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Laboratory Investigation; a Journal of Technical Methods and Pathology

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https://read.qxmd.com/read/30996296/optimized-cultivation-of-porcine-choroid-plexus-epithelial-cells-a-blood-cerebrospinal-fluid-barrier-model-for-studying-granulocyte-transmigration
#1
Alexa N Lauer, Martin März, Svenja Meyer, Marita Meurer, Nicole de Buhr, Julia Borkowski, Christel Weiß, Horst Schroten, Christian Schwerk
The blood-cerebrospinal fluid barrier (BCSFB) plays important roles during the transport of substances into the brain, the pathogenesis of central nervous system (CNS) diseases, and neuro-immunological processes. Along these lines, transmigration of granulocytes across the blood-cerebrospinal fluid (CSF) barrier (BCSFB) is a hallmark of inflammatory events in the CNS. Choroid plexus (CP) epithelial cells are an important tool to generate in vitro models of the BCSFB. A porcine CP epithelial cell line (PCP-R) has been shown to present properties of the BCSFB, including a strong barrier function, when cultivated on cell culture filter inserts containing a membrane with 0...
April 17, 2019: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://read.qxmd.com/read/30996295/therapeutic-potential-of-plk1-inhibition-in-triple-negative-breast-cancer
#2
Ai Ueda, Keiki Oikawa, Koji Fujita, Akio Ishikawa, Eiichi Sato, Takashi Ishikawa, Masahiko Kuroda, Kohsuke Kanekura
Triple negative breast cancer (TNBC) is responsible for significant number of breast cancer-associated deaths because of lacking of successful molecular-targeted therapy. To explore a therapeutic target for TNBC, we performed a siRNA-mediated knockdown screening and identified Polo-like kinase 1 (PLK1) as a potential therapeutic target for TNBC. Knockdown of PLK1 as well as a small compound inhibitor for PLK1, BI-2536, induced G2/M arrest and created polyploid cell population, shown by increased DNA content and nuclear size...
April 17, 2019: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://read.qxmd.com/read/30988371/autophagy-related-7-modulates-tumor-progression-in-triple-negative-breast-cancer
#3
Mingyang Li, Jingwei Liu, Sihui Li, Yanling Feng, Fei Yi, Liang Wang, Shi Wei, Liu Cao
The exact role of autophagy in breast cancers remains elusive. In this study, we explored the potential functions of autophagy-related 7 (Atg7) in breast cancer cell lines and tissues. Compared to normal breast tissue, a significantly lower expression of Atg7 was observed in triple-negative breast cancer (TNBC), but not other subtypes. A higher Atg7 expression was significantly associated with favorable clinicopathologic factors and better prognostic outcomes in patients with TNBC. Reflecting the clinical and pathologic observations, Atg7 was found to inhibit proliferation and migration, but promotes apoptosis in TNBC cell lines...
April 15, 2019: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://read.qxmd.com/read/30976056/micheliolide-ameliorates-renal-fibrosis-by-suppressing-the-mtdh-bmp-mapk-pathway
#4
Fenfen Peng, Hongyu Li, Shuting Li, Yuxian Wang, Wenting Liu, Wangqiu Gong, Bohui Yin, Sijia Chen, Ying Zhang, Congwei Luo, Weidong Zhou, Yihua Chen, Peilin Li, Qianyin Huang, Zhaozhong Xu, Haibo Long
Micheliolide (MCL), derived from parthenolide (PTL), is known for its antioxidant and anti-inflammatory effects and has multiple roles in inflammatory diseases and tumours. To investigate its effect on renal disease, we intragastrically administrated DMAMCL, a dimethylamino Michael adduct of MCL for in vivo use, in two renal fibrosis models-the unilateral ureteral occlusion (UUO) model and an ischaemia-reperfusion injury (IRI) model and used MCL in combination with transforming growth factor beta 1 (TGF-β1) on mouse tubular epithelial cells (mTEC) in vitro...
April 11, 2019: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://read.qxmd.com/read/30952940/inhibition-of-prolyl-hydroxylase-domain-phd-by-jtz-951-reduces-obesity-related-diseases-in-the-liver-white-adipose-tissue-and-kidney-in-mice-with-a-high-fat-diet
#5
Hisako Saito, Tetsuhiro Tanaka, Mai Sugahara, Shinji Tanaka, Kenji Fukui, Takeshi Wakashima, Masaomi Nangaku
The epidemic of obesity and its complications is rapidly increasing worldwide. Recent drug discoveries established the utility of prolyl hydroxylase domain (PHD) inhibitors as stabilizers of hypoxia-inducible factors (HIFs) in vivo, which are currently in human clinical studies for the treatment of anemia in chronic kidney disease (CKD). These studies suggest a role for PHD inhibitors in ameliorating obesity and hyperlipidemia. We hypothesized that HIF activation using a PHD inhibitor, JTZ-951, protects from obesity-related diseases in the white adipose tissue (WAT), liver, and kidney in mice fed with high-fat diet (HFD)...
April 5, 2019: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://read.qxmd.com/read/30918326/repeat-associated-non-aug-ran-translation-insights-from-pathology
#6
REVIEW
Monica Banez-Coronel, Laura P W Ranum
More than 40 different neurological diseases are caused by microsatellite repeat expansions. Since the discovery of repeat-associated non-AUG (RAN) translation by Zu et al. in 2011, nine expansion disorders have been identified as RAN-positive diseases. RAN proteins are translated from different types of nucleotide repeat expansions and can be produced from both sense and antisense transcripts. In some diseases, RAN proteins have been shown to accumulate in affected brain regions. Here we review the pathological and molecular aspects associated with RAN protein accumulation for each particular disorder, the correlation between disease pathology and the available in vivo models and the common aspects shared by some of the newly discovered RAN proteins...
March 27, 2019: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://read.qxmd.com/read/30918325/human-relaxin-2-attenuates-hepatic-steatosis-and-fibrosis-in-mice-with-non-alcoholic-fatty-liver-disease
#7
Kuei-Chuan Lee, Yun-Cheng Hsieh, Che-Chang Chan, Hao-Jhe Sun, Yi-Hsiang Huang, Ming-Chih Hou, Han-Chieh Lin
Human relaxin-2 reduces hepatic fibrosis in mice. However, the effects of relaxin-2 on hepatic steatosis and fibrosis in animals with non-alcoholic fatty liver disease (NAFLD) remain to be elucidated. C57BL/6 mice fed a high-fat diet (HFD) or methionine-choline-deficient (MCD) diet were randomly assigned to receive recombinant human relaxin-2 (25 or 75 μg/kg/day) or vehicle for 4 weeks. In HFD-fed mice, relaxin-2 decreased systemic insulin resistance and reduced body weight, epididymal fat mass and serum leptin and insulin concentrations...
March 27, 2019: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://read.qxmd.com/read/30914782/b7h3-regulates-differentiation-and-serves-as-a-potential-biomarker-and-theranostic-target-for-human-glioblastoma
#8
Jingwen Zhang, Jinhua Wang, Diego M Marzese, Xiaowen Wang, Zixiao Yang, Chunjie Li, Haibo Zhang, Jinsen Zhang, Clark C Chen, Daniel F Kelly, Wei Hua, Dave S B Hoon, Ying Mao
B7H3 (CD276), a co-stimulator molecule of the cell surface B7 protein superfamily, is expressed on glioblastomas (GBM). Recently, B7H3 functions beyond immune costimulation have been demonstrated. However, the mechanisms underlying B7H3 function are diverse and not well understood. GBM tumors contain undifferentiated self-renewing cells, which confound therapeutic attempts. We investigated the role of B7H3 in the regulation of GBM cell differentiation and the regulatory pathways involved. Analysis of public databases (TCGA, Rembrandt, and GEO NCBI) and RNA sequencing were performed to explore the role of B7H3 in GBM...
March 26, 2019: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://read.qxmd.com/read/30911151/endotoxemia-induced-endothelial-fibrosis-inhibition-improves-hypotension-tachycardia-multiple-organ-dysfunction-syndrome-cytokine-response-oxidative-stress-and-survival
#9
Alejandro Vallejos, Pedro Olivares, Sebastian Gatica, Vicente Villegas, Cesar Echeverria, Claudio Cabello-Verrugio, Felipe Simon
Sepsis syndrome is the leading cause of mortality in critically ill patients admitted to intensive care. However, current therapies for sepsis treatment are unsatisfactory, and the mortality rate is still high. The main pathological characteristics observed during sepsis syndrome and endotoxemia include hypotension, tachycardia, multiple organ dysfunction syndrome (MODS), tissue damage, and cytokine and oxidative bursts. These conditions severely decrease the survival rates of endotoxemic patients. As a consequence of endotoxemia, large amounts of endotoxin circulate in the bloodstream throughout the vascular system and interact directly with endothelial cells that cover the inner wall of blood vessels...
March 25, 2019: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://read.qxmd.com/read/30911150/activation-of-death-associated-protein-kinase-1-promotes-neutrophil-apoptosis-to-accelerate-inflammatory-resolution-in-acute-respiratory-distress-syndrome
#10
Shu-Nan Cui, Lin Chen, Yi-Yi Yang, Ya-Xin Wang, Sheng-Nan Li, Ting Zhou, Hai-Rong Xiao, Lu Qin, Wen Yang, Shi-Ying Yuan, Shang-Long Yao, You Shang
Acute respiratory distress syndrome (ARDS) is a uniform progression of overwhelming inflammation in lung tissue with extensive infiltration of inflammatory cells. Neutrophil apoptosis is thought to be a significant process in the control of the resolution phase of inflammation. It has been proved that 5-Aza-2'-deoxycytidine (Aza) can inhibit cancer by activating death-associated protein kinase 1 (DAPK1) to promote apoptosis. However, the effect of DAPK1 on neutrophil apoptosis is unclear, and research on the role of Aza in inflammation is lacking...
March 25, 2019: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://read.qxmd.com/read/30894671/mitochondrial-localization-of-pabpn1-in-oculopharyngeal-muscular-dystrophy
#11
Tsukasa Doki, Satoshi Yamashita, Fan-Yan Wei, Kentaro Hara, Takahiro Yamamoto, Ziwei Zhang, Xiao Zhang, Nozomu Tawara, Hirotake Hino, Eiichiro Uyama, Takashi Kurashige, Hirofumi Maruyama, Kazuhito Tomizawa, Yukio Ando
Oculopharyngeal muscular dystrophy (OPMD) is a late-onset disorder characterized by ptosis, dysphagia, and weakness of proximal limbs. OPMD is caused by the expansion of polyalanine in poly(A)-binding protein, nuclear 1 (PABPN1). Although mitochondrial abnormality has been proposed as the possible etiology, the molecular pathogenesis is still poorly understood. The aim of the study was to specify the mechanism by which expanded PABPN1 causes mitochondrial dysfunction in OPMD. We evaluated whether transgenic mouse model of OPMD, by expressing expanded PABPN1, indeed causes mitochondrial abnormality associated with muscle degeneration...
March 20, 2019: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://read.qxmd.com/read/30837678/reversal-of-tet-mediated-5-hmc-loss-in-hypoxic-fibroblasts-by-ascorbic-acid
#12
Yukun Liu, Shuyun Xu, Tingjian Zu, Feng Li, Shengbo Sang, Cynthia Liu, Yang An, Bobin Mi, Dennis P Orgill, George F Murphy, Christine G Lian
Hypoxia resulting in hypoxia-inducible factor-1 alpha (HIF-1α) induction is known to drive scar formation during cutaneous wound healing, and may be responsible for excessive fibrosis inherent to hypertrophic scars and keloids. Because epigenetic pathways play an important role in regulation of fibrosing processes, we evaluated patient scars for DNA hydroxymethylation (5-hydroxymethylcytosine; 5-hmC) status and documented a significant decrease in scar fibroblasts. To test this finding in vitro, human fibroblasts were cultured with cobalt chloride (CoCl2 ), a known stimulant of HIF-1α...
March 5, 2019: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://read.qxmd.com/read/30808930/polydatin-mediates-parkin-dependent-mitophagy-and-protects-against-mitochondria-dependent-apoptosis-in-acute-respiratory-distress-syndrome
#13
Tao Li, Youtan Liu, Wei Xu, Xingui Dai, Ruimeng Liu, Youguang Gao, Zhongqing Chen, Yunfeng Li
Mitophagy removes dysfunctional mitochondria and is known to play an important role in the pathogenesis of several diseases; however, the role of mitophagy in acute respiratory distress syndrome (ARDS) remains poorly understood. While we have previously demonstrated that polydatin (PD) improves lipopolysaccharide (LPS)-induced ARDS, the specific mechanism remains unclear. In present study, we aimed to determine whether PD activates Parkin-dependent mitophagy to protect against LPS-induced mitochondria-dependent apoptosis and lung injury...
February 26, 2019: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://read.qxmd.com/read/30808929/the-beneficial-effects-of-physical-exercise-in-the-brain-and-related-pathophysiological-mechanisms-in-neurodegenerative-diseases
#14
REVIEW
Yan Liu, Tim Yan, John Man-Tak Chu, Ying Chen, Sophie Dunnett, Yuen-Shan Ho, Gordon Tin-Chun Wong, Raymond Chuen-Chung Chang
Growing evidence has shown the beneficial influence of exercise on humans. Apart from classic cardioprotection, numerous studies have demonstrated that different exercise regimes provide a substantial improvement in various brain functions. Although the underlying mechanism is yet to be determined, emerging evidence for neuroprotection has been established in both humans and experimental animals, with most of the valuable findings in the field of mental health, neurodegenerative diseases, and acquired brain injuries...
February 26, 2019: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://read.qxmd.com/read/30778164/opposing-roles-of-tcf7-lef1-and-tcf7l2-in-cyclin-d2-and-bmp4-expression-and-cardiomyocyte-cell-cycle-control-during-late-heart-development
#15
Bo Ye, Liwen Li, Haodong Xu, Yiping Chen, Faqian Li
Bone morphogenetic protein (BMP) and Wnt pathways regulate cell proliferation and differentiation, but how these two pathways interact and mediate their nuclear actions in the heart, especially during late cardiac development, remains poorly defined. T-cell factor (TCF) and lymphoid enhancer factor (LEF) family transcriptional factors, including Lef1, Tcf7, Tcf7l1, and Tcf7l2, are important nuclear mediators of canonical Wnt/β-catenin signaling throughout cardiac development. We reveal that these TCF/LEF family members direct heart maturation through distinct temporal and spatial control...
February 18, 2019: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://read.qxmd.com/read/30770886/artificial-intelligence-in-neuropathology-deep-learning-based-assessment-of-tauopathy
#16
Maxim Signaevsky, Marcel Prastawa, Kurt Farrell, Nabil Tabish, Elena Baldwin, Natalia Han, Megan A Iida, John Koll, Clare Bryce, Dushyant Purohit, Vahram Haroutunian, Ann C McKee, Thor D Stein, Charles L White, Jamie Walker, Timothy E Richardson, Russell Hanson, Michael J Donovan, Carlos Cordon-Cardo, Jack Zeineh, Gerardo Fernandez, John F Crary
Accumulation of abnormal tau in neurofibrillary tangles (NFT) occurs in Alzheimer disease (AD) and a spectrum of tauopathies. These tauopathies have diverse and overlapping morphological phenotypes that obscure classification and quantitative assessments. Recently, powerful machine learning-based approaches have emerged, allowing the recognition and quantification of pathological changes from digital images. Here, we applied deep learning to the neuropathological assessment of NFT in postmortem human brain tissue to develop a classifier capable of recognizing and quantifying tau burden...
February 15, 2019: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://read.qxmd.com/read/30760866/autonomous-trisomic-rescue-of-down-syndrome-cells
#17
Momoko Inoue, Kazuhiro Kajiwara, Ayumi Yamaguchi, Tohru Kiyono, Osamu Samura, Hidenori Akutsu, Haruhiko Sago, Aikou Okamoto, Akihiro Umezawa
Down syndrome is the most frequent chromosomal abnormality among live-born infants. All Down syndrome patients have mental retardation and are prone to develop early onset Alzheimer's disease. However, it has not yet been elucidated whether there is a correlation between the phenotype of Down syndrome and the extra chromosome 21. In this study, we continuously cultivated induced pluripotent stem cells (iPSCs) with chromosome 21 trisomy for more than 70 weeks, and serendipitously obtained revertant cells with normal chromosome 21 diploids from the trisomic cells during long-term cultivation...
February 13, 2019: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://read.qxmd.com/read/30760865/lipopolysaccharide-promotes-lung-fibroblast-proliferation-through-autophagy-inhibition-via-activation-of-the-pi3k-akt-mtor-pathway
#18
Tingting Xie, Qiaoyi Xu, Hanxi Wan, Shunpeng Xing, Chen Shang, Yuan Gao, Zhengyu He
Pulmonary fibrosis is a major cause of death in patients with acute respiratory distress syndrome (ARDS). Our previous study revealed that lipopolysaccharide (LPS) challenge could lead to mouse lung fibroblast proliferation. Additionally, inhibition of autophagy in lung fibroblasts was also reported to be crucial during the process of pulmonary fibrosis. However, the correlation between proliferation and inhibition of autophagy of lung fibroblasts and the underlying mechanism remain unknown. In this study, we report that autophagy was inhibited in mouse lung fibroblasts after LPS challenge, and was accompanied by activation of the PI3K-Akt-mTOR signaling pathway...
February 13, 2019: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://read.qxmd.com/read/30760864/transmission-of-%C3%AE-synuclein-seeds-in-neurodegenerative-disease-recent-developments
#19
REVIEW
Richard J Karpowicz, John Q Trojanowski, Virginia M-Y Lee
Cell-to-cell transmission of proteopathic alpha-synuclein (α-syn) seeds is increasingly thought to underlie the progression of neurodegenerative diseases including Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and related synucleinopathies. As such, it is important to understand the chemical and biological relationships between cells and pathological aggregates of α-syn. This brief review updates our understanding of the templated spread of α-syn pathology in neurodegenerative disease from the perspective of proteopathic α-syn seeds, including how these seeds are processed by cells as well as their effects on cellular function...
February 13, 2019: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://read.qxmd.com/read/30760863/the-amyloid-cascade-and-alzheimer-s-disease-therapeutics-theory-versus-observation
#20
REVIEW
Rudy J Castellani, Germán Plascencia-Villa, George Perry
The identification of amyloid-β precursor protein (APP) pathogenic mutations in familial early onset Alzheimer's disease (AD), along with knowledge that amyloid-β (Aβ) was the principle protein component of senile plaques, led to the establishment of the amyloid cascade hypothesis. Down syndrome substantiated the hypothesis, given an extra copy of the APP gene and invariable AD pathology hallmarks that occur by middle age. An abundance of support for the amyloid cascade hypothesis followed. Prion-like protein misfolding and non-Mendelian transmission of neurotoxicity are among recent areas of investigation...
February 13, 2019: Laboratory Investigation; a Journal of Technical Methods and Pathology
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