bluuebunny/crossref_metadata_2025 huggingface dataset:
Stability of reagents used for chiral amino acid analysis during spaceflight missions in high‐radiation environments
Authors: Creamer Jessica S. , Mora Maria F. , Willis Peter A.
Published: September 2018

The search for biosignatures on spaceflight missions requires in situ instrumentation capable of highly selective and sensitive organic analyses. To this end, CE–LIF is a uniquely promising technique, capable of determining the type, abundance, and chirality of amino acids present in environmental samples at nanomolar concentrations. However, this type of assay requires several reagents that have not yet been used on spaceflight missions. A key concern, particularly for future missions to Europa, is the survivability of these critical components for CE separation and LIF detection under high levels of radiation. Here we present an investigation of the chemical stability of the reagents and associated fused silica capillary after a total ionizing dose of 300 krad, exceeding the predicted total ionizing dose for the potential Europa Lander Mission payload by two‐fold. Neither the fused silica capillary nor the fluorescent dye (5‐carboxyfluorescein succinimidyl ester) showed significant change in performance following irradiation. Following the irradiation of the pre‐mixed background electrolyte, both migration time and resolution were affected. However, when the reagents (sodium tetraborate, sodium taurocholate, and γ‐cyclodextrin) and the acetonitrile solution were irradiated separately and mixed afterwards, there was no change in the separation performance.
Searching for biomarkers of chronic obstructive pulmonary disease using proteomics: The current state
Authors: Cagnone Maddalena , Salvini Roberta , Bardoni Anna , Fumagalli Marco , Iadarola Paolo , Viglio Simona
Published: September 2018

Detection of proteins which may be potential biomarkers of disorders represents a big step forward in understanding the molecular mechanisms that underlie pathological processes. In this context proteomics plays the important role of opening a path for the identification of molecular signatures that can potentially assist in early diagnosis of several clinical disturbances. Aim of this report is to provide an overview of the wide variety of proteomic strategies that have been applied to the investigation of chronic obstructive pulmonary disease (COPD), a severe disorder that causes an irreversible damage to the lungs and for which there is no cure yet. The results in this area published over the past decade show that proteomics indeed has the ability of monitoring alterations in expression profiles of proteins from fluids/tissues of patients affected by COPD and healthy controls. However, these data also suggest that proteomics, while being an attractive tool for the identification of novel pathological mediators of COPD, remains a technique mainly generated and developed in research laboratories. Great efforts dedicated to the validation of these biological signatures will result in the proof of their clinical utility.
Running‐down phenomenon captured with chronic electrocorticography
Authors: Geller Aaron S. , Friedman Daniel , Fang May , Doyle Werner K. , Devinsky Orrin , Dugan Patricia
Published: September 2018

The running‐down phenomenon refers to 2 analogous but distinct entities that may be seen after epilepsy surgery. The first is clinical, and denotes a progressive diminution in seizures after epilepsy surgery in which the epileptogenic zone could not be completely removed (Modern Problems of Psychopharmacology 1970;4:306, Brain 1996:989). The second is electrographic, and refers to a progressive deactivation of a secondary seizure focus after removal of the primary epileptogenic zone. This progressive decrease in epileptiform activity may represent a reversal of secondary epileptogenesis, where a primary epileptogenic zone is postulated to activate epileptiform discharges at a second site and may become independent.3 The electrographic running‐down phenomenon has been reported in only limited numbers of patients, using serial postoperative routine scalp electroencephalography (EEG) (Arch Neurol 1985;42:318). We present what is, to our knowledge, the most detailed demonstration of the electrographic running‐down phenomenon in humans, made possible by chronic electrocorticography (ECoG). Our patient's left temporal seizure focus overlapped with language areas, limiting the resection to a portion of the epileptogenic zone, followed by implantation of a direct brain‐responsive neurostimulator (RNS System, NeuroPace Inc.) to treat residual epileptogenic tissue. Despite the limited extent of the resection, the patient remains seizure‐free more than 2 years after surgery, with the RNS System recording ECoG without delivering stimulation. We reviewed the chronic recordings with automated spike detection and inspection of electrographic episodes marked by the neurostimulator. These recordings demonstrate progressive diminution in spiking and rhythmic discharges, consistent with an electrographic running‐down phenomenon.
A small‐sample kernel association test for correlated data with application to microbiome association studies
Authors: Zhan Xiang , Xue Lingzhou , Zheng Haotian , Plantinga Anna , Wu Michael C. , Schaid Daniel J. , Zhao Ni , Chen Jun
Published: September 2018

Recent research has highlighted the importance of the human microbiome in many human disease and health conditions. Most current microbiome association analyses focus on unrelated samples; such methods are not appropriate for analysis of data collected from more advanced study designs such as longitudinal and pedigree studies, where outcomes can be correlated. Ignoring such correlations can sometimes lead to suboptimal results or even possibly biased conclusions. Thus, new methods to handle correlated outcome data in microbiome association studies are needed. In this paper, we propose the correlated sequence kernel association test (CSKAT) to address such correlations using the linear mixed model. Specifically, random effects are used to account for the outcome correlations and a variance component test is used to examine the microbiome effect. Compared to existing genetic association tests for longitudinal and family samples, we implement a correction procedure to better calibrate the null distribution of the score test statistic to accommodate the small sample size nature of data collected from a typical microbiome study. Comprehensive simulation studies are conducted to demonstrate the validity and efficiency of our method, and we show that CSKAT achieves a higher power than existing methods while correctly controlling the Type I error rate. We also apply our method to a microbiome data set collected from a UK twin study to illustrate its potential usefulness. A free implementation of our method in R software is available at https://github.com/jchen1981/SSKAT.
Limited self‐control and longevity
Authors: Strulik Holger
Published: September 2018

This paper proposes a new framework to discuss self‐control problems in the context of life‐cycle health and longevity. Individual decisions are conceptualized as the partial control of impulsive desires of a short‐run self by a rationally forward‐looking long‐run self. The short‐run self strives for immediate gratification through consumption of health‐neutral and unhealthy goods. The long‐run self reflects the long‐term consequences of unhealthy behavior on health outcomes and longevity and invests time and money to improve current and future health. The model is calibrated with data from the United States and used to provide an assessment of the impact of imperfect self‐control on unhealthy consumption, health investments, lifetime health, and the age at death.
A hexagonal Fourier model of grid cells
Authors: Rodríguez‐Domínguez Ulises , Caplan Jeremy B.
Published: September 2018

Grid cells in rat medial entorhinal cortex are widely thought to play a major role in spatial behavior. However, the exact computational role of the population of grid cells is not known. Here we provide a descriptive model, which nonetheless considers biologically feasible mechanisms, whereby the grid cells are viewed as a two‐dimensional Fourier basis set, in hexagonal coordinates, with restricted availability of basis functions. With known properties imposed in the model parameters, we demonstrate how various empirical benchmark findings are straight‐forward to understand in this model. We also explain how complex computations, inherent in a Fourier model, are feasible in the medial entorhinal cortex with simple mechanisms. We further suggest, based on model experiments, that grid cells may support a form of lossy compression of contextual information, enabling its representation in an efficient manner. In sum, this hexagonal Fourier model suggests how the entire population of grid cells may be modeled in a principled way, incorporates biologically feasible mechanisms and provides a potentially powerful interpretation of the relationship between grid‐cell activity and contextual information beyond spatial knowledge. This enables various phenomena to be modeled with relatively simple mechanisms, and leads to novel and testable predictions.
Implementation process and quality of a primary health care system improvement initiative in a decentralized context: A retrospective appraisal using the quality implementation framework
Authors: Eboreime Ejemai Amaize , Eyles John , Nxumalo Nonhlanhla , Eboreime Oghenekome Lauretta , Ramaswamy Rohit
Published: September 2018

Background

Effective implementation processes are essential in achieving desired outcomes of health initiatives. Whereas many approaches to implementation may seem straightforward, careful advanced planning, multiple stakeholder involvements, and addressing other contextual constraints needed for quality implementation are complex. Consequently, there have been recent calls for more theory‐informed implementation science in health systems strengthening. This study applies the quality implementation framework (QIF) developed by Meyers, Durlak, and Wandersman to identify and explain observed implementation gaps in a primary health care system improvement intervention in Nigeria.

Methods

We conducted a retrospective process appraisal by analyzing contents of 39 policy document and 15 key informant interviews. Using the QIF, we assessed challenges in the implementation processes and quality of an improvement model across the tiers of Nigeria's decentralized health system.

Results

Significant process gaps were identified that may have affected subnational implementation quality. Key challenges observed include inadequate stakeholder engagements and poor fidelity to planned implementation processes. Although needs and fit assessments, organizational capacity building, and development of implementation plans at national level were relatively well carried out, these were not effective in ensuring quality and sustainability at the subnational level.

Conclusions

Implementing initiatives between levels of governance is more complex than within a tier. Adequate preintervention planning, understanding, and engaging the various interests across the governance spectrum are key to improving quality.
Review of polyphenol‐rich products as potential protective and therapeutic factors against cadmium hepatotoxicity
Authors: Mężyńska Magdalena , Brzóska Malgorzata M.
Published: September 2018

Recently, the growing attention of the scientific community has been focused on the threat to health created by environmental pollutants, including toxic metals such as cadmium (Cd), and on the need of finding effective ways to prevent and treat the unfavorable health effects of exposure to them. Particularly promising for Cd, and thus arousing the greatest interest, is the possibility of using various ingredients present in plants, including mainly polyphenolic compounds. As the liver is one of the target organs for this toxic metal and disturbances in the proper functioning of this organ have serious consequences for health, the aim of the present review was to discuss the possibility of using polyphenol‐rich food products (e.g., chokeberry, black and green tea, blueberry, olive oil, rosemary and ginger) as the strategy in protection from this xenobiotic hepatotoxicity and treatment of this heavy metal‐induced liver damage. Owing to the ability of polyphenols to bind ions of Cd and the strong antioxidative potential of these compounds, as well as their abundance in dietary products, it seems to be of high importance to consider the possibility of using polyphenols as potential preventive and therapeutic agents against Cd hepatotoxicity, determined by its strong pro‐oxidative properties. Although most of the data on the effectiveness of polyphenols comes from studies in animals, the fact that some of them are derived from experimental models that reflect human exposure to this metal allows us to assume that some polyphenol‐rich food products may be promising protective agents against Cd hepatotoxicity in humans.
Electrophoretic deposition of lawsone loaded bioactive glass (BG)/chitosan composite on polyetheretherketone (PEEK)/BG layers as antibacterial and bioactive coating
Authors: Ur Rehman Muhammad Atiq , Bastan Fatih Erdem , Nawaz Qaisar , Goldmann Wolfgang H. , Maqbool Muhammad , Virtanen Sannakaisa , Boccaccini Aldo R.
Published: September 2018

In this study, chitosan/bioactive glass (BG)/lawsone coatings were deposited by electrophoretic deposition (EPD) on polyetheretherketone (PEEK)/BG layers (previously deposited by EPD on 316‐L stainless steel) to produce bioactive and antibacterial coatings. First, the EPD of chitosan/BG/lawsone was optimized on stainless steel in terms of suspension stability, homogeneity and thickness of coatings. Subsequently, the optimized EPD parameters were used to produce bioresorbable chitosan/bioactive glass (BG)/lawsone coatings on PEEK/BG layers. The produced layered coatings were characterized in terms of composition, microstructure, corrosion resistance, in vitro bioactivity, drug release kinetics and antibacterial activity. Ultraviolet/Visible (UV/VIS) spectroscopic analyses confirmed the release of lawsone from the coatings. Moreover, the deposition of chitosan/BG coatings was confirmed by Scanning Electron Microscopy (SEM) and Fourier Transform Infrared spectroscopy (FTIR). The coated specimens presented higher corrosion resistance (10 times) in comparison to that of bare 316‐L stainless steel and showed convenient wettability for initial protein attachment. The presence of lawsone in the top layer provided antibacterial effects againstStaphylococcus carnosus.Moreover, the developed coatings formed apatite‐like crystals upon immersion in simulated body fluid, indicating the possibility of achieving close interaction between the coating surface and bone. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 3111–3122, 2018.
Acute Tissue Mineral Deposition in Response to a Phosphate Pulse in Experimental CKD
Authors: Zelt Jason GE , Svajger Bruno A , Quinn Kieran , Turner Mandy E , Laverty Kimberly J , Shum Bonnie , Holden Rachel M , Adams Michael A
Published: September 2018

Pathogenic accumulation of calcium (Ca) and phosphate (PO4) in vasculature is a sentinel of advancing cardiovascular disease in chronic kidney disease (CKD). This study sought to characterize acute distribution patterns of radiolabeled 33PO4 and 45Ca in cardiovascular tissues of rats with CKD (0.25% dietary adenine). The disposition of 33PO4 and 45Ca was assessed in blood and 36 tissues after a 10-minute intravenous infusion of one of the following: (i) PO4 pulse + tracer 33PO4; (ii) PO4 pulse + tracer 45Ca; or (iii) saline + tracer 45Ca in CKD and non-CKD animals. After the infusion, 33PO4 in blood was elevated (2.3× at 10 minutes, 3.5× at 30 minutes, p < 0.05) in CKD compared with non-CKD. In contrast, there was no difference in clearance of 45Ca from the blood. Compared with controls, CKD rats had a markedly increased 33PO4 incorporation in several tissues (skeletal muscle, 7.8×; heart, 5.5×), but accrual was most pronounced in the vasculature (24.8×). There was a significant, but smaller, increase in 45Ca accrual in the vasculature of CKD rats (1.25×), particularly in the calcified rat, in response to the acute phosphate load. Based on the pattern of tissue uptake of 33PO4 and 45Ca, this study revealed that an increase in circulating PO4 is an important stimulus for the accumulation of these minerals in vascular tissue in CKD. This response is further enhanced when vascular calcification is also present. The finding of enhanced vascular mineral deposition in response to an acute PO4 pulse provides evidence of significant tissue-specific susceptibility to calcification. © 2018 American Society for Bone and Mineral Research.
TIMP Loss Activates Metalloproteinase-TNFα-DKK1 Axis To Compromise Wnt Signaling and Bone Mass
Authors: Chen Yan , Aiken Alison , Saw Sanjay , Weiss Ashley , Fang Hui , Khokha Rama
Published: September 2018

Deregulated proteolysis invariably underlies most human diseases including bone pathologies. Metalloproteinases constitute the largest of the five protease families, and the metzincin metalloproteinases are inhibited by the four tissue inhibitors of metalloproteinase called TIMPs. We hypothesized that Timp genes are essential for skeletal homeostasis. We bred individual Timp knockout mice to generate unique mouse models, the quadruple Timp null strain (QT) as well as mice harboring only a single Timp3 allele (QT3+/–). QT mice are grossly smaller and exhibit a dramatic reduction of trabeculae in long bones by μCT imaging with a corresponding increase in metalloproteinase activity. At the cellular level, Timp deficiency compromised differentiation markers, matrix deposition and mineralization in neonatal osteoblasts from calvariae, as well as the fibroblastic colony-forming unit (CFU-F) capacity of bone marrow–derived stromal cells. In contrast, we observed that osteoclasts were overactive in the Timp null state, consistent with the noted excessive bone resorption of QT bones. Immunohistochemistry (IHC) and immunofluorescence (IF) analyses of bone sections revealed higher Cathepsin K and RANKL signals upon Timp loss. Seeking the molecular mechanism, we identified abnormal TNFα bioactivity to be a central event in Timp-deficient mice. Specifically, TNFα triggered induction of the Wnt signaling inhibitor Dkk1 in the osteoblasts at the mRNA and protein levels, with a simultaneous increase in RANKL. Neutralizing TNFα antibody was capable of rescuing the induction of Dkk1 as well as RANKL. Therefore, the generation of novel Timp-deficient systems allowed us to uncover the essential and collective function of TIMP proteins in mammalian long-bone homeostasis. Moreover, our study discovers a functional TIMP/metalloproteinase-TNFα-Dkk1/RANKL nexus for optimal control of the bone microenvironment, which dictates coexistence of the osteoblast and osteoclast lineages. © 2018 American Society for Bone and Mineral Research.
Effect of sitagliptin, a DPP‐4 inhibitor, against DENA‐induced liver cancer in rats mediated via NF‐κB activation and inflammatory cytokines
Authors: Jiang Weidong , Wen Dacheng , Cheng Zhaohua , Yang Yongsheng , Zheng Ge , Yin Fangying
Published: September 2018

The target of the current research was to investigate the anticancer activity of sitagliptin on diethylnitrosamine (DENA)‐induced cancer in the liver. Wistar rats were treated with or without sitagliptin before DENA treatment. We detected liver weight, blood glucose, and histopathology of the liver. Serum biochemical markers like serum glutamate pyruvate transaminase (SGPT), serum glutamate oxaloacetate transaminase (SGOT), serum alkaline phosphatase (SALP), gamma‐glutamyl transpeptidase (GGTP), total bilirubin (TBR), total protein (TPR), and albumin (ALB) were also evaluated. In addition, lipid profile parameters comprising total cholesterol (TC), triglycerides, and high‐density lipoprotein were also measured. Inflammatory mediators like interleukin‐6 (IL‐6), interleukin‐1beta (IL‐1β), and tumor necrosis factor‐alpha (TNF‐α) were determined in liver homogenate. Furthermore, the activity of nuclear factor (NF‐κB) was also measured. Our results showed that sitagliptin (10 and 20 mg/kg) in a dose‐dependent manner expressively decreased the DENA‐induced elevation of SGPT, SGOT, SALP, and GGTP. Whereas sitagliptin (10 and 20 mg/kg) in a dose‐dependent mode reduced the level of TBR and increased the TPR and ALB as well as improved the liver histopathology alterations in DENA‐exposed rats. Lipid profile was also restored by the sitagliptin (10 and 20 mg/kg) in a DENA‐treated rats. The level of IL‐1β, IL‐6, and TNF‐α were suggestively suppressed. Moreover, pretreatment with sitagliptin (10 and 20 mg/kg) prevented the activation of NF‐κB. In conclusion, sitagliptin (10 and 20 mg/kg) has a potential protective effect against DENA‐induced liver cancer by inhibition of inflammation and NF‐κB activation.
Retracted: microRNA‐542‐5p protects against acute lung injury in mice with severe acute pancreatitis by suppressing the mitogen‐activated protein kinase signaling pathway through the negative regulation of P21‐activated kinase 1
Authors: Wu Xing‐Mao , Ji Kai‐Qiang , Wang Hai‐Yuan , Zhao Yang , Jia Jia , Gao Xiao‐Peng , Zang Bin
Published: September 2018

Severe acute pancreatitis (SAP) is a condition associated with high rates of mortality and lengthy hospital stays. In the current study, SAP mouse models were established in BALB/c wild‐type and P21‐activated kinase 1 (PAK1) knockdown mice with the objective of determining the expression of microRNA‐542‐5p (miR‐542‐5p) and the subsequent elucidation of the mechanism by which it influences acute lung injury (ALI) by mediating mitogen‐activated protein kinase (MAPK) signaling and binding to PAK1.

The targeting relationship between miR‐542‐5p and PAK1 was verified using the bioinformatics prediction website and by the means of a dual‐luciferase reporter assay. Following the SAP model establishment, the mice were assigned into various groups with the introduction of different mimic and inhibitors in an attempt to investigate the effects involved with miR‐542‐5p on inflammatory reactions among mice with SAP‐associated ALI. Our results indicated that PAK1 was targeted and negatively mediated by miR‐542‐5p. Mice with SAP‐associated ALI exhibited an increased wet‐to‐dry weight ratio, myeloperoxidase activity, serum amylase activity, TNF‐α, interleukin‐1 beta (IL‐1β), and intercellular adhesion molecule‐1 (ICAM‐1) contents, p‐p38MAPK, p‐ERK1/2, and p‐JNK protein levels as well as PAK1 positive expression, while decreased miR‐542‐5p levels were observed. Functionally, overexpression of miR‐542‐5p improves ALI in mice with SAP via inhibition of the MAPK signaling pathway by binding to PAK1.Based on the evidence from experimental models, miR‐542‐5p was shown to improve ALI among mice with SAP, while suggesting that the effect may be related to the inactivation of the MAPK signaling pathway and downregulation of PAK1 gene. Thus, miR‐542‐5p could serve as a promising target for ALI treatment.
Nitric oxide inhibits hypoxia‐induced impairment of human RBC deformability through reducing the cross‐linking of membrane protein band 3
Authors: Zhao Yajin , Wang Xiang , Wang Ruofeng , Chen Dong , Noviana Milody , Zhu Hongliang
Published: September 2018

Aim

Nitric oxide (NO) prevents the decline of RBC deformability under high altitude and other ischemic and hypoxic conditions, but the clear mechanisms remain unknown. Here, we have carried out a systematic study to find the mechanisms of NO‐induced regulation of RBC deformability under hypoxia.

Methods

NO levels, RBCs membrane elongation index (EI), membrane protein band 3 methemoglobin (MetHb) were determined during hypoxia (0 to 120 minutes). To validate the role of NO in regulating RBC deformability, tests were also performed with a NO donor (sodium nitroprusside) or a NO synthase inhibitor (l‐nitro‐arginine methylester) under 60 minutes hypoxia.

Results

Hypoxia for 45 minutes increased NO levels from 25.65 ± 1.95 to 35.26 ± 2.01 μmol/L, and there was a plateau after 60 minutes hypoxia. The EI did not change before 45 minutes hypoxia, but decreased from 0.567 ± 0.019 to 0.409 ± 0.042 (30 Pa) after 60 minutes hypoxia. The cross‐linking of band 3 and phosphotyrosine increased after 45 minutes hypoxia. All can be alleviated by supplement NO and aggregated by inhibiting NOS. However, the MetHb was not present this trend.

Conclusion

NO may prevent decreased of RBCs deformability through reducing the cross‐linking of membrane band 3 under hypoxia; this helps microvascular perfusion of RBCs during ischemic and hypoxic disease states.
Retracted: Suppression of BMX‐ARHGAP fusion gene inhibits epithelial‐mesenchymal transition in gastric cancer cells via RhoA‐mediated blockade of JAK/STAT axis
Authors: Xu Xiao‐Feng , Wang Jian‐Jiang , Ding Li , Ye Jin‐Song , Huang Li‐Juan , Tao Lan , Gao Feng , Ji Yong
Published: September 2018

Gastric cancer (GC) is one of the main causes of cancer‐related mortality worldwide. Epithelial‐mesenchymal transition (EMT) is an important biological process involving the process by which malignant tumor cells obtain the ability of migration, invasion, resistance of apoptosis, and degradation in the extracellular matrix. The current study aimed at investigating whether bone marrow X kinase Rho GTPase activating protein 12 (BMX‐ARHGAP) fusion gene affects GC. First, short hairpin RNA (shRNA) against BMX‐ARHGAP or BMX‐ARHGAP were introduced to treat SGC‐7901 cells with the highest BMX‐ARHGAP among the five GC cell lines (SGC‐7901, MKN‐45, NCI‐N87, SNU‐5, and AGS). Next, cell vitality, drug resistance, migration, and invasion of SGC‐7901 cells, activities of Rho and JAK/STAT axis, as well as EMT and lymph node metastasis (LNM) were evaluated. The survival rate of the mice was then determined through the transfection of the specific pathogen‐free NOD‐SCID mice with treated SGC‐7901 cells. The results showed that BMX‐ARHGAP expression was associated with the infiltration degree of GC tumor and poor prognosis for patients with GC. BMX‐ARHGAP silencing was found to play an inhibitory role in the Rho and JAK/STAT axis to reduce cell vitality, drug resistance, migration and invasion, reverse EMT process, as well as inhibit LNM. BMX‐ARHGAP overexpression was observed to have induced effects on GC cells as opposed to those inhibited by BMX‐ARHGAP silencing. The survival rate of mice was increased after transfection with silenced BMX‐ARHGAP. These findings provided evidence that the suppression of BMX‐ARHGAP resulted in the inhibition of RhoA to restraint the development of GC cells by blocking the JAK/STAT axis.
Peroxisome proliferator‐activated receptor gamma coactivator‐1α/HSF1 axis effectively alleviates lipopolysaccharide‐induced acute lung injury via suppressing oxidative stress and inflammatory response
Authors: Dang Xingbo , Du Gongliang , Hu Wei , Ma Longyang , Wang Pei , Li Yi
Published: September 2018

Acute lung injury (ALI) interferes with lung function by causing pulmonary inflammation and oxidative stress. Suppressing intracellular reactive oxygen species (ROS) may block intracellular inflammation. Thus, the purpose of the current study was to investigate the roles of peroxisome proliferator‐activated receptor gamma coactivator‐1α (PGC1α)/HSF1 axis in an lipopolysaccharide (LPS)‐induced ALI murine model and in RAW264.7 macrophages. In the LPS‐administrated mouse model, the addition of PGC1α obviously ameliorated secretion of pro‐inflammatory mediators tumor necrosis factor‐α and Interleukin 6 as well as MCP‐1 expression triggered by LPS stimulation, accompanied with reduced infiltration of inflammatory cells. Meanwhile, introduction of PGC1α strongly diminished the expression of cyclooxygenase‐2 and inducible nitric oxide synthase as well as their products PGE2 and NO. In addition, administering PGC1α also dramatically alleviated LPS‐triggered oxidative stress, as reflected by a reduction of ROS production, and also reduced malondialdehyde and O
2 content, concomitant with enhancement of superoxide dismutase, catalase, and glutathione peroxidase. Similarly, PGC1α effectively ameliorated LPS‐induced inflammation response and oxidative stress, as exemplified by reduced pro‐inflammatory cytokines and ROS production in LPS‐induced RAW264.7 macrophages. Interestingly, PGC1α modulated the expression of HSF1 and the transcriptional activity of X‐linked inhibitor of apoptosis (XIAP)‐associated factor 1, whereas silencing of HSF1 abolished these effects. More importantly, deletion of HSF1 impeded the anti‐inflammatory and anti‐oxidant effects of PGC1α in LPS‐induced macrophages. Taken together, PGC1α/HSF1 axis have an anti‐oxidant and anti‐inflammatory effects, indicating that PGC1α/HSF1 may protect against LPS‐induced ALI, and thus may be a promising therapy to treat ALI.
FOXO1 associated with sensitivity to chemotherapy drugs and glial‐mesenchymal transition in glioma
Authors: Chen Chao , Han Guosheng , Li Yanan , Yue Zhijian , Wang Laixing , Liu Jianmin
Published: September 2018

Mesenchymal subtype of glioblastoma (GBM), identified as one of four clinically relevant molecular subtypes, has worst prognosis because of its close relation with the malignant biological properties induced by glial‐mesenchymal transition (GMT). However, the molecular mechanism of GMT and its characterized molecule of GBM have not been studied. Forkhead box protein O1 (FOXO1) is at a convergence point of receptor tyrosine kinase signaling as one of the three core pathways implicated in GBM. Our previous study indicated that the inactivation of FOXO1 involved in the inhibition of GMT is an independent prognosis factor of GBM. In this study, we will further confirm the role of FOXO1 in GMT through cytological experiments to clarify how FOXO1 regulates GMT and its clinical significance. We established virus‐infected FOXO1 overexpression and FOXO1 knockdown cells of U373 MG and U251 mediated by lentivirus, based on the effect of which FOXO1‐correlated‐GMT experiments were performed in vitro and in vivo. Our data suggested that FOXO1 played a crucial role in resistance to TMZ, BCNU, and CDDP; migration and invasion; and stem cell properties of glioma cells. FOXO1 may serve as a targeted biomarker for prediction of sensitivity to chemotherapy drugs, metastasis, and prognosis, which provides a new idea for mesenchymal GBM treatment.
Interleukin‐1β/nuclear factor‐κB signaling promotes osteosarcoma cell growth through the microRNA‐181b/phosphatase and tensin homolog axis
Authors: Wang Weiguo , Wang Zhengguang , Chen Shijie , Zang Xiaofang , Miao Jinglei
Published: September 2018

So far, microRNA has attracted plenty of interest due to its role in tumorigenesis. Reportedly, miR‐181b may be involved in the tumorigenesis of osteosarcoma (OS). In the current study, we attempted to investigate the detailed function and mechanism of miR‐181b in OS carcinogenesis. Herein, miR‐181a, miR‐181b, miR‐181c, and miR‐181d expressions in OS tissues were higher than that in nontumor tissue samples as examined real‐time polymerase chain reaction. Via direct targeting, miR‐181b negatively regulated the expression of phosphatase and tensin homolog (PTEN), a well‐known tumor suppressor. Furthermore, a small interfering RNA strategy was used to find that interleukin (IL)‐1B and nuclear factor‐κB (NF‐κB) regulate miR‐181b and PTEN expression. Consequently, the repression of PTEN by miR‐181b promotes OS cell proliferation. In summary, our data support a critical role for NF‐κB‐dependent upregulation of miR‐181b, which further inhibited PTEN expression and promoted the cell proliferation of OS cell lines. The above findings represent a new pathway for the repression of PTEN and the promotion of cell proliferation upon IL‐1β induction.
Let‐7g inhibits synthesis of estradiol by downregulating activity of aromatase in JEG3 cells
Authors: Guan Yong‐Hong , Lu Ying‐Li , Wang Yi‐Nan , Xue Kai
Published: September 2018

Background

Increased production of estrogen in human placenta during pregnancy closely associates with parturition. Aromatase, encoded by CYP19A1 gene, is an enzyme critical for biosynthesis of estrogen. Despite numerous efforts in the past few decades ascribed to characterizing the mechanisms of transcriptional control of aromatase, the posttranscriptional control of CYP19A1 remains poorly understood.

Objective

In this study, we sought to investigate the role of microRNA, let‐7g, in posttranscriptional regulation of aromatase in human trophoblast choriocarcinoma cell line, JEG3.

Methods and results

We show that the expression of let‐7g was downregulated in JEG3 cell line, but upregulated in primary term trophoblast; conversely, aromatase was upregulated in JEG3 but downregulated in primary trophoblast. We further show that let‐7g antagomirs and mimics increased and decreased aromatase expression, respectively; and let‐7g directly targeted 3′‐untranslated region of CYP19A1 mRNA by using dual luciferase assay. Using ELISA, we also demonstrate that let‐7g antagomirs and mimics robustly increased and decreased production of estradiol, respectively.

Discussion

Our results suggest that aromatase expression is regulated at multiple molecular layers in the placenta. These results further suggest that JEG3 cell line is a valuable tool to study additional mechanisms associated with human birth.
ROS‐challenged keratinocytes as a new model for oxidative stress‐mediated skin diseases
Authors: Barygina Victoria , Becatti Matteo , Lotti Torello , Moretti Silvia , Taddei Niccolò , Fiorillo Claudia
Published: September 2018

In the current study, the effects of the reactive oxygen species (ROS) generator 2,2′‐azobis(2‐amidinopropane) dihydrochloride (AAPH) on extracellular and intracellular ROS production in human keratinocytes (HACAT) were studied. AAPH is a water‐soluble compound able to generate ROS at known and constant rates at 37°C. The short treatment (2 h) with AAPH brought a significant dose‐dependent increase in NADPH oxidase activity in intact keratinocytes. The long‐term treatment (24 h) with AAPH led to a persistent increase in NADPH oxidase activity for up to 48 hour following the AAPH removal from cell incubation medium. ROS and nitric oxide levels, lipoperoxidation, intracellular calcium, mitochondrial superoxide production, and membrane potential were significantly modified in AAPH‐treated HACAT. Superoxide dismutase (SOD) and/or catalase addition to HACAT revealed that untreated keratinocytes produce mostly superoxide anion (O
2
−), while AAPH‐treated keratinocytes overproduce hydrogen peroxide (H
2O
2) in extracellular medium. H
2O
2 is particularly stable and plays important roles in several cell signaling pathways. Taken together, our findings suggest a cost‐effective and easily reproducible in vitro model of stressed human keratinocytes releasing significantly elevated ROS amounts in extracellular medium with respect to control keratinocytes. The possible application of the proposed model for keratinocytes‐melanocytes cross‐talk studies is also suggested. The model of AAPH‐stressed human keratinocytes described here can represent a useful tool for redox cross‐talk studies between keratinocytes and other skin cell types, and applied for researches regarding skin pathologies associated with oxidative stress.
The sphingosine 1‐phosphate receptor agonist FTY720 interfered the distribution of dendritic cell and induced the maternal‐fetal immune tolerance
Authors: Xiong Miao , Li Li , Liu Yang , Zhou Fangfang , Shi Nana , Huang Hongling , Wang Jun , Zhu Jieping
Published: September 2018

Objective

The aim of this study was to investigate the effect of FTY720, an agonist of the sphingosine 1‐phosphate (S1P) receptor, on the embryo loss rate in mice of spontaneous abortion model and the underlying mechanism.

Methods

The effect of intraperitoneal injection of FTY720 on the embryo loss rate in mice of spontaneous abortion model was observed. The expression of S1PR on the dendritic cell (DC) surface was detected by reverse transcription polymerase chain reaction. The quantity and maturation of DCs in peripheral blood and local tissues of pregnant mice, and the expression of CCL19 as well as its receptor C‐C chemokine receptor 7 (CCR7) were detected by flow cytometry and immunohistochemistry. Chemotaxis assay was performed to verify the effect of FTY720 on the chemotaxis of DCs.

Results

(1) FTY720 had no significant effect on the embryo loss rate in normal pregnant rats. In contrast, adoptive transferring of FTY720 significantly reduced the embryo loss rate of the spontaneous abortion mouse model (P < 0.05). (2) S1PR was extensively expressed on DC surface. The S1P receptor agonist FTY720 reduced the expressions of DC surface chemokines and its receptor (P < 0.05), resulting in a significant reduction in the number of DCs that were chemoattracted to maternal‐fetal interface flow cytometry (P < 0.05). (3) FTY720 had no significant effect on the differentiation and apoptosis rate of DCs (P > 0.05).

Conclusion

We hypothesized that FTY720 may reduce the number of DCs that were chemoattracted to the maternal‐fetal interface by downregulating the expression of CCR7, which ultimately induces maternal‐fetal immune tolerance.
Interaction of estrogen receptor β5 and interleukin 6 receptor in the progression of non–small cell lung cancer
Authors: Tang Hexiao , Bai Yuquan , Xiong Lecai , Zhang Li , Wei Yanhong , Zhu Minglin , Wu Xiaoling , Long Ding , Yang Junhui , Yu Li , Xu Shufang , Zhao Jinping
Published: September 2018

Numerous studies have shown that the estrogen receptor beta (ERβ) and interleukin 6 receptor (IL‐6R) had interaction in many tumors, including lung cancer. Previous studies found that ERβ5 exhibits a different biological function compared with the other subtypes of ERβ. Therefore, this study mainly explores the interaction between ERβ5 and IL‐6R in the progression of lung cancer. We found that the expression of ERβ5, IL‐6 and glycoprotein 130 (GP130) were significantly increased (P < 0.001) and the 5‐year survival rate with the co‐expression of ERβ5 and GP130 is significantly lower (P = 0.0315) in non‐small cell lung cancer (NSCLC) patients. The cell proliferation, invasion, and cell cycle were markedly increased, and the cell apoptotic was markedly inhibited with the concurrent action of ERβ5 and IL‐6 in A549 cells (P < 0.05). In addition, the expression of ERβ5, GP130, p‐AKT, and p‐44/42 MAPK was also significantly increased in A549 cells (P < 0.05). These results indicate that ERβ5 and GP130 can synergistically promote the progression of NSCLC and maybe combined as an independent prognostic factor in patients. In addition, these results also provide a theoretical basis for the combined targeting therapy of ERβ5 and GP130 in NSCLC.
High levels of methionine and methionine sulfoxide: Impact on adenine nucleotide hydrolysis and redox status in platelets and serum of young rats
Authors: Soares Mayara Sandrielly Pereira , da Silveira de Mattos Bruna , Ávila Anita Almeida , Spohr Luiza , Pedra Nathalia Stark , Teixeira Fernanda Cardoso , Bona Natália Pontes , Oliveira Pathise Souto , Stefanello Francieli Moro , Spanevello Roselia Maria
Published: September 2018

We investigated acute and chronic effects administration of methionine (Met) and/or methionine sulfoxide (MetO) on ectonucleotidases and oxidative stress in platelets and serum of young rats. Wistar rats were divided into four groups: control, Met, MetO, and Met + MetO. In acute treatment, the animals received a single subcutaneous injection of amino acid(s) and were euthanized after 1 and 3 hours. In chronic protocol, Met and/or MetO were administered twice a day with an 8‐hour interval from the 6th to the 28th day of life. Nucleoside triphosphate phosphohydrolase and 5′‐nucleotidase activities were reduced in platelets and serum by Met, MetO, and Met + MetO after 3 hours and 21 days. Adenosine deaminase activity reduced in platelets at 3 hours after MetO and Met + MetO administration and increased after 21 days in animals treated with Met + MetO. Superoxide dismutase and catalase activities decreased in platelets in MetO and Met + MetO groups after 3 hours, while reactive oxygen species (ROS) levels increased in same groups. Catalase activity in platelets decreased in all experimental groups after chronic treatment. Met, MetO, and Met + MetO administration increased plasmatic ROS levels in acute and chronic protocols; glutathione
S‐transferase activity increased by MetO and Met + MetO administration at 3 hours, and ascorbic acid decreased in all experimental groups in acute and chronic protocols. Thiobarbituric acid reactive substances increased, superoxide dismutase and catalase activities reduced in the Met and/or MetO groups at 3 hours and in chronic treatment. Our data demonstrated that Met and/or MetO induced changes in adenine nucleotide hydrolysis and redox status of platelets and serum, which can be associated with platelet dysfunction in hypermethioninemia.
Methotrexate chemotherapy–induced damages in bone marrow sinusoids: An in vivo and in vitro study
Authors: Hassanshahi Mohammadhossein , Su Yu‐Wen , Fan Chia‐Ming , Khabbazi Samira , Hassanshahi Alireza , Xian Cory J.
Published: September 2018

Chemotherapeutic agents are very well evident extrinsic stimuli for causing damage to endothelial cells. Methotrexate is an antimetabolite commonly used to treat solid tumours and paediatric cancers. However, studies on the effect(s) of methotrexate on bone marrow microvascular system are inadequate. In the current study, we observed a significant bone marrow microvascular dilation following methotrexate therapy in rats, accompanied by apoptosis induction in bone marrow sinusoidal endothelial cells, and followed by recovery of bone marrow sinusoids associated with increased proliferation of remaining bone marrow sinusoidal endothelial cells. Our in vitro studies revealed that methotrexate is cytotoxic for cultured sinusoidal endothelial cells and can also induce apoptosis which is associated with upregulation of expression ratio of Bax and
Bcl‐2 genes and
Bax/Bcl‐2 expression ratio. Furthermore, it was shown that methotrexate can negatively affect proliferation of cultured sinusoidal endothelial cells and also inhibit their abilities of migration and formation of microvessel like tubes. The data from this study indicates that methotrexate can cause significant bone marrow sinusoidal endothelium damage in vivo and induce apoptosis and inhibit proliferation, migration and tube‐forming abilities of sinusoidal endothelial cells in vitro.
Knockdown of RPL34 inhibits the proliferation and migration of glioma cells through the inactivation of JAK/STAT3 signaling pathway
Authors: Ji Peigang , Wang Liang , Liu Jinghui , Mao Ping , Li Ruichun , Jiang Haitao , Lou Miao , Xu Meng , Yu Xiao
Published: September 2018

Ribosomal protein L34 (RPL34), belonging to the L34E family of ribosomal proteins, was reported to be dysregulated in several types of cancers and plays important roles in tumor progression. However, the expression and roles of RPL34 in human glioma remain largely unknown. Thus, the objective of this study was to investigate the expression and role of RPL34 in glioma. We report here that RPL34 is highly expressed in human glioma tissues and cell lines. Knockdown of RPL34 markedly inhibited the proliferation, migration, and invasion, as well as prevented the epithelial‐mesenchymal transition phenotype in glioma cells. Further, mechanistic analysis showed that knockdown of RPL34 significantly downregulated the levels of p‐JAK and p‐STAT3 in glioma cells. Taken together, our findings indicated that knockdown of RPL34 inhibits the proliferation and migration of glioma cells through the inactivation of JAK/STAT3 signaling pathway. Thus, RPL34 may serve as a potential therapeutic target for the treatment of glioma.
Sodium selenite induces apoptosis via ROS‐mediated NF‐κB signaling and activation of the Bax–caspase‐9–caspase‐3 axis in 4T1 cells
Authors: Zhang Tao , Zhao Gan , Zhu Xinying , Jiang Kangfeng , Wu Haichong , Deng Ganzhen , Qiu Changwei
Published: September 2018

Sodium selenite (SSE), a source of inorganic selenium, has been widely used as a clinical cancer treatment, but the precise molecular mechanisms of SSE remain to be elucidated. Our in vitro experiments have confirmed that SSE treatment causes a transient increase in intracellular reactive oxygen species (ROS) levels, resulting in the inhibition of nuclear transcription factor‐κB (NF‐κB) signaling and p65 and nuclear factor of kappa light polypeptide gene enhancer in B‐cells inhibitor, alpha phosphorylation levels in 4T1 cells. The inhibition of NF‐κB subsequently increased the expression of the apoptosis gene B‐cell lymphoma‐2‐associated X (Bax) and downregulated the transcription of antiapoptosis genes, such as B‐cell lymphoma‐2, cellular inhibitor of apoptosis 1, and X‐linked inhibitor of apoptosis. Additionally, the accumulation of ROS caused mitochondrial dysfunction, leading to the activation of caspase‐9 and ‐3, thereby resulting in apoptosis. However, modulation of the ROS level by the chemical inhibitor N‐acetyl‐cysteine reversed these events. Similarly, in vitro murine syngeneic breast tumor models showed that SSE inhibits tumor growth by promoting apoptosis. These results indicate that SSE induces apoptosis via ROS‐mediated inhibition of NF‐κB signaling and activation of the Bax–caspase‐9–caspase‐3 axis.
Downregulated miR‐187 contributes to the keratinocytes hyperproliferation in psoriasis
Authors: Tang Lipeng , He Songmin , Zhu Ying , Feng Bing , Su Zuqing , Liu Bo , Xu Fangfang , Wang Xieqi , Liu Hongying , Li Chutian , Zhao Jie , Zheng Xirun , Li Caiyun , Sun Chaoyue , Lu Chuanjian , Zheng Guangjuan
Published: September 2018

Psoriasis is a common chronic skin disease characterized by epidermal hyperplasia and inflammation. However, the pathogenesis of psoriasis is multifactorial and is not fully understood. MicroRNAs (miRNAs) represent a promising class of small, noncoding RNA molecules that have a large impact on cellular functions by regulating gene expression. Here we reported that microRNA‐187 (miR‐187), which is one of the most dynamic microRNAs identified in the deep screening miRNAs profile, is downregulated in inflammatory cytokines‐stimulated keratinocytes and psoriatic skins. By luciferase activity assay and gain‐of‐function studies, we showed that miR‐187 inhibits keratinocytes hyperproliferation by targeting CD276. Moreover, overexpression of miR‐187 decreases acanthosis and reduces the disease severity in psoriasis mouse models. Taken together, the results of our study implies miR‐187 as a critical factor in psoriasis pathogenesis, which could be a potent target for psoriasis treatment.
Mitochondrial inner membrane protein, Mic60/mitofilin in mammalian organ protection
Authors: Feng Yansheng , Madungwe Ngonidzashe B. , Bopassa Jean C.
Published: September 2018

The identification of the mitochondrial contact site and cristae organizing system (MICOS) in the inner mitochondrial membrane shed light on the intricate components necessary for mitochondria to form their signature cristae in which many protein complexes including the electron transport chain are localized. Mic60/mitofilin has been described as the core component for the assembly and maintenance of MICOS, thus controlling cristae morphology, protein transport, mitochondrial DNA transcription, as well as connecting the inner and outer mitochondrial membranes. Although Mic60 homologs are present in many species, mammalian Mic60 is only recently gaining attention as a critical player in several organ systems and diseases with mitochondrial‐defect origins. In this review, we summarize what is currently known about the ever‐expanding role of Mic60 in mammals, and highlight some new studies pushing the field of mitochondrial cristae organization towards potentially new and exciting therapies targeting this protein.