluted in IPRP could be further separated by HILIC, with both separation dimensions capable of resolving some isomeric oligosaccharides. We demonstrate this method using both unpurified reaction products from isomeric synthetic hexasaccharides and an octasaccharide fraction from enoxaparin, identifying isomers resolved by this multi-dimensional separation method. We demonstrate both structural analysis by MS, as well as functional analysis by microarray printing and screening using a prototypical Hp/HS binding protein: basic-fibroblast growth factor (FGF2). Collectively, this method provides a strategy for efficient Hp/HS structure-function characterization.

A Review on Flavonoid Apigenin: Dietary Intake, ADME, Antimicrobial Effects, and Interactions with Human Gut Microbiota.

Apigenin is a flavonoid of low toxicity and multiple beneficial bioactivities. Published reviews all focused on the findings using eukaryotic cells, animal models, or epidemiological studies covering the pharmacokinetics, cancer chemoprevention, and drug interactions of apigenin; however, no review is available on the antimicrobial effects of apigenin. Research proves that dietary apigenin passes through the upper gastrointestinal tract and reaches the colon after consumption. For that reason, it is worthwhile to study the potential interactions between apigenin and human gut microbiota. This review summarizes studies on antimicrobial effects of apigenin as well as what has been reported on apigenin and human gut microbiota. Various levels of effectiveness have been reported on apigenin's antibacterial, antifungal, and antiparasitic capability. It has been shown that apigenin or its glycosides are degraded into smaller metabolites by certain gut bacteria which can regulate the human body after absorption. How apigenin contributes to the structural and functional changes in human gut microbiota as well as the bioactivities of apigenin bacterial metabolites are worth further investigation.

Correction: SNV discovery and functional candidate gene identification for milk composition based on whole genome resequencing of Holstein bulls with extremely high and low breeding values.

[This corrects the article DOI: 10.1371/journal.pone.0220629.].

The influence of l-carnitine on the expression of miRNAs in asthenospermia spermatozoa and the network regulation of the associated molecules.

l-carnitine is a natural compound that is indispensable for energy metabolism in mammals. The efficiency and safety of l-carnitine in improving sperm activity, enhancing epididymal function and treating male infertility has been widely acknowledged by clinicians. CircRNAs can regulate gene expression at the transcriptional or post-transcriptional level by serving as a molecular sponge of miRNAs with miRNA response elements. However, the detailed mechanism linking miRNA, circRNA and asthenospermia remains unclear. The present study demonstrated that hsa-miR-27b-3p, hsa-miR-151a-5p and hsa-miR-206 play an important role in the effects of l-carnitine treatment of the spermatozoa in asthenospermia patients. Furthermore, the target mRNAs of hsa-miR-206 were analysed by GO and KEGG. The results show that the target mRNAs of hsa-miR-206 may change the activity of ATP synthase and participate in the cAMP signalling pathway and the calcium signalling pathway, which may play an important role in sperm motility.

Preliminary Studies of 177Lu-Diethylenetriamine Penta-Acetic Acid-Deoxyglucose in Hepatic Tumor-Bearing Mice.

Objective: The purpose of this study was to explore the potential use of 177Lu-diethylenetriamine penta-acetic acid-deoxyglucose (177Lu-DTPA-DG) as a radiopharmaceutical for hepatic tumor treatment. Methods: Lutetium-177 (177Lu) was labeled with DTPA-DG by adding 2 mCi 177LuCl3 to 0.05 mg DTPA-DG (pH 5-6) at room temperature for 1 h. The quality of the177Lu-DTPA-DG solutions was determined by thin-layer chromatography and high-performance liquid chromatography. Cellular uptake studies with 18F-fluorodeoxyglucose (FDG), 177Lu-DTPA-DG and 177Lu-DTPA and a blocking study with 1.0 mg d-glucose were performed. Biodistribution, imaging, and radiotherapy studies of 177Lu-DTPA-DG were performed with the SMMC-7721 model. Results: 177Lu-DTPA-DG had a high radiochemical purity (>97%). The cellular uptake of 177Lu-DTPA-DG was much higher than that of the 177Lu-DTPA. The biodistribution of 177Lu-DTPA-DG demonstrated that the complex accumulated in the tumor with high tumor/blood and tumor/muscle ratios. The tumors in mice in the 177Lu-DTPA-DG group clearly displayed the high uptake of 177Lu-DTPA-DG. After radiotherapy with 177Lu-DTPA-DG, tumor growth decreased, and the overall survival was longer than that in the 177LuCl3 group (268.58 ± 17.96 mm3 vs. 507.43 ± 55.72 mm3, p = 0.002) and the normal saline group (268.58 ± 17.96 mm3 vs. 483.68 ± 27.51 mm3, p < 0.05). Conclusions: This preliminary study suggests that 177Lu-DTPA-DG has the potential to become a liver radiopharmaceutical agent and should be further investigated.

Differential expression of ghrelin and GHSR via the mTOR pathway during the dynamic carcinogenic process involving oral, potentially malignant disorders.

The purpose was to explore the sequence changes in ghrelin and GHSR in the mTOR signaling pathway during carcinogenesis involving oral, potentially malignant disorders (OPMD). The samples were confirmed through in vivo pathologic tissue screening and diagnosis. The immunohistochemical method was used to detect the expression of the ghrelin/growth hormone secretagogue receptor (GHSR) protein. The expression of ghrelin, GHSR 1ɑ, GHSR 1ß, and mammalian target of rapamycin (mTOR) RNA were detected by real-time PCR. The expression of ghrelin, GHSR, mTOR, and phosphorylated mTOR (phosphor-mTOR) protein were detected by western blot. The expression of ghrelin/GHSR increased gradually in the dynamic process of OPMD carcinogenesis. There was a correlation between the increase in ghrelin, GHSR, mTOR, and phospho-mTOR. The in vivo expression of ghrelin/GHSR protein was the most apparent pathologic change from normal-to-mild, moderate, and severe dysplasia, and finally to the dynamic process from normal-to-mild-to-moderate dysplasia. The in vitro cell experiments based on QPCR results also proved that GHSR 1a functional receptor of ghrelin, had a peak expression in LEUK-1 cells. In conclusioin, the close relationship between ghrelin and OPMD carcinogenesis can be used as a new biological target to assess the carcinogenesis of OPMD.

Hierarchical extension based on Boolean matrix for LncRNA-disease association prediction.

Background: Accumulating experimental studies have demonstrated that long non-coding RNAs (LncRNAs) play crucial roles in the occurrence and development progress of various complex human diseases. Nonetheless, only a small portion of LncRNA­disease associations have been experimentally verified at present. Automatically predict LncRNA­disease associations based on computational model can save the huge cost of wet-lab experiments. Result: To develop effective computational models to integrate various heterogeneous biological data for the identification of potential disease-LncRNA, we propose a hierarchical extension based on Boolean matrix for LncRNA-disease association prediction model (HEBLDA). HEBLDA discover the intrinsic hierarchical correlation based on the property of Boolean matrix from various relational sources. Then, HEBLDA integrate these hierarchical associated matrices by fusion weights. Finally, HEBLDA uses the hierarchical associated matrix to reconstruct the LncRNA­disease association matrix by hierarchical extending. HEBLDA is able to work for potential diseases or LncRNA without known association data. In 5-fold cross validation experiments, HEBLDA obtained an area under the receiver operating characteristic curve (AUC) of 0.8913, improving previous classical methods. Beside, case studies show that HEBLDA can accurately predict candidate disease for several LncRNAs. Conclusion: Based on its ability of discovering more-richer correlated structure of various data sources, we can anticipate that HEBLDA is a potential method can obtain more comprehensive association prediction in a broad field.

Maternal diet intervention before pregnancy primes offspring lipid metabolism in liver.

Nonalcoholic fatty liver disease (NAFLD) has a developmental origin and is influenced in utero. We aimed to evaluate if maternal diet intervention before pregnancy would be beneficial to reduce the risk of offspring NAFLD. In our study, female mice were either on a normal-fat diet (NF group), or a high-fat diet for 12 weeks and continued on this diet throughout pregnancy and lactation (HF group), or switched from HF-to-NF diet 1 week (H1N group), or 9 weeks (H9N group) before pregnancy. Compared with the NF offspring, the H1N and HF, but not the H9N offspring, displayed more severe hepatic steatosis and glucose intolerance. More specifically, an abnormal blood lipid panel was seen in the H1N offspring and abnormal hepatic free fatty acid composition was present in both the HF and H1N offspring, while the H9N offspring displayed both at normal levels. These physiological changes were associated with desensitized hepatic insulin/AKT signaling, increased expression of genes and proteins for de novo lipogenesis and cholesterol synthesis, decreased expression of genes and proteins for fatty acid oxidation, increased Pcsk9 expression, and hypoactivation of 5' AMP-activated protein kinase (AMPK) signaling in the HF and H1N offspring. However, these effects were completely or partially rescued in the H9N offspring. In summary, we found that early maternal diet intervention is effective in reducing the risk of offspring NAFLD caused by maternal HF diet. These findings provide significant support to develop effective diet intervention strategies and policies for prevention of obesity and NAFLD to promote optimal health outcomes for mothers and children.

Peg-interferon and nucleos(t)ide analogue combination at inception of antiviral therapy improves both anti-HBV efficacy and long-term survival among HBV DNA positive hepatocellular carcinoma patients after hepatectomy/ablation.

Antiviral therapy has been shown to improve the prognosis of hepatitis B virus (HBV) DNA-positive hepatocellular carcinoma (HCC) after radical treatment, but antiviral treatments require further optimization. This study aimed to evaluate the efficacies of different antiviral strategies with HCC patients after hepatectomy/ablation. This prospective, randomized, controlled, and multi-center trial enrolled HBV DNA-positive primary HCC patients after hepatectomy/ablation between January 2007 and January 2009. Patients were divided into four groups: early-combination (entecavir plus Peg-interferon [IFN]α-2a co-administration during year 1); late-combination (addition of Peg-IFNα-2a for 48 weeks after 1 year of entecavir); nucleos(t)ide analogue[NA] monotherapy; and non-antiviral treatment. Primary endpoints included recurrence-free survival and overall survival. A total of 447 patients were enrolled. The 2-year and 8-year recurrence free survival and 8-year overall survival rates were significantly higher in the early-combination group than in the other two antiviral groups (P<0.05). After 48 weeks treatment, more patients achieved an HBsAg reduction >1500 IU/ml and the mean HBsAg level was significantly lower in the early-combination group compared with the late-combination and NA monotherapy groups (P<0.05). Multivariate analysis showed that early-combination therapy and a reduction in HBsAg by >1500 IU/mL after 48 weeks of therapy correlated with reduced mortality and disease recurrence. Early introduction of combination antiviral treatment may represent a more effective therapeutic strategy for patients with HBV DNA-positive HCC after hepatectomy/ablation. A reduction in HBsAg by >1500 IU/mL after 48 weeks treatment is associated with reduced mortality and disease recurrence of HBV DNA-positive HCC patients after hepatectomy/ablation.

Metabolic Analysis of Regionally Distinct Gut Microbial Communities Using an In Vitro Platform.

The colon gut microbiota is responsible for complex chemical conversions of nutrients and subsequent release of metabolites that have diverse biological consequences. However, information on the metabolic dynamics that occur longitudinally through the colon is limited. Here, gas and liquid chromatographies coupled with mass spectrometry were applied to generate metabolic profiles of the region-specific microbial communities cultured using an in vitro platform simulating the ascending (AC), transverse (TC), and descending (DC) colon regions. Comparative analysis revealed a large divergence between metabolic profiles of the AC and the TC and DC regions in terms of short-chain fatty acid production, metabolic spectrum, and conversion of bile acids. Metagenomic evaluation revealed that the regionally derived metabolic profiles had strong correlation to community composition and genetic potential. Together, the results provide key insights regarding the metabolic divergence of the regional communities that are integral to understand the structure-function relationship of the gut microbiota.

Characteristics and Health Risk Assessment of Semi-Volatile Organic Contaminants in Rural Pond Water of Hebei Province.

Pond water as surface water has certain environmental impacts on environmental media such as groundwater, lakes, atmosphere, and soil. Organic pollutants present in pond water may pose health risks to humans, but research on organic pollutants in pond water is rare. Here, taking pond water collected in rural areas of Hebei province as the sample, we analyzed and evaluated four categories of semi-volatile organic compounds (SVOCs), including 11 phenolic compounds, 7 aniline compounds, 16 parent polycyclic aromatic hydrocarbons (PAHs), 14 PAH derivatives, and 16 phthalate esters (PAEs). The results show that the 10 water samples contained 26.2-17034 ng/L of Σ phenols, 33.7-2612 ng/L of Σ anilines, 33.9-1651 ng/L of Σ PAHs, and 59.0-2800 ng/L of Σ PAEs. Furthermore, non-carcinogenic risk and carcinogenic risk caused by SVOCs through direct ingestion and dermal exposure were also assessed. The current levels of non-carcinogenic risks and carcinogenic risks through these two means of exposure are within acceptable limits, except for the site 1 and site 5 in Hebei province where a total cancer risk exceeds 10-6. It can be concluded that the pond water studied had a low risk of carcinogenicity to the human.

Long non­coding RNAs in HBV­related hepatocellular carcinoma (Review).

Hepatitis B virus (HBV)­related hepatocellular carcinoma (HCC) is a global health problem that accounts for more than half of total liver cancer cases in developing countries. Despite the growing number of researches conducted, the molecular mechanism underlying the development of HCC remains elusive. Long non­coding RNAs (lncRNAs), which are non­coding RNAs >200 nt in length that were previously considered to be transcriptional noise, have been found to be dysregulated in HBV­related HCC with the help of high­throughput omics techniques. Subsequent investigations revealed that aberrant expression of lncRNAs may affect the risk of HBV­related HCC through diverse mechanisms, including epigenetic silencing of transcriptional activation, alternative splicing, molecular sponging, modulating protein stability, and by serving as precursors of miRNAs. Although the sensitivity and specificity of lncRNAs must be further validated, a number of circulating lncRNAs have been identified as useful biomarkers for HBV­related HCC. In addition to these findings, recent studies also unveiled that certain genetic polymorphisms in lncRNAs may affect the occurrence and prognosis of HBV­related HCC. The aim of the present review was to provide an overview of the mechanisms underlying the involvement of lncRNAs in HBV­related HCC. Subsequently, lncRNAs found to be dysregulated in HBV­related HCC were focused on and current findings on circulating lncRNAs and their genetic polymorphisms were discussed.

lncRNA FENDRR Exhibits Anti-Fibrotic Activity in Pulmonary Fibrosis.

RATIONALE: Abnormal activation of lung fibroblasts contributes to the initiation and progression of idiopathic pulmonary fibrosis (IPF). OBJECTIVES: The objective of the current study was to investigate the role of FENDRR in the activation of lung fibroblasts. METHODS: Dysregulated lncRNAs in IPF lungs were identified by next generation sequencing analysis from the two online datasets. FENDRR expression in lung tissues from patients with IPF and mice with bleomycin-induced pulmonary fibrosis was determined by quantitative real-time polymerase chain reaction. Iron-responsive element-binding protein 1 (IRP1), a protein partner of FENDDR, was identified by RNA pulldown-coupled mass spectrometry analysis and confirmed by RNA immunoprecipitation. The interaction region between FENDRR and IRP1 was determined by cross-linking immunoprecipitation. The in vivo role of FENDRR in pulmonary fibrosis was studied using adenovirus-mediated gene transfer in mice. MEASUREMENTS AND MAIN RESULTS: The expression of FENDRR was down-regulated in fibrotic human and mouse lungs as well as primary lung fibroblasts isolated from bleomycin-treated mice. TGFß1-SMAD3 signaling inhibited FENDRR expression in lung fibroblasts. FENDRR was preferentially localized in the cytoplasm of adult lung fibroblasts and bound IRP1, suggesting its role in iron metabolism. FENDRR reduced pulmonary fibrosis by inhibiting fibroblast activation by reducing iron level and acting as a competing endogenous RNA of the profibrotic miR-214. Adenovirus-mediated FENDRR gene transfer in the mouse lung attenuated bleomycin-induced lung fibrosis and improved lung function. CONCLUSIONS: Our data suggest that FENDRR is an anti-fibrotic lncRNA and a potential therapeutic target for pulmonary fibrosis.