bluuebunny/crossref_metadata_2025 huggingface dataset:
Eight Elements in Soils from a Typical Light Industrial City, China: Spatial Distribution, Ecological Assessment, and the Source Apportionment
Authors: Pan Yujie , Peng Hongxia , Xie Shuyun , Zeng Min , Huang Changsheng
Published: July 2019

Contamination with the eight elements, Hg, As, Cr, Cu, Ni, Pb, Zn, and Cd, is a serious concern in Zhongshan, which is a typical light industrial city, China. 60 surface soil samples were collected to investigate the concentrations, spatial distribution, human health risk, and sources of these elements in the soils in Zhongshan. The concentrations of the eight elements were analyzed while using ordinary kriging analysis, pollution load index (PLI), potential ecological risk index (RI), human health risk, correlation analysis, and factor analysis. The mean concentrations of the tested elements, excluding Pb and As, were higher than the soil background values in the Pearl River Delta. The spatial distribution of the tested elements revealed a zonal distribution pattern and high values in several areas. The mean PLI and RI indicated slight and moderate risk levels. Health risk assessment demonstrates that both children and adults were more exposed to Cu than to Cr, As, and Cd. However, the associated carcinogenic risk is acceptable. Hg that originated from human activities; As, Cr, Cu, Ni, and Cd originated from industrial activities; and, Pb and Zn originated from transportation activities. Cd was the main pollutant in the study area and it was present at higher concentrations when compared with those of the other elements. Therefore, Zhongshan should encourage enterprises to conduct industrial transformation to control the ecological risk.
The Life Expectancy Gap between Registered Disabled and Non-Disabled People in Korea from 2004 to 2017
Authors: Bahk Jinwook , Kang Hee-Yeon , Khang Young-Ho
Published: July 2019

This study aimed to estimate and compare life expectancy at birth among people with and without officially registered disabilities in Korea between 2004 and 2017. We used the National Health Information Database in Korea to obtain aggregate data on the numbers of population and deaths according to calendar year (2004 to 2017), sex, age groups, and officially registered disability status. A total of 697,503,634 subjects and 3,536,778 deaths, including 33,221,916 disabled subjects (829,464 associated deaths), were used to construct life tables. Between 2004 and 2017, life expectancy for people with disabilities increased by 9.1 years in men and 8.3 years in women, while life expectancy for the non-disabled increased by 5.5 years in men and 4.6 years in women. The average life expectancy difference between non-disabled and disabled people was 18.2 years during the study period, decreasing from 20.4 years in 2004 to 16.4 years in 2017. In 2017, the life expectancy of people with the most severe grade of disabilities was 49.7 years, while the life expectancy of people with the least severe grade of disabilities was 77.7 years. The government should implement more effective policies to protect the health of people with officially registered disabilities.
Hip and Wrist-Worn Accelerometer Data Analysis for Toddler Activities
Authors: Kwon Soyang , Zavos Patricia , Nickele Katherine , Sugianto Albert , Albert Mark V.
Published: July 2019

Although accelerometry data are widely utilized to estimate physical activity and sedentary behavior among children age 3 years or older, for toddlers age 1 and 2 year(s), accelerometry data recorded during such behaviors have been far less examined. In particular, toddler’s unique behaviors, such as riding in a stroller or being carried by an adult, have not yet been examined. The objective of this study was to describe accelerometry signal outputs recorded during participation in nine types of behaviors (i.e., running, walking, climbing up/down, crawling, riding a ride-on toy, standing, sitting, riding in a stroller/wagon, and being carried by an adult) among toddlers. Twenty-four toddlers aged 13 to 35 months (50% girls) performed various prescribed behaviors during free play in a commercial indoor playroom while wearing ActiGraph wGT3X-BT accelerometers on a hip and a wrist. Participants’ performances were video-recorded. Based on the video data, accelerometer data were annotated with behavior labels to examine accelerometry signal outputs while performing the nine types of behaviors. Accelerometer data collected during 664 behavior assessments from the 21 participants were used for analysis. Hip vertical axis counts for walking were low (median = 49 counts/5 s). They were significantly lower than those recorded while a toddler was “carried” by an adult (median = 144 counts/5 s; p < 0.01). While standing, sitting, and riding in a stroller, very low hip vertical axis counts were registered (median ≤ 5 counts/5 s). Although wrist vertical axis and vector magnitude counts for “carried” were not higher than those for walking, they were higher than the cut-points for sedentary behaviors. Using various accelerometry signal features, machine learning techniques showed 89% accuracy to differentiate the “carried” behavior from ambulatory movements such as running, walking, crawling, and climbing. In conclusion, hip vertical axis counts alone may be unable to capture walking as physical activity and “carried” as sedentary behavior among toddlers. Machine learning techniques that utilize additional accelerometry signal features could help to recognize behavior types, especially to differentiate being “carried” from ambulatory movements.
Exposure to Indoor Mouldy Odour Increases the Risk of Asthma in Older Adults Living in Social Housing
Authors: Moses Loveth , Morrissey Karyn , Sharpe Richard A. , Taylor Tim
Published: July 2019

Background: Indoor dampness is thought to affect around 16% of European homes. It is generally accepted that increased exposure to indoor dampness and mould contamination (e.g., spores and hyphae) increases the risk of developing and/or exacerbating asthma. Around 30% of people in the Western world have an allergic disease (e.g., allergy, wheeze and asthma). The role of indoor mould contamination in the risk of allergic diseases in older adults is yet to be fully explored. This is of interest because older people spend more time indoors, as well as facing health issues due to the ageing process, and may be at greater risk of developing and/or exacerbating asthma as a result of indoor dampness. Methods: Face-to-face questionnaires were carried out with 302 participants residing in social housing properties located in South West England. Self-reported demographic, mould contamination (i.e., presence of mould growth and mouldy odour) and health information was linked with the asset management records (e.g., building type, age and levels of maintenance). Multivariate logistic regression was used to calculate the odd ratios and confidence intervals of developing and/or exacerbating asthma, wheeze and allergy with exposure to reported indoor mould contamination. We adjusted for a range of factors that may affect asthma outcomes, which include age, sex, current smoking, presence of pets, education, and building type and age. To assess the role of mould contamination in older adults, we compared younger adults to those aged over 50 years. Results: Doctor-diagnosed adult asthma was reported by 26% of respondents, 34% had current wheeze while 18% had allergies. Asthma was common among subjects exposed to reported visible mould (32%) and reported mouldy odour (42%). Exposure to visible mould growth and mouldy odour were risk factors for asthma, but not for wheeze or allergy. Exposure to mouldy odour increased the risk of asthma in adults over the age of 50 years (odds ratio (OR) 2.4, 95% confidence interval (CI) 1.10–5.34) and the risk was higher for females than for males (OR 3.5, 95% CI 1.37–9.08). These associations were modified by a range of built environment characteristics. Conclusions: We found that older adults living in social (public) housing properties, specifically women, may be at higher risk of asthma when exposed to mouldy odour, which has a number of implications for policy makers and practitioners working in the health and housing sector. Additional measures should be put in place to protect older people living in social housing against indoor damp and mould contamination.
Correlation of Internal Exposure Levels of Polycyclic Aromatic Hydrocarbons to Methylation of Imprinting Genes of Sperm DNA
Authors: Ma Yufeng , Lu Zhaoxu , Wang Li , Qiang Mei
Published: July 2019

Human exposure to polycyclic aromatic hydrocarbons (PAHs) results in adverse health implications. However, the specific impact of paternal preconception PAHs exposure has not been fully studied. In this study, a total of 219 men aged 24–53 were recruited and an investigation was conducted using a questionnaire requesting information about age, occupation, education, family history, lifestyle, and dietary preferences. Urine and semen samples were examined for the levels of the hydroxyl metabolites of PAHs (OH-PAHs) using ultra-high-performance liquid chromatography–tandem mass spectrometry and sperm DNA methylation by pyrosequencing. The results from the correlation analysis using seven OH-PAHs and the average methylation levels of the imprinting genes H19, PEG3, and MEG3 indicated that 1-OHPH is positively correlated with H19/PEG3 methylation levels. We further examined the correlation between each OH-PAH and the methylation levels at the individual CpGs. The results showed 1-OHPH is specifically correlated with CpG4 and CpG6 of the imprinted gene H19, CpG1 and CpG2 of PEG3, and CpG2 of MEG3; whereas 1-OHP is positively correlated with PEG3 at CpG1. Multivariate regression model analysis confirmed that 1-OHPH and 1-OHP are independent risk factors for the methylation of H19. These data show that sperm DNA imprinting genes are sensitive to adverse environmental perturbations.
Minireview: The Epigenetic Modulation of KISS1 in Reproduction and Cancer
Authors: Motti Maria Letizia , Meccariello Rosaria
Published: July 2019

Epigenetics describes how both lifestyle and environment may affect human health through the modulation of genome functions and without any change to the DNA nucleotide sequence. The discovery of several epigenetic mechanisms and the possibility to deliver epigenetic marks in cells, gametes, and biological fluids has opened up new perspectives in the prevention, diagnosis, and treatment of human diseases. In this respect, the depth of knowledge of epigenetic mechanisms is fundamental to preserving health status and to developing targeted interventions. In this minireview, we summarize the epigenetic modulation of the KISS1 gene in order to provide an example of epigenetic regulation in health and disease.
Smith-Magenis Syndrome: Molecular Basis of a Genetic-Driven Melatonin Circadian Secretion Disorder
Authors: Poisson Alice , Nicolas Alain , Bousquet Idriss , Raverot Véronique , Gronfier Claude , Demily Caroline
Published: July 2019

Smith-Magenis syndrome (SMS), linked to Retinoic Acid Induced (RAI1) haploinsufficiency, is a unique model of the inversion of circadian melatonin secretion. In this regard, this model is a formidable approach to better understand circadian melatonin secretion cycle disorders and the role of the RAI1 gene in this cycle. Sleep-wake cycle disorders in SMS include sleep maintenance disorders with a phase advance and intense sleepiness around noon. These disorders have been linked to a general disturbance of sleep-wake rhythm and coexist with inverted secretion of melatonin. The exact mechanism underlying the inversion of circadian melatonin secretion in SMS has rarely been discussed. We suggest three hypotheses that could account for the inversion of circadian melatonin secretion and discuss them. First, inversion of the circadian melatonin secretion rhythm could be linked to alterations in light signal transduction. Second, this inversion could imply global misalignment of the circadian system. Third, the inversion is not linked to a global circadian clock shift but rather to a specific impairment in the melatonin secretion pathway between the suprachiasmatic nuclei (SCN) and pinealocytes. The development of diurnal SMS animal models that produce melatonin appears to be an indispensable step to further understand the molecular basis of the circadian melatonin secretion rhythm.
Pitavastatin Exerts Potent Anti-Inflammatory and Immunomodulatory Effects via the Suppression of AP-1 Signal Transduction in Human T Cells
Authors: Chen Liv Weichien , Lin Chin-Sheng , Tsai Min-Chien , Shih Shao-Fu , Lim Zhu Wei , Chen Sy-Jou , Tsui Pi-Fen , Ho Ling-Jun , Lai Jenn-Haung , Liou Jun-Ting
Published: July 2019

Statins inhibiting 3-hydroxy-3-methylglutaryl-CoA reductase are the standard treatment for hypercholesterolemia in atherosclerotic cardiovascular disease (ASCVD), mediated by inflammatory reactions within vessel walls. Several studies highlighted the pleiotropic effects of statins beyond their lipid-lowering properties. However, few studies investigated the effects of statins on T cell activation. This study evaluated the immunomodulatory capacities of three common statins, pitavastatin, atorvastatin, and rosuvastatin, in activated human T cells. The enzyme-linked immunosorbent assay (ELISA) and quantitative real time polymerase chain reaction (qRT-PCR) results demonstrated stronger inhibitory effects of pitavastatin on the cytokine production of T cells activated by phorbol 12-myristate 13-acetate (PMA) plus ionomycin, including interleukin (IL)-2, interferon (IFN)-γ, IL-6, and tumor necrosis factor α (TNF-α). Molecular investigations revealed that pitavastatin reduced both activating protein-1 (AP-1) DNA binding and transcriptional activities. Further exploration showed the selectively inhibitory effect of pitavastatin on the signaling pathways of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK), but not c-Jun N-terminal kinase (JNK). Our findings suggested that pitavastatin might provide additional benefits for treating hypercholesterolemia and ASCVD through its potent immunomodulatory effects on the suppression of ERK/p38/AP-1 signaling in human T cells.
RNase L Induces Expression of A Novel Serine/Threonine Protein Kinase, DRAK1, to Promote Apoptosis
Authors: Manivannan Praveen , Reddy Vidita , Mukherjee Sushovita , Clark Kirsten Neytania , Malathi Krishnamurthy
Published: July 2019

Apoptosis of virus-infected cells is an effective antiviral mechanism in addition to interferon induction to establish antiviral state to restrict virus spread. The interferon-inducible 2′–5′ oligoadenylate synthetase/RNase L pathway results in activation of RNase L in response to double stranded RNA and cleaves diverse RNA substrates to amplify interferon induction and promote apoptosis. Here we show that RNase L induces expression of Death-associated protein kinase-Related Apoptosis-inducing protein Kinase 1 (DRAK1), a member of the death-associated protein kinase family and interferon-signaling pathway is required for induction. Overexpression of DRAK1 triggers apoptosis in the absence of RNase L activation by activating c-Jun N-terminal kinase (JNK), translocation of BCL2 Associated X (Bax) to the mitochondria accompanied by cytochrome C release and loss of mitochondrial membrane potential promoting cleavage of caspase 3 and Poly(ADP-Ribose) Polymerase 1 (PARP). Inhibitors of JNK and caspase 3 promote survival of DRAK1 overexpressing cells demonstrating an important role of JNK signaling pathway in DRAK1-mediated apoptosis. DRAK1 mutant proteins that lack kinase activity or nuclear localization fail to induce apoptosis highlighting the importance of cellular localization and kinase function in promoting cell death. Our studies identify DRAK1 as a mediator of RNase L-induced apoptosis.
MiR-1208 Increases the Sensitivity to Cisplatin by Targeting TBCK in Renal Cancer Cells
Authors: Kim Eun-Ae , Jang Ji-Hoon , Sung Eon-Gi , Song In-Hwan , Kim Joo-Young , Lee Tae-Jin
Published: July 2019

MicroRNAs (miRNAs) can be used to target a variety of human malignancies by targeting their oncogenes or tumor suppressor genes. Recent evidence has shown that miRNA-1208 (miR-1208) was rarely expressed in a variety of cancer cells, suggesting the possibility that miR-1208 functions as a tumor suppressor gene. Herein, ectopic expression of miR-1208 induced the accumulation of sub-G1 populations and the cleavage of procaspase-3 and PARP, which could be prevented by pre-treatment with the pan-caspase inhibitor, Z-VAD. In addition, miR-1208 increased the susceptibility to cisplatin and TRAIL in Caki-1 cells. Luciferase reporter assay results showed that miR-1208 negatively regulates TBC1 domain containing kinase (TBCK) expression by binding to the miR-1208 binding sites in the 3′-untranslated region of TBCK. In addition, miR-1208 specifically repressed TBCK expression at the transcriptional level. In contrast, inhibition of endogenous miR-1208 by anti-miRs resulted in an increase in TBCK expression. Downregulation of TBCK induced by TBCK-specific siRNAs increased susceptibility to cisplatin and TRAIL. These findings suggest that miR-1208 acts as a tumor suppressor and targets TBCK directly, thus possessing great potential for use in renal cancer therapy.
Correction: Santos, J., et al. Proteomic Analysis of Cyclic Ketamine Compounds Ability to Induce Neural Differentiation in Human Adult Mesenchymal Stem Cells. International Journal of Molecular Sciences 2019, 20, 523
Authors: Santos Jerran , Milthorpe Bruce , Padula Matthew
Published: July 2019

The authors wish to make the following corrections to this paper [...]
Sex-Dimorphic Behavioral Alterations and Altered Neurogenesis in U12 Intron Splicing-Defective Zrsr1 Mutant Mice
Authors: Alén Francisco , Gómez-Redondo Isabel , Rivera Patricia , Suárez Juan , Ramos-Ibeas Priscila , Pericuesta Eva , Fernández-González Raul , Perez-Cerezales Serafín , Horiuchi Keiko , Orio Laura , Rodriguez de Fonseca Fernando , Gutiérrez-Adán Alfonso
Published: July 2019

Mutant mice with respect to the splicing factor Zrsr1 present altered spermatogenesis and infertility. To investigate whether Zrsr1 is involved in the homeostatic control that the hypothalamus exerts over reproductive functions, we first analyzed both differential gene and isoform expression and alternative splicing alterations in Zrsr1 mutant (Zrsr1mu) hypothalamus; second, we analyzed the spontaneous and social behavior of Zrsr1mu mice; and third, we analyzed adult cell proliferation and survival in the Zrsr1mu hypothalamus. The Zrsr1mu hypothalamus showed altered expression of genes and isoforms related to the glutathione metabolic process, synaptonemal complex assembly, mRNA transport, and altered splicing events involving the enrichment of U12-type intron retention (IR). Furthermore, increased IR in U12-containing genes related with the prolactin, progesterone, and gonadotropin-releasing hormone (GnRH) reproductive signaling pathway was observed. This was associated with a hyperactive phenotype in both males and females, with an anxious phenotype in females, and with increased social interaction in males, instead of the classical aggressive behavior. In addition, Zrsr1mu females but not males exhibited reduced cell proliferation in both the hypothalamus and the subventricular zone. Overall, these results suggest that Zrsr1 expression and function are relevant to organization of the hypothalamic cell network controlling behavior.
Role of Tricellular Tight Junction Protein Lipolysis-Stimulated Lipoprotein Receptor (LSR) in Cancer Cells
Authors: Kohno Takayuki , Konno Takumi , Kojima Takashi
Published: July 2019

Maintaining a robust epithelial barrier requires the accumulation of tight junction proteins, LSR/angulin-1 and tricellulin, at the tricellular contacts. Alterations in the localization of these proteins temporarily cause epithelial barrier dysfunction, which is closely associated with not only physiological differentiation but also cancer progression and metastasis. In normal human endometrial tissues, the endometrial cells undergo repeated proliferation and differentiation under physiological conditions. Recent observations have revealed that the localization and expression of LSR/angulin-1 and tricellulin are altered in a menstrual cycle-dependent manner. Moreover, it has been shown that endometrial cancer progression affects these alterations. This review highlights the differences in the localization and expression of tight junction proteins in normal endometrial cells and endometrial cancers and how they cause functional changes in cells.
Neuroprotective Potential of GDF11: Myth or Reality?
Authors: Rochette Luc , Malka Gabriel
Published: July 2019

In the brain, aging is accompanied by cellular and functional deficiencies that promote vulnerability to neurodegenerative disorders. In blood plasma from young and old animals, various factors such as growth differentiation factor 11 (GDF11), whose levels are elevated in young animals, have been identified. The blood concentrations of these factors appear to be inversely correlated with the age-related decline of neurogenesis. The identification of GDF11 as a “rejuvenating factor” opens up perspectives for the treatment of neurodegenerative diseases. As a pro-neurogenic and pro-angiogenic agent, GDF11 may constitute a basis for novel therapeutic strategies.
The Key Role of Epithelial to Mesenchymal Transition (EMT) in Hypertensive Kidney Disease
Authors: Seccia Teresa , Caroccia Brasilina , Piazza Maria , Rossi Gian Paolo
Published: July 2019

Accumulating evidence indicates that epithelial-to-mesenchymal transition (EMT), originally described as a key process for organ development and metastasis budding in cancer, plays a key role in the development of renal fibrosis in several diseases, including hypertensive nephroangiosclerosis. We herein reviewed the concept of EMT and its role in renal diseases, with particular focus on hypertensive kidney disease, the second leading cause of end-stage renal disease after diabetes mellitus. After discussing the pathophysiology of hypertensive nephropathy, the ‘classic’ view of hypertensive nephrosclerosis entailing hyalinization, and sclerosis of interlobular and afferent arterioles, we examined the changes occurring in the glomerulus and tubulo-interstitium and the studies that investigated the role of EMT and its molecular mechanisms in hypertensive kidney disease. Finally, we examined the reasons why some studies failed to provide solid evidence for renal EMT in hypertension.
Cell Type-Specific TGF-β Mediated EMT in 3D and 2D Models and Its Reversal by TGF-β Receptor Kinase Inhibitor in Ovarian Cancer Cell Lines
Authors: Al Ameri Wafa , Ahmed Ikhlak , Al-Dasim Fatima M. , Ali Mohamoud Yasmin , Al-Azwani Iman K. , Malek Joel A. , Karedath Thasni
Published: July 2019

Transcriptome profiling of 3D models compared to 2D models in various cancer cell lines shows differential expression of TGF-β-mediated and cell adhesion pathways. Presence of TGF-β in these cell lines shows an increased invasion potential which is specific to cell type. In the present study, we identified exogenous addition of TGF-β can induce Epithelial to Mesenchymal Transition (EMT) in a few cancer cell lines. RNA sequencing and real time PCR were carried out in different ovarian cancer cell lines to identify molecular profiling and metabolic profiling. Since EMT induction by TGF-β is cell-type specific, we decided to select two promising ovarian cancer cell lines as model systems to study EMT. TGF-β modulation in EMT and cancer invasion were successfully depicted in both 2D and 3D models of SKOV3 and CAOV3 cell lines. Functional evaluation in 3D and 2D models demonstrates that the addition of the exogenous TGF-β can induce EMT and invasion in cancer cells by turning them into aggressive phenotypes. TGF-β receptor kinase I inhibitor (LY364947) can revert the TGF-β effect in these cells. In a nutshell, TGF-β can induce EMT and migration, increase aggressiveness, increase cell survival, alter cell characteristics, remodel the Extracellular Matrix (ECM) and increase cell metabolism favorable for tumor invasion and metastasis. We concluded that transcriptomic and phenotypic effect of TGF-β and its inhibitor is cell-type specific and not cancer specific.
Deciphering the Origin and Evolution of the X1X2Y System in Two Closely-Related Oplegnathus Species (Oplegnathidae and Centrarchiformes)
Authors: Xu Dongdong , Sember Alexandr , Zhu Qihui , Oliveira Ezequiel Aguiar de , Liehr Thomas , Al-Rikabi Ahmed B. H. , Xiao Zhizhong , Song Hongbin , Cioffi Marcelo de Bello
Published: July 2019

Oplegnathus fasciatus and O. punctatus (Teleostei: Centrarchiformes: Oplegnathidae), are commercially important rocky reef fishes, endemic to East Asia. Both species present an X1X2Y sex chromosome system. Here, we investigated the evolutionary forces behind the origin and differentiation of these sex chromosomes, with the aim to elucidate whether they had a single or convergent origin. To achieve this, conventional and molecular cytogenetic protocols, involving the mapping of repetitive DNA markers, comparative genomic hybridization (CGH), and whole chromosome painting (WCP) were applied. Both species presented similar 2n, karyotype structure and hybridization patterns of repetitive DNA classes. 5S rDNA loci, besides being placed on the autosomal pair 22, resided in the terminal region of the long arms of both X1 chromosomes in females, and on the X1 and Y chromosomes in males. Furthermore, WCP experiments with a probe derived from the Y chromosome of O. fasciatus (OFAS-Y) entirely painted the X1 and X2 chromosomes in females and the X1, X2, and Y chromosomes in males of both species. CGH failed to reveal any sign of sequence differentiation on the Y chromosome in both species, thereby suggesting the shared early stage of neo-Y chromosome differentiation. Altogether, the present findings confirmed the origin of the X1X2Y sex chromosomes via Y-autosome centric fusion and strongly suggested their common origin.
Bakuchiol Suppresses Inflammatory Responses Via the Downregulation of the p38 MAPK/ERK Signaling Pathway
Authors: Lim Hye-Sun , Kim Yu Jin , Kim Bu-Yeo , Jeong Soo-Jin
Published: July 2019

The purpose of the present study was to evaluate the effects of bakuchiol on the inflammatory response and to identify the molecular mechanism of the inflammatory effects in a lipopolysaccharide (LPS)-stimulated BV-2 mouse microglial cell line and mice model. The production of prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) was measured by enzyme-linked immunosorbent assay. The mRNA expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), TNF-α, and IL-6 was measured using reverse transcription–polymerase chain reaction analysis. Mitogen-activated protein kinase (MAPK) phosphorylation was determined by western blot analysis. In vitro experiments, bakuchiol significantly suppressed the production of PGE2 and IL-6 in LPS-stimulated BV-2 cells, without causing cytotoxicity. In parallel, bakuchiol significantly inhibited the LPS-stimulated expression of iNOS, COX-2, and IL-6 in BV-2 cells. However, bakuchiol had no effect on the LPS-stimulated production and mRNA expression of TNF-α or on LPS-stimulated c-Jun NH2-terminal kinase phosphorylation. In contrast, p38 MAPK and extracellular signal-regulated kinase (ERK) phosphorylation were inhibited by bakuchiol. In vivo experiments, Bakuchiol reduced microglial activation in the hippocampus and cortex tissue of LPS-injected mice. Bakuchiol significantly suppressed LPS-injected production of TNF-α and IL-6 in serum. These results indicate that the anti-neuroinflammatory effects of bakuchiol in activated microglia are mainly regulated by the inhibition of the p38 MAPK and ERK pathways. We suggest that bakuchiol may be beneficial for various neuroinflammatory diseases.
Reactive Oxygen Species in Osteoclast Differentiation and Possible Pharmaceutical Targets of ROS-Mediated Osteoclast Diseases
Authors: Agidigbi Taiwo Samuel , Kim Chaekyun
Published: July 2019

Reactive oxygen species (ROS) and free radicals are essential for transmission of cell signals and other physiological functions. However, excessive amounts of ROS can cause cellular imbalance in reduction–oxidation reactions and disrupt normal biological functions, leading to oxidative stress, a condition known to be responsible for the development of several diseases. The biphasic role of ROS in cellular functions has been a target of pharmacological research. Osteoclasts are derived from hematopoietic progenitors in the bone and are essential for skeletal growth and remodeling, for the maintenance of bone architecture throughout lifespan, and for calcium metabolism during bone homeostasis. ROS, including superoxide ion (O2−) and hydrogen peroxide (H2O2), are important components that regulate the differentiation of osteoclasts. Under normal physiological conditions, ROS produced by osteoclasts stimulate and facilitate resorption of bone tissue. Thus, elucidating the effects of ROS during osteoclast differentiation is important when studying diseases associated with bone resorption such as osteoporosis. This review examines the effect of ROS on osteoclast differentiation and the efficacy of novel chemical compounds with therapeutic potential for osteoclast related diseases.
Biological Functions and Molecular Mechanisms of Antibiotic Tigecycline in the Treatment of Cancers
Authors: Dong Zhen , Abbas Muhammad Nadeem , Kausar Saima , Yang Jie , Li Lin , Tan Li , Cui Hongjuan
Published: July 2019

As an FDA-approved drug, glycylcycline tigecycline has been used to treat complicated microbial infections. However, recent studies in multiple hematologic and malignant solid tumors reveal that tigecycline treatment induces cell cycle arrest, apoptosis, autophagy and oxidative stress. In addition, tigecycline also inhibits mitochondrial oxidative phosphorylation, cell proliferation, migration, invasion and angiogenesis. Importantly, combinations of tigecycline with chemotherapeutic or targeted drugs such as venetoclax, doxorubicin, vincristine, paclitaxel, cisplatin, and imatinib, have shown to be promising strategies for cancer treatment. Mechanism of action studies reveal that tigecycline leads to the inhibition of mitochondrial translation possibly through interacting with mitochondrial ribosome. Meanwhile, this drug also interferes with several other cell pathways/targets including MYC, HIFs, PI3K/AKT or AMPK-mediated mTOR, cytoplasmic p21 CIP1/Waf1, and Wnt/β-catenin signaling. These evidences indicate that antibiotic tigecycline is a promising drug for cancer treatment alone or in combination with other anticancer drugs. This review summarizes the biological function of tigecycline in the treatment of tumors and comprehensively discusses its mode of action.
The Cytoskeleton of the Retinal Pigment Epithelium: from Normal Aging to Age-Related Macular Degeneration
Authors: Tarau Ioana-Sandra , Berlin Andreas , Curcio Christine A. , Ach Thomas
Published: July 2019

The retinal pigment epithelium (RPE) is a unique epithelium, with major roles which are essential in the visual cycle and homeostasis of the outer retina. The RPE is a monolayer of polygonal and pigmented cells strategically placed between the neuroretina and Bruch membrane, adjacent to the fenestrated capillaries of the choriocapillaris. It shows strong apical (towards photoreceptors) to basal/basolateral (towards Bruch membrane) polarization. Multiple functions are bound to a complex structure of highly organized and polarized intracellular components: the cytoskeleton. A strong connection between the intracellular cytoskeleton and extracellular matrix is indispensable to maintaining the function of the RPE and thus, the photoreceptors. Impairments of these intracellular structures and the regular architecture they maintain often result in a disrupted cytoskeleton, which can be found in many retinal diseases, including age-related macular degeneration (AMD). This review article will give an overview of current knowledge on the molecules and proteins involved in cytoskeleton formation in cells, including RPE and how the cytoskeleton is affected under stress conditions—especially in AMD.
BNP as a Major Player in the Heart-Kidney Connection
Authors: Okamoto Ryuji , Ali Yusuf , Hashizume Ryotaro , Suzuki Noboru , Ito Masaaki
Published: July 2019

Brain natriuretic peptide (BNP) is an important biomarker for patients with heart failure, hypertension and cardiac hypertrophy. Although it is known that BNP levels are relatively higher in patients with chronic kidney disease and no heart disease, the mechanism remains unknown. Here, we review the functions and the roles of BNP in the heart-kidney interaction. In addition, we discuss the relevant molecular mechanisms that suggest BNP is protective against chronic kidney diseases and heart failure, especially in terms of the counterparts of the renin-angiotensin-aldosterone system (RAAS). The renal medulla has been reported to express depressor substances. The extract of the papillary tips from kidneys may induce the expression and secretion of BNP from cardiomyocytes. A better understanding of these processes will help accelerate pharmacological treatments for heart-kidney disease.
In Silico Analysis of Gene Expression Change Associated with Copy Number of Enhancers in Pancreatic Adenocarcinoma
Authors: Kumar Rajesh , Patiyal Sumeet , Kumar Vinod , Nagpal Gandharva , Raghava Gajendra P.S.
Published: July 2019

Understanding the gene regulatory network governing cancer initiation and progression is necessary, although it remains largely unexplored. Enhancer elements represent the center of this regulatory circuit. The study aims to identify the gene expression change driven by copy number variation in enhancer elements of pancreatic adenocarcinoma (PAAD). The pancreatic tissue specific enhancer and target gene data were taken from EnhancerAtlas. The gene expression and copy number data were taken from The Cancer Genome Atlas (TCGA). Differentially expressed genes (DEGs) and copy number variations (CNVs) were identified between matched tumor-normal samples of PAAD. Significant CNVs were matched onto enhancer coordinates by using genomic intersection functionality from BEDTools. By combining the gene expression and CNV data, we identified 169 genes whose expression shows a positive correlation with the CNV of enhancers. We further identified 16 genes which are regulated by a super enhancer and 15 genes which have high prognostic potential (Z-score > 1.96). Cox proportional hazard analysis of these genes indicates that these are better predictors of survival. Taken together, our integrative analytical approach identifies enhancer CNV-driven gene expression change in PAAD, which could lead to better understanding of PAAD pathogenesis and to the design of enhancer-based cancer treatment strategies.
Ureaplasma Species Modulate Cytokine and Chemokine Responses in Human Brain Microvascular Endothelial Cells
Authors: Silwedel Christine , Speer Christian P. , Haarmann Axel , Fehrholz Markus , Claus Heike , Schlegel Nicolas , Glaser Kirsten
Published: July 2019

Ureaplasma species are common colonizers of the adult genitourinary tract and often considered as low-virulence commensals. Intraamniotic Ureaplasma infections, however, facilitate chorioamnionitis and preterm birth, and cases of Ureaplasma-induced neonatal sepsis, pneumonia, and meningitis raise a growing awareness of their clinical relevance. In vitro studies are scarce but demonstrate distinct Ureaplasma-driven impacts on immune mechanisms. The current study addressed cytokine and chemokine responses upon exposure of native or lipopolysaccharide (LPS) co-stimulated human brain microvascular endothelial cells (HBMEC) to Ureaplasma urealyticum or U. parvum, using qRT-PCR, RNA sequencing, multi-analyte immunoassay, and flow cytometry. Ureaplasma exposure in native HBMEC reduced monocyte chemoattractant protein (MCP)-3 mRNA expression (p < 0.01, vs. broth). In co-stimulated HBMEC, Ureaplasma spp. attenuated LPS-evoked mRNA responses for C-X-C chemokine ligand 5, MCP-1, and MCP-3 (p < 0.05, vs. LPS) and mitigated LPS-driven interleukin (IL)-1α protein secretion, as well as IL-8 mRNA and protein responses (p < 0.05). Furthermore, Ureaplasma isolates increased C-X-C chemokine receptor 4 mRNA levels in native and LPS co-stimulated HBMEC (p < 0.05). The presented results may imply immunomodulatory capacities of Ureaplasma spp. which may ultimately promote chronic colonization and long-term neuroinflammation.
The Probing Behavior Component of Disease Transmission in Insect-Transmitted Bacterial Plant Pathogens
Authors: Ebert Timothy A.
Published: July 2019

Insects can be effective vectors of plant diseases and this may result in billions of dollars in lost agricultural productivity. New, emerging or introduced diseases will continue to cause extensive damage in afflicted areas. Understanding how the vector acquires the pathogen and inoculates new hosts is critical in developing effective management strategies. Management may be an insecticide applied to kill the vector or a host plant resistance mechanism to make the host plant less suitable for the vector. In either case, the tactic must act before the insect performs the key behavior(s) resulting in either acquisition or transmission. This requires knowledge of the timing of behaviors the insect uses to probe the plant and commence ingestion. These behaviors are visualized using electropenetrography (EPG), wherein the plant and insect become part of an electrical circuit. With the tools to define specific steps in the probing process, we can understand the timing of acquisition and inoculation. With that understanding comes the potential for more relevant testing of management strategies, through insecticides or host plant resistance. The primary example will be Candidatus Liberibacter asiaticus transmitted by Diaphorina citri Kuwayama in the citrus agroecosystem, with additional examples used as appropriate.
Pollen Release Dynamics and Daily Patterns of Pollen-Collecting Activity of Honeybee Apis mellifera and Bumblebee Bombus lantschouensis in Solar Greenhouse
Authors: Zhang Hong , Zhou Zhiyong , An Jiandong
Published: July 2019

Pollen is important not only for pollination and fertilization of plants, but also for colony development of bee pollinators. Anther dehiscence determines the available pollen that can be collected by foragers. In China, honeybees and bumblebees are widely used as pollinators in solar greenhouse agriculture. To better understand the effect of solar greenhouse microclimates on pollen release and pollen-foraging behaviour, we observed the anther dehiscence dynamics and daily pollen-collecting activity of Apis mellifera and Bombus lantschouensis during peach anthesis in a solar greenhouse in Beijing. Microclimate factors had a significant effect on anther dehiscence and bee foraging behaviour. The proportion of dehisced anthers increased with increasing temperature and decreasing relative humidity and peaked from 11:00 h to 14:00 h, coinciding with the peak pollen-collecting activity of bees. On sunny days, most pollen grains were collected by the two pollinators within two hours after anther dehiscence, at which time the viability of pollen had not yet significantly decreased. Our study helps us to better understand the relationship between food resources and pollinator foraging behaviour and to make better use of bees for pollination in Chinese solar greenhouses.
Multidirectional Pin-on-Disk Testing Device to Evaluate the Cross-shear Effect on the Wear of Biocompatible Materials
Authors: Cortes Vicente , Rodriguez Betancourth Carlos A. , Ortega Javier A. , Huq Hasina
Published: July 2019

One of the main causes of hip prostheses failure is the premature wear of their components. Multi-directional motion or “cross-shear” motion has been identified as one of the most significant factors affecting the wear rate of UHMWPE in total hip joint replacement prostheses. To better evaluate the effect of this cross-shear motion on the tribological behavior of different biomaterials, a new wear testing device has been designed and developed. This new instrument is capable to reproduce the “cross-shear” effect with bidirectional motion on bearing materials and to determine coefficient of friction (COF) between surfaces during testing. To validate the functionality of this new testing platform, alumina balls were articulated against Ti-6Al-4V ELI alloy disks in Ringer’s solution. Four different articulation patterns, all with identical path lengths per cycle, were tested. Gravimetric weight loss was converted to volumetric wear data in order to determine the effects of motion patterns on the wear. Worn surfaces were analyzed by scanning electron microscopy. This scientific approach to quantifying the tribological effects of cross-shear provides fundamental data that are crucial in evaluating potential biomaterials for use in knee and hip joint replacements.
Serum Vitamin E Levels of Adults with Nonalcoholic Fatty Liver Disease: An Inverse Relationship with All-Cause Mortality in Non-Diabetic but Not in Pre-Diabetic or Diabetic Subjects
Authors: Tsou Peiling , Wu Chang-Jiun
Published: July 2019

Nonalcoholic fatty liver disease (NAFLD) is a growing health threat worldwide. Vitamin E supplementation is recommended for nonalcoholic steatohepatitis (NASH) patients, but only for non-diabetic subjects. We aimed to investigate whether serum vitamin E levels differently impact long-term prognosis in diabetic versus non-diabetic NAFLD individuals. A total of 2404 ultrasonographically defined NAFLD individuals from National Health and Nutrition Examination Survey (NHANES) III were stratified by their glycemic statuses into diabetic (N = 662), pre-diabetic (N = 836) and non-diabetic (N = 906), and the relationship between serum vitamin E levels and all-cause mortality was analyzed. The serum vitamin E concentrations were 31.1 ± 14.1, 26.7 ± 9.6, and 24.7 ± 9.8 µmol/L and vitamin E: total cholesterol ratios were 5.16 ± 1.70, 4.81 ± 1.46, and 4.80 ± 1.34 µmol/mmol in in diabetic, pre-diabetic, and non-diabetic groups, respectively. Of 2404 NAFLD subjects, 2403 have mortality information and 152 non-diabetic, 244 pre-diabetic, and 342 diabetic participants died over a median follow-up period of 18.8 years. Both serum vitamin E levels and vitamin E: total cholesterol ratios were negatively associated with all-cause mortality after adjusting for possible confounders in non-diabetic subjects (HR = 0.483, and 0.451, respectively, p < 0.005), but not in either diabetic or pre-diabetic subjects. In NAFLD individuals, both serum vitamin E and lipid-corrected vitamin E were (1) higher in the diabetic group; and (2) negatively associated with all-cause mortality only in the non-diabetic group. Further investigations are warranted to elucidate the underlying mechanism of this inverse association of serum vitamin E concentration with all-cause mortality in non-diabetic but not pre-diabetic or diabetic subjects.
The Potential of Cannabidiol as a Treatment for Psychosis and Addiction: Who Benefits Most? A Systematic Review
Authors: Batalla Albert , Janssen Hella , Gangadin Shiral S. , Bossong Matthijs G.
Published: July 2019

The endogenous cannabinoid (eCB) system plays an important role in the pathophysiology of both psychotic disorders and substance use disorders (SUDs). The non-psychoactive cannabinoid compound, cannabidiol (CBD) is a highly promising tool in the treatment of both disorders. Here we review human clinical studies that investigated the efficacy of CBD treatment for schizophrenia, substance use disorders, and their comorbidity. In particular, we examined possible profiles of patients who may benefit the most from CBD treatment. CBD, either as monotherapy or added to regular antipsychotic medication, improved symptoms in patients with schizophrenia, with particularly promising effects in the early stages of illness. A potential biomarker is the level of anandamide in blood. CBD and THC mixtures showed positive effects in reducing short-term withdrawal and craving in cannabis use disorders. Studies on schizophrenia and comorbid substance use are lacking. Future studies should focus on the effects of CBD on psychotic disorders in different stages of illness, together with the effects on comorbid substance use. These studies should use standardized measures to assess cannabis use. In addition, future efforts should be taken to study the relationship between the eCB system, GABA/glutamate, and the immune system to reveal the underlying neurobiology of the effects of CBD.
Recent Updates on Molecular Imaging Reporting and Data Systems (MI-RADS) for Theranostic Radiotracers—Navigating Pitfalls of SSTR- and PSMA-Targeted PET/CT
Authors: Werner Rudolf A. , Thackeray James T. , Pomper Martin G. , Bengel Frank M. , Gorin Michael A. , Derlin Thorsten , Rowe Steven P.
Published: July 2019

The theranostic concept represents a paradigmatic example of personalized treatment. It is based on the use of radiolabeled compounds which can be applied for both diagnostic molecular imaging and subsequent treatment, using different radionuclides for labelling. Clinically relevant examples include somatostatin receptor (SSTR)-targeted imaging and therapy for the treatment of neuroendocrine tumors (NET), as well as prostate-specific membrane antigen (PSMA)-targeted imaging and therapy for the treatment of prostate cancer (PC). As such, both classes of radiotracers can be used to triage patients for theranostic endoradiotherapy using positron emission tomography (PET). While interpreting PSMA- or SSTR-targeted PET/computed tomography scans, the reader has to navigate certain pitfalls, including (I.) varying normal biodistribution between different PSMA- and SSTR-targeting PET radiotracers, (II.) varying radiotracer uptake in numerous kinds of both benign and malignant lesions, and (III.) resulting false-positive and false-negative findings. Thus, two novel reporting and data system (RADS) classifications for PSMA- and SSTR-targeted PET imaging (PSMA- and SSTR-RADS) have been recently introduced under the umbrella term molecular imaging reporting and data systems (MI-RADS). Notably, PSMA- and SSTR-RADS are structured in a reciprocal fashion, i.e., if the reader is familiar with one system, the other system can readily be applied. Learning objectives of the present case-based review are as follows: (I.) the theranostic concept for the treatment of NET and PC will be briefly introduced, (II.) the most common pitfalls on PSMA- and SSTR-targeted PET/CT will be identified, (III.) the novel framework system for theranostic radiotracers (MI-RADS) will be explained, applied to complex clinical cases and recent studies in the field will be highlighted. Finally, current treatment strategies based on MI-RADS will be proposed, which will demonstrate how such a generalizable framework system truly paves the way for clinically meaningful molecular imaging-guided treatment of either PC or NET. Thus, beyond an introduction of MI-RADS, the present review aims to provide an update of recently published studies which have further validated the concept of structured reporting systems in the field of theranostics.