bluuebunny/crossref_metadata_2025 huggingface dataset:
Body size–dependent bioaccumulation, tissue distribution, and trophic and maternal transfer of phenolic endocrine-disrupting contaminants in a freshwater ecosystem
Authors: Peng Xianzhi , Zheng Ke , Liu Jun , Fan Yujuan , Tang Caiming , Xiong Songsong
Published: April 2018

Parabens, bisphenol A (BPA), triclosan, and triclocarban are recognized endocrine-disrupting contaminants (EDCs); and their occurrence in the environment has attracted increasing concern. Body size–dependent bioaccumulation, tissue distribution, trophic magnification, and maternal transfer of methyl-, ethyl-, propyl-, and butylparabens; 2-phenylphenol (PHP); BPA; triclosan; and triclocarban were investigated in freshwater fish of the Pearl River catchment, China. Most of the EDCs were detected in more than half of the biota samples, ranging from not detected to 6750 ng g−1 lipid weight, with median concentrations of 5 to 72 ng g−1 lipid weight. Livers generally contained the highest EDC levels (1609 ± 1860 ng g−1 lipid wt, mean ± standard deviation), followed in decreasing order by eggs (842 ± 1317 ng g−1 lipid wt), belly fats (488 ± 465 ng g−1 lipid wt), and dorsal muscles (240 ± 239 ng g−1 lipid wt) of the wildlife. Body size–dependent bioaccumulation of the EDCs was observed in the freshwater fish, which varied according to species, tissue, and compound. The concentrations of triclosan, PHP, and BPA usually showed decreasing trends, whereas parabens mostly demonstrated increasing tendency with increasing fish weights, indicating effects of growth dilution and bioaccumulation, respectively. Potential biomagnification was shown by triclosan with trophic magnification factors of 3.0, 4.3, and 4.0 in liver, belly fat, and dorsal muscle, respectively. In addition, the potential of maternal transfer in the fish was primarily revealed for methyl- and propylparabens, PHP, triclosan, and BPA. Presence of the EDCs in the freshwater organisms of the Pearl River catchment warrants more attention considering the potential of trophic magnification and maternal transfer. Environ Toxicol Chem 2018;37:1811–1823. © 2018 SETAC
Combined effects of Deepwater Horizon crude oil and environmental stressors on Fundulus grandis embryos
Authors: Rodgers Maria L. , Jones Elizabeth R. , Klinkhamer Christopher , Mahapatra Cecon T. , Serafin Jennifer , Bosker Thijs , Perkins Christopher , Griffitt Robert J. , De Guise Sylvain , Sepúlveda Maria S.
Published: April 2018

In the present study, we examined how sensitivity to oil changes in combination with environmental stressors in Fundulus grandis embryos. We exposed embryos (<24 h post fertilization) to a range of high-energy water accommodated fraction (HEWAF) concentrations (0–50 parts per billion [ppb] total polycyclic aromatic hydrocarbons [PAHs]) made from Macondo crude oil in conjunction with various environmental conditions (temperature: 20 and 30 °C; salinity: 3, 7, and 30 practical salinity units [PSU]; and dissolved oxygen: 2 and 6 mg/L). Endpoints included mortality, hatching rates, and expression of cytochrome p450 1a and 1c (cyp1a, cyp1c) in hatched larvae. There was 100% mortality for all fish under the 2 parts per million (ppm) dissolved oxygen regimes. For the 6 mg/L dissolved oxygen treatments, mortality and median lethal time (LT50) were generally higher in the 30 °C treatments versus the 20 °C treatments. Oil increased mortality in fish exposed to the highest concentration in the 20-3-6 (°C-PSU-mg/L), 25-7-6, and 30-30-6 conditions. Hatching was driven by environmental conditions, with oil exposure having a significant impact on hatching in only the 25-7-6 and 30-30-6 groups at the greatest HEWAF exposure. Expression of cyp1a was up-regulated in most treatment groups versus the controls, with cyp1c expression exhibiting a similar pattern. These data suggest interactive effects among temperature, salinity, and PAHs, highlighting a need to further assess the effects of oil exposure under various environmental conditions. Environ Toxicol Chem 2018;37:1916–1925. © 2018 SETAC
A review of fire growth and fully developed fires in railcars
Authors: Lattimer Brian Y. , McKinnon Mark
Published: April 2018

A literature review was performed to assess the state of knowledge of the effects of railcar interior finish materials on fire growth and fully developed fires from railcars. An overview is provided on standards and requirements currently used to regulate interior finish materials. Following this review, an overview of experimental and computational research is provided on railcar interior finish flammability and its impact on fire growth. A survey of the research on fully developed fires and the potential heat release rates of railcars is then presented. This includes scaling laws, experimental research, and model development. Future research recommendations are then presented.
Ultra‐high‐field fMRI insights on insight: Neural correlates of the Aha!‐moment
Authors: Tik Martin , Sladky Ronald , Luft Caroline Di Bernardi , Willinger David , Hoffmann André , Banissy Michael J , Bhattacharya Joydeep , Windischberger Christian
Published: April 2018

Finding creative solutions to difficult problems is a fundamental aspect of human culture and a skill highly needed. However, the exact neural processes underlying creative problem solving remain unclear. Insightful problem solving tasks were shown to be a valid method for investigating one subcomponent of creativity: the Aha!‐moment. Finding insightful solutions during a remote associates task (RAT) was found to elicit specific cortical activity changes. Considering the strong affective components of Aha!‐moments, as manifested in the subjectively experienced feeling of relief following the sudden emergence of the solution of the problem without any conscious forewarning, we hypothesized the subcortical dopaminergic reward network to be critically engaged during Aha. To investigate those subcortical contributions to insight, we employed ultra‐high‐field 7 T fMRI during a German Version of the RAT. During this task, subjects were exposed to word triplets and instructed to find a solution word being associated with all the three given words. They were supposed to press a button as soon as they felt confident about their solution without further revision, allowing us to capture the exact event of Aha!‐moment. Besides the finding on cortical involvement of the left anterior middle temporal gyrus (aMTG), here we showed for the first time robust subcortical activity changes related to insightful problem solving in the bilateral thalamus, hippocampus, and the dopaminergic midbrain comprising ventral tegmental area (VTA), nucleus accumbens (NAcc), and caudate nucleus. These results shed new light on the affective neural mechanisms underlying insightful problem solving.
The adenosine monophosphate–activated protein kinase—vacuolar adenosine triphosphatase–pH axis: A key regulator of the profibrogenic phenotype of human hepatic stellate cells
Authors: Marrone Giusi , De Chiara Francesco , Böttcher Katrin , Levi Ana , Dhar Dipok , Longato Lisa , Mazza Giuseppe , Zhang Zhenzhen , Marrali Martina , Fernández‐Iglesias Anabel , Hall Andrew , Luong Tu Vinh , Viollet Benoit , Pinzani Massimo , Rombouts Krista
Published: April 2018

Liver fibrosis and cirrhosis are characterized by activation of hepatic stellate cells (HSCs), which is associated with higher intracellular pH (pHi). The vacuolar H+ adenosine‐triphosphatase (v‐ATPase) multisubunit complex is a key regulator of pHi homeostasis. The present work investigated the functional role of v‐ATPase in primary human HSC (hHSC) activation and its modulation by specific adenosine monophosphate–activated protein kinase (AMPK) subunits. We demonstrate that the expression of different v‐ATPase subunits was increased in in vivo and in vitro activated hHSCs compared to nonactivated hHSCs. Specific inhibition of v‐ATPase with bafilomycin and KM91104 induced a down‐regulation of the HSC fibrogenic gene profile, which coincided with increased lysosomal pH, decreased pHi, activation of AMPK, reduced proliferation, and lower metabolic activity. Similarly, pharmacological activation of AMPK by treatment with diflunisal, A769662, and ZLN024 reduced the expression of v‐ATPase subunits and profibrogenic markers. v‐ATPase expression was differently regulated by the AMPK α1 subunit (AMPKα1) and AMPKα2, as demonstrated in mouse embryo fibroblasts specifically deficient for AMPK α subunits. In addition, activation of v‐ATPase in hHSCs was shown to be AMPKα1‐dependent. Accordingly, pharmacological activation of AMPK in AMPKα1‐depleted hHSCs prevented v‐ATPase down‐regulation. Finally, we showed that v‐ATPase expression was increased in fibrotic livers from bile duct–ligated mice and in human cirrhotic livers. Conclusion: The down‐regulation of v‐ATPase might represent a promising target for the development of antifibrotic strategies. (Hepatology 2018).
Hepatocellular Carcinoma‐Associated Protein TD26 Interacts and Enhances Sterol Regulatory Element‐Binding Protein 1 Activity to Promote Tumor Cell Proliferation and Growth
Authors: Wang Chenchen , Tong Ying , Wen Yankai , Cai Jie , Guo Han , Huang Lifeng , Xu Min , Feng Mingxuan , Chen Xiaosong , Zhang Jianjun , Wu Hailong , Kong Xiaoni , Xia Qiang
Published: April 2018

Hepatocellular carcinoma (HCC) is a leading cause of cancer‐related death worldwide. Increased lipogenesis has been reported to play a critical role in HCC progression. However, the underlying mechanism contributing to lipogenesis increase in HCC remains elusive. Here, we show that HCC‐associated protein TD26 (TD26) was highly expressed in HCC tumor tissues compared to matched normal tissues. From the clinicopathologic analyses of two independent HCC cohorts, we demonstrate that TD26 expression was positively correlated with tumor size and was an independent predictor of overall survival (OS) and recurrence‐free survival (RFS) in HCC patients. Our metabolomics assays demonstrate that TD26 had no effect on glycometabolism, but significantly increased lipogenesis in HCC cells. In addition, our functional assays indicate that TD26 promoted HCC cell proliferation and tumor growth. We further demonstrate that TD26‐mediated increase in lipogenesis and tumor cell proliferation was SREBP1 dependent. Mechanistically, we demonstrate that, through its C‐terminus (amino acids [aa] from 121 to 198), TD26 interacted with the truncated nuclear sterol regulatory element‐binding protein 1 (SREBP1) form (nSREBP1), but not full‐length SREBP1 (flSREBP1), to block adenosine 5′‐monophosphate (AMP)‐activated protein kinase (AMPK)‐mediated inhibition on SREBP1 activity, resulting in increased lipogenesis, elevated tumor cell proliferation, and enhanced tumor progression. Conclusion: We propose that TD26 is a positive regulator on SREBP1 transactivity, and the interaction between TD26 and SREBP1 can serve as a potential therapeutic target for HCC treatment.
Metabolic Features of Nonalcoholic Fatty Liver (NAFL) in Obese Adolescents: Findings From a Multiethnic Cohort
Authors: Tricò Domenico , Caprio Sonia , Rosaria Umano Giuseppina , Pierpont Bridget , Nouws Jessica , Galderisi Alfonso , Kim Grace , Mata Mariana M. , Santoro Nicola
Published: April 2018

We conducted a prospective study in a large, multiethnic cohort of obese adolescents to characterize clinical and genetic features associated with pediatric nonalcoholic fatty liver (NAFL), the most common cause of chronic liver disease in youth. A total of 503 obese adolescents were enrolled, including 191 (38.0%) whites, 134 (26.6%) blacks, and 178 (35.4%) Hispanics. Participants underwent abdominal magnetic resonance imaging (MRI) to quantify hepatic fat fraction (HFF), an oral glucose tolerance test (OGTT) to assess glucose tolerance and insulin sensitivity, and the genotyping of three single‐nucleotide polymorphisms (SNPs) associated with nonalcoholic fatty liver disease (NAFLD) (patatin‐like phospholipase domain‐containing protein 3 [PNPLA3] rs738409, glucokinase regulatory protein [GCKR] rs1260326, and transmembrane 6 superfamily member 2 [TM6SF2] rs58542926). Assessments were repeated in 133 subjects after a 2‐year follow‐up. Prevalence of nonalcoholic fatty liver (NAFL) was 41.6% (209 patients) and ranged widely among ethnicities, being 42.9% in whites, 15.7% in blacks, and 59.6% in Hispanics (P < 0.0001). Among adolescents with NAFL, blacks showed the highest prevalence of altered glucose homeostasis (66%; P = 0.0003). Risk factors for NAFL incidence were white or Hispanic ethnicity (P = 0.021), high fasting C‐peptide levels (P = 0.0006), and weight gain (P = 0.0006), whereas baseline HFF (P = 0.004) and weight loss (P = 0.032) predicted resolution of NAFL at follow‐up. Adding either gene variant to these variables improved significantly the model predictive performance. Conclusion: Black obese adolescents are relatively protected from liver steatosis, but are more susceptible to the deleterious effects of NAFL on glucose metabolism. The combination of ethnicity/race with markers of insulin resistance and genetic factors might help identify obese youth at risk for developing NAFL.
Inhibition of insulin‐like growth factor 1 receptor enhances the efficacy of sorafenib in inhibiting hepatocellular carcinoma cell growth and survival
Authors: Wang Fang , Bank Thomas , Malnassy Gregory , Arteaga Maribel , Shang Na , Dalheim Annika , Ding Xianzhong , Cotler Scott J. , Denning Mitchell F. , Nishimura Michael I. , Breslin Peter , Qiu Wei
Published: April 2018

Hepatocellular carcinoma (HCC) is the fifth most common primary cancer and second largest cause of cancer‐related death worldwide. The first‐line oral chemotherapeutic agent sorafenib only increases survival in patients with advanced HCC by less than 3 months. Most patients with advanced HCC have shown limited response rates and survival benefits with sorafenib. Although sorafenib is an inhibitor of multiple kinases, including serine/threonine‐protein kinase c‐Raf, serine/threonine‐protein kinase B‐Raf, vascular endothelial growth factor receptor (VEGFR)‐1, VEGFR‐2, VEGFR‐3, and platelet‐derived growth factor receptor β, HCC cells are able to escape from sorafenib treatment using other pathways that the drug insufficiently inhibits. The aim of this study was to identify and target survival and proliferation pathways that enable HCC to escape the antitumor activity of sorafenib. We found that insulin‐like growth factor 1 receptor (IGF1R) remains activated in HCC cells treated with sorafenib. Knockdown of IGF1R sensitizes HCC cells to sorafenib treatment and decreases protein kinase B (AKT) activation. Overexpression of constitutively activated AKT reverses the effect of knockdown of IGF1R in sensitizing HCC cells to treatment with sorafenib. Further, we found that ceritinib, a drug approved by the U.S. Food and Drug Administration for treatment of non‐small cell lung cancer, effectively inhibits the IGF1R/AKT pathway and enhances the inhibitory efficacy of sorafenib in human HCC cell growth and survival in vitro, in a xenograft mouse model and in the c‐Met/β‐catenin‐driven HCC mouse model. Conclusion: Our study provides a biochemical basis for evaluation of a new combination treatment that includes IGF1R inhibitors, such as ceritinib and sorafenib, in patients with HCC. (Hepatology Communications 2018;2:732‐746)
HPV16 increases the number of migratory cancer stem cells and modulates their miRNA expression profile in oropharyngeal cancer
Authors: Hufbauer Martin , Maltseva Margaret , Meinrath Jeannine , Lechner Axel , Beutner Dirk , Huebbers Christian U. , Akgül Baki
Published: April 2018

Human papillomavirus type 16 (HPV16) is a major risk for development of oropharyngeal squamous‐cell‐carcinoma (OPSCC). Although HPV+ OPSCC metastasize faster than HPV− tumors, they have a better prognosis. The molecular and cellular alterations underlying this pathobiology of HPV+ OPSCC remain elusive. In this study, we examined whether expression of HPV16‐E6E7 targets the number of migratory and stationary cancer stem cells (CSC). Furthermore, we wanted to elucidate if aberrantly expressed miRNAs in migratory CSC may be responsible for progression of OPSCCs and whether they may serve as potential novel biomarkers for increased potential of metastasis. Our studies revealed that HPV16‐E6E7 expression leads to an increase in the number of stationary (CD44high/EpCAMhigh) stem cells in primary keratinocyte cultures. Most importantly, expression of E6E7 in the cell line H357 increased the migratory (CD44high/EpCAMlow) CSC pool. This increase in migratory CSCs could also be confirmed in HPV+ OPSCC. Differentially expressed miRNAs from HPV16‐E6E7 positive CD44high/EpCAMlow CSCs were validated by RT‐qPCR and in situ hybridization on HPV16+ OPSCCs. These experiments led to the identification of miR‐3194‐5p, which is upregulated in primary HPV16+ OPSCC and matched metastasis. MiR‐1281 was also found to be highly expressed in HPV+ and HPV− metastasis. As inhibition of this miRNA led to a markedly reduction of CD44high/EpCAMlow cells, it may prove to be a promising drug target. Taken together, our findings highlight the capability of HPV16 to modify the phenotype of infected stem cells and that miR‐1281 and miR3194‐5p may represent promising targets to block metastatic spread of OPSCC.
Dairy product consumption and risk of colorectal cancer in an older mediterranean population at high cardiovascular risk
Authors: Barrubés Laura , Babio Nancy , Mena‐Sánchez Guillermo , Toledo Estefania , Ramírez‐Sabio Judith B. , Estruch Ramón , Ros Emilio , Fitó Montserrat , Arós Fernando , Fiol Miquel , Santos‐Lozano José Manuel , Serra‐Majem Lluís , Pintó Xavier , Martínez‐González Miguel Ángel , Sorlí José Vicente , Basora Josep , Salas‐Salvadó Jordi ,   on behalf of the PREvención con DIeta MEDiterránea Study Investigators
Published: April 2018

Prospective studies have reported an inverse association between the consumption of total dairy products and milk and the risk of colorectal cancer (CRC). Nonetheless, there is little and inconsistent evidence regarding subtypes of dairy product and CRC risk. We assessed the associations between the consumption of total dairy products, their different subtypes and CRC risk in older Mediterranean individuals at high cardiovascular risk. We analyzed data from 7,216 men and women (55–80 years) without CRC at baseline from the PREvención con DIeta MEDiterránea study. Individuals were recruited between 2003 and 2009 and followed up until December 2012. At baseline and yearly thereafter, consumption of total and specific dairy products was assessed using a validated 137‐item food‐frequency questionnaire. Cox proportional hazards ratios (HRs) of CRC incidence were estimated for tertiles of mean consumption of dairy products during the follow‐up. During a median [interquartile range] follow‐up of 6.0 [4.4–7.3] years, we documented 101 incident CRC cases. In the multivariable‐adjusted models, HRs and 95% confidence intervals (CIs) of CRC for the comparison of extreme tertiles of total dairy product and low‐fat milk consumption were 0.55 (95% CI: 0.31–0.99; p‐trend = 0.037) and 0.54 (95% CI: 0.32–0.92; p‐trend = 0.022), respectively. No significant associations with other dairy products (whole‐fat and low‐fat dairy products; total, low‐fat and whole‐fat yogurt; cheese; total, low‐fat and whole‐fat milk; concentrated full‐fat dairy products, sugar‐enriched dairy products and fermented dairy products) were found. A high consumption of total dairy products and low‐fat milk was significantly associated with a reduced CRC risk.
Private debt overhang and the government spending multiplier: Evidence for the United States
Authors: Bernardini Marco , Peersman Gert
Published: April 2018

Using state‐dependent local projections and historical US data, we find that government spending multipliers are considerably larger in periods of private debt overhang. In particular, while multipliers are below or close to one in low private debt states, we find significant crowding‐in of private spending in periods of debt overhang, resulting in multipliers that are much larger than one. In high private debt episodes, more government purchases even reduce the ratio of government debt to gross domestic product. These results are robust for the type of shocks, and when we control for the business cycle, financial crises, deleveraging episodes, government debt overhang, and the zero‐lower‐bound.
Chondrogenic response in presence of cartilage extracellular matrix nanoparticles
Authors: Zahiri Saeed , Masaeli Elahe , Poorazizi Elahe , Nasr‐Esfahani Mohammad Hossein
Published: April 2018

Current studies based on regenerative medicine suggest, decellularized extracellular matrix (DC‐ECM) components can regulate cell phenotype. In this regard, it is believed, presence of cartilage extracellular matrix particles in culture condition could produce physical and biochemical supportive cues for chondrogenesis. In this study, DC‐ECM nanoparticles with average size of 61.5± 22.4 nm were produced by decellularization and mechanical processing. Homogenous distribution and nanoscale size of yield particles were observed by scanning electron microscopy (SEM) and transmission electron microscopy (TEM) microscopy imaging. Chemical structure preservation of cartilage ECM after decellularization was also confirmed by typical Fourier transform infrared (FTIR) spectrum mapping. The influence these nanoparticles on chondrogenic response of chondrocyte cells was investigated by direct and indirect addition of nanoparticles to culture medium. A clinical devitalized cartilage powder (DV‐ECM) was also used as a positive control. Totally, MTS results showed that direct and indirect presence of both DC‐ECM and DV‐ECM particles in culture medium enhanced cellular metabolic activity except on day one of culture. Furthermore, on day 21, SOX9 and COL2 expression of cultured chondrocytes in the medium containing DC‐ECM nanoparticles were up‐regulated in comparison to negative control, which was further confirmed by presence more frequent number of larger size lacunae in micromass spheroids. Our findings support the use of ECM nanoparticles as condition supplement in culture medium and injectable biomaterials, especially for cell‐based therapies for cartilage regeneration. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A:2463–2471, 2018.
Healing bone lesion defects using injectable CaSO4/CaPO4‐TCP bone graft substitute compared to cancellous allograft bone chips in a canine model
Authors: Hall Deborah J. , Turner Thomas M. , Urban Robert M.
Published: April 2018

CaSO4/CaPO4‐TCP bone graft substitute has been shown to be effective for treatment of bone lesion defects, but its mechanical, histological, and radiographic characteristics have not been studied in direct comparison with a conventional treatment such as cancellous allograft bone. Thirteen canines had a critical‐size axial defect created bilaterally into the proximal humerus. CaSO4/CaPO4‐TCP bone graft substitute (PRO‐DENSE™, Wright Medical Technology) was injected into the defect in one humerus, and an equal volume of freeze‐dried cancellous allograft bone chips was placed in the contralateral defect. The area fraction of new bone, residual graft, and fibrous tissue and the compressive strength and elastic modulus of bone within the defects were determined after 6, 13, or 26 weeks and correlated with radiographic changes. The data were analyzed using Friedman and Mann–Whitney tests. There was more bone in defects treated with the CaSO4/CaPO4‐TCP bone graft substitute compared to defects treated with cancellous bone allograft at all three time points, and the difference at 13 weeks was significant (p = 0.025). The new bone was significantly stronger and stiffer in defects treated with the CaSO4/CaPO4‐TCP bone graft substitute compared to defects treated with cancellous bone allograft at 13 (p = 0.046) and 26 weeks (p = 0.025). At 26 weeks, all defects treated with CaSO4/CaPO4‐TCP bone graft substitute demonstrated complete healing with new bone, whereas healing was incomplete in all defects treated with cancellous allograft chips. The CaSO4/CaPO4‐TCP bone graft substitute could provide faster and significantly stronger healing of bone lesions compared to the conventional treatment using freeze‐dried cancellous allograft bone. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 107B: 408–414, 2019.
Retracted: Protective effects of Progranulin against focal cerebral ischemia‐reperfusion injury in rats by suppressing endoplasmic reticulum stress and NF‐κB activation in reactive astrocytes
Authors: Shu Qing , Fan Hua , Li Shi‐Jun , Zhou Dan , Ma Wei , Zhao Xiao‐Yan , Yan Jun‐Qiang , Wu Gang
Published: April 2018

The aim of this study is to explore the effect progranulin (PGRN) has on endoplasmic reticulum (ER) stress and the NF‐κB activation in reactive astrocytes found in rat models with focal cerebral ischemia‐reperfusion (I/R) injury. Sprague‐Dawley (SD) rats were grouped into the sham, I/R, PGRN‐high dose, PGRN‐low dose, and negative control (NC) groups. TTC staining was applied in order to detect the cerebral infarction volume, a TUNEL assay to detect the apoptosis rate of neurons, an ELISA to measure MDA, SOD, iNOS, LDH, TNF‐α, IL‐1β, IL‐6, and IL‐10 levels, and both RT‐qPCR and western blotting methods in order to detect PGRN, GFAP, GRP78, CHOP, and NF‐κB p65 expressions. The astrocytes (AST) cells were then assigned into the normal, I/R, negative control (NC), PGRN‐high dose, and PGRN‐low dose groups. After completing the transfection process, the proliferative capacity of AST cells was detected by use of the CCK‐8 assay. Both the in vivo and in vitro results, in comparison with the I/R and the NC groups, the PGRN‐high dose and PGRN‐low dose groups both presented a decrease in cerebral infarction volume, apoptosis rate of neurons, MDA, LDH, iNOS, TNF‐α, IL‐1β, IL‐6 levels, and GFAP, GRP78, CHOP, NF‐κB p65 expressions, and an increase in SOD, IL‐10, and PGRN levels as well as cell proliferation depending on dosage. Based on our results, we came to the confirmation that PGRN can reduce neuronal apoptosis by mitigating ER stress in the reactive astrocytes as well as downregulating the inflammatory levels by suppressing the NF‐κB signaling pathway.
The role of high‐mobility group protein box 1 in lung cancer
Authors: Wu Xiao‐Jin , Chen Yuan‐Yuan , Gong Chan‐Chan , Pei Dong‐Sheng
Published: April 2018

High‐mobility group protein box 1(HMGB1)is a ubiquitous highly conserved nuclear protein. Acting as a chromatin‐binding factor, HMGB1 binds to DNA and plays an important role in stabilizing nucleosome formation, facilitating gene transcription, DNA repairing, inflammation, cell differentiation, and regulating the activity of steroid hormone receptors. Currently, HMGB1 is discovered to be related to development, progression, and targeted therapy of lung cancer, which makes it an attractive biomarker, and therapeutic target. This review aims to encapsulate the relationship between HMGB1 and lung cancer, suggesting that HMGB1 plays a pivotal role in initiation, development, invasion, metastasis, and prognosis of lung cancer.
S6K1 controls epigenetic plasticity for the expression of pancreatic α/β cell marker genes
Authors: Yi Sang Ah , Lee Jieun , Park Jong Woo , Han Jihoon , Lee Min Gyu , Nam Ki Hong , Park Jee Hun , Oh Hwamok , Ahn Sung Jin , Kim Saetbyul , Kwon So Hee , Jo Dong‐Gyu , Han Jeung‐Whan
Published: April 2018

The failure of insulin production by pancreatic β cells is a common hallmark of type 1 diabetes mellitus (T1DM). Because administration of exogenous insulin is associated with diabetes‐derived complications, endogenous α to β cell transition can be an attractive alternative. Although decreased β cell size and hypoinsulinaemia have been observed in S6K1‐deficient mice, the molecular mechanism underlying the involvement of S6K1 in the transcriptional regulation of insulin remains elusive. Here, we show that the hypoinsulinaemic phenotype of S6K1‐deficient mice stems from the dysregulated transcription of a set of genes required for insulin and glucagon production. First, we observed that increased expression of α cell marker genes and decreased expression of β cell marker genes in pancreas tissues from S6K1‐deficient mice. Furthermore, S6K1 was highly activated in murine β cell line, βTC6, compared to murine α cell line αTC1. In both α and β cells, active S6K1 promoted the transcription of β cell marker genes, including insulin, whereas S6K1 inhibition increased the transcription of α cell marker genes. Moreover, S6K1 mediated pancreatic gene regulation by modifying two histone marks (activating H3K4me3 and repressing H3K27me3) on gene promoters. These results suggest that S6K1 drives the α to β transition through the epigenetic regulation of cell‐specific genes, including insulin and glucagon. This novel role of S6K1 in islet cells provides basic clues to establish therapeutic strategies against T1DM.
Hyperbaric oxygen treatment sensitizes gastric cancer cells to melatonin‐induced apoptosis through multiple pathways
Authors: Wei Xiang , Qi Yinliang , Jia Ning , Zhou Qing , Zhang Sumei , Wang Yuan
Published: April 2018

Although extensive efforts have been made in recent decades to treat advanced gastric cancer with comprehensive therapy based on chemotherapy, effective anti‐gastric cancer therapeutics are still lacking in the clinics. Therefore, potent novel anti‐gastric cancer ways are greatly needed. Here, we explored hyperbaric oxygen treatment as a novel and effective adjuvant treatment method which has anti‐gastric cancer effects when used together with melatonin. When performed together with MLT, HBO effectively inhibited tumorigenicity of gastric cancer through selectively inducing a robust tumor suppressive apoptosis response. Mechanistic studies revealed that the sensitizing effect of hyperbaric oxygen is due to decreased ratio of Bcl‐2/Bax, increased level of p53, cleaved Caspase3, GRP78, CHOP, and LC3. These results give a vivid picture that classic apoptosis pathways including mitochondrial pathway, tumor suppressive endoplasmic reticulum stress (ERS), and autophagy are all involved in the process. From the preliminary results got from the current study, we identified that HBO sensitizes human gastric cancer cells to MLT‐induced apoptosis through a variety of complicated molecular mechanisms. HBO may provide a novel candidate supplemental treatment method for further development of potential anti‐gastric cancer therapeutics. The combination of HBO and MLT could be a promising treatment for advanced gastric cancer.
The MAPK‐activator protein‐1 signaling regulates changes in lung tissue of rat exposed to hypobaric hypoxia
Authors: Singh Mrinalini , Yadav Seema , Kumar Meetul , Saxena Shweta , Saraswat Deepika , Bansal Anju , Singh Shashi B.
Published: April 2018

This study reports the role of MAPKs (JNK, ERK, and p38), and activator protein‐1 (AP‐1) transcription factor in the hypobaric hypoxia induced change in lung tissue. Healthy male Sprague–Dawley rats were exposed to hypobaric hypoxia for 6, 12, 24, 48, 72, and 120 hr. Hypoxia resulted in significant increase in reactive oxygen species (ROS), vascular endothelial growth factor (VEGF) and decreased nitric oxide (NO), these act as signaling molecules for activation of MAPK and also contribute in development of vascular leakage (an indicator of pulmonary edema) as confirmed by histological studies. Our results confirmed JNK activation as an immediate early response (peaked at 6–48 hr), activation of ERKs (peaked at 24–72 hr) and p38 (peaked at 72–120 hr) as a secondary response to hypoxia. The MAPK pathway up regulated its downstream targets phospho c‐Jun (peaked at 6–120 hr), JunB (peaked at 24–120 hr) however, decreased c‐Fos, and JunD levels. DNA binding activity also confirmed activation of AP‐1 transcription factor in lung tissue under hypobaric hypoxia. Further, we analyzed the proliferative and inflammatory genes regulated by different subunits of AP‐1 to explore its role in vascular leakage. Increased expression of cyclin D1 (peaked at 12–72 hr) and p16 level (peaked at 48–120 hr) were correlated to the activation of c‐jun, c‐Fos and JunB. Administration of NFκB inhibitor caffeic acid phenethyl ester (CAPE) and SP600125 (JNK inhibitor) had no effect on increased levels of Interferon‐γ (IFN‐γ), Interleukin‐1 (IL‐1), and Tumor Necrosis Factor‐α (TNF‐α) thereby confirming the involvement of AP‐1 as well as NFκB in inflammation. Expression of c‐jun, c‐Fos were correlated with activation of proliferative genes and JunB, Fra‐1 with pro‐inflammatory cytokines. In conclusion immediate response to hypobaric hypoxia induced c‐Jun:c‐Fos subunits of AP‐1; responsible for proliferation that might cause inhomogeneous vasoconstriction leading to vascular leakage and inflammation at increased duration of hypobaric hypoxia exposure.
LncRNA DGCR5 contributes to CSC‐like properties via modulating miR‐330‐5p/CD44 in NSCLC
Authors: Wang Ren , Dong Hui‐Xing , Zeng Jian , Pan Jing , Jin Xiao‐Yan
Published: April 2018

Non‐coding RNAs can exert significant roles various cancers, including NSCLC. Previously, we indicated that lncRNA DGCR5 can promote lung cancer progression through inhibiting hsa‐mir‐22‐3p. In our current study, we investigated the role of DGCR5 in cancer stem cell‐like properties of NSCLC. CSCs have been recognized as the frequent cause of tumor metastasis, tumor recurrence, and chemotherapy resistance. Here, lung cancer stem cells were successfully enriched from the parental NSCLC A549, H460, and H1299 cells by using tumor sphere formation assays and side population (SP) assays. We observed that DGCR5 was up‐regulated in the enriched CSCs of NSCLC. DGCR5 can inhibit the stemness of NSLCL while overexpression of DGCR5 promoted CSC‐like traits. In addition, miR‐330‐5p was predicted as target of DGCR5 and the correlation between them was validated by dual‐luciferase reporter assay, RIP assay, and RNA pull‐down assay. Meanwhile, it was found that miR‐330‐5p was decreased in CSCs of NSCLC. miR‐330‐5p mimics repressed the stemness while miR‐330‐5p inhibition enhanced CSC‐like properties by targeting CD44. Taken these together, DGCR5 can act as a crucial regulator of CSCs in NSCLC by modulating miR‐330‐5p/CD44 axis.
Nanoparticle‐based targeted cancer strategies for non‐invasive prostate cancer intervention
Authors: Farina Nicholas H. , Zingiryan Areg , Vrolijk Michael A. , Perrapato Scott D. , Ades Steven , Stein Gary S. , Lian Jane B. , Landry Christopher C.
Published: April 2018

Prostate cancer is screened by testing circulating levels of the prostate‐specific antigen (PSA) biomarker, monitoring changes over time, or a digital rectal exam. Abnormal results often lead to prostate biopsy. Prostate cancer positive patients are stratified into very low‐risk, low‐risk, intermediate‐risk, and high‐risk, based on clinical classification parameters, to assess therapy options. However, there remains a gap in our knowledge and a compelling need for improved risk stratification to inform clinical decisions and reduce both over‐diagnosis and over‐treatment. Further, current strategies for clinical intervention do not distinguish clinically aggressive prostate cancer from indolent disease. This mini‐review takes advantage of a large number of functionally characterized microRNAs (miRNA), epigenetic regulators of prostate cancer, that define prostate cancer cell activity, tumor stage, and circulate as biomarkers to monitor disease progression. Nanoparticles provide an effective platform for targeted delivery of miRNA inhibitors or mimics specifically to prostate tumor cells to inhibit cancer progression. Several prostate–specific transmembrane proteins expressed at elevated levels in prostate tumors are under investigation for targeting therapeutic agents to prostate cancer cells. Given that prostate cancer progresses slowly, circulating miRNAs can be monitored to identify tumor progression in indolent disease, allowing identification of miRNAs for nanoparticle intervention before the crucial point of transition to aggressive disease. Here, we describe clinically significant and non‐invasive intervention nanoparticle strategies being used in clinical trials for drug and nucleic acid delivery. The advantages of mesoporous silica‐based nanoparticles and a number of candidate miRNAs for inhibition of prostate cancer are discussed.
Thiostrepton degrades mutant p53 by eliciting an autophagic response in SW480 cells
Authors: Kalathil Dhanya , Prasad Manu , Chelladurai Maharrish , John Samu , Nair Asha S.
Published: April 2018

Mutations in p53 gene are one of the hallmarks of tumor development. Specific targeting of mutant p53 protein has a promising role in cancer therapeutics. Our preliminary observation showed destabilization of mutant p53 protein in SW480, MiaPaCa and MDAMB231 cell lines upon thiostrepton treatment. In order to elucidate the mechanism of thiostrepton triggered mutant p53 degradation, we explored the impact of proteasome inhibition on activation of autophagy. Combined treatment of thiostrepton and cycloheximide/chloroquine prevented the degradation of mutant p53 protein, reinforcing autophagy as the means of mutant p53 destabilization. Our initial studies suggested that mutant p53 degradation post THSP treatment was carried out by BAG3 mediated autophagy, based on the evidence of BAG1 to BAG3 switching. Subsequent interactome analysis performed post thiostrepton treatment revealed an association of p53 with autophagosome complex associated proteins such as BAG3, p62 and HSC70. Reaccumulation of p53 was seen in BAG3 silenced cells treated with thiostrepton, thereby confirming the role of BAG3 in destabilization of this molecule. Further, localization of p53 into the lysosome upon THSP treatment substantiated our findings that mutant p53 was degraded by an autopahgic process.
UBIAD1 protects against oxygen‐glucose deprivation/reperfusion‐induced multiple subcellular organelles injury through PI3K/AKT pathway in N2A cells
Authors: Huang Yan , Hu Zhiping
Published: April 2018

Cerebral ischemia/reperfusion‐induced injury plays a significant role in the development of multi‐subcellular organelles injury after ischemic stroke. UBIAD1 was discovered originally as a potential tumor suppressor protein. Recently, analysis of UBIAD1 has indicated it is a prenyltransferase enzyme for both non‐mitochondrial CoQ10 and vitamin K2 production. Further, UBIAD1 has been localized to multiple subcellular organelles. Particularly, UBIAD1 plays an important role in the regulation of oxidative stress, apoptosis and cell proliferation, cholesterol and lipid metabolism, which was closely associated with the cerebral ischemic/reperfusion mechanism. However, the mechanism underlying effects of UBIAD1 on cerebral ischemia/reperfusion‐induced injury remains largely unknown. We aimed to investigate the effects of UBIAD1 on ischemia/reperfusion‐induced multiple subcellular organelles injury in vitro, mouse N2A cells were subjected to a classical oxygen‐glucose deprivation and reperfusion (OGD/R) insult. The expression of UBIAD1 was reduced in mouse N2A cells after OGD/R. UBIAD1 exhibits multi‐subcellular organelles co‐localization in N2a cells, including in the mitochondria, endoplasmic reticulum, and Golgi apparatus. The over‐expression of UBIAD1 significantly protects against OGD/R‐induced cell death. UBIAD1 over‐expression also attenuated OGD/R‐induced mitochondrial fragmentation and dysfunction and mediated the level of apoptosis‐associated protein. Moreover, we observed that the over‐expression of UBIAD1 ameliorated OGD/R‐induced fragmentation and reduced the level of oxidative stress‐related protein expression in both the endoplasmic reticulum and Golgi apparatus. Besides, the neuroprotective effect of UBIAD1 was correlated with the PI3K/AKT pathway, which was demonstrated using the PI3K inhibitor LY294002 and perifosion. Collectively, these findings identified that UBIAD1 protects against OGD/R‐induced multiple subcellular organelles injury through PI3K/AKT Pathway.
Transglutaminase activity regulates differentiation, migration and fusion of osteoclasts via affecting actin dynamics
Authors: Sun Huifang , Kaartinen Mari T.
Published: April 2018

Osteoclasts, bone resorbing cells, derive from monocyte/macrophage cell lineage. Increased osteoclast activity is responsible for bone destruction in diseases such as osteoporosis, periodontitis and rheumatoid arthritis. Transglutaminases (TGs), protein crosslinking enzymes, were recently found involved in osteoclastogenesis in vivo, however their mechanisms of action have remained unknown. In this study, we have investigated the role of TG activity in osteoclastogenesis in vitro using four TG inhibitors, NC9, Z006, T101, and monodansyl cadaverine. Our results showed that all TG inhibitors were capable of blocking the entire osteoclastogenesis process. The most potent of the inhibitors, NC9 when added to cultures at different phases of osteoclastogenesis, inhibited differentiation, migration, and fusion of pre‐osteoclasts as well as resorption activity of mature osteoclasts. Further investigation into the mechanisms revealed that NC9 increased RhoA levels and blocked podosome belt formation suggesting that TG activity regulates actin dynamics in pre‐osteoclasts. The inhibitory effect of NC9 on osteoclastogenesis as well as podosome belt formation was completely reversed with a Rho‐family inhibitor Exoenzyme C3. Microtubule architecture, acetylation, and detyrosination of α‐tubulin were not affected. Finally, we demonstrated that macrophages and osteoclasts expressed mRNA of three TGs:TG1, TG2, and Factor XIII‐A which were all differentially regulated in these cells during differentiation. Immunofluoresence microscopic analysis showed that all three enzymes co‐localized to podosomes in osteoclasts. Taken together, our data suggests that TG activity regulates differentiation, migration and fusion of osteoclasts via affecting actin dynamics and that this may involve contribution from all three TG enzymes.
Protective effect of miR378* on doxorubicin‐induced cardiomyocyte injury via calumenin
Authors: Wang Yu , Cui Xiaoxue , Wang Yilin , Fu Yao , Guo Xin , Long Jie , Wei Chengxi , Zhao Ming
Published: April 2018

Doxorubicin (Dox) is a highly effective antitumor antibiotic, however myocardial toxicity severely limits its use clinically. The pathogenesis of doxorubicin‐induced cardiomyopathy is unclear. In Dox cardiomyopathy mice, there is a decline in cardiac function, a change in myocardial pathology and a reduction in miR378* expression. Expression changes in calumenin, an endoplasmic reticulum stress (ERS) chaperone protein and pathway factor, as well as apoptosis, were observed in cardiomyocytes after doxorubicin‐induced injury. However, miR378* increased calumenin expression, eased ERS, and reduced cardiomyocyte apoptosis, while, silencing miR378* reduced calumenin expression, aggravated ERS, and increased cardiomyocyte apoptosis. The above results indicate that miR378* alleviates ERS and inhibits the activation of the ERS‐mediated apoptosis signaling pathway in cardiomyocytes via regulating calumenin expression, thereby reducing cardiomyocyte apoptosis after doxorubicin‐induced injury. Increasing miR378* expression may be a new way to improve cardiac function and quality of life in patients with Dox cardiomyopathy.
Dual Targeting Autoimmunity and Cancer: From Biology to Medicine
Authors: Chen Daohong
Published: April 2018

Cancer is known to be often associated with autoimmunity/inflammation epidemically and pathologically. Although comprehensive mechanisms behind the link of these 2 medical conditions are yet to be elucidated, cumulated biological evidence has pointed to an array of molecular pathways that are shared in the pathogenesis of cancer and autoimmunity. Herein, this article presents the representative druggable cellular proteins that substantially contribute to the development of the 2 medical conditions, in particular highlighting the recently approved medications that target these molecular pathways to corroborate the link between autoimmunity and cancer from the therapeutic perspective. It will ideally help to minimize a knowledge gap, not only regarding mechanistic information across these biomedical fields but also for clinicians and pharmaceutical innovation to deal with the challenges of preventing or managing patients with concomitant cancer and autoimmunity taking advantage of an optimally efficient medication.
Bidirectional Pharmacokinetic Interaction Between Amodiaquine and Pioglitazone in Healthy Subjects
Authors: Edema Opeyemi , Adeagbo Babatunde A. , Adehin Ayorinde , Olugbade Tiwalade A.
Published: April 2018

Amodiaquine (AQ) and pioglitazone (PGZ) are both metabolized by CYP2C8, an enzyme also inhibited by PGZ. These drugs are likely to be administered in instances of comorbidity of malaria with type 2 diabetes. This study, hence, evaluated the possibility of a drug interaction resulting from the concurrent use of both drugs. A 3‐period crossover design in 10 healthy subjects, that assessed the disposition of AQ and PGZ alone and when coadministered, was implemented with the administration of single oral doses of AQ and PGZ. Whole‐blood samples collected between 0 and 24 hours on protein saver cards across the study periods were processed and analyzed for AQ and PGZ contents. Pharmacokinetic parameters were derived by a noncompartmental analysis. Geometric mean ratios for the Cmax, area under the concentration‐time curve for 24 hours (AUC0‐24h), and AUC0‐∞, alongside their corresponding 90%CIs, were compared across the study periods to infer clinically significant changes in disposition. The coadministration of AQ and PGZ resulted in decreases of about 38% and 54% in the Cmax and AUC0‐24h of AQ, respectively. For PGZ, the Cmax increased by about 50%, and AUC0‐24 rose by 48%. The 90%CIs of geometric mean ratios for the Cmax, AUC0‐24h, and AUC0‐∞ were all outside the expected bioequivalence interval of 80% to 125% for both drugs, implying significant interactions. These findings suggest that a bidirectional interaction between AQ and PGZ, with likely implications for the therapy and toxicity of both drugs, may occur in the event of their coadministration.
Phase 1 First‐in‐Human, Single‐ and Multiple‐Ascending Dose, and Food Effect Studies to Assess the Safety, Tolerability, and Pharmacokinetics of Presatovir for the Treatment of Respiratory Syncytial Virus Infection
Authors: German Polina , Xin Yan , Chien Jason W. , Weng Winnie , Mackman Richard , Lewis Sandra A. , Meng Amy , Ling John , Mathias Anita
Published: April 2018

Respiratory syncytial virus (RSV)‐associated respiratory tract infection is a leading cause of hospitalizations in infants for which no effective treatment exists. RSV infection is also an important cause of respiratory disease in adults and immunocompromised patients. Presatovir (GS‐5806) is an orally bioavailable antiviral agent that inhibits fusion of RSV with host cell membranes. Here, results from 2 phase 1 studies that evaluated safety, tolerability, and pharmacokinetics of presatovir in healthy adults following administration of single and multiple (7 days) once‐ or twice‐daily ascending doses (first‐in‐human study) and in the presence or absence of food (food effect study) are described. Presatovir exhibited favorable safety and pharmacokinetic profiles that supported once‐daily dosing. Presatovir exposure increased in an approximately dose‐proportional manner across the evaluated dose range (single doses 25‐300 mg; multiple doses 10‐75 mg once daily for 7 days). Administration of presatovir with a high‐fat meal did not alter exposure, supporting administration without regard to a meal in further clinical studies. These data were subsequently used to inform presatovir dosing regimens in a phase 2a challenge study of adults experimentally infected with RSV. Collectively, results from phase 1 evaluations and a phase 2a challenge study support further clinical investigation of presatovir for the treatment of RSV infection.