Subjects -> MEDICAL SCIENCES (Total: 8529 journals)
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PATHOLOGY (98 journals)

Showing 1 - 98 of 98 Journals sorted alphabetically
Academic Pathology     Open Access   (Followers: 5)
Acta Neuropathologica Communications     Open Access   (Followers: 1)
Advances in Anatomic Pathology     Hybrid Journal   (Followers: 21)
Advances in Molecular Pathology     Hybrid Journal   (Followers: 1)
Advances in Plant Pathology     Full-text available via subscription   (Followers: 6)
American Journal of Clinical Pathology     Full-text available via subscription   (Followers: 30)
American Journal of Dermatopathology     Hybrid Journal   (Followers: 17)
American Journal of Forensic Medicine and Pathology     Hybrid Journal   (Followers: 29)
American Journal of Pathology     Hybrid Journal   (Followers: 33)
American Journal of Surgical Pathology     Hybrid Journal   (Followers: 38)
Analytical Cellular Pathology     Open Access   (Followers: 3)
Annals of Cytology and Pathology     Open Access   (Followers: 1)
Annals of Diagnostic Pathology     Hybrid Journal   (Followers: 15)
Annals of Oral & Maxillofacial Surgery     Open Access   (Followers: 7)
Annals of Tropical Pathology     Open Access  
Annual Review of Pathology Mechanisms of Disease     Full-text available via subscription   (Followers: 7)
Archives of Pathology & Laboratory Medicine     Full-text available via subscription   (Followers: 31)
Assessment and Treatment of Child Psychopathology and Developmental Disabilities     Full-text available via subscription   (Followers: 4)
Basic and Applied Pathology     Open Access   (Followers: 3)
BMC Clinical Pathology     Open Access   (Followers: 7)
Brain Pathology     Hybrid Journal   (Followers: 5)
Brain Tumor Pathology     Hybrid Journal   (Followers: 6)
Bulletin de la Société de pathologie exotique     Hybrid Journal   (Followers: 1)
Cancer Cytopathology     Partially Free   (Followers: 22)
Cardiovascular Pathology     Hybrid Journal   (Followers: 4)
Case Reports in Pathology     Open Access   (Followers: 7)
Clinical Neuropathology     Full-text available via subscription   (Followers: 1)
Clinical Pathology     Open Access   (Followers: 3)
Comparative Clinical Pathology     Hybrid Journal   (Followers: 3)
Critical Values     Full-text available via subscription  
Cytopathology     Hybrid Journal   (Followers: 12)
Der Pathologe     Hybrid Journal   (Followers: 2)
Dermatopathology     Open Access   (Followers: 3)
Diagnostic Cytopathology     Hybrid Journal   (Followers: 13)
Diagnostic Histopathology     Full-text available via subscription   (Followers: 14)
Diagnostic Pathology     Open Access   (Followers: 13)
Egyptian Journal of Pathology     Partially Free   (Followers: 1)
Endocrine Pathology     Hybrid Journal   (Followers: 4)
Experimental and Molecular Pathology     Hybrid Journal   (Followers: 5)
Experimental and Toxicologic Pathology     Hybrid Journal   (Followers: 10)
Fetal and Pediatric Pathology     Hybrid Journal   (Followers: 4)
Folia Neuropathologica     Open Access  
Forensic Science, Medicine, and Pathology     Hybrid Journal   (Followers: 34)
Head and Neck Pathology     Hybrid Journal   (Followers: 7)
Hepatoma Research     Open Access   (Followers: 2)
Histopathology     Hybrid Journal   (Followers: 28)
Human Pathology     Hybrid Journal   (Followers: 30)
Indian Journal of Pathology and Microbiology     Open Access   (Followers: 3)
Inflammation and Cell Signaling     Open Access   (Followers: 3)
International Journal of Clinical and Experimental Pathology     Open Access   (Followers: 2)
International Journal of Experimental Pathology     Hybrid Journal   (Followers: 1)
International Journal of Gynecological Pathology     Hybrid Journal   (Followers: 9)
International Journal of Ophthalmic Pathology     Hybrid Journal   (Followers: 2)
International Journal of Oral & Maxillofacial Pathology     Open Access   (Followers: 8)
International Journal of Surgical Pathology     Hybrid Journal   (Followers: 9)
Iranian Journal of Pathology     Open Access  
Journal of Clinical & Experimental Pathology     Open Access   (Followers: 3)
Journal of Clinical Pathology     Hybrid Journal   (Followers: 13)
Journal of Clinical Pathology and Forensic Medicine     Open Access   (Followers: 9)
Journal of Comorbidity     Open Access  
Journal of Comparative Pathology     Hybrid Journal   (Followers: 5)
Journal of Cutaneous Pathology     Hybrid Journal   (Followers: 11)
Journal of Depression and Anxiety     Open Access   (Followers: 2)
Journal of Diagnostic Pathology     Open Access   (Followers: 9)
Journal of Hematopathology     Hybrid Journal   (Followers: 5)
Journal of Morphological Sciences     Open Access  
Journal of Neuropathology & Experimental Neurology     Hybrid Journal   (Followers: 1)
Journal of Oral and Maxillofacial Pathology     Open Access   (Followers: 3)
Journal of Oral Pathology & Medicine     Hybrid Journal   (Followers: 5)
Journal of Pathology     Hybrid Journal   (Followers: 13)
Journal of Pathology : Clinical Research     Open Access   (Followers: 1)
Journal of Pathology Informatics     Open Access   (Followers: 2)
Journal of Pathology of Nepal     Open Access   (Followers: 1)
Journal of Physiology and Pathophysiology     Open Access   (Followers: 1)
Modern Pathology     Hybrid Journal   (Followers: 32)
Molecular and Cellular Biomedical Sciences     Open Access   (Followers: 3)
Molecular Diagnosis & Therapy     Hybrid Journal   (Followers: 3)
Neuropathology     Hybrid Journal   (Followers: 1)
Neuropathology and Applied Neurobiology     Hybrid Journal  
Ocular Oncology and Pathology     Full-text available via subscription  
Open Journal of Bacteriology     Open Access   (Followers: 1)
Open Journal of Pathology     Open Access   (Followers: 3)
Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology     Full-text available via subscription   (Followers: 9)
Pathogenesis     Open Access  
Pathology     Hybrid Journal   (Followers: 12)
Pathology & Oncology Research     Hybrid Journal   (Followers: 4)
Pathology - Research and Practice     Hybrid Journal   (Followers: 4)
Pathology and Laboratory Medicine International     Open Access   (Followers: 7)
Pathology International     Hybrid Journal   (Followers: 2)
Pathology Research International     Open Access   (Followers: 1)
Pediatric and Developmental Pathology     Hybrid Journal   (Followers: 4)
Revista de Patologia do Tocantins     Open Access  
Revista de Senología y Patología Mamaria     Full-text available via subscription  
Seminars in Diagnostic Pathology     Hybrid Journal   (Followers: 10)
Seminars in Immunopathology     Hybrid Journal   (Followers: 3)
Surgical Pathology Clinics     Full-text available via subscription   (Followers: 9)
Ultrastructural Pathology     Hybrid Journal   (Followers: 1)
Патологія     Open Access  
Similar Journals
Journal Cover
Experimental and Molecular Pathology
Journal Prestige (SJR): 1.023
Citation Impact (citeScore): 3
Number of Followers: 5  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0014-4800 - ISSN (Online) 1096-0945
Published by Elsevier Homepage  [3203 journals]
  • Mutational heterogeneity between different regional tumour grades of clear
           cell renal cell carcinoma
    • Abstract: Publication date: Available online 4 April 2020Source: Experimental and Molecular PathologyAuthor(s): Paranita Ferronika, Gursah Kats-Ugurlu, Sofia M. Haryana, Totok Utoro, Hanggoro Tri Rinonce, Raden Danarto, Kim de Lange, Martijn M. Terpstra, Rolf H. Sijmons, Helga Westers, Klaas Kok
       
  • Bile acids aggravate nonalcoholic steatohepatitis and cardiovascular
           disease in SHRSP5/Dmcr rat model
    • Abstract: Publication date: Available online 1 April 2020Source: Experimental and Molecular PathologyAuthor(s): Shusei Yamamoto, Ikumi Sato, Natsuki Fukuhama, Natsumi Akiyama, Miku Sakai, Shota Kumazaki, Shang Ran, Satoshi Hirohata, Kazuya Kitamori, Yukio Yamori, Shogo Watanabe
       
  • LncRNA MALAT1 induces the dysfunction of β cells via reducing the histone
           acetylation of the PDX-1 promoter in type 1 diabetes
    • Abstract: Publication date: Available online 31 March 2020Source: Experimental and Molecular PathologyAuthor(s): Haixia Ding, Fujun Wang, Xuelian Shi, Hongfang Ma, Yaping Du, Lin Hou, Na Xing
       
  • Retrotransposition and senescence in mouse heart tissue by viral protein R
           of human immunodeficiency virus-1
    • Abstract: Publication date: Available online 31 March 2020Source: Experimental and Molecular PathologyAuthor(s): Mikako Ueno, Akihiro Matsunaga, Yoichi Teratake, Yukihito Ishizaka
       
  • LNCRNA Gas5 suppression protected Hl-1 cells against hypoxia injury by
           sponging Mir-222-3p
    • Abstract: Publication date: Available online 30 March 2020Source: Experimental and Molecular PathologyAuthor(s): Jie He, Henhua Dai, Qian Zhao, Jianshu Guo, Chi Chen
       
  • Long non-coding RNA ROR sponges miR-138 to aggravate
           hypoxia/reoxygenation-induced cardiomyocyte apoptosis via upregulating
           Mst1
    • Abstract: Publication date: Available online 30 March 2020Source: Experimental and Molecular PathologyAuthor(s): Yan-Hui Hu, Jing Sun, Jing Zhang, Fu-Zhou Hua, Qin Liu, Ying-Ping Liang
       
  • Elevated TLR5 expression in vivo and loss of NF-κΒ activation via TLR5
           in vitro detected in HPV-negative oropharyngeal squamous cell carcinoma
    • Abstract: Publication date: Available online 30 March 2020Source: Experimental and Molecular PathologyAuthor(s): Anna Kaisa Kylmä, Tuomas Aleksi Tolvanen, Timo Carpén, Caj Haglund, Antti Mäkitie, Petri S. Mattila, Reidar Grenman, Lauri Jouhi, Timo Sorsa, Sanna Lehtonen, Jaana Hagström
       
  • 1,25(OH)2D3 provides protection against diabetic kidney disease by
           downregulating the TLR4-MyD88-NF-κB pathway
    • Abstract: Publication date: Available online 30 March 2020Source: Experimental and Molecular PathologyAuthor(s): Ping Liu, Fengao Li, Xiaoyan Xu, Suning Li, Xiaoying Dong, Ling Chen, Bin Bai, Yarong Wang, Mingcai Qiu, Youping Dong
       
  • PCAT1: An oncogenic lncRNA in diverse cancers and a putative therapeutic
           target
    • Abstract: Publication date: Available online 24 March 2020Source: Experimental and Molecular PathologyAuthor(s): Soudeh Ghafouri-Fard, Sepideh Dashti, Mohammad Taheri
       
  • MCCC2 overexpression predicts poorer prognosis and promotes cell
           proliferation in colorectal cancer
    • Abstract: Publication date: Available online 20 March 2020Source: Experimental and Molecular PathologyAuthor(s): Wenxin Dai, Huiyin Feng, Dongwon Lee
       
  • Propofol alleviates ventilator-induced lung injury through regulating the
           Nrf2/NLRP3 signaling pathway
    • Abstract: Publication date: Available online 19 March 2020Source: Experimental and Molecular PathologyAuthor(s): Hongyan Ruan, Wei Li, Jilan Wang, Gang Chen, Bin Xia, Zhou Wang, Mengyuan Zhang
       
  • Gene expression of indoleamine and tryptophan dioxygenases and three long
           non-coding RNAs in breast cancer
    • Abstract: Publication date: Available online 9 March 2020Source: Experimental and Molecular PathologyAuthor(s): Soudeh Ghafouri-Fard, Zahra Taherian-Esfahani, Sepideh Dashti, Vahid Kholghi Oskooei, Mohammad Taheri, Majid Samsami
       
  • HIF-1α/SDF-1/CXCR4 axis reduces neuronal apoptosis via enhancing the bone
           marrow-derived mesenchymal stromal cell migration in rats with traumatic
           brain injury
    • Abstract: Publication date: Available online 9 March 2020Source: Experimental and Molecular PathologyAuthor(s): Kai Guo, Xinyu Yao, Weijing Wu, Ziyi Yu, Zhenzhong Li, Zenglu Ma, Dengxiang Liu
       
  • Expression analysis of growth arrest specific 8 and its anti-sense in
           breast cancer tissues
    • Abstract: Publication date: Available online 9 March 2020Source: Experimental and Molecular PathologyAuthor(s): Sepideh Dashti, Zahra Taherian-Esfahani, Vahid Kholghi-Oskooei, Soudeh Ghafouri-Fard, Mohammad Taheri
       
  • Time-restricted feeding ameliorates maternal high-fat diet-induced fetal
           lung injury
    • Abstract: Publication date: Available online 6 March 2020Source: Experimental and Molecular PathologyAuthor(s): Aditya Upadhyay, Rohit A. Sinha, Alok Kumar, Madan M. Godbole
       
  • The alterations of mitochondrial DNA in coronary heart disease
    • Abstract: Publication date: Available online 28 February 2020Source: Experimental and Molecular PathologyAuthor(s): Haochang Hu, Ying Lin, Xiaofeng Xu, Shaoyi Lin, Xiaomin Chen, Shuangshuang Wang
       
  • Antioxidant/stress response in mouse epidermis following exposure to
           nitrogen mustard
    • Abstract: Publication date: Available online 28 February 2020Source: Experimental and Molecular PathologyAuthor(s): Gabriella Wahler, Diane E. Heck, Ned D. Heindel, Debra L. Laskin, Jeffrey D. Laskin, Laurie B. Joseph
       
  • Non-coding RNA profile in lung cancer
    • Abstract: Publication date: Available online 26 February 2020Source: Experimental and Molecular PathologyAuthor(s): Soudeh Ghafouri-Fard, Hamed Shoorei, Wojciech Branicki, Mohammad Taheri
       
  • Atrial fibrosis and decreased connexin 43 in rat hearts after exposure to
           high-intensity infrasound
    • Abstract: Publication date: Available online 21 February 2020Source: Experimental and Molecular PathologyAuthor(s): Ana Lousinha, Gonçalo Pereira, Gonçalo Borrecho, José Brito, António Oliveira de Carvalho, Diamantino Freitas, Pedro Oliveira, Maria João R. Oliveira, Eduardo Antunes BackgroundNoise is an important environmental risk factor. Industrial environments are rich in high-intensity infrasound (hi-IFS), which we have found to induce myocardial and coronary perivascular fibrosis in rats. The effects of exposure to IFS on the ventricles have been studied, but not on the atria. We hypothesized that rats exposed to hi-IFS develop atrial remodeling involving fibrosis and connexin 43, which we sought to evaluate.Material and methodsSeventy-two Wistar rats, half exposed to hi-IFS (120 dB,
       
  • Quantitative assessment and clinical relevance of VEGFRs-positive tumor
           cells in refractory brain tumors
    • Abstract: Publication date: Available online 21 February 2020Source: Experimental and Molecular PathologyAuthor(s): Ryota Tamura, Mizuto Sato, Yukina Morimoto, Kentaro Ohara, Kenzo Kosugi, Yumiko Oishi, Yuki Kuranari, Makoto Murase, Kazunari Yoshida, Masahiro Toda Vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)1 and 2 signaling is a potent activator of tumor angiogenesis. Although the expressions of VEGFR1 and VEGFR2 were initially thought to be limited to the endothelial cells, it is now known that both the receptors are expressed in tumor cells. This is the first study wherein VEGFRs-positive tumor cells are quantitatively evaluated for brain tumors with upregulated VEGF/VEGFR signaling. The percentage of VEGFRs-positive tumor cells was quantitatively evaluated in various brain tumors (10 glioblastomas, 22 neurofibromatosis type 2 [NF2]-related schwannomas, 21 sporadic schwannomas, 27 chordomas, 36 meningiomas, 29 hemangioblastomas, 11 hemangiopericytoma, and 13 ependymomas) using immunohistochemistry. VEGF-A expression was also analyzed using quantitative real-time polymerase chain reaction. Double immunofluorescence staining using anti-PDGFR-β and anti-CD34 antibody, microvessel density, and vessel diameter were analyzed to evaluate the vascular characteristics. Chordomas demonstrated an extremely higher percentage of VEGFR1 and VEGFR2-positive tumor cells than other tumors. In contrast, meningiomas and hemangiopericytomas showed few VEGFRs-positive tumor cells. The percentage of positive tumor cells in chordomas, hemangioblastomas, and NF2 schwannomas was associated with clinical courses, such as shorter progression free survival, and growth speed. Glioblastomas and NF2 schwannomas showed larger tumor vessels without pericyte coverage. The present study is the first to quantitatively analyze VEGFR1- and VEGFR2- positive tumor cells in various types of refractory brain tumors. This novel parameter significantly correlated with the progressive clinical courses.
       
  • The role and function of long non-coding RNAs in osteoarthritis
    • Abstract: Publication date: Available online 21 February 2020Source: Experimental and Molecular PathologyAuthor(s): Mitra Abbasifard, Zahra Kamiab, Iman Sadeghi, Zahra Bagheri-Hosseinabadi Osteoarthiritis (OA) is the most prevalent disease of articulating joints in human that frequently results in joint pain, movement limitations, inflammation and progressive degradation of articular cartilage. The etiology of OA is no completely clear and there is no full treatment for this disease. Molecular investigations have revealed the involvement of non-coding RNAs such as Long non-coding RNAs (lncRNAs) in OA pathogenesis. LncRNAs play roles in multiple cellular and biological processes. Moreover, numerous lncRNAs are differentially expressed in human OA cartilage. In this review, we underlie the increasing evidence for the critical role of lncRNAs OA pathogenesis including the latest researches.
       
  • B7-H4 is a potential prognostic biomarker of prostate cancer
    • Abstract: Publication date: Available online 20 February 2020Source: Experimental and Molecular PathologyAuthor(s): Haoyue Li, Lihua Piao, Sicen Liu, Yan Cui, Yanhua Xuan B7-H4 is a member of B7 family which regulates immune responses by delivering costimulatory signals. However, it negatively regulates T cell-mediated immunity and may play an important role in tumor immune evasion. Although several studies have been reported that expression of B7-H4 is elevated in the several types of human cancer with a poor clinical outcome, its clinical significance in the prostate cancer (PCa) has not been well studied. In this study, we investigated the clinical significance of B7-H4 in human PCa and determined if B7-H4 expression is associated with the cancer cell stemness in PCa. Our studies show that expression of B7-H4 is correlated with the pathologic tumor (pT) stage and the clinical stage of PCa. The Kaplan-Meier survival analysis revealed that PCa patients with high expression of B7-H4 exhibits a shorter overall survival (OS) rate. Univariate and multivariate Cox regression analysis indicated that B7-H4 is an independent poor prognostic factor of PCa. In addition, the expression of B7-H4 is correlated with the cancer cell stemness associated genes expression in PCa. Further, our studies show that B7-H4 regulates cancer cell stemness associated genes expression and effects on the cell cycle and PI3K/Akt signaling related genes expression in PCa. These results indicate that B7-H4 expression is associated with cancer cell stemness, and B7-H4 is a potential prognostic biomarker and a therapeutic target of PCa.
       
  • Ghrelin protects against obesity-induced myocardial injury by regulating
           the lncRNA H19/miR-29a/IGF-1 signalling axis
    • Abstract: Publication date: Available online 19 February 2020Source: Experimental and Molecular PathologyAuthor(s): Yang Liu, Xin-Yue Xu, Yang Shen, Chun-Feng Ye, Na Hu, Qing Yao, Xiu-Zi Lv, Sheng-Lan Long, Chao Ren, Yuan-Yuan Lang, Yan-Ling Liu BackgroundObesity is associated with the impairment of cardiac fitness and consequent ventricular dysfunction and heart failure. Ghrelin has been largely documented to be cardioprotective against ischaemia/reperfusion injury. However, the role of ghrelin in obesity-induced myocardial injury is largely unknown. This study sought to determine the cardiac effect of ghrelin against obesity-induced injury and the underlying mechanisms.MethodsThe effect of ghrelin was evaluated in a mouse model of obesity and a palmitic acid (PA)-treated cardiomyocyte cell line with or without ghrelin transfection. Gene and protein expression levels were determined by real-time PCR and western blot, respectively. Cell apoptosis was measured by flow cytometry analysis.ResultsIn the present study, we found that both a high-fat diet (HFD) and PA treatment caused myocardial injury by increasing apoptosis and the expression of inflammatory cytokines. Overexpression of ghrelin reversed the effects induced by HFD or PA treatment. Knockdown of lncRNA H19 or overexpression of miR-29a abrogated the cardioprotective effects of ghrelin against apoptosis and inflammation. We also found that IGF-1 was a target gene of miR-29a and that H19 regulated IGF-1 expression via miR-29a. Overexpression of IGF-1 partially reversed the apoptosis and inflammation promoting effects of miR-29a.ConclusionsOur findings suggested that ghrelin protected against obesity-induced myocardial injury by regulating the H19/miR-29a/IGF-1 signalling axis, providing further evidence for the clinical application of ghrelin.
       
  • Comparative expression of immunohistochemical biomarkers in cribriform and
           pattern 4 non-cribriform prostatic adenocarcinoma
    • Abstract: Publication date: June 2020Source: Experimental and Molecular Pathology, Volume 114Author(s): Guang-Qian Xiao, Elise Nguyen, Pamela D. Unger, Andy E. Sherrod The morphology of Gleason 4 prostate cancer (PCa) can be subdivided into cribriform and non-cribriform patterns. A large body of evidence has shown that pattern 4 cribriform PCa (especially non-glomeruloid type) is associated with adverse pathologic features and clinical outcomes compared with non-cribriform pattern 4 PCa. The underlying mechanisms for the aggressiveness of cribriform PCa are not fully understood. The aim of this study is to compare the immunohistochemical expression of various biomarkers and to determine the potential proteins that may account for their biologic and clinical differences. A total of 14 biomarkers were studied. The number of non-glomeruloid cribriform PCa cases studied for each biomarker ranged from 18 to 74 and the number of non-cribriform pattern 4 PCa studied for each biomarker ranged from 29 to 112. We demonstrated that, compared with non-cribriform Gleason pattern 4 PCa, EGFR was significantly upregulated and standard CD44 (CD44s) was significantly downregulated in cribriform PCa; no significant differences were found in the expression of AR, NKX3.1, ERG, EZH2, p53, Rb, C-Myc, BCL2, p16, CyclinD1, Her2/Neu, and Synaptophysin between these two groups of pattern 4 PCa. The study also showed, compared to non-cribriform PCa, cribriform PCa presented with significantly higher serum PSA and more advanced tumor stage. The significant overexpression of EGFR and downregulation of CD44s in non-glomeruloid cribriform PCa may, at least, partly explain the unfavorable pathology and clinical results for this growth pattern. Given that EGFR targeted inhibitors are now available, the findings may also have significant therapeutic implications.
       
  • The clinicomolecular landscape of de novo versus relapsed stage IV
           metastatic breast cancer
    • Abstract: Publication date: Available online 14 February 2020Source: Experimental and Molecular PathologyAuthor(s): Sean Seltzer, Mark Corrigan, Seamus O'Reilly Backgroundde novo metastatic breast cancer (dnMBC) is responsible for 6–10% of breast cancer presentations with increasing incidence and has remained resistant to detection by mammography screening. Recent publications hypothesized that in addition to poor screening uptake, the presentation of dnMBC may be due to its unfavourable biology which remains unknown at the molecular level. Here we investigated the tumour biology of dnMBC in the form of clinicopathology, genomic alterations and differential gene expression to create a comparative landscape of de novo versus relapsed metastatic breast cancer (rMBC). Additionally, to address the current screening limitations, we conducted a preliminary biomarker investigation for early dnMBC detection.MethodsIn this retrospective case-control study, gene expression and clinical data were accessed from the Cancer Genome Atlas (TCGA) for primary tumours of treatment-naïve patients with dnMBC (n = 17), rMBC (n = 49), and normal tissue (n = 113). The clinical and histological data were assessed categorically using Fisher's Exact-Test for significance (p 
       
  • Feasibility and clinical utility of a pan-solid tumor targeted RNA fusion
           panel: A single center experience
    • Abstract: Publication date: Available online 13 February 2020Source: Experimental and Molecular PathologyAuthor(s): Issa Hindi, Guomiao Shen, Qian Tan, Paolo Cotzia, Matija Snuderl, Xiaojun Feng, George Jour Gene fusions are caused by chromosomal rearrangements and encode fusion proteins that can act as oncogenic drivers in cancers. Traditional methods for detecting oncogenic fusion transcripts include fluorescence in situ hybridization (FISH), reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC). However, these methods are limited in scalability and pose significant technical and interpretational challenges. Next-generation sequencing (NGS) is a high-throughput method for detecting genetic abnormalities and providing prognostic and therapeutic information for cancer patients. We present our experience with the validation of a custom-designed Archer Anchored Multiplex PCR (AMP™) technology-based NGS technology, “NYU FUSION-SEQer” using RNA sequencing. We examine both analytical performance and clinical utility of the panel using 75 retrospective validation samples and 84 prospective clinical samples of solid tumors. Our panel showed robust sequencing performance with strong enrichment for target regions. The lower limit of detection was 12.5% tumor fraction at 125 ng of RNA input. The panel demonstrated excellent analytic accuracy, with 100% sensitivity, 100% specificity and 100% reproducibility on validation samples. Finally, in the prospective cohort, the panel detected fusions in 61% cases (n = 51), out of which 41% (n = 21) enabling diagnosis and 59% (n = 30) enabling treatment and prognosis. We demonstrate that the fusion panel can accurately, efficiently and cost-effectively detect the majority of known fusion genes, novel clinically relevant fusions and provides an excellent tool for discovery of new fusion genes in solid tumors.
       
  • Effects of acute noise exposure on DNA damage response genes in the
           cochlea, cortex, heart and liver
    • Abstract: Publication date: Available online 13 February 2020Source: Experimental and Molecular PathologyAuthor(s): Li Yang, O'neil W. Guthrie Noise as a systemic stressor induces various organ dysfunctions and the underlying molecular pathology is unknown. Previous studies have shown that noise exposure results in the accumulation of DNA damage in auditory and non-auditory organs. The DNA damage response (DDR) is a global protective mechanism that plays a critical role in maintaining DNA integrity. However, the role of DDR genes in noise induced systemic (non-auditory) pathology has not been investigated. The current pilot study was designed to test the hypothesis that an acute noise exposure would alter the normal expression of DDR genes (e.g., ATM, p53 & XPC) in auditory (cochlea) and non-auditory organs, such as the cortex, heart and liver. Mice were used as subjects in this study and consisted of a baseline group, a one-hour noise exposure (@105 dB) group, and a four-hour noise exposure (@105 dB) group. ATM, p53 and XPC expression levels were quantified through end-point polymerize chain reactions. The current study demonstrated that noise exposure failed to elicit statistically significant changes in DDR genes (relative to baseline) across the various organs. The failure of the cochlea, heart, cortex and liver to upregulate protective DDR genes during acute noise exposure might help to explain their susceptibility to noise-induced DNA damage. This suggests that, biomedical interventions to upregulate DDR genes may need to be implemented before noise exposure or during the early stages of noise exposure.
       
  • CD4+ T cells and TGFβ1/MAPK signal pathway involved in the valvular
           hyperblastosis and fibrosis in patients with rheumatic heart disease
    • Abstract: Publication date: Available online 13 February 2020Source: Experimental and Molecular PathologyAuthor(s): Zhiwei Zhao, Danqing He, Fei Ling, Tianshu Chu, Dake Huang, Huaxun Wu, Jianjun Ge The aim of this study was to investigate the roles of CD4+ T cells and transforming growth factor beta (TGFβ1) in the pathological process of valvular hyperblastosis and fibrosis of patients with rheumatic heart disease (RHD). A total of 151 patients were enrolled, among whom, 78 patients were with RHD, and 73 were age and gender matched RHD negative patients. Blood samples and valve specimens were collected for analysis. Pathological changes and collagen fibers contents of valves were analyzed using HE and Masson staining. Percentage of peripheral blood CD4+ T cells was tested through flow cytometry. TGFβ1 level in serum were identified by ELISA. CD4+ T cells infiltration and expression of TGFβ1, p-p38, p-JNK, p-ERK in valves were detected by immunohistochemistry. The mRNA and protein levels of p38, JNK, ERK, TGFβ1, I-collagen and α-SMA were detected by qRT-PCR and western blotting, respectively. The heart valve tissues of RHD patients showed higher degrees of fibrosis, calcification and lymphocytes infiltration, which were mainly CD4+ T cells. In addition, compared with control group, RHD patients had more total CD4+ T cells in peripheral blood and valve tissues. Expression of TGFβ1, phosphorylation of JNK and p38, and synthesis of I-collagen in valve tissues of RHD patients were also significantly increased. Furthermore, we found a strong positive correlation between TGFβ1 expression and phosphorylation of JNK and p38. CD4+ T cells, and fibrogenic cytokine TGFβ1, which activate the intracellular MAPK signaling pathway may participate in the fibrosis of heart valve in RHD patients.
       
  • Dual biomarkers long non-coding RNA GAS5 and its target, NR3C1, contribute
           to acute myeloid leukemia
    • Abstract: Publication date: Available online 4 February 2020Source: Experimental and Molecular PathologyAuthor(s): Fereshteh Nasiri Ganjineh Ketab, Jalal Gharesouran, Soudeh Ghafouri-Fard, Saba Dastar, Shamsi Abdi Mazraeh, Hassan Hosseinzadeh, Mohsen Moradi, Masoumeh Javadlar, Amirataollah Hiradfar, Azim Rezamand, Mohammad Taheri, Maryam Rezazadeh Acute myeloid leukemia (AML) is a complex hematological neoplasm with poor prognosis. At present, overwhelming evidence indicates that different genetic abnormalities are relevant to the pathogenesis of AML. Nevertheless, its exact molecular mechanism is still unknown. Recently, it was reported that lncRNAs play crucial roles in tumorigenesis. But, their role in the molecular pathogenesis of AML has not been extensively explored. GAS5, one of the earliest known lncRNAs, has an essential role in the formation and progression of multiple human cancers. It was recently demonstrated that GAS5 acts as a riborepressor of the Glucocorticoid receptor) GR) and abnormal levels of GAS5 may alter response of hematopoietic cells to glucocorticoids. GAS5 can have interaction with the GR that encoded by NR3C1 gene and inhibit its transcriptional activity.To test whether the genetic variants can be associated with AML risk, we genotyped rs55829688 (T > C) polymorphism in GAS5 and three NR3C1 SNPs namely rs6195, rs41423247 and rs6189/rs6190 in a population of 100 Iranian AML patients and 100 healthy subjects.The analysis of the data showed the frequency of alleles and genotypes of rs55829688 and rs6189/rs6190 polymorphisms did not differ between patients and healthy subjects. But, rs41423247 and rs6195 demonstrated a significant correlation with AML risk. The rs6195 was associated with higher AML susceptibility in the co-dominant (OR = 4.58, 95% CI = 2.11–9.981, P 
       
  • Siglec1 enhances inflammation through miR-1260-dependent degradation of
           IκBα in COPD
    • Abstract: Publication date: Available online 31 January 2020Source: Experimental and Molecular PathologyAuthor(s): Sensen Li, Longfeng Jiang, Yanbing Yang, Juan Cao, Qi Zhang, Jinghai Zhang, Rui Wang, Xiaozhao Deng, Yaojun Li It has been documented that sialic acid-binding Ig-like lectin 1 (Siglec1) is a cell surface protein with a variety of functions in the immune system. In the present study, we evaluated whether Siglec1 plays a role in chronic obstructive pulmonary disease (COPD). Results show that the expression of Siglec1 was increased in the lung of COPD rats, and that Siglec1 overexpression greatly enhanced the expression of inflammatory cytokines including tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β) and IL-6 in cigarette smoke extract (CSE)-treated NR8383 cells, a rat lung-derived macrophage cell line. Notably, the proinflammatory effect of Siglec1 was totally inhibited by overexpression of nuclear factor of κ light polypeptide gene enhancer in B-cells inhibitor α (IκBα). Importantly, Siglec1 overexpression increased miR-1260, which then degraded IκBα through its 3′ untranslated region (3′UTR). Further study demonstrated that miR-1260 inhibitor attenuated inflammation in CSE-induced rat COPD lung and in CSE-treated NR8383 cells. Finally, the inhibitory effect of miR-1260 on inflammation was totally lost when IκBα was inhibited. In summary, the present study demonstrated that Siglec1 exerts its proinflammatory effects through increasing miR-1260, leading to decreased expression of IκBα.
       
  • SFRP1 promotor methylation analysis of FTA card touch-prep samples derived
           from colonic polyps
    • Abstract: Publication date: Available online 30 January 2020Source: Experimental and Molecular PathologyAuthor(s): Veronika Buxhofer-Ausch, Christoph Ausch, Angelika Reiner, Kirsten Müllner-Ammer, Alfons Schmid, Stephan Kriwanek, Christian Sebesta, Gabriele Halwachs-Baumann, Gernot Kriegshäuser Whatman FTA® cards provide the most reliable method for DNA storage and extraction, however, the literature lacks reports on the epigenetic analysis of FTA card-derived tumor DNA. Therefore, this study aimed at demonstrating that punches from colonic adenoma samples preserved on FTA filter cards are suitable for methylation analysis by real-time methylation-specific PCR (MSP). Genomic DNA was isolated from a total of 40 sporadic colorectal adenoma samples stored on FTA cards for a median of 59.60 (range 48–72) months. After bisulfite treatment, deaminated DNA was analyzed by SYBR Green real-time MSP using primers specific for methylated and unmethylated promotor sequences of the secreted frizzled-related protein 1 (SFRP1) gene. Amplifiable DNA could be isolated from all FTA card punches while SFRP1 promotor methylation was present in 34/40 (85.0%) colorectal adenomas. Our results indicate that genomic DNA isolated from colonic tumor samples preserved on FTA cards is suitable for downstream methylation detection methodologies such as MSP even after prolonged storage periods.
       
  • Analyses of VEGFC/VEGF-D expressions, density and endothelial lymphatic
           proliferation in salivary gland neoplasms
    • Abstract: Publication date: Available online 28 January 2020Source: Experimental and Molecular PathologyAuthor(s): Keila Martha Amorim Barroso, Pedro Paulo de Andrade Santos, Leorik Pereira da Silva, Cassiano Francisco Weege Nonaka, Aquiles Sales Craveiro Sarmento, Leão Pereira Pinto, Lélia Batista de Souza ObjectiveThe aim of this study was to assess vascular endothelial growth factor C (VEGF-C) and VEGF-D expressions, tumor lymphatic density (D2–40) and endothelial lymphatic proliferation (D2–40/Ki-67 double labeling) in a series of salivary gland neoplasm cases.Materials and methodsTwenty pleomorphic adenomas (PA), 20 adenoid cystic carcinomas (ACC) and 20 mucoepidermoid carcinomas (MEC) were assessed, as well as 10 normal minor salivary gland (SG) tissues for comparison.ResultsAll cases presented positive VEGF-C expression in the peritumoral and intratumoral regions, and no differences in immunoexpression were detected between groups. However, the ACC group presented a significant difference in VEGF-C immunoexpression according to the predominant histological pattern. Most cases presented poor VEGF-D labeling in the peritumoral and intratumoral regions. Concerning peritumoral, intratumoral and total lymphatic endothelial density, the assessed groups revealed an increasing gradient, with lower values  for PA, followed by MEC and ACC.ConclusionNo correlation was detected between VEGF-C and VEGF-D immunoexpression in relation to lymphatic tumor density and endothelial lymphatic proliferation. Western blotting (WB) revealed no difference between VEGF-C and VEGF-D expression among the lesions, corroborating the immunohistochemistry findings.
       
  • miR-133 inhibits proliferation and promotes apoptosis by targeting LASP1
           in lupus nephritis
    • Abstract: Publication date: Available online 24 January 2020Source: Experimental and Molecular PathologyAuthor(s): Zhimin Huang, Guozhen Pang, Yu Ge Huang, Chengyan Li Lupus nephritis (LN) is a chronic autoimmune disease. Recently, microRNA (miR)-133 has been demonstrated to play an important role in renal cell carcinoma. Our current study was designed to test the role of miR-133 and its potential target in LN. First, significant correlation of LASP1 and miR-133 levels was observed in the human LN tissue. Modification of miR-133 level in the human mesangial cells (HMCs) by either overexpression or knockdown demonstrated a suppressive role of miR-133 in cell proliferation and an inductive role in cell apoptosis. Modification of LASP1 level in the HMCs demonstrated the opposing effects of LASP1 to miR-133 on proliferation and apoptosis. In addition, luciferase assay showed miR-133 directly regulates LASP1 expression through its binding site in the 3’UTR of LASP1. At last, our data showed that the changes in properties, such as suppression in proliferation and induction in apoptosis, induced by overexpression of miR-133 were restored by additional expression of LASP1. In summary, our obtained data demonstrated that miR-133 suppresses proliferation and promotes apoptosis through its binding with LASP1 in human mesangial cells. This study revealed a new mechanism involving the interaction of miR-133 and LASP1 in the pathogenesis of LN.
       
  • Expression assessment of a panel of long non-coding RNAs in gastric
           malignancy
    • Abstract: Publication date: Available online 23 January 2020Source: Experimental and Molecular PathologyAuthor(s): Farbod Esfandi, Tayebeh Salehnezhad, Mohammad Taheri, Mandana Afsharpad, Asghar Ashrafi Hafez, Vahid Kholghi Oskooei, Soudeh Ghafouri-Fard BackgroundLong non-coding RNAs (lncRNAs) have several important functions in the regulation of cell homeostasis and cell fate. Consequently, abnormal transcription of lncRNAs has been correlated with malignant transformation of cells. These human transcripts have been shown to participate in the progression of gastric cancer.MethodsIn the current project, we evaluated expression of a panel of lncRNAs including HULC, MALAT1, FAS-AS1, GAS5, PVT1, OIP5-AS1 and THRIL in 30 gastric cancer tissues and paired adjacent non-cancerous tissues (ANCTs) using quantitative real-time PCR.ResultsHULC, OIP5-AS1 and THRIL transcription quantities were significantly lower in gastric tumors compared to ANCTs (P values = .02, 0.02 and 0.007, respectively). Relative transcription quantities of HULC, MALAT1, OIP5-AS1, PVT1, FAS-AS1 and THRIL were associated with the site of the primary tumor (P values = .002, 0.003, 0.002, 0.002, 0.002, and 0.001, respectively). Moreover, relative expression levels of PVT1 were associated with history of smoking (P value = .04). Correlations were identified between transcript quantities of these lncRNAs in both tumor samples and ANCTs. Receiver operating characteristic curve assessment demonstrated that THRIL had the highest diagnostic power among the mentioned lncRNAs (area under curve (AUC) = 0.72, P value = .001). HULC and OIP5-AS1 ranked afterwards (AUC values of 0.69 and 0.68; P values = .005 and 0.007, respectively).ConclusionThe current investigation underscores the dysregulation of these transcripts in gastric cancer specimens and suggests a number of these transcripts for further assessments of their suitability as cancer biomarkers.
       
  • The need for rapid therapeutic efficacy testing for cancer therapy
    • Abstract: Publication date: Available online 23 January 2020Source: Experimental and Molecular PathologyAuthor(s): David G. Kaufman
       
  • miRNA profile in ovarian cancer
    • Abstract: Publication date: Available online 16 January 2020Source: Experimental and Molecular PathologyAuthor(s): Soudeh Ghafouri-Fard, Hamed Shoorei, Mohammad Taheri Ovarian cancer is a gynecological cancer with high mortality and a heterogeneous nature which complicates its early detection and primary prevention. Numerous studies have evaluated expression profile microRNAs (miRNAs) in tissue and serum samples of ovarian cancer patients to find appropriate biomarkers for this malignancy. Functional experiments also verified the oncogenic or suppressor effects of a number of miRNAs. miRNAs exert their role through degradation or inhibition of translation of the target mRNA. Through this regulatory function, they modulate numerous cellular processes which are ultimately associated with carcinogenesis. A number of miRNAs including miR-135a-3p, miR-200c, miR-216a and miR-340 regulate epithelial-mesenchymal transition program thus modulate invasiveness of ovarian cancer cell. Others have been shown to regulate some fundamental pathways in carcinogenesis such as mTOR and PI3K/AKT pathways. Such vast area of function of miRNAs in ovarian cancer has suggested them as putative therapeutic options for future years. In this review, we summarize the recent findings regarding the role of miRNAs in ovarian cancer pathogenesis, their application as biomarkers and the future perspectives of this research area.
       
  • Transcriptome profiling and pathway analysis in squamous cell carcinoma of
           buccal mucosa
    • Abstract: Publication date: Available online 11 January 2020Source: Experimental and Molecular PathologyAuthor(s): Kinjal D. Patel, Hemangini H. Vora, Trupti I. Trivedi, Jayendra B. Patel, Shashank J. Pandya, Dhaval H. Jetly, Prabhudas S. Patel BackgroundHigh recurrence and poor overall survival in buccal mucosa squamous cell carcinoma (BMSCC) are not well addressed due to lack of efficient prognostic biomarkers and targeted therapies. To uncover gene candidates for the same, transcriptome profiling has been examined in BMSCC, which is not explored yet.MethodsWe compared 9 BMSCC and 2 normal oral FFPE tissues using Agilent SurePrint G3 Human gene expression v3 microarray chips. The obtained RNA signatures were interrogated in the cancer genome atlas (TCGA) dataset for alteration values and survival data.ResultsWe found total 237 protein coding RNAs and 85 long non-coding RNAs (lncRNAs) which displayed significant differential expression with criteria of at-least 2 fold change and Benjamini Hochberg FDR
       
  • Down-regulation of the human major histocompatibility complex class I
           chain-related gene A (MICA) and its receptor is mediated by
           microRNA-146b-5p and is a potential mechanism of immunoediting in
           papillary thyroid carcinoma
    • Abstract: Publication date: Available online 11 January 2020Source: Experimental and Molecular PathologyAuthor(s): Abeer Al-Abdallah, Iman Jahanbani, Heba Mehdawi, Rola H. Ali, Nabeel Al-Brahim, Olusegun Mojiminiyi, Thamradeen A. Junaid Immune escape is one of the main reasons for the rapid progression of cancer and the poor efficacy of immunotherapy. Papillary thyroid cancer (PTC) is usually accompanied by intra-tumoral lymphocytic infiltration. The mechanisms regulating this tumor associated immune response or its evasion are not well understood. The major histocompatibility complex class I chain-related proteins A (MICA) and its receptor the natural killer group 2 member D (NKG2D) are major executers of the anti-tumor defense. This work aimed to study the expression and regulation of MICA-NKG2D and its association with the lymphocytic infiltration and miRNAs in PTC. Expression of MICA and NKG2D in thyroid tissues, and in cultured primary thyroid cancer cells and lymphocytes transfected with miR-146b-5p inhibitor/mimic was tested by RT-PCR. Results were confirmed by immunofluorescence staining and confocal microscopy. MICA is expressed in malignant and benign thyroid tissues with no association with aggressive behavior. Expression of MICA and NKG2D in PTC is concomitant with the presence of tumor associated lymphocytic response and is regulated by miR-146b-5p. MiR-146b-5p indirectly downregulates NKG2D expression in cancer cells and in lymphocytes. Overexpression of miR-146b-5p in PTC down-regulates MICA expression possibly to reduce the immunogenicity of the tumor cells. Targeting of the MICA-NKG2D axis by miR-146b-5p might be one of the ways adopted by thyroid cancer cells to aid the tumor in evading the immune response. The importance of our findings resides in the potential therapeutic use of MICA, NKG2D and miRNA-146b-5p as targets or modulators to enable the immune response against cancer.
       
  • Knockdown of long non-coding RNA CCAT1 suppresses proliferation and EMT of
           human cervical cancer cell lines by down-regulating Runx2
    • Abstract: Publication date: Available online 11 January 2020Source: Experimental and Molecular PathologyAuthor(s): Ruiping Li, Jinyu Liu, Jinhong Qi BackgroundCervical cancer (CC) is one of the common malignant tumors in women. CCAT1 is a novel lncRNA and its knockdown can inhibit viability, migration and invasion in CC cells. Here, we aimed to further explore the roles of CCAT1 knockdown and underlying mechanism to provide theoretical support for the application of CCAT1 knockdown in treating CC.MethodsThe expression level of CCAT1 in CC tissues was examined by using qRT-PCR. Si-CCAT1, pc-Runx2 and relative control were transfected into HeLa and SiHa cells to explore the functional mechanism of CCAT1. The effects of CCAT1 on cell proliferation, apoptosis, migration and invasion were examined via BrdU incorporation assay, flow cytometry and transwell assay. The expression of Runx2 and other relative factors was examined via qRT-PCR and western blot analysis.ResultsOur findings indicated that CCAT1 was highly expressed in CC tissues contrasted with adjacent tissues. The proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) were suppressed, while the apoptosis was promoted by CCAT1 knockdown. Moreover, knockdown of CCAT1 could negatively regulate Runx2 to play anti-tumor roles in HeLa and SiHa cells. Further, CCAT1 knockdown could suppress PI3K/AKT signal pathway.ConclusionKnockdown of CCAT1 suppressed proliferation, EMT, migration and invasion in HeLa and SiHa cells through down-regulating Runx2, which provided theoretical support for its application in CC treatment.
       
  • Expression of nucleostemin in odontogenic cysts and tumors
    • Abstract: Publication date: Available online 9 January 2020Source: Experimental and Molecular PathologyAuthor(s): Azadeh Andisheheh-Tadbir, Mohammad Ali Ranjbar, Amir Abbas Shiri, Maryam Mardani Considering the unique clinical behavior of odontogenic cysts and tumors, this study aimed to assess the expression of nucleostemin in odontogenic cysts and tumors by immunohistochemical (IHC) staining. This retrospective study evaluated 50 samples including 13 samples of unicystic ameloblastoma (UA), 10 samples of solid ameloblastoma (SA), 10 samples of odontogenic keratocyst (OKC) and 17 samples of dentigerous cyst (DC) by IHC staining. The stained slides were evaluated under a light microscope. Number of positively stained cells for nucleostemin marker was counted in five random areas per 100 cells under x400 magnification. The labeling index (LI) for nucleostemin was calculated by dividing the number of positively stained cells by the total number of counted cells in each lesion multiplied by 100. Positive staining for nucleostemin marker was observed in 100% of UA, 100% of OKC and 5 samples of DC (29.4%). The LI for nucleostemin marker in SA (median: 70.5), UA (median: 50) and OKC (median: 52) samples was significantly higher than that in DC (median: 0.00) (P = .001). This study showed an increased expression of nucleostemin in ameloblastoma and OKC, which suggests that stemness may be related to development of these lesions, their invasive behavior and high rate of recurrence.
       
  • Assessment of CMKLR1 level in colorectal cancer and its correlation with
           angiogenic markers
    • Abstract: Publication date: Available online 9 January 2020Source: Experimental and Molecular PathologyAuthor(s): Paweł Kiczmer, Alicja Prawdzic Seńkowska, Agnieszka Kula, Miriam Dawidowicz, Joanna Katarzyna Strzelczyk, Ewa Nowakowska Zajdel, Katarzyna Walkiewicz, Dariusz Waniczek, Zofia Ostrowska, Elżbieta Świętochowska IntroductionColorectal cancer (CRC) is the second most common malignant neoplasm in men and third in women. It is also the third leading cause of cancer-related death, killing annually>700,000 patients in the world. The global burden of CRC is expected to increase by 60% to>2.2 million new cases and 1.1 million deaths by 2030. The pathogenesis of cancer mainly depends on angiogenesis. This process plays a key role in the growth and infiltration of tumors which is essential for distant metastases. A large number of biochemical pathways is involved in the regulation of angiogenesis. As a subject of our study, we chose chemerin/chemokine-like receptor 1 (CMKLR1) pathway which is responsible for the angiogenic processes in malignant neoplasms.Aim of the studyTo assess the CMKLR1 level and the concentrations of the two markers of angiogenesis, matrix metalloproteinase (MMP)-9 and vascular cell adhesion molecule (VCAM)-1, in tumor and margin tissues of CRC in relation to histological grade and TNM classification.Materials and methodsThe study used 47 samples of tumor and margin tissues derived from CRC patients. To determine the concentration of CMKLR1, MMP-9, and VCAM-1, we used the commercially available enzyme-linked immunosorbent assay kit.ResultsWe found a significantly higher concentration of CMKLR1 and MMP-9 in tumor tissue compared to margin. There was no difference in VCAM-1 concentration between tumor and margin. The margin concentration of CMKLR1 was significantly correlated with that of both MMP-9 and VCAM-1. The margin concentration of VCAM-1 was correlated with that of MMP-9. Additionally, we observed that the tumor levels of CMKLR1 and MMP-9 were positively correlated with the tumor size (T parameter).ConclusionCMKLR1 activity may be associated with the angiogenic process in CRC via MMP-9 activity. Further research, involving a larger sample, may verify whether chemerin/CMKLR1 axis could be considered as a suitable target in novel molecular therapies.
       
  • Effect of astaxanthin on metabolic cataract in rats with type 1 diabetes
           mellitus
    • Abstract: Publication date: Available online 7 January 2020Source: Experimental and Molecular PathologyAuthor(s): Ming Yang, You Chen, Tong Zhao, Zhijun Wang ObjectiveThe purpose of this study was to investigate the effect of astaxanthin on metabolic cataract in rats with type 1 diabetes and its antioxidant capacity to lens.MethodsRats were randomly divided into four groups (n = 8): control group, diabetes mellitus (DM) group, low-dose astaxanthin (DM + AL) and low-dose astaxanthin (DM + AH) group. A rat model of type I diabetes mellitus was established by intraperitoneal injection of 60 mg/kg streptozotocin (STZ). After successful modeling, rats in the administration group were given different doses of astaxanthin (AST) for 12 weeks. The lens opacity of rats was observed by slit-lamp camera system. The double antibody sandwich method was used to detect the levels of advanced glycation end product (AGE), lipid peroxide/malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD) and glutathione (GSH) in the lens. Hematoxylin-eosin (HE) staining was used to examine the morphologic changes in the lens.ResultsThe severity of cataract in the lens was obviously increased after induced by STZ, whereas it was significantly decreased after treatment with AST (p 
       
  • Expression and methylation levels of suppressor of cytokine signaling 3 in
           rheumatic arthritis synovial fibroblasts
    • Abstract: Publication date: April 2020Source: Experimental and Molecular Pathology, Volume 113Author(s): Chunqing Meng, Hong Qi, Xiaohong Wang, Xinghuo Wu, Wei Huang, Hong Wang, Yu He BackgroundIn the present study, we aimed to understand the expression and methylation levels of the suppressor of cytokine signaling 3 (SOCS3) in rheumatoid arthritis (RA) synovial fibroblasts.MethodThe RA model was established using Freund's complete adjuvant, and then the synovial fibroblasts were isolated and cultured. Next, RNA extraction and reverse transcription were performed. The SOCS3 transcription level was detected using qPCR, and SOCS3 protein expression was detected using western blotting (WB). Lastly, methylation-specific PCR (MSP) was performed.ResultsThe RA model was successfully demonstrated. SOCS3 gene (p 
       
  • Association of DNA repair gene polymorphisms with colorectal cancer risk
           and treatment outcomes
    • Abstract: Publication date: April 2020Source: Experimental and Molecular Pathology, Volume 113Author(s): Fawaz N. Al-Shaheri, Kamal M. Al-Shami, Eshrak H. Gamal, Amjad A. Mahasneh, Nehad M. Ayoub Colorectal cancer (CRC) is the third most common carcinoma worldwide. Despite the progress in screening and treatment, CRC remains a leading cause of cancer-related mortality. Alterations to normal nucleic acid processing may drive neoplastic transformation of colorectal epithelium. DNA repair machinery performs an essential function in the protection of genome by reducing the number of genetic polymorphisms/variations that may drive carcinogenicity. Four essential DNA repair systems are known which include nucleotide excision repair (NER), base excision repair (BER), mismatch repair (MMR), and double-strand break repair (DSBR). Polymorphisms of DNA repair genes have been shown to influence the risk of cancer development as well as outcomes of treatment. Several studies demonstrated the association between genetic polymorphism of DNA repair genes and increased risk of CRC in different populations. In this review, we have summarized the impact of DNA repair gene polymorphisms on risk of CRC development and treatment outcomes. Advancements of the current understanding for the impact of DNA repair gene polymorphisms on the risk and treatment of CRC may support diagnostic and predictive roles in patients with CRC.
       
  • Alpha-syntrophin deficiency protects against non-alcoholic steatohepatitis
           associated increase of macrophages, CD8+ T-cells and galectin-3 in the
           liver
    • Abstract: Publication date: April 2020Source: Experimental and Molecular Pathology, Volume 113Author(s): Lisa Rein-Fischboeck, Elisabeth M. Haberl, Ganimete Bajraktari, Susanne Feder, Rebekka Pohl, Elke Eggenhofer, Christa Buechler Non-alcoholic steatohepatitis (NASH) is characterized by immune cell infiltration. Loss of the scaffold protein alpha-syntrophin (SNTA) protected mice from hepatic inflammation in the methionine-choline-deficient (MCD) diet model. Here, we determined increased numbers of macrophages and CD8+ T-cells in MCD diet induced NASH liver of wild type mice. In the mutant animals these NASH associated changes in immune cell composition were less pronounced. Further, there were more γδ T-cells in the NASH liver of the null mice. Galectin-3 protein in the hepatic non-parenchymal cell fraction was strongly induced in MCD diet fed wild type but not mutant mice. Antioxidant enzymes declined in NASH liver with no differences between the genotypes. To identify the target cells responsive to SNTA loss in-vitro experiments were performed. In the human hepatic stellate cell line LX-2, SNTA did not regulate pro-fibrotic or antioxidant proteins like alpha-smooth muscle actin or catalase. Soluble galectin-3 was, however, reduced upon SNTA knock-down and increased upon SNTA overexpression. SNTA deficiency neither affected cell proliferation nor cell death of LX-2 cells. In the macrophage cell line RAW264.7 low SNTA indeed caused higher galectin-3 production whereas release of TNF and cell viability were normal. Moreover, SNTA had no effect on hepatocyte chemerin and CCL2 expression. Overall, SNTA loss improved NASH without causing major effects in macrophage, hepatocyte and hepatic stellate cell lines. SNTA null mice fed the MCD diet had less body weight loss and this seems to contribute to improved liver health of the mutant mice.
       
  • IGFBP-2 in cervical cancer development
    • Abstract: Publication date: April 2020Source: Experimental and Molecular Pathology, Volume 113Author(s): Gurjeet Kaur, Shandra Devi Balasubramaniam, Yung Jen Lee ObjectiveIncreased expression of insulin-like growth factor binding protein 2, IGFBP-2, is associated with many cancers, though its role in cervical cancer is unclear. The aim of this study was to investigate the expression of IGFBP-2 protein and the transcriptomics profile of genes involved in the IGF signaling pathway during cervical cancer development.DesignImmunohistochemical expression of IGFBP-2 protein was semi-quantitatively assessed in tissue microarrays containing 9 normal cervix, 10 low grade cervical intraepithelial neoplasia (LGCIN), 10 high grade cervical intraepithelial neoplasia (HGCIN) and 42 squamous cell carcinoma (SCC) cases. The gene expression profiles of IGFBP-2, IGF-1, IGF-1R, PTEN, MDM2, AKT1 and TP53 were determined in three cervical tissue samples each from normal cervix, human papillomavirus (HPV)-infected LGCIN, HGCIN and SCC, using Human Transcriptome Array 2.0.ResultsIGFBP-2 protein was highly expressed in the cytoplasm of SCC cells compared to normal cervix (p = .013). The expression was not significantly associated with CIN grade or SCC stage. Transcriptomics profiling demonstrated upregulation of IGFBP-2 and TP53 in HGCIN and SCC compared to normal cervix. IGF-1, IGF-1R and PTEN genes were downregulated in all histological groups. IGF-1 gene was significantly downregulated in SCC (p = .031), while PTEN gene was significantly downregulated in HGCIN (p = .012), compared to normal cervix. MDM2 and AKT1 genes were downregulated in LGCIN and HGCIN, while upregulated in SCC.ConclusionIn cervical carcinogenesis, IGFBP-2 appears to play an oncogenic role, probably through an IGF-independent mechanism.
       
  • LncRNA GAS5 suppresses inflammatory responses and apoptosis of alveolar
           epithelial cells by targeting miR-429/DUSP1
    • Abstract: Publication date: April 2020Source: Experimental and Molecular Pathology, Volume 113Author(s): Jianzhong Li, Shiwen Liu Acute lung injury (ALI) is a life-threatening syndrome characterized by excessive inflammation and apoptosis of alveolar epithelial cells. This study firstly investigated the role and mechanism of long non-coding RNA (lncRNA) growth arrest-specific 5 (GAS5) in regulating lipopolysaccharide (LPS)-induced inflammatory response and apoptosis of murine alveolar epithelial cell line MLE-12. The expression of GAS5, miR-429, and dual-specificity phosphatase 1 (DUSP1) were examined using quantitative Real-Time PCR (qRT-PCR) and western blot. The inflammatory responses were evaluated by detecting the levels of pro-inflammatory cytokines using ELISA. Cell apoptosis was assessed by TUNEL assay. The interactions among GAS5, miR-429, and DUSP1 were examined using luciferase reporter assay. The results showed that GAS5 and DUSP1 expression were decreased, whereas miR-429 was increased in lung tissues from LPS-induced ALI mice and LPS-treated MLE-12 cells. Furthermore, GAS5 overexpression decreased cell inflammatory responses and apoptosis in LPS-treated MLE-12 cells, which was reversed by miR-429 mimic and DUSP1 knockdown. Mechanistically, GAS5 acted as a competitive endogenous RNA by sponging miR-429 to facilitate DUSP1 expression. Our findings suggest that GAS5 suppresses inflammatory responses and apoptosis of alveolar epithelial cell MLE-12 by targeting miR-429/DUSP1 axis.
       
  • MiR-1258 promotes the apoptosis of cervical cancer cells by regulating the
           E2F1/P53 signaling pathway
    • Abstract: Publication date: Available online 7 January 2020Source: Experimental and Molecular PathologyAuthor(s): Xing Peng, Yumei Zhang, Jinyu Gao, Chunyan Cai ObjectiveCervical cancer is the most common malignant tumor in gynaecology with high mortality. MiRNA has been reported to regulate cell biological processes in cervical cancer. This study aimed to explore the expression of miR-1258 and role of miR-1258 by targeting E2F1 in cervical cancer cells.MethodsThe expression of miR-1258 and E2F1 in cervical cancer cells and transfection effects was determined by RT-qPCR analysis. The expression of E2F1, MMP2, MMP7, MMP9, Bcl2, Bax, cleaved caspase3, caspase3, KI67, p-AKT, cyclinD1, CDK2, P53 and AKT in cervical cancer cells was detected by western blot analysis. The proliferation, invasion, migration and apoptosis were respectively analyzed by CCK-8 assay, transwell assay, wound healing assay and flow cytometry analysis. E2F1 was a potential target of miR-1258, which demonstrated by a dual-luciferase reporter assay.ResultsmiR-1258 expression was decreased while E2F1 expression was increased in cervical cancer cells. MiR-1258 overexpression could down-regulate the E2F1 expression. Overexpression of miR-1258 inhibited the proliferation, invasion and migration and promoted the apoptosis of cervical cancer cells by AKT and P53 signal pathway. And, Overexpression of miR-1258 also suppressed the tumor growth by AKT and P53 signal pathway. Overexpression of E2F1 reduced the inhibition effects of miR-1258 in cervical cancer.ConclusionTaken together, miR-1258 overexpression exerts its inhibition effects on the proliferation, invasion and migration and promotion effects on the apoptosis of cervical cancer cells by targeting the E2F1, which might provide new ideas for clinical treatment of cervical cancer.
       
  • Luteolin retards CXCL12-induced Jurkat cells migration by disrupting
           transcription of CXCR4
    • Abstract: Publication date: Available online 7 January 2020Source: Experimental and Molecular PathologyAuthor(s): Yunwen Bu, Dandan Zhao Luteolin has been reported to impede migration via repressing tumor-associated macrophage-secreted chemokine ligand 2 expression. However, it's still unexplored whether luteolin represses the metastasis progression of leukemia cells via regulating the expression of C-X-C motif chemokine receptor 4 (CXCR4). Jurkat cells were stimulated by lactacystin and chloroquine after luteolin preincubation. C-X-C motif chemokine ligand 12 (CXCL12) was applied to induce migration of Jurkat cells after the cells were pre-incubated with luteolin (50, 100, 150, and 200 μM). CXCR4 was quantified by Western blot assay. Next, cell counting kit-8 (CCK-8) was used to detect cell viability. Apoptotic cells were observed with flow cytometry after staining. Migration assay was performed using a modified Boyden's chamber. We found that luteolin repressed CXCR4 expression at mRNA levels and restrained CXCL12-induced proliferation as well as migration. Furthermore, luteolin facilitated Jurkat cells apoptosis which was associated with the cleavage of caspase. Additionally, luteolin impeded the phosphorylated expression of PI3K, AKT, and ERK which was enhanced by CXCL12. In conclusion, luteolin exhibited anti-proliferation and anti-metastasis functions in CXCL12-treated Jurkat cells and inactivated PI3K/AKT and ERK signaling pathways via repressing the transcription of CXCR4.
       
  • Ataxia telangiectasia mutated pathway disruption affects hepatic DNA and
           tissue damage in nonalcoholic fatty liver disease
    • Abstract: Publication date: Available online 7 January 2020Source: Experimental and Molecular PathologyAuthor(s): Preeti Viswanathan, Yogeshwar Sharma, Luka Maisuradze, Tatyana Tchaikovskaya, Sanjeev Gupta To overcome the rising burdens of nonalcoholic fatty liver disease, mechanistic linkages in mitochondrial dysfunction, inflammation and hepatic injury are critical. As ataxia telangiectasia mutated (ATM) gene oversees DNA integrity and mitochondrial homeostasis, we analyzed mRNAs and total proteins or phosphoproteins by arrays in subjects with healthy liver, fatty liver or nonalcoholic steatohepatitis. Functional genomics approaches were used for DNA damage or cell growth events. The effects of fatty acid-induced toxicity in mitochondrial health, DNA integrity and cell proliferation were validated in HuH-7 cells, including ATM kinase inhibition or mRNA downregulation. In fatty liver, DNA damage and ATM pathway activation was observed. During steatosis in cells, less ATM activity produced mitochondrial dysregulation, DNA damage and cell growth inhibition. In steatohepatitis, ATM was depleted with increased hepatic DNA damage and growth-arrest due to cell cycle checkpoint activations. Moreover, molecular signatures of oncogenesis were associated with upstream mechanistic networks directing cell metabolism, inflammation or growth that were either activated (in fatty liver) or inactivated (in steatohepatitis). To compensate for hepatic growth arrest, preoncogenic oval cell populations expressing connexin-43 and/or albumin emerged. These oval cells avoided DNA damage and proliferated actively. We concluded that ATM is a major contributor to the onset and progression of nonalcoholic fatty liver disease. Therefore, specific markers for ATM pathway dysregulation will allow prospective segregation of cohorts for disease susceptibility and progression. This will offer superior design and evaluation parameters for clinical trials. Restoration of ATM activity with targeted therapies should be appropriate for nonalcoholic fatty liver disease.
       
  • Dexmedetomidine reduces the inflammation and apoptosis of
           doxorubicin-induced myocardial cells
    • Abstract: Publication date: Available online 7 January 2020Source: Experimental and Molecular PathologyAuthor(s): Ying He, Zhaoying Yang, Jinliang Li, Enyou Li As the number of elderly patients increases, some patients with heart problems may also need surgery. The purpose of this study was to investigate whether dexmedetomidine (DEX), a common used anesthetic, was beneficial to the patients with heart problems. Myocardial cells induced by doxorubicin (DOX) was to simulate the myocardium injury in vitro. H9c2 cells were treated with DOX, DEX/DOX, Compound C and Compound C/DEX/DOX, respectively. The expression of p-AMPK, AMPK, p-GSK3β, GSK3β, Bcl2, Bax, Cleaved caspase3, Caspase3, TXNIP, NLRP3, ASC, Cleaved caspase-1 and Caspase-1 were analyzed by Western blot. CCK-8 assay and flow cytometry analysis were used to detect the cell viability and cell apoptosis. The levels of TNF-α, IL-1β and IL-18 were detected by ELISA assay and the levels of NO, ROS, LDH, SOD, MDA and taurine were detected by corresponding assay kits. As a result, DEX promoted the cell viability and inhibited the inflammation, oxidative stress and apoptosis. In addition, DEX suppressed the expression of taurine, TXNIP, NLRP3, ASC and cleaved caspase-1 and activated the expression of p-AMPK and p-GSK3β. However, those above changes could be reversed by Compound C. In conclusion, this study indicated that DEX could reduce the inflammation and apoptosis of DOX-induced myocardial cells through activating the AMPK-GSK3β signaling pathway. Because of the above effects of DEX, it may be beneficial for surgical patients with heart problems.
       
  • Perinatal exposure to bisphenol A impacts in the mammary gland morphology
           of adult Mongolian gerbils
    • Abstract: Publication date: Available online 7 January 2020Source: Experimental and Molecular PathologyAuthor(s): Ellen Cristina Rivas Leonel, Silvana Gisele Pegorin Campos, Carolina Marques Baraldi Bedolo, Luiz Henrique Alves Guerra, Patrícia Simone Leite Vilamaior, Marilia Freitas Calmon, Paula Rahal, Christiani Andrade Amorim, Sebastião Roberto Taboga The endocrine disruptive effects caused by bisphenol A (BPA) are well known. Despite this, to date, evaluation of its long term effects is limited, meaning that there is still much to be unveiled in terms of alterations caused by perinatal exposure to BPA. Our aim was to determine if perinatal exposure to two different doses of BPA causes long term morphological and molecular alteration effects in the mammary gland (MG). We evaluated MG from Mongolian gerbil offspring exposed perinatally (during gestation and lactation) to 50 or 5000 μg/kg/day BPA. At 90 days of age the animals were subjected to a single dose of N-nitroso-N-methylurea in order to mimic a carcinogenic environment. At 6 months of age, animals in estrous were euthanized for morphological evaluation of the MGs. The MG architecture presented considerable changes in terms of detached epithelial cells, inflammation, glandular hyperplasia, and collagen fiber deposition. Furthermore, a higher index of epithelial cell proliferation was detected in comparison to the intact control group. In addition, we verified a higher molecular expression of EZH2 in the vehicle treated group, indicating that corn oil applied alone can alter the expression of this epigenetic biomarker. In conclusion, BPA perinatal exposure promotes significant changes in glandular cytoarchitecture and increases glandular epithelium proliferation rate, leading to the retention of stem-like properties. This event could compromise the fate and differentiation potential of mammary epithelium.
       
  • Icariside II attenuates eosinophils-induced airway inflammation and
           remodeling via inactivation of NF-κB and STAT3 in an asthma mouse model
    • Abstract: Publication date: Available online 7 January 2020Source: Experimental and Molecular PathologyAuthor(s): Chunyan Tian, Fengli Gao, Xing Li, Zhuying Li Asthma is a chronic inflammatory airway disease. Icariside II has been reported to exert anti-inflammatory effect in multiple human diseases. The present study aimed to investigate the effects and mechanisms of Icariside II on airway inflammation and remodeling in asthma. We established an asthma mouse model with ovalbumin (OVA) immunization. Histological analysis using H&E, PAS and Masson staining showed that administration of Icariside II attenuated OVA-induced airway inflammation and remodeling. Icariside II reduced the numbers of total white blood cells and eosinophils in bronchoalveolar lavage fluid (BALF). The levels of interleukin (IL)-4, IL-5, IL-13 and transforming growth factor (TGF)-β1 in peripheral blood and the expression of α-smooth muscle actin (α-SMA), connective tissue growth factor (CTGF), eotaxin-1, CC-chemokine receptor-3 (CCR-3), Toll-like receptor (TLR)-2 and TLR-4 were significantly down-regulated in lung tissues of OVA-induced mouse model. These results suggested that Icariside II inhibited eosinophil activation and thus decreased eosinophils-induced airway inflammation and remodeling in asthma. Moreover, Icariside II suppressed TGF-β1-induced cell proliferation, migration, and CTGF expression in airway smooth muscle cells (ASMCs). In both OVA-induced mouse model of asthma and TGF-β1-induced ASMCs, Icariside II decreased IκBα degradation, nuclear translocation of NF-κB p65 and STAT3 phophorylation, indicating an inactivation of NF-κB and STAT3 in the presence of Icariside II. Therefore, we demonstrate that Icariside II attenuates eosinophils-induced airway inflammation and remodeling in asthmatic mice and inhibits TGF-β1-induced cell proliferation and migration in ASMCs via suppressing NF-κB and STAT3 signalings.
       
  • TIPE2 suppressed cisplatin resistance by inducing autophagy via mTOR
           signalling pathway
    • Abstract: Publication date: Available online 7 January 2020Source: Experimental and Molecular PathologyAuthor(s): Hua Guo, Hui Ren, Jie Li, Minfeng Hao, Jie Hao, Huanrui Ren, Ling Guo, Rui Liu Tumour necrosis factor-α-induced protein-8-like-2 (TIPE2) has been associated with the progression of numerous cancers. Cisplatin, as a classical chemotherapy strategy for cancers, has been applied in non-small-cell lung cancer (NSCLC) clinical therapy but bears the disadvantage of chemoresistance. The aim of this study was to investigate the role of TIPE2 in cisplatin resistance and illustrate the detailed molecular mechanism. In this study, we proved that TIPE2 was down-regulated in cisplatin (DDP)-resistant NSCLC tissues and DDP-resistant NSCLC cells compared with the sensitive control. The inhibition of TIPE2 contributed to cell cisplatin-resistance, and the overexpression of TIPE2 enhanced cisplatin sensitivity and autophagy. Furthermore, increased TIPE2 elevated apoptosis in DDP-resistant NSCLC cells. In addition, TIPE2 restored the activity of mTOR signalling. Preconditioning with the mTOR activator 3BDO abrogated TIPE2-mediated depression in cisplatin-evoked autophagy. In conclusion, aberrant TIPE2 expression may contribute to the occurrence of chemoresistance by interfering with autophagy in NSCLC in an mTOR-dependent manner. TIPE2 could be used as a novel therapeutic target to overcome cisplatin-resistant NSCLC.
       
  • Smad2 and Smad3 play antagonistic roles in high glucose-induced renal
           tubular fibrosis via the regulation of SnoN
    • Abstract: Publication date: Available online 7 January 2020Source: Experimental and Molecular PathologyAuthor(s): Yuanyuan Wang, Xiaohuan Zhang, Yanwen Mao, Luqun Liang, Lingling Liu, Wei Peng, Huiming Liu, Ying Xiao, Yingying Zhang, Fan Zhang, Mingjun Shi, Lirong Liu, Bing Guo Diabetic nephropathy (DN) is a serious microvascular complication of diabetes mellitus.The main pathological features of DN include glomerular sclerosis and renal tubular interstitial fibrosis, which results in epithelial mesenchymal transition (EMT) and excessive extracellular matrix (ECM) deposition.Transforming growth factor-β1(TGF-β1) is a critical factor that regulates the manifestation of renal fibrosis.Smad2 and Smad3 are the main downstream of the TGF-β1 pathway. Ski-related novel protein N(SnoN) is a negative regulator of TGF-β1, and inhibits the activation of the TGF-β1/Smad2/3 signalling pathway. In this study, the expression of Smad2 and Smad3 proteins, SnoN mRNA, SnoN proteins, and the ubiquitination levels of SnoN were determined in DN rats and renal tubular epithelial cells(NRK52E cells). Knockdown and overexpression of Smad2 or Smad3 in NRK52E cells were used to investigate the specific roles of Smad2 and Smad3 in the development of high glucose-induced renal tubular fibrosis, with a specific focus on their effect on the regulation of SnoN expression. Our study demonstrated that Smad3 could inhibit SnoN expression and increase ECM deposition in NRK52E cells, to promote high glucose-induced renal tubular fibrosis. In contrast, Smad2 could induce SnoN expression and reduce ECM deposition, to inhibit high glucose-induced fibrosis. The underlying mechanism involves regulation of SnoN expression. These findings provide a novel mechanism to understanding the significant role of the TGF-β1/ Smad2/3 pathway in DN.
       
  • Long non-coding RNA signature in gastric cancer
    • Abstract: Publication date: Available online 31 December 2019Source: Experimental and Molecular PathologyAuthor(s): Soudeh Ghafouri-Fard, Mohammad Taheri Gastric cancer as a common human malignancy has been associated with aberrant expressions of several coding and non-coding genes. Long non-coding RNAs (lncRNAs) as regulators of gene expressions at different genomic, transcriptomic and post-transcriptomic levels are among putative biomarkers and therapeutic targets in gastric cancer. In the present study, we have searched available literature and listed lncRNAs that are involved in the pathogenesis of gastric cancer. In addition, we discuss associations between expressions of these lncRNAs and tumoral features or risk factors for gastric cancer. Based on the established role of lncRNAs in regulation of genomic stability, cell cycle, apoptosis, angiogenesis and other aspects of cell physiology, the potential of these transcripts as therapeutic targets in gastric cancer should be evaluated in future studies.
       
  • Interference of miR-212 and miR-384 promotes osteogenic differentiation
           via targeting RUNX2 in osteoporosis
    • Abstract: Publication date: Available online 28 December 2019Source: Experimental and Molecular PathologyAuthor(s): Yun Zhang, Ying Jiang, Yong Luo, Yu Zeng The increasing level of osteogenic (OS) differentiation of bone marrow derived mesenchymal stem cells (MSCs) could be potentially used to relieve the signs and symptoms associated with osteoporosis (OP). Inhibition of osteoprotegerin (OPG)/Receptor Activator of Nuclear factor-Kappa B Ligand (RANKL) pathway plays an important role in OS differentiation, leading to excessive osteoclasts and reduction of osteoblasts, and finally causing OP. Recent studies revealed that microRNAs exert an essential role in regulating OS differentiation. Here, we investigated the dysregulation of miR-212 and miR-384 and the mechanism by which they are involved in OS differentiation-induced MSCs. Quantitative real-time PCR revealed that miR-212 and miR-384 were significantly upregulated in an OP animal model, but markedly downregulated in OS differentiation-induced MSCs. Interference of miR-212 and miR-384 promoted OS differentiation and alleviated OP by targeting RUNX2 in vitro and in vivo. Notably, the inhibition of miR-212 and miR-384 promoted OS differentiation via upregulating RUNX2, and activating OPG/RANKL pathway. Together, our findings demonstrated that interference of miR-212 and miR-384 alleviated OP via RUNX2/OPG/RANKL pathway, providing a novel target of treating OP.
       
  • The inhibitory effect and safety of GANT61 on HeLa cells in nude mice
    • Abstract: Publication date: Available online 3 December 2019Source: Experimental and Molecular PathologyAuthor(s): Yanan Chang, Hong Chen, Jie Duan, Wang Wu, Fangshu Le, Fen Mou The Hedgehog (Hh) pathway effector Gli1 plays an important role in cervical cancer, and GANT61 is an Hh signaling inhibitor. In this study, we aimed to investigate the inhibitory effect of GANT61 on cervical cancer and to study its safety in nude mice. We used in vivo experiments to assess the effect of GANT61 on the growth of cervical cancer HeLa cells, and we measured the WBC, HGB, PLT, ALT, AST and Cre levels in nude mice. Next, we examined the organ and tumor morphology and distant metastasis by HE staining. We used immunohistochemistry to monitor the expression levels of Gli1, FoxM1, Ki-67, cyclinD1, E-cadherin, vimentin, survivin, caspase-3 and CD34+. Western blotting and RT-RCR were used to measure Gli1 expression. GANT61 inhibited the growth and metastasis of HeLa cervical cancer cells upon their transplantation into nude mice, and we preliminarily propose that GANT61 is safe for nude mice. These findings suggest that GANT61 could be used as a Hedgehog inhibitor to inhibit EMT and proliferation and to promote apoptosis via Gli1 downregulation.
       
  • Overexpression of cortistatin alleviates
           oxygen/glucose-deprivation-induced ER stress and prompts neural stem cell
           proliferation via SSTR2
    • Abstract: Publication date: Available online 3 December 2019Source: Experimental and Molecular PathologyAuthor(s): Xiulin Liang, Qing Mao, Donghong Huang, Jian Tang, Jinou Zheng Cerebral infarction (CI), a blood circulatory disorder, causes a high mortality and disability rate worldwide. Intriguingly, a newly discovered neuropeptide, Cortistatin (CST), has been indicated to inhibit the cortical activity. In our research, we aimed to explore the functional relevance of CST in neural stem cells (NSCs) in CI rats. The expression of CST was determined in NSCs induced by oxygen-glucose deprivation (OGD). NSCs isolated from the embryonic rat brain were treated with OGD to establish an in vitro CI model while dithiothreitol (DTT) was introduced to induce endoplasmic reticulum stress (ERS), which were evaluated by assessment of GRP94, caspase-12 and CHOP expression. Then CST expression was restored by transfection of oe-CST, followed by assessment of NSC proliferation ability and cytotoxicity. Finally, the expression of CST and its receptor Somatostatin receptor subtype 2 (SSTR2) was quantified for mechanism exploration. CST was downregulated in CI, which was further confirmed in NSCs under OGD treatment. Overexpressed CST was found to promote cell activity and attenuate OGD-induced cytotoxicity of NSCs. Meanwhile, it was observed that the injured proliferation ability of NSCs was restored by CST overexpression. Besides, lower expression of GRP94, caspase-12 and CHOP was indicative of suppressed occurrence of ERS by CST. Mechanically, CST inhibited ERS through SSTR2. CST could facilitate the proliferation of NSCs in CI induced by OGD, ultimately highlighting a novel therapeutic target for CI treatment.
       
  • ACE2 exhibits protective effects against LPS-induced acute lung injury in
           mice by inhibiting the LPS-TLR4 pathway
    • Abstract: Publication date: Available online 2 December 2019Source: Experimental and Molecular PathologyAuthor(s): Rensong Ye, Zhenwei Liu This study aimed to investigate the protective effect of angiotensin converting enzyme 2 (ACE2) on lipopolysaccharide (LPS)-induced acute lung injury (ALI). After generating ALI mouse models by injecting LPS, the levels of ACE2, inflammatory factors, and downstream proteins of the LPS-TLR4 pathway were analyzed. LPS-challenged BEAS-2B cells were established in vitro. Next, a eukaryotic expression vector, pm-ACE2, was constructed and validated. Challenged cells were transfected with pm-ACE2 containing enhanced green fluorescent protein, or they were treated with D-Ala-Ang-(1-7), angiotensin converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB) and the LPS-TLR4 pathway inhibitor dimethyl fumarate (DMF) for analysis of how the above factors contribute to ACE2 regulation. Expression of renin, Ang II, ACE and angiotensin II type 1 receptor (AT1R) was subsequently assessed. In the ALI model, mice exhibited decreased expression of ACE2, lung pathological injury, inflammatory injury, and abnormal activation of the LPS-TLR4 pathway. LPS-challenged BEAS-2B cells demonstrated upregulated expression of renin, Ang II, ACE and AT1R. After injection of ACE2, lung function and lung pathological injury were significantly improved, and that effect was accompanied by attenuated inflammation, and inactivation of the LPS-TLR4 pathway. Cell studies showed similar results. The above observations were further enhanced when there was a combined treatment with DMF and pm-ACE2. D-Ala-Ang-(1-7) treatment attenuated the protective effect of ACE2, while ACEI and ARB treatment alleviated LPS-induced pneumonic injury. In conclusion, ACE2 was expressed at low levels in response to LPS-induced ALI. Overexpression of ACE2 regulates the ACE2/Ang-(1-7)/Mas and ACE/Ang II/AT1 axes to maintain dynamic balance of the renin-angiotensin system, and attenuate inflammatory response.
       
  • Cathelicidin attenuates hyperoxia-induced intestinal injury through
           inhibition of NF-κB activity in newborn rats
    • Abstract: Publication date: Available online 14 June 2019Source: Experimental and Molecular PathologyAuthor(s): Hsiu-Chu Chou, Chung-Ming Chen Supplemental oxygen is often used to treat neonates with respiratory disorders. Preclinical studies have demonstrated that neonatal hyperoxia injures the distal small intestine and activates nuclear factor-κB (NF-κB). Cathelicidin inhibits NF-κB activity and ameliorates lipopolysaccharide-induced intestinal barrier disruption in rats. Sprague–Dawley rat pups were reared in either room air (RA) or hyperoxia (85% O2) and were randomly treated with low-dose cathelicidin (4 mg/kg, LDC) and high-dose cathelicidin (HDC, 8 mg/kg) in 0.05 mL of normal saline (NS) administered intraperitoneally on postnatal days 1–6. The following six groups were obtained: RA + NS, RA + LDC, RA + HDC, O2 + NS, O2 + LDC, and O2 + HDC. The animals were sacrificed and the terminal ileum was removed for Western blot and histological analyses on postnatal day 7. The hyperoxia-reared rats exhibited significantly lower body weights, higher intestinal injury scores, lower occludin and ZO-1 expression, higher intestinal permeability and inducible IκB kinase inhibitor (IKKi) and NF-κB expression than the RA-reared rats. Cathelicidin treatment attenuated intestinal injury as evidenced by lower intestinal injury scores and intestinal permeability and higher intestinal barrier protein expression. The decrease in intestinal injury was accompanied by a decrease in IKKi and NF-κB. Cathelicidin attenuated hyperoxia-induced intestinal injury in the newborn rats, likely through NF-κB activity inhibition.
       
 
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