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Laboratory Investigation; a Journal of Technical Methods and Pathology

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https://www.readbyqxmd.com/read/29977037/knockout-of-secretin-receptor-reduces-biliary-damage-and-liver-fibrosis-in-mdr2-mice-by-diminishing-senescence-of-cholangiocytes
#1
Tianhao Zhou, Nan Wu, Fanyin Meng, Julie Venter, Thao K Giang, Heather Francis, Konstantina Kyritsi, Chaodong Wu, Antonio Franchitto, Domenico Alvaro, Marco Marzioni, Paolo Onori, Romina Mancinelli, Eugenio Gaudio, Shannon Glaser, Gianfranco Alpini
Secretin receptor (SR), only expressed by cholangiocytes, plays a key role in the regulation of biliary damage and liver fibrosis. The aim of this study was to determine the effects of genetic depletion of SR in Mdr2-/- mice on intrahepatic biliary mass, liver fibrosis, senescence, and angiogenesis. 12 wk SR-/- , Mdr2-/- , and SR-/- /Mdr2-/- mice with corresponding wild-type mice were used for the in vivo studies. Immunohistochemistry or immunofluorescence was performed in liver sections for (i) biliary expression of SR; (ii) hematoxylin and eosin; (iii) intrahepatic biliary mass by CK-19; (iv) fibrosis by Col1a1 and α-SMA; (v) senescence by SA-β-gal and p16; and (vi) angiogenesis by VEGF-A and CD31...
July 5, 2018: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/29968852/establishment-and-analysis-of-a-mouse-model-that-regulates-sex-related-differences-in-liver-drug-metabolism
#2
Hiromi Chikada, Kinuyo Ida, Emi Ando, Yutaka Inagaki, Akemi Sakamoto, Akihide Kamiya
The adult liver performs many metabolic functions for maintaining homeostasis. There are several sex differences in liver function and disease pathogenesis. One important function of the liver is drug metabolism, where cytochrome p450s (CYPs) in hepatocytes are the main enzymes involved. The toxicity of various drugs and chemicals differs with sex due to differences in hepatocytic CYP expression. However, the molecular mechanism regulating sex-related differences in drug metabolism remains unknown. In this study, we identified transcriptional regulator B-cell lymphoma 6 (Bcl6) as an important factor in sex-biased differential CYP expression...
July 3, 2018: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/29967343/differential-effects-of-gli2-and-gli3-in-regulating-cervical-cancer-malignancy-in-vitro-and-in-vivo
#3
Haiyan Zhu, Lu Xia, Qi Shen, Menghuang Zhao, Xiang Gu, Hakim Bouamar, Bingzhi Wang, Lu-Zhe Sun, Xueqiong Zhu
Advanced, recurrent, or persistent cervical cancer is often incurable. Therefore, in-depth insights into the molecular mechanisms are needed for the development of novel therapeutic targets and the improvement of current therapeutic strategies. In this study, we investigated the role of GLI2 and GLI3 in the regulation of the malignant properties of cervical cancer. We showed that down-regulation of GLI2, but not GLI3, with an inducible GLI2 shRNA inhibited the growth and migration of cervical cancer cell lines, which could be rescued by ectopic expression of GLI2...
July 2, 2018: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/29967342/thyroid-cancer-stem-like-cell-exosomes-regulation-of-emt-via-transfer-of-lncrnas
#4
Heather Hardin, Holly Helein, Kristy Meyer, Samantha Robertson, Ranran Zhang, Weixiong Zhong, Ricardo V Lloyd
Thyroid cancers are the most common endocrine malignancy and approximately 2% of thyroid cancers are anaplastic thyroid carcinoma (ATC), one of the most lethal and treatment resistant human cancers. Cancer stem-like cells (CSCs) may initiate tumorigenesis, induce resistance to chemotherapy and radiation therapy, have multipotent capability and may be responsible for recurrent and metastatic disease. The production of CSCs has been linked to epithelial-mesenchymal transition (EMT) and the acquisition of stemness...
July 2, 2018: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/29967341/the-adhesion-molecule-cadherin-11-is-essential-for-acquisition-of-normal-hearing-ability-through-middle-ear-development-in-the-mouse
#5
Yuji Kiyama, Yayoi S Kikkawa, Makoto Kinoshita, Yu Matsumoto, Kenji Kondo, Chisato Fujimoto, Shinichi Iwasaki, Tatsuya Yamasoba, Toshiya Manabe
Cadherin 11 (Cdh11), a member of the cadherin adhesion molecule family, is expressed in various regions of the brain as well as the head and ear. To gain further insights into the roles of Cdh11 in the development of the ear, we performed behavioral tests using Cdh11 knockout (KO) mice. KO mice showed reduced acoustic startle responses and increased thresholds for auditory brainstem responses, indicating moderate hearing loss. The auditory bulla volume and ratio of air-filled to non-air-filled space in the middle ear cavity were reduced in KO mice, potentially causing conductive hearing loss...
July 2, 2018: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/29959421/nuclear-shape-and-orientation-features-from-h-e-images-predict-survival-in-early-stage-estrogen-receptor-positive-breast-cancers
#6
Cheng Lu, David Romo-Bucheli, Xiangxue Wang, Andrew Janowczyk, Shridar Ganesan, Hannah Gilmore, David Rimm, Anant Madabhushi
Early-stage estrogen receptor-positive (ER+) breast cancer (BCa) is the most common type of BCa in the United States. One critical question with these tumors is identifying which patients will receive added benefit from adjuvant chemotherapy. Nuclear pleomorphism (variance in nuclear shape and morphology) is an important constituent of breast grading schemes, and in ER+ cases, the grade is highly correlated with disease outcome. This study aimed to investigate whether quantitative computer-extracted image features of nuclear shape and orientation on digitized images of hematoxylin-stained and eosin-stained tissue of lymph node-negative (LN-), ER+ BCa could help stratify patients into discrete (<10 years short-term vs...
June 29, 2018: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/29959420/osteopontin-isoforms-differentially-promote-arteriogenesis-in-response-to-ischemia-via-macrophage-accumulation-and-survival
#7
Grace Sanghee Lee, Hector F Salazar, Giji Joseph, Zoe Shin Yee Lok, Courtney M Caroti, Daiana Weiss, W Robert Taylor, Alicia N Lyle
Osteopontin (OPN) is critical for ischemia-induced neovascularization. Unlike rodents, humans express three OPN isoforms (a, b, and c); however, the roles of these isoforms in post-ischemic neovascularization and cell migration remain undefined. Our objective was to determine if OPN isoforms differentially affect post-ischemic neovascularization and to elucidate the mechanisms underlying these differences. To investigate if human OPN isoforms exert divergent effects on post-ischemic neovascularization, we utilized OPN-/- mice and a loss-of-function/gain-of-function approach in vivo and in vitro...
June 29, 2018: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/29959419/high-mobility-group-box-1-induces-endoplasmic-reticulum-stress-and-activates-hepatic-stellate-cells
#8
Qin He, Yu Fu, Xiangming Ding, Dongxiao Li, Zi Wang, Dean Tian, Wei Yan
Liver fibrosis is a worldwide clinical issue. The activation of hepatic stellate cells (HSCs) is the central event during the hepatic fibrotic response. However, the exact mechanisms related to HSC activation and the connection between hepatocytes and HSCs remain unclear. We elucidated the mechanism by which the nuclear-damage-associated molecular pattern molecule, high-mobility group box 1 (HMGB1) was released from the impaired hepatocytes and induced endoplasmic reticulum stress to activate HSCs. In this work, we demonstrated that HMGB1 can be released from hepatocytes and the released HMGB1 activates the HSCs via ER stress at the transcriptional level which was dependent on the activation of both the TLR4 and RAGE signaling pathways rather than the TLR2 signaling pathway...
June 29, 2018: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/29959418/characterization-of-a-murine-nonalcoholic-steatohepatitis-model-induced-by-high-fat-high-calorie-diet-plus-fructose-and-glucose-in-drinking-water
#9
Xue-Jing Liu, Na-Na Duan, Chang Liu, Chen Niu, Xiu-Ping Liu, Jian Wu
There are varieties of murine models of nonalcoholic steatohepatitis (NASH) with different pathophysiologic characteristics. For preclinical assessment, a standardized model would allow comparisons of various pharmacotherapeutic candidates in efficacy, pharmacokinetics, pharmaco-metabolism, and adverse effects under a same system. The present study aims to characterize murine NASH models by comparing end-points of major abnormalities. NASH was induced by feeding high fructose/glucose in drinking water (HF/G), high-fat/calorie diet (HFCD), and in combination (HFCD-HF/G) in mice for 8 or 16 weeks...
June 29, 2018: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/29959417/inflammatory-mediators-reduce-surface-prp-c-on-human-bmvec-resulting-in-decreased-barrier-integrity
#10
Bezawit W Megra, Eliseo A Eugenin, Joan W Berman
The cellular prion protein (PrPc ) is a surface adhesion molecule expressed at junctions of various cell types including brain microvascular endothelial cells (BMVEC) that are important components of the blood-brain barrier (BBB). PrPc is involved in several physiological processes including regulation of epithelial cell barrier function and monocyte migration across BMVEC. BBB dysfunction and disruption are significant events in central nervous system (CNS) inflammatory processes including HIV neuropathogenesis...
June 29, 2018: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/29955087/mir-137-is-a-tumor-suppressor-in-endometrial-cancer-and-is-repressed-by-dna-hypermethylation
#11
Wei Zhang, Jo-Hsin Chen, Tianjiao Shan, Irene Aguilera-Barrantes, Li-Shu Wang, Tim Hui-Ming Huang, Janet S Rader, Xiugui Sheng, Yi-Wen Huang
Endometrial cancer is the most common gynecological cancer in the United States. We wanted to identify epigenetic aberrations involving microRNAs (miRNAs), whose genes become hypermethylated in endometrial primary tumors. By integrating known miRNA sequences from the miRNA database (miRBase) with DNA methylation data from methyl-CpG-capture sequencing, we identified 111 differentially methylated regions (DMRs) associated with CpG islands (CGIs) and miRNAs. Among them, 22 DMRs related to 29 miRNAs and within 8 kb of CGIs were hypermethylated in endometrial tumors but not in normal endometrium...
June 28, 2018: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/29955086/interleukin-6-determines-protein-stabilization-of-dna-methyltransferases-and-alters-dna-promoter-methylation-of-genes-associated-with-insulin-signaling-and-angiogenesis
#12
Aswath Balakrishnan, Kanive Parashiva Guruprasad, Kapaettu Satyamoorthy, Manjunath B Joshi
Individuals with type 2 diabetes (T2D) display vascular insulin resistance and decreased nitric oxide production leading to vasoconstriction and atherosclerosis. Soluble factors such as pro-inflammatory molecules, and various genetic and epigenetic mechanisms have been implicated to induce insulin resistance in vascular endothelial cells. Epigenetic mechanisms such as altered promoter DNA methylation have been demonstrated in development and progression of metabolic disorders and atherosclerosis. However, underlying precise epigenetic mechanisms regulating cross talk between insulin signaling genes and inflammation in vascular cells remains to be fully understood...
June 28, 2018: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/29946134/an-in-vivo-model-for-thyroid-regeneration-and-folliculogenesis
#13
Manabu Iwadate, Yoshinori Takizawa, Yo-Taro Shirai, Shioko Kimura
While thyroid is considered to be a dormant organ, when required, it can regenerate through increased cell proliferation. However, the mechanism for regeneration remains unknown. Nkx2-1(fl/fl);TPO-cre mouse thyroids exhibit a very disorganized appearance because their thyroids continuously degenerate and regenerate. In mouse thyroids, a cluster of cells are found near the tracheal cartilage and muscle, which are positive for expression of NKX2-1, the master transcription factor governing thyroid development and function...
June 26, 2018: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/29946133/phenotypic-characterization-of-murine-models-of-cerebral-cavernous-malformations
#14
Hussein A Zeineddine, Romuald Girard, Laleh Saadat, Le Shen, Rhonda Lightle, Thomas Moore, Ying Cao, Nick Hobson, Robert Shenkar, Kenneth Avner, Kiranj Chaudager, Janne Koskimäki, Sean P Polster, Maged D Fam, Changbin Shi, Miguel Alejandro Lopez-Ramirez, Alan T Tang, Carol Gallione, Mark L Kahn, Mark Ginsberg, Douglas A Marchuk, Issam A Awad
Cerebral cavernous malformations (CCMs) are clusters of dilated capillaries that affect around 0.5% of the population. CCMs exist in two forms, sporadic and familial. Mutations in three documented genes, KRIT1(CCM1), CCM2, and PDCD10(CCM3), cause the autosomal dominant form of the disease, and somatic mutations in these same genes underlie lesion development in the brain. Murine models with constitutive or induced loss of respective genes have been applied to study disease pathobiology and therapeutic manipulations...
June 26, 2018: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/29925938/loss-of-fezf2-promotes-malignant-progression-of-bladder-cancer-by-regulating-the-nf-%C3%AE%C2%BAb-signaling-pathway
#15
Zhaohui Chen, Lijie Zhou, Xuehan Liu, Longwang Wang, Gallina Kazobinka, Xiaoping Zhang, Teng Hou
Forebrain embryonic zinc finger 2 (Fezf2) is an evolutionarily conserved zinc finger transcription repressor. It has been reported to be a tumor suppressor; however, neither the role that Fezf2 plays in bladder cancer nor the mechanisms involved have been investigated. In this study, we showed that Fezf2 expression is downregulated in bladder cancer tissues and cell lines compared to adjacent non-tumor tissues and normal urothelial cells. We also retrospectively analyzed the association between Fezf2 and various clinicopathologic characteristics in 196 bladder cancer patients, and showed that low expression of Fezf2 is correlated with larger tumor size, advanced tumor stage, and poor clinical prognosis...
June 20, 2018: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/29925937/attenuation-of-ventilation-induced-diaphragm-dysfunction-through-toll-like-receptor-4-and-nuclear-factor-%C3%AE%C2%BAb-in-a-murine-endotoxemia-model
#16
Li-Fu Li, Yung-Yang Liu, Ning-Hung Chen, Yen-Huey Chen, Chung-Chi Huang, Kuo-Chin Kao, Chih-Hao Chang, Li-Pang Chuang, Li-Chung Chiu
Mechanical ventilation (MV) is often used to maintain life in patients with sepsis and sepsis-related acute lung injury. However, controlled MV may cause diaphragm weakness due to muscle injury and atrophy, an effect termed ventilator-induced diaphragm dysfunction (VIDD). Toll-like receptor 4 (TLR4) and nuclear factor-κB (NF-κB) signaling pathways may elicit sepsis-related acute inflammatory responses and muscle protein degradation and mediate the pathogenic mechanisms of VIDD. However, the mechanisms regulating the interactions between VIDD and endotoxemia are unclear...
June 20, 2018: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/29884911/rac1-gtp-promotes-epithelial-mesenchymal-transition-and-invasion-of-colorectal-cancer-by-activation-of-stat3
#17
Kai Zhou, Jun Rao, Zhi-Hua Zhou, Xiao-Hong Yao, Feng Wu, Jing Yang, Lang Yang, Xia Zhang, You-Hong Cui, Xiu-Wu Bian, Yu Shi, Yi-Fang Ping
Epithelial-mesenchymal transition (EMT) plays a critical role in initiating tumor invasion and metastasis of colorectal cancer (CRC), although the underlying mechanisms remain to be clarified. Herein, we demonstrate that the active form of Rac family small GTPase 1 (RAC1-GTP) is overexpressed in CRCs and promotes the EMT-mediated invasion of CRC cells through activation of the signal transducers and activators of transcription 3 (STAT3) pathway. Increased expression of RAC1-GTP in CRC tissues was positively correlated with the TNM stages of CRCs and indicated poor prognosis of CRC patients...
June 8, 2018: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/29884910/nlrp3-asc-mediated-alveolar-macrophage-pyroptosis-enhances-hmgb1-secretion-in-acute-lung-injury-induced-by-cardiopulmonary-bypass
#18
Lei Hou, Zhongwei Yang, Zhankui Wang, Xiao Zhang, Yanhua Zhao, Hao Yang, Beijie Zheng, Weitian Tian, Shaocheng Wang, Zhengyu He, Xiangrui Wang
Our previous study showed that high levels of HMGB1 existed in rats following cardiopulmonary bypass (CPB)-induced acute lung injury (ALI) and neutralization of high-mobility group box 1(HMGB1) reduced CPB-induced ALI. However, the mechanism by which CPB increases HMGB1 secretion is unclear. Recent studies have shown that inflammasome-mediated cell pyroptosis promotes HMGB1 secretion. This study aimed to investigate the relationship between inflammasome-mediated pyroptosis and HMGB1 in CPB-related ALI. We employed oxygen-glucose deprivation (OGD)-induced alveolar macrophage (AM) NR8383 pyroptosis to measure HMGB1 secretion...
June 8, 2018: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/29884909/zbtb46-is-a-shear-sensitive-transcription-factor-inhibiting-endothelial-cell-proliferation-via-gene-expression-regulation-of-cell-cycle-proteins
#19
Yu Wang, He-Ying Sun, Sandeep Kumar, Maria Del Mar Puerta, Hanjoong Jo, Amir Rezvan
ZBTB46 is a transcription factor identified in classical dendritic cells and keeps dendritic cells in a quiescent state. Chromatin immunoprecipitation sequencing in dendritic cells has identified over 1300 potential gene targets of ZBTB46, affecting many processes including cell cycle. Endothelial cells (ECs) also express ZBTB46 and are mostly in a quiescent non-proliferative state. While EC proliferation is a critical process in development, dysregulation of EC proliferation as seen in areas of disturbed flow play an important role in many disease processes such as atherosclerosis, pulmonary hypertension, transplant vasculopathy, neointimal hyperplasia, and in-stent restenosis...
June 8, 2018: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/29884908/thioredoxin-interacting-protein-deficiency-ameliorates-kidney-inflammation-and-fibrosis-in-mice-with-unilateral-ureteral-obstruction
#20
Ming Wu, Ruoyu Li, Yanjuan Hou, Shan Song, Weixia Han, Nan Chen, Yunxia Du, Yunzhuo Ren, Yonghong Shi
Thioredoxin-interacting protein (TXNIP) is associated with inflammation, tubulointerstitial fibrosis, and oxidative stress in diabetic kidney disease, yet the potential role of TXNIP in nondiabetic renal injury is not well known. This study aimed to investigate the effect of TXNIP on renal injury by creating a unilateral ureteral obstruction (UUO) model in TXNIP knockout (TKO) mice. We performed sham or UUO surgery in 8-week-old TXNIP KO male mice and age and sex-matched wild-type (WT) mice. Animals were killed at 3, 5, 7, or 14 days after surgery, and renal tissues were obtained for RNA, protein, and other analysis...
June 8, 2018: Laboratory Investigation; a Journal of Technical Methods and Pathology
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