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Sutton PJ, Mosqueda N, Brownlee CW. Palmitoylated importin α regulates mitotic spindle orientation through interaction with NuMA. EMBO Rep 2025:10.1038/s44319-025-00484-8. [PMID: 40425783 DOI: 10.1038/s44319-025-00484-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 04/02/2025] [Accepted: 05/07/2025] [Indexed: 05/29/2025] Open
Abstract
Regulation of cell division orientation is a fundamental process critical to differentiation and tissue homeostasis. Microtubules emanating from the mitotic spindle pole bind a conserved complex of proteins at the cell cortex which orients the spindle and ultimately the cell division plane. Control of spindle orientation is of particular importance in developing tissues, such as the developing brain. Misorientation of the mitotic spindle and thus subsequent division plane misalignment can contribute to improper segregation of cell fate determinants in developing neuroblasts, leading to a rare neurological disorder known as microcephaly. We demonstrate that the nuclear transport protein importin α, when palmitoylated, plays a critical role in mitotic spindle orientation through localizing factors, such as NuMA, to the cell cortex. We also observe craniofacial developmental defects in Xenopus laevis when importin α palmitoylation is abrogated, including smaller head and brains, a hallmark of spindle misorientation and microcephaly. These findings characterize not only a role for importin α in spindle orientation, but also a broader role for importin α palmitoylation which has significance for many cellular processes.
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Affiliation(s)
- Patrick James Sutton
- Department of Pharmacological Sciences, Stony Brook University, Stony Brook, 11794, USA.
| | - Natalie Mosqueda
- Department of Pharmacological Sciences, Stony Brook University, Stony Brook, 11794, USA
| | - Christopher W Brownlee
- Department of Pharmacological Sciences, Stony Brook University, Stony Brook, 11794, USA.
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Klamminger GG, Eltze E, Bitterlich A, Degirmenci Y, Hasenburg A, Wagner M, Nigdelis MP. Ki-67 as a Prognostic Marker in Squamous Cell Carcinomas of the Vulva: A Systematic Review. J Clin Med 2025; 14:2045. [PMID: 40142853 PMCID: PMC11942767 DOI: 10.3390/jcm14062045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Revised: 03/14/2025] [Accepted: 03/15/2025] [Indexed: 03/28/2025] Open
Abstract
Background/Objectives: To evaluate the prognostic impact of immunohistochemical ki-67 staining analysis regarding lymph node involvement and survival data (overall/progression-free survival) in squamous cell carcinoma of the vulva. Methods: A systematic literature search of English and German articles was conducted (PubMed, Embase, Scopus, Web of Science) from 1980 to December 2023, including the search terms "vulvar Neoplasms", "vulvar cancer", "vulvar carcinoma", "vulvar tumor", "vulvar tumour", "vulvar malignancy", "vulvar malignant", "ki-67", "MIB-1", "MIB1", "proliferative index", "proliferative activity", "mitotic index", and "mitotic count". Study quality was assessed using a two-step "mixed-criteria" approach; to synthesize study results, a narrative summary is provided. Results: In total, 13 studies were included in this systematic literature review. In general, two distinct methods of staining interpretation could be retrieved: A "pattern-based" method, as well as a cell count-based method. Ten of the included studies examined the relationship between ki-67 and lymph node involvement, nine studies included survival data as a parameter of interest; and only five studies defined both groin lymph node metastasis and survival data as outcome variables. While nine out of ten studies found no statistically significant association between ki-67 staining and lymph node metastasis, five out of nine studies determined an association between ki-67 status and overall survival, especially when employing a "pattern-based" method of staining interpretation. Conclusions: The prognostic value of ki-67 staining in terms of survival data has been reported ambivalently and should be subject to future studies. Furthermore, we did not find convincing evidence of an association between ki-67 and lymph node involvement.
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Affiliation(s)
- Gilbert Georg Klamminger
- Department of Obstetrics and Gynecology, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany
| | - Elke Eltze
- Department of General and Special Pathology, Saarland University (USAAR), Saarland University Medical Center (UKS), 66421 Homburg, Germany
- Institute of Pathology, Saarbrücken-Rastpfuhl, 66113 Saarbrücken, Germany
| | - Annick Bitterlich
- Department of General and Special Pathology, Saarland University (USAAR), Saarland University Medical Center (UKS), 66421 Homburg, Germany
| | - Yaman Degirmenci
- Department of Obstetrics and Gynecology, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany
| | - Annette Hasenburg
- Department of Obstetrics and Gynecology, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany
| | - Mathias Wagner
- Department of General and Special Pathology, Saarland University (USAAR), Saarland University Medical Center (UKS), 66421 Homburg, Germany
| | - Meletios P. Nigdelis
- Department of Gynecology and Obstetrics, Saarland University Medical Center (UKS), 66421 Homburg, Germany
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Sutton PJ, Mosqueda N, Brownlee CW. Palmitoylated Importin α Regulates Mitotic Spindle Orientation Through Interaction with NuMA. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2024.10.25.620315. [PMID: 39484393 PMCID: PMC11527331 DOI: 10.1101/2024.10.25.620315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2024]
Abstract
Regulation of cell division orientation is a fundamental process critical to differentiation and tissue homeostasis. Microtubules emanating from the mitotic spindle pole bind a conserved complex of proteins at the cell cortex which orients the spindle and ultimately the cell division plane. Control of spindle orientation is of particular importance in developing tissues, such as the developing brain. Misorientation of the mitotic spindle and thus subsequent division plane misalignment can contribute to improper segregation of cell fate determinants in developing neuroblasts, leading to a rare neurological disorder known as microcephaly. We demonstrate that the nuclear transport protein importin α, when palmitoylated, plays a critical role in mitotic spindle orientation through localizing factors, such as NuMA, to the cell cortex. We also observe craniofacial developmental defects in Xenopus laevis when importin α palmitoylation is abrogated, including smaller head and brains, a hallmark of spindle misorientation and microcephaly. These findings characterize not only a role for importin α in spindle orientation, but also a broader role for importin α palmitoylation which has significance for many cellular processes.
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Wu F, Ge C, Pan H, Han Y, Mishina Y, Kaartinen V, Franceschi RT. Discoidin domain receptor 2 is an important modulator of BMP signaling during heterotopic bone formation. Bone Res 2025; 13:7. [PMID: 39746922 PMCID: PMC11696679 DOI: 10.1038/s41413-024-00391-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 09/19/2024] [Accepted: 11/13/2024] [Indexed: 01/04/2025] Open
Abstract
Bone morphogenetic proteins are essential for bone regeneration/fracture healing but can also induce heterotopic ossification (HO). Understanding accessory factors modulating BMP signaling would provide both a means of enhancing BMP-dependent regeneration while preventing HO. This study focuses on the ability of the collagen receptor, discoidin domain receptor 2 (DDR2), to regulate BMP activity. As will be shown, induction of bone formation by subcutaneous BMP2 implants is severely compromised in Ddr2-deficient mice. In addition, Ddr2 deficiency attenuates HO in mice expressing the ACVR1 mutation associated with human fibrodysplasia ossificans progressiva. In cells migrating into BMP2 implants, DDR2 is co-expressed with GLI1, a skeletal stem cell marker, and DDR2/GLI1-positive cells participate in BMP2-induced bone formation where they contribute to chondrogenic and osteogenic lineages. Consistent with this distribution, conditional knockout of Ddr2 in Gli1-expressing cells inhibited bone formation to the same extent seen in globally Ddr2-deficient animals. This response was explained by selective inhibition of Gli1+ cell proliferation without changes in apoptosis. The basis for this DDR2 requirement was explored further using bone marrow stromal cells. Although Ddr2 deficiency inhibited BMP2-dependent chondrocyte and osteoblast differentiation and in vivo, bone formation, early BMP responses including SMAD phosphorylation remained largely intact. Instead, Ddr2 deficiency reduced the nuclear/cytoplasmic ratio of the Hippo pathway intermediates, YAP and TAZ. This suggests that DDR2 regulates Hippo pathway-mediated responses to the collagen matrix, which subsequently affect BMP responsiveness. In summary, DDR2 is an important modulator of BMP signaling and a potential therapeutic target both for enhancing regeneration and treating HO.
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Affiliation(s)
- Fashuai Wu
- Department of Periodontics & Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chunxi Ge
- Department of Periodontics & Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA
| | - Haichun Pan
- Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, MI, USA
| | - Yuanyuan Han
- Department of Periodontics & Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA
| | - Yuji Mishina
- Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, MI, USA
| | - Vesa Kaartinen
- Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, MI, USA
| | - Renny T Franceschi
- Department of Periodontics & Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA.
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Santhanam AP, Joel A, Paul A, Zachariah UG, Rebekah GJ, Kodiatte TA. Anti-phosphohistone H3 (PHH3) as a proliferation marker to assess mitotic activity and to grade neuroendocrine neoplasms of hepatopancreaticobiliary (HPB) system. INDIAN J PATHOL MICR 2025; 68:30-35. [PMID: 39133254 DOI: 10.4103/ijpm.ijpm_625_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 03/19/2024] [Indexed: 08/13/2024] Open
Abstract
BACKGROUND The world health organization (WHO) classification of neuroendocrine neoplasms (NENs, i.e. neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs)) of the gastrointestinal system involves grading of these tumors by mitotic count (i.e. H and E mitotic index or Haematoxylin and Eosin mitotic index [HE-MI] and Mindbomb E3 ubiquitin protein ligase 1 labelling index (MIB1-LI) into Grade 1 (G1), Grade 2 (G2), or Grade 3 (G3). However, the assessment of HE-MI and MIB1-LI is hindered by several factors that contribute to discordance between these two grading methods. Clinical data demonstrate the dependency of prognosis on grade. OBJECTIVES The objective of this study was to compare the grading of NENs of the hepatopancreatobiliary (HPB) system using Anti-phosphohistone H3 mitotic index (i.e. PHH3-MI), HE-MI and MIB1-LI. MATERIALS AND METHODS In a cohort of 140 NENs selected from January 2011 to August 2019, the concordance and correlation between HE-MI, MIB1-LI and PHH3-MI grading methods were analysed using Cohen's weighted kappa ( κ ) statistics and Spearman's correlation (ρ), respectively. Receiver operating characteristic (ROC) curve and cut-off analyses were done to determine optimal PHH3-MI cut-off values to grade NENs. RESULTS The rates of discordance between HE-MI vs. MIB1-LI, PHH3-MI vs. MIB1-LI and PHH3-MI vs. HE-MI were 52% ( κ =0.416), 29% ( κ =0.64) and 41% ( κ =0.508), respectively. There was a significant correlation between the grading methods. PHH3-MI had good overall sensitivity and specificity at cut-offs 2 and 17 in distinguishing between G1 vs. G2, and G2 vs. G3 tumors, respectively. CONCLUSION PHH3 immunolabeling allowed for quick and easy identification of mitotic figures (MF). It had the highest concordance with MIB1-LI. At cut-off values of 2 and 17, there was good overall sensitivity and specificity. The interobserver agreement was excellent.
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Affiliation(s)
- A Prisca Santhanam
- Department of Pathology, Christian Medical College, Vellore, Tamil Nadu, India
| | - Anjana Joel
- Department of Medical Oncology, Christian Medical College, Vellore, Tamil Nadu, India
| | - Anoop Paul
- Department of HPB Surgery, Christian Medical College, Vellore, Tamil Nadu, India
| | - Uday G Zachariah
- Department of Hepatology, Christian Medical College, Vellore, Tamil Nadu, India
| | - Grace J Rebekah
- Department of Biostatistics, Christian Medical College, Vellore, Tamil Nadu, India
| | - Thomas A Kodiatte
- Department of Pathology, Christian Medical College, Vellore, Tamil Nadu, India
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Shen Z, Simard M, Brand D, Andrei V, Al-Khader A, Oumlil F, Trevers K, Butters T, Haefliger S, Kara E, Amary F, Tirabosco R, Cool P, Royle G, Hawkins MA, Flanagan AM, Collins-Fekete CA. A deep learning framework deploying segment anything to detect pan-cancer mitotic figures from haematoxylin and eosin-stained slides. Commun Biol 2024; 7:1674. [PMID: 39702417 DOI: 10.1038/s42003-024-07398-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Accepted: 12/12/2024] [Indexed: 12/21/2024] Open
Abstract
Mitotic activity is an important feature for grading several cancer types. However, counting mitotic figures (cells in division) is a time-consuming and laborious task prone to inter-observer variation. Inaccurate recognition of MFs can lead to incorrect grading and hence potential suboptimal treatment. This study presents an artificial intelligence-based approach to detect mitotic figures in digitised whole-slide images stained with haematoxylin and eosin. Advances in this area are hampered by the small size and variety of datasets available. To address this, we create the largest dataset of mitotic figures (N = 74,620), combining an in-house dataset of soft tissue tumours with five open-source datasets. We then employ a two-stage framework, named the Optimised Mitoses Generator Network (OMG-Net), to identify mitotic figures. This framework first deploys the Segment Anything Model to automatically outline cells, followed by an adapted ResNet18 that distinguishes mitotic figures. OMG-Net achieves an F1 score of 0.84 in detecting pan-cancer mitotic figures, including human breast carcinoma, neuroendocrine tumours, and melanoma. It outperforms previous state-of-the-art models in hold-out test sets. To summarise, our study introduces a generalisable data creation and curation pipeline and a high-performance detection model, which can largely contribute to the field of computer-aided mitotic figure detection.
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Affiliation(s)
- Zhuoyan Shen
- Department of Medical Physics and Biomedical Engineering, University College London, London, UK.
| | - Mikaël Simard
- Department of Medical Physics and Biomedical Engineering, University College London, London, UK
| | - Douglas Brand
- Department of Medical Physics and Biomedical Engineering, University College London, London, UK
- Department of Radiotherapy, University College London Hospitals NHS Foundation Trust, London, UK
| | - Vanghelita Andrei
- Research Department of Pathology, University College London Cancer Institute, London, UK
- Cellular and Molecular Pathology, Royal National Orthopaedic Hospital NHS Foundation Trust, Middlesex, UK
| | - Ali Al-Khader
- Research Department of Pathology, University College London Cancer Institute, London, UK
- Cellular and Molecular Pathology, Royal National Orthopaedic Hospital NHS Foundation Trust, Middlesex, UK
| | - Fatine Oumlil
- Cellular and Molecular Pathology, Royal National Orthopaedic Hospital NHS Foundation Trust, Middlesex, UK
| | - Katherine Trevers
- Research Department of Pathology, University College London Cancer Institute, London, UK
- Cellular and Molecular Pathology, Royal National Orthopaedic Hospital NHS Foundation Trust, Middlesex, UK
| | - Thomas Butters
- Research Department of Pathology, University College London Cancer Institute, London, UK
| | - Simon Haefliger
- Research Department of Pathology, University College London Cancer Institute, London, UK
- Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, CH, Switzerland
| | - Eleanna Kara
- Department of Neurology, Rutgers Biomedical and Health Sciences, Rutgers University, NJ, USA
| | - Fernanda Amary
- Research Department of Pathology, University College London Cancer Institute, London, UK
- Cellular and Molecular Pathology, Royal National Orthopaedic Hospital NHS Foundation Trust, Middlesex, UK
| | - Roberto Tirabosco
- Research Department of Pathology, University College London Cancer Institute, London, UK
- Cellular and Molecular Pathology, Royal National Orthopaedic Hospital NHS Foundation Trust, Middlesex, UK
| | - Paul Cool
- Department of Orthopaedics, The Robert Jones and Agnes Hunt Orthopaedic Hospital, Oswestry, UK
- School of Medicine, Keele University, Newcastle, UK
| | - Gary Royle
- Department of Medical Physics and Biomedical Engineering, University College London, London, UK
| | - Maria A Hawkins
- Department of Medical Physics and Biomedical Engineering, University College London, London, UK
- Department of Radiotherapy, University College London Hospitals NHS Foundation Trust, London, UK
| | - Adrienne M Flanagan
- Research Department of Pathology, University College London Cancer Institute, London, UK
- Cellular and Molecular Pathology, Royal National Orthopaedic Hospital NHS Foundation Trust, Middlesex, UK
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Choromańska A, Szwedowicz U, Szewczyk A, Daczewska M, Saczko J, Kruszakin R, Pawlik KJ, Baczyńska D, Kulbacka J. Electroporation-derived melanoma extracellular particles activate fibroblasts. Biochim Biophys Acta Gen Subj 2024; 1868:130723. [PMID: 39426760 DOI: 10.1016/j.bbagen.2024.130723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Revised: 10/05/2024] [Accepted: 10/15/2024] [Indexed: 10/21/2024]
Abstract
Although the pulse electric field (PEF) has been used in electrochemotherapy (ECT) for many years, the kinetics and profile of extracellular particles (EPs) released as a result of reversible electroporation have yet to be studied. It also needs to be clarified whether and how the profile of released EPs depends on the parameters of the applied PEF. The presented studies investigated the effect of EPs released from human melanoma cells after various parameters of reversible electroporation on markers indicating EP-mediated transformation of normal fibroblasts into tumor-associated fibroblasts. The expression levels of the vascular cell adhesion molecule-1 (VCAM-1) and changes in the expression of phosphor-histone H3 (pHH3), a biomarker specific for cells in mitosis, cell viability, and the migration capacity of the studied fibroblast cells, were analyzed. EPs were isolated from two commercial malignant melanoma cell lines previously subjected to reversible electroporation. Human primary fibroblasts (HPFs) were selected for EPs exposure. It was observed that after incubation with melanoma-derived EPs, HPFs showed differences in cell viability, migration capacity, VCAM-1, pHH3, and N-cadherin expression, depending on PEF parameters and the grade of melanoma cells. This study highlights that small extracellular particles (sEPs) from cancer cells can promote metastasis by carrying specific signals that lead to the upregulation of molecules like FAK, MMP-9, and N-cadherin in recipient cells.
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Affiliation(s)
- Anna Choromańska
- Department of Molecular and Cellular Biology, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland.
| | - Urszula Szwedowicz
- Department of Molecular and Cellular Biology, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Anna Szewczyk
- Department of Molecular and Cellular Biology, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Małgorzata Daczewska
- Department of Animal Developmental Biology, Institute of Experimental Biology, University of Wroclaw, 50-328 Wroclaw, Poland
| | - Jolanta Saczko
- Department of Molecular and Cellular Biology, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Roksana Kruszakin
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland
| | - Krzysztof J Pawlik
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland
| | - Dagmara Baczyńska
- Department of Molecular and Cellular Biology, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Julita Kulbacka
- Department of Molecular and Cellular Biology, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland; Department of Immunology, State Research Institute Centre for Innovative Medicine, Santariškių 5, 08410 Vilnius, Lithuania
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Wang S, Miao S, Li Y, Wang J, Li C, Lu Y, Li B. Morphological and functional characterization of circulating hemocytes in Tribolium castaneum larvae. INSECT SCIENCE 2024. [PMID: 39361781 DOI: 10.1111/1744-7917.13455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 08/15/2024] [Accepted: 08/22/2024] [Indexed: 10/05/2024]
Abstract
Hemocytes are pivotal in the immune response of insects against invasive pathogens. However, our knowledge of hemocyte types and their specific function in Tribolium castaneum, an increasingly important Coleoptera model insect in various research fields, remains limited. Presently, a combination of morphological criteria and dye-staining properties were used to characterize hemocyte types from T. castaneum larvae, and 4 distinct types were identified: granulocytes, oenocytoids, plasmatocytes and prohemocytes. Following different immune challenges, the total hemocyte counts declined rapidly in the initial phase (at 2 h), then increased over time (at 4 and 6 h) and eventually returned to the naive state by 24 h post-injection. Notably, the morphology of granulocytes underwent dramatic changes, characterized by an expansion of the surface area and an increased production of pseudopods, and with the number of granulocytes rising significantly through mitotic division. Granulocytes and plasmatocytes, the main hemocyte types in T. castaneum larvae, can phagocytose bacteria or latex beads injected into the larval hemolymph in vivo. Furthermore, these hemocytes participate in the encapsulation and melanization processes in vitro, forming capsules to encapsulate and melanize nickel-nitrilotriacetic acid (Ni-NTA) beads. This study provides the first comprehensive characterization of circulating hemocytes in T. castaneum larvae, offering valuable insights into cell-mediated immunity in response to bacterial infection and the injection of latex beads. These results deepen our understanding of the cellular response mechanisms in T. castaneum larvae and lay a solid foundation for subsequent investigations of the involvement of T. castaneum hemocytes in combating pathogens.
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Affiliation(s)
- Suisui Wang
- Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China
| | - Shiyuan Miao
- School of Grain Science and Technology, Jiangsu University of Science and Technology, Zhenjiang, Jiangsu Province, China
- College of Environmental and Life Science, Murdoch University, Murdoch, WA, Australia
| | - Yusi Li
- Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China
| | - Jianhui Wang
- Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China
| | - Chengjun Li
- Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China
| | - Yujie Lu
- School of Grain Science and Technology, Jiangsu University of Science and Technology, Zhenjiang, Jiangsu Province, China
| | - Bin Li
- Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China
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Yu HH, Wu LY, Hsu PL, Lee CW, Su BC. Marine Antimicrobial Peptide Epinecidin-1 Inhibits Proliferation Induced by Lipoteichoic acid and Causes cell Death in non-small cell lung cancer Cells via Mitochondria Damage. Probiotics Antimicrob Proteins 2024; 16:1724-1733. [PMID: 37523113 PMCID: PMC11445356 DOI: 10.1007/s12602-023-10130-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/20/2023] [Indexed: 08/01/2023]
Abstract
Non-small cell lung cancer (NSCLC) is among the deadliest cancers worldwide. Despite the recent introduction of several new therapeutic approaches for the disease, improvements in overall survival and progression-free survival have been minimal. Conventional treatments for NSCLC include surgery, chemotherapy and radiotherapy. Except for surgery, these treatments can impair a patient's immune system, leaving them susceptible to bacterial infections. As such, Staphylococcus aureus infections are commonly seen in NSCLC patients receiving chemotherapy, and a major constituent of the S. aureus cell surface, lipoteichoic acid (LTA), is thought to stimulate NSCLC cancer cell proliferation. Thus, inhibition of LTA-mediated cell proliferation might be a useful strategy for treating NSCLC. Epinecidin-1 (EPI), a marine antimicrobial peptide, exhibits broad-spectrum antibacterial activity, and it also displays anti-cancer activity in glioblastoma and synovial sarcoma cells. Furthermore, EPI has been shown to inhibit LTA-induced inflammatory responses in murine macrophages. Nevertheless, the anti-cancer and anti-LTA activities of EPI and the underlying mechanisms of these effects have not been fully tested in the context of NSCLC. In the present study, we demonstrate that EPI suppresses LTA-enhanced proliferation of NSCLC cells by neutralizing LTA and blocking its effects on toll-like receptor 2 and interleukin-8. Moreover, we show that EPI induces necrotic cell death via mitochondrial damage, elevated reactive oxygen species levels, and disrupted redox balance. Collectively, our results reveal dual anti-cancer activities of EPI in NSCLC, as the peptide not only directly kills cancer cells but it also blocks LTA-mediated enhancement of cell proliferation.
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Affiliation(s)
- Hsin-Hsien Yu
- Division of General Surgery, Department of Surgery, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
- Division of General Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Luo-Yun Wu
- School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Pei-Ling Hsu
- Department of Anatomy, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, 80708, Taiwan
| | - Chu-Wan Lee
- Department of Nursing, National Tainan Junior College of Nursing, 78, Section 2, Minzu Road, West Central District, Tainan, 70007, Taiwan
| | - Bor-Chyuan Su
- Department of Anatomy and Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
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10
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Oleksak P, Rysanek D, Vancurova M, Vasicova P, Urbancokova A, Novak J, Maurencova D, Kashmel P, Houserova J, Mikyskova R, Novotny O, Reinis M, Juda P, Hons M, Kroupova J, Sedlak D, Sulimenko T, Draber P, Chlubnova M, Nepovimova E, Kuca K, Lisa M, Andrys R, Kobrlova T, Soukup O, Janousek J, Prchal L, Bartek J, Musilek K, Hodny Z. Discovery of a 6-Aminobenzo[ b]thiophene 1,1-Dioxide Derivative (K2071) with a Signal Transducer and Activator of Transcription 3 Inhibitory, Antimitotic, and Senotherapeutic Activities. ACS Pharmacol Transl Sci 2024; 7:2755-2783. [PMID: 39296273 PMCID: PMC11406704 DOI: 10.1021/acsptsci.4c00190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 07/25/2024] [Accepted: 07/29/2024] [Indexed: 09/21/2024]
Abstract
6-Nitrobenzo[b]thiophene 1,1-dioxide (Stattic) is a potent signal transducer and activator of the transcription 3 (STAT3) inhibitor developed originally for anticancer therapy. However, Stattic harbors several STAT3 inhibition-independent biological effects. To improve the properties of Stattic, we prepared a series of analogues derived from 6-aminobenzo[b]thiophene 1,1-dioxide, a compound directly obtained from the reduction of Stattic, that includes a methoxybenzylamino derivative (K2071) with optimized physicochemical characteristics, including the ability to cross the blood-brain barrier. Besides inhibiting the interleukin-6-stimulated activity of STAT3 mediated by tyrosine 705 phosphorylation, K2071 also showed cytotoxicity against a set of human glioblastoma-derived cell lines. In contrast to the core compound, a part of K2071 cytotoxicity reflected a STAT3 inhibition-independent block of mitotic progression in the prophase, affecting mitotic spindle formation, indicating that K2071 also acts as a mitotic poison. Compared to Stattic, K2071 was significantly less thiol-reactive. In addition, K2071 affected cell migration, suppressed cell proliferation in tumor spheroids, exerted cytotoxicity for glioblastoma temozolomide-induced senescent cells, and inhibited the secretion of the proinflammatory cytokine monocyte chemoattractant protein 1 (MCP-1) in senescent cells. Importantly, K2071 was well tolerated in mice, lacking manifestations of acute toxicity. The structure-activity relationship analysis of the K2071 molecule revealed the necessity of the para-substituted methoxyphenyl motif for antimitotic but not overall cytotoxic activity of its derivatives. Altogether, these results indicate that compound K2071 is a novel Stattic-derived STAT3 inhibitor and a mitotic poison with anticancer and senotherapeutic properties that is effective on glioblastoma cells and may be further developed as an agent for glioblastoma therapy.
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Affiliation(s)
- Patrik Oleksak
- Faculty of Science, Department of Chemistry, University of Hradec Kralove, Rokitanskeho 62, Hradec Kralove 500 03, Czech Republic
| | - David Rysanek
- Laboratory of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic
| | - Marketa Vancurova
- Laboratory of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic
| | - Pavla Vasicova
- Laboratory of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic
| | - Alexandra Urbancokova
- Laboratory of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic
| | - Josef Novak
- Laboratory of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic
| | - Dominika Maurencova
- Laboratory of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic
| | - Pavel Kashmel
- Laboratory of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic
| | - Jana Houserova
- Laboratory of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic
| | - Romana Mikyskova
- Laboratory of Immunological and Tumour Models, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic
| | - Ondrej Novotny
- Laboratory of Immunological and Tumour Models, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic
| | - Milan Reinis
- Laboratory of Immunological and Tumour Models, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic
| | - Pavel Juda
- BIOCEV, First Faculty of Medicine, Charles University, Prumyslova 595, Vestec 252 50, Czech Republic
| | - Miroslav Hons
- BIOCEV, First Faculty of Medicine, Charles University, Prumyslova 595, Vestec 252 50, Czech Republic
| | - Jirina Kroupova
- Laboratory of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic
| | - David Sedlak
- CZ-OPENSCREEN, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic
| | - Tetyana Sulimenko
- Laboratory of Biology of Cytoskeleton, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic
| | - Pavel Draber
- Laboratory of Biology of Cytoskeleton, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic
| | - Marketa Chlubnova
- Faculty of Science, Department of Chemistry, University of Hradec Kralove, Rokitanskeho 62, Hradec Kralove 500 03, Czech Republic
| | - Eugenie Nepovimova
- Faculty of Science, Department of Chemistry, University of Hradec Kralove, Rokitanskeho 62, Hradec Kralove 500 03, Czech Republic
| | - Kamil Kuca
- Faculty of Science, Department of Chemistry, University of Hradec Kralove, Rokitanskeho 62, Hradec Kralove 500 03, Czech Republic
| | - Miroslav Lisa
- Faculty of Science, Department of Chemistry, University of Hradec Kralove, Rokitanskeho 62, Hradec Kralove 500 03, Czech Republic
| | - Rudolf Andrys
- Faculty of Science, Department of Chemistry, University of Hradec Kralove, Rokitanskeho 62, Hradec Kralove 500 03, Czech Republic
| | - Tereza Kobrlova
- Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, Hradec Kralove 500 05, Czech Republic
| | - Ondrej Soukup
- Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, Hradec Kralove 500 05, Czech Republic
| | - Jiri Janousek
- Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, Hradec Kralove 500 05, Czech Republic
| | - Lukas Prchal
- Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, Hradec Kralove 500 05, Czech Republic
| | - Jiri Bartek
- Laboratory of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic
- Danish Cancer Institute, Strandboulevarden 49, DK-2100 Copenhagen, Denmark
- Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Karolinska Institutet, Stockholm 171 77, Sweden
| | - Kamil Musilek
- Faculty of Science, Department of Chemistry, University of Hradec Kralove, Rokitanskeho 62, Hradec Kralove 500 03, Czech Republic
| | - Zdenek Hodny
- Laboratory of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic
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Ying SQ, Cao Y, Zhou ZK, Luo XY, Zhang XH, Shi K, Qiu JY, Xing SJ, Li YY, Zhang K, Jin F, Zheng CX, Jin Y, Sui BD. Hepatocyte-derived tissue extracellular vesicles safeguard liver regeneration and support regenerative therapy. J Nanobiotechnology 2024; 22:521. [PMID: 39210346 PMCID: PMC11363633 DOI: 10.1186/s12951-024-02790-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Accepted: 08/20/2024] [Indexed: 09/04/2024] Open
Abstract
Tissue-derived extracellular vesicles (EVs) are emerging as pivotal players to maintain organ homeostasis, which show promise as a next-generation candidate for medical use with extensive source. However, the detailed function and therapeutic potential of tissue EVs remain insufficiently studied. Here, through bulk and single-cell RNA sequencing analyses combined with ultrastructural tissue examinations, we first reveal that in situ liver tissue EVs (LT-EVs) contribute to the intricate liver regenerative process after partial hepatectomy (PHx), and that hepatocytes are the primary source of tissue EVs in the regenerating liver. Nanoscale and proteomic profiling further identify that the hepatocyte-specific tissue EVs (Hep-EVs) are strengthened to release with carrying proliferative messages after PHx. Moreover, targeted inhibition of Hep-EV release via AAV-shRab27a in vivo confirms that Hep-EVs are required to orchestrate liver regeneration. Mechanistically, Hep-EVs from the regenerating liver reciprocally stimulate hepatocyte proliferation by promoting cell cycle progression through Cyclin-dependent kinase 1 (Cdk1) activity. Notably, supplementing with Hep-EVs from the regenerating liver demonstrates translational potential and ameliorates insufficient liver regeneration. This study provides a functional and mechanistic framework showing that the release of regenerative Hep-EVs governs rapid liver regeneration, thereby enriching our understanding of physiological and endogenous tissue EVs in organ regeneration and therapy.
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Affiliation(s)
- Si-Qi Ying
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Disease, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Yuan Cao
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Disease, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
- Department of Orthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Ze-Kai Zhou
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Disease, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
- School of Basic Medicine, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Xin-Yan Luo
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Disease, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
- School of Basic Medicine, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Xiao-Hui Zhang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Disease, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
- Department of Orthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Ke Shi
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Disease, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
- Xi'an Institute of Tissue Engineering and Regenerative Medicine, Xi'an, Shaanxi, 710032, China
| | - Ji-Yu Qiu
- Department of VIP Dental Care, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Shu-Juan Xing
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Disease, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
- College of Life Science, Northwest University, Xi'an, Shaanxi, 710069, China
| | - Yuan-Yuan Li
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Disease, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Kai Zhang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Disease, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
- Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Fang Jin
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Disease, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
- Department of Orthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Chen-Xi Zheng
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Disease, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
| | - Yan Jin
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Disease, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
- Xi'an Institute of Tissue Engineering and Regenerative Medicine, Xi'an, Shaanxi, 710032, China.
| | - Bing-Dong Sui
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Disease, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
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12
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Abdellatif AM, Basha WAA. Insights into microstructure and expression of markers of proliferation, apoptosis and T cells in the spleen of cattle egret (Bubulcus ibis). Anat Histol Embryol 2024; 53:e13082. [PMID: 38944689 DOI: 10.1111/ahe.13082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 05/23/2024] [Accepted: 06/22/2024] [Indexed: 07/01/2024]
Abstract
The spleen is the largest secondary lymphoid organ with significant roles in pathogen clearance. It is involved in several avian diseases. The cattle egret is a wild insectivorous bird of agricultural and socioeconomic importance. Data related to microstructural features of cattle egret spleen are lacking. The present study investigated the gross anatomical, histological and immunohistochemical characteristics of the cattle egret spleen. Proliferation (PCNA and PHH3), apoptosis (cleaved caspase 3, C.CASP3) and T-cell (CD3 and CD8) markers were assessed. Grossly, the spleen appeared brownish red, oval-shaped and located at the oesophago-proventricular junction. Histologically, the spleen was surrounded by a thin capsule sending a number of trabeculae which contained branches of the splenic vessels. The white pulp consisted of the periarteriolar lymphoid sheath and periellipsoidal lymphatic sheath (PELS). The red pulp was formed of sinusoids and cords. The penicillar capillaries, which represent the terminal segments of the splenic arterial tree were highly branched, wrapped by prominent ellipsoids and directly connected to the splenic sinusoids, suggesting a closed type of circulation. Immunohistochemically, proliferating cell nuclear antigen (PCNA)-expressing cells were distributed with high counts throughout the splenic parenchyma, being highest within the splenic cords and PELS. Both PHH3- and C.CASP3-expressing cells revealed a similar pattern to that of PCNA, although with fewer counts. Large numbers of T cells were observed throughout the splenic parenchyma, mainly within the cords, as revealed by CD3 and CD8 immunoreaction. The present study provides a clear insight into the precise structure of the spleen in cattle egrets and thus improves our understanding about birds' immunity.
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Affiliation(s)
- Ahmed M Abdellatif
- Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt
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13
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Aung TM, Ngamjarus C, Proungvitaya T, Saengboonmee C, Proungvitaya S. Biomarkers for prognosis of meningioma patients: A systematic review and meta-analysis. PLoS One 2024; 19:e0303337. [PMID: 38758750 PMCID: PMC11101050 DOI: 10.1371/journal.pone.0303337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 04/23/2024] [Indexed: 05/19/2024] Open
Abstract
Meningioma is the most common primary brain tumor and many studies have evaluated numerous biomarkers for their prognostic value, often with inconsistent results. Currently, no reliable biomarkers are available to predict the survival, recurrence, and progression of meningioma patients in clinical practice. This study aims to evaluate the prognostic value of immunohistochemistry-based (IHC) biomarkers of meningioma patients. A systematic literature search was conducted up to November 2023 on PubMed, CENTRAL, CINAHL Plus, and Scopus databases. Two authors independently reviewed the identified relevant studies, extracted data, and assessed the risk of bias of the studies included. Meta-analyses were performed with the hazard ratio (HR) and 95% confidence interval (CI) of overall survival (OS), recurrence-free survival (RFS), and progression-free survival (PFS). The risk of bias in the included studies was evaluated using the Quality in Prognosis Studies (QUIPS) tool. A total of 100 studies with 16,745 patients were included in this review. As the promising markers to predict OS of meningioma patients, Ki-67/MIB-1 (HR = 1.03, 95%CI 1.02 to 1.05) was identified to associate with poor prognosis of the patients. Overexpression of cyclin A (HR = 4.91, 95%CI 1.38 to 17.44), topoisomerase II α (TOP2A) (HR = 4.90, 95%CI 2.96 to 8.12), p53 (HR = 2.40, 95%CI 1.73 to 3.34), vascular endothelial growth factor (VEGF) (HR = 1.61, 95%CI 1.36 to 1.90), and Ki-67 (HR = 1.33, 95%CI 1.21 to 1.46), were identified also as unfavorable prognostic biomarkers for poor RFS of meningioma patients. Conversely, positive progesterone receptor (PR) and p21 staining were associated with longer RFS and are considered biomarkers of favorable prognosis of meningioma patients (HR = 0.60, 95% CI 0.41 to 0.88 and HR = 1.89, 95%CI 1.11 to 3.20). Additionally, high expression of Ki-67 was identified as a prognosis biomarker for poor PFS of meningioma patients (HR = 1.02, 95%CI 1.00 to 1.04). Although only in single studies, KPNA2, CDK6, Cox-2, MCM7 and PCNA are proposed as additional markers with high expression that are related with poor prognosis of meningioma patients. In conclusion, the results of the meta-analysis demonstrated that PR, cyclin A, TOP2A, p21, p53, VEGF and Ki-67 are either positively or negatively associated with survival of meningioma patients and might be useful biomarkers to assess the prognosis.
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Affiliation(s)
- Tin May Aung
- Centre of Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand
| | - Chetta Ngamjarus
- Department of Epidemiology and Biostatistics, Faculty of Public Health, Khon Kaen University, Khon Kaen, Thailand
| | - Tanakorn Proungvitaya
- Centre of Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand
| | - Charupong Saengboonmee
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
| | - Siriporn Proungvitaya
- Centre of Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
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14
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Peng M, Keppeke GD, Tsai LK, Chang CC, Liu JL, Sung LY. The IMPDH cytoophidium couples metabolism and fetal development in mice. Cell Mol Life Sci 2024; 81:210. [PMID: 38717553 PMCID: PMC11078715 DOI: 10.1007/s00018-024-05233-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 04/04/2024] [Accepted: 04/05/2024] [Indexed: 05/12/2024]
Abstract
The cytoophidium is an evolutionarily conserved subcellular structure formed by filamentous polymers of metabolic enzymes. In vertebrates, inosine monophosphate dehydrogenase (IMPDH), which catalyses the rate-limiting step in guanosine triphosphate (GTP) biosynthesis, is one of the best-known cytoophidium-forming enzymes. Formation of the cytoophidium has been proposed to alleviate the inhibition of IMPDH, thereby facilitating GTP production to support the rapid proliferation of certain cell types such as lymphocytes, cancer cells and pluripotent stem cells (PSCs). However, past studies lacked appropriate models to elucidate the significance of IMPDH cytoophidium under normal physiological conditions. In this study, we demonstrate that the presence of IMPDH cytoophidium in mouse PSCs correlates with their metabolic status rather than pluripotency. By introducing IMPDH2 Y12C point mutation through genome editing, we established mouse embryonic stem cell (ESC) lines incapable of forming IMPDH polymers and the cytoophidium. Our data indicate an important role of IMPDH cytoophidium in sustaining a positive feedback loop that couples nucleotide biosynthesis with upstream metabolic pathways. Additionally, we find that IMPDH2 Y12C mutation leads to decreased cell proliferation and increased DNA damage in teratomas, as well as impaired embryo development following blastocoel injection. Further analysis shows that IMPDH cytoophidium assembly in mouse embryonic development begins after implantation and gradually increases throughout fetal development. These findings provide insights into the regulation of IMPDH polymerisation in embryogenesis and its significance in coordinating cell metabolism and development.
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Affiliation(s)
- Min Peng
- Institute of Biotechnology, National Taiwan University, Taipei, 106, Taiwan
| | - Gerson D Keppeke
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
- Departamento de Ciencias Biomédicas, Facultad de Medicina, Universidad Católica del Norte, Coquimbo, Chile
| | - Li-Kuang Tsai
- Institute of Biotechnology, National Taiwan University, Taipei, 106, Taiwan
| | - Chia-Chun Chang
- Institute of Biotechnology, National Taiwan University, Taipei, 106, Taiwan.
| | - Ji-Long Liu
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, UK.
| | - Li-Ying Sung
- Institute of Biotechnology, National Taiwan University, Taipei, 106, Taiwan.
- Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, 106, Taiwan.
- Center for Biotechnology, National Taiwan University, Taipei, 106, Taiwan.
- Agricultural Biotechnology Research Center, Academia Sinica, Taipei, 115, Taiwan.
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15
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Rajagopalan K, Christyraj JDS, Chelladurai KS, Christyraj JRSS, Das P, Roy A, Vrushali C, Chemmet NSM. The molecular mechanisms underlying the regeneration process in the earthworm, Perionyx excavatus exhibit indications of apoptosis-induced compensatory proliferation (AICP). In Vitro Cell Dev Biol Anim 2024; 60:222-235. [PMID: 38504086 DOI: 10.1007/s11626-023-00843-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Accepted: 12/16/2023] [Indexed: 03/21/2024]
Abstract
Regeneration is a multifaceted biological phenomenon that necessitates the intricate orchestration of apoptosis, stem cells, and immune responses, culminating in the regulation of apoptosis-induced compensatory proliferation (AICP). The AICP context of research is observed in many animal models like in Hydra, Xenopus, newt, Drosophila, and mouse but so far not reported in earthworm. The earthworm Perionyx excavatus is used in the present study to understand the relationship between AICP-related protein expression and regeneration success in different conditions (normal regeneration and abnormal multiple bud formation). Initially, the worms are amputated into five equal portions and it is revealed that regeneration in P. excavatus is clitellum independent and it gives more preference for anterior regeneration (regrowth of head portion) than for posterior regeneration (regrowth of tail portion). The posterior segments of the worm possess enormous regeneration ability but this is lacking in anterior segments. Alkaline phosphate, a stem cell marker, shows strong signals throughout all the posterior segments but it decreases in the initial 1st to 15th anterior segments which lack the regeneration ability. While regenerating normally, it was suggested that the worm follow AICP principles. This is because there was increased expression of apoptosis signals throughout the regeneration process along with constant expression of stem cell proliferation response together with cellular proliferation. In amputated posterior segments maintained in vitro, the apoptosis signals were extensively detected on the 1st day. However, on the 4th and 6th days, caspase-3 and H2AX expression are significantly suppressed, which may eventually alter the Wnt3a and histone H3 patterns that impair the AICP and result in multiple bud formation. Our results suggest that AICP-related protein expression pattern is crucial for initiating proper regeneration.
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Affiliation(s)
- Kamarajan Rajagopalan
- Molecular Biology and Stem Cell Biology Lab, Centre for Molecular and Nanomedical Sciences, International Research Centre, Sathyabama Institute of Science and Technology (Deemed to Be University), Jeppiaar Nagar, SH 49A, Chennai, Tamil Nadu, 621306, India
| | - Jackson Durairaj Selvan Christyraj
- Molecular Biology and Stem Cell Biology Lab, Centre for Molecular and Nanomedical Sciences, International Research Centre, Sathyabama Institute of Science and Technology (Deemed to Be University), Jeppiaar Nagar, SH 49A, Chennai, Tamil Nadu, 621306, India.
| | - Karthikeyan Subbiahanadar Chelladurai
- Molecular Biology and Stem Cell Biology Lab, Centre for Molecular and Nanomedical Sciences, International Research Centre, Sathyabama Institute of Science and Technology (Deemed to Be University), Jeppiaar Nagar, SH 49A, Chennai, Tamil Nadu, 621306, India
| | - Johnson Retnaraj Samuel Selvan Christyraj
- Molecular Biology and Stem Cell Biology Lab, Centre for Molecular and Nanomedical Sciences, International Research Centre, Sathyabama Institute of Science and Technology (Deemed to Be University), Jeppiaar Nagar, SH 49A, Chennai, Tamil Nadu, 621306, India.
| | - Puja Das
- Molecular Biology and Stem Cell Biology Lab, Centre for Molecular and Nanomedical Sciences, International Research Centre, Sathyabama Institute of Science and Technology (Deemed to Be University), Jeppiaar Nagar, SH 49A, Chennai, Tamil Nadu, 621306, India
| | - Apoorva Roy
- Department of Biotechnology, Alagappa University, Karaikudi, Tamil Nadu, India
| | - Chaughule Vrushali
- Department of Biotechnology, Alagappa University, Karaikudi, Tamil Nadu, India
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Robinson GI, Ye F, Lu X, Laviolette SR, Feng Q. Maternal Delta-9-Tetrahydrocannabinol Exposure Induces Abnormalities of the Developing Heart in Mice. Cannabis Cannabinoid Res 2024; 9:121-133. [PMID: 36255470 DOI: 10.1089/can.2022.0180] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Introduction: Cannabis is increasingly being consumed by pregnant women for recreational purposes as well as for its antiemetic and anxiolytic effects despite limited studies on its safety during pregnancy. Importantly, phytocannabinoids found in cannabis can pass through the placenta and enter the fetal circulation. Recent reports suggest gestational cannabis use is associated with negative fetal outcomes, including fetal growth restriction and perinatal intensive care, however, the effects of delta-9-tetrahydrocannabinol (THC) on fetal heart development remains to be elucidated. Materials and Methods: We aimed to determine the outcomes of maternal THC exposure on fetal heart development in mice by administering 0, 5, or 10 mg/kg/day of THC orally to C57BL/6 dams starting at embryonic day (E)3.5. Offspring were collected at E12.5 for molecular analysis, at E17.5 to analyze cardiac morphology or at postnatal day (PND)21 to assess heart function. Results: Maternal THC exposure in E17.5 fetuses resulted in an array of cardiac abnormalities with an incidence of 44% and 55% in the 5 and 10 mg/kg treatment groups, respectively. Maternal THC exposure in offspring resulted in ventricular septal defect, higher semilunar valve volume relative to orifice ratio, and higher myocardial wall thickness. Notably, cell proliferation within the ventricular myocardium was increased, and expression of multiple cardiac transcription factors was downregulated in THC-exposed E12.5 fetuses. Furthermore, heart function was compromised with lower left ventricular ejection fraction, fractional shortening, and cardiac output in PND21 pups exposed to THC compared to controls. Discussion: The results show that maternal THC exposure during gestation induces myocardial hyperplasia and semilunar valve thickening in the fetal heart and postnatal cardiac dysfunction. Our study suggests that maternal cannabis consumption may induce abnormalities in the developing heart and cardiac dysfunction in postnatal life.
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Affiliation(s)
- Gregory I Robinson
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Canada
| | - Fang Ye
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Canada
| | - Xiangru Lu
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Canada
| | - Steven R Laviolette
- Department of Anatomy and Cell Biology, and Schulich School of Medicine and Dentistry, Western University, London, Canada
| | - Qingping Feng
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Canada
- Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Canada
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Hong J, Wang X, Jin H, Chen Y, Jiang Y, Du K, Chen D, Zheng S, Cao L. Environment relevant exposure of perfluorooctanoic acid accelerates the growth of hepatocellular carcinoma cells through mammalian target of rapamycin (mTOR) signal pathway. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2024; 341:122910. [PMID: 37967710 DOI: 10.1016/j.envpol.2023.122910] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Revised: 10/25/2023] [Accepted: 11/08/2023] [Indexed: 11/17/2023]
Abstract
Perfluorooctanoic acid (PFOA), a synthetic alkyl chain fluorinated compound, has emerged as a persistent organic pollutant of grave concern, casting a shadow over both ecological integrity and humans. Its insidious presence raises alarms due to its capacity to bioaccumulate within the human liver, potentially paving the treacherous path toward liver cancer. Yet, the intricate mechanisms underpinning PFOA's role in promoting the growth of hepatocellular carcinoma (HCC) remain shrouded in ambiguity. Here, we determined the proliferation and transcription changes of HCC after PFOA exposure through integrated experiments including cell culture, nude mice tests, and colony-forming assays. Based on our findings, PFOA effectively promotes the proliferation of HCC cells within the experimental range of concentrations, both in vivo and in vitro. The proliferation efficiency of HCC cells was observed to increase by approximately 10% due to overexposure to PFOA. Additionally, the cancer weight of tumor-bearing nude mice increased by 87.0% (p < 0.05). We systematically evaluated the effects of PFOA on HCC cells and found that PFOA's exposure can selectively activate the PI3K/AKT/mTOR/4E-BP1 signaling pathway, thereby playing a pro-cancer effect on HCC cells Confirmation echoed through western blot assays and inhibitor combination analyses. These insights summon a response to PFOA's dual nature as both an environmental threat and a promoter of liver cancer. Our work illuminates the obscured domain of PFOA-induced hepatoxicity, shedding light on its ties to hepatocellular carcinoma progression.
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Affiliation(s)
- Jiawei Hong
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, PR China; Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310003, PR China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310003, PR China
| | - Xiaoyan Wang
- Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310003, PR China
| | - Hangbiao Jin
- Key Laboratory of Microbial Technology for Industrial Pollution Control of Zhejiang Province, College of Environment, Zhejiang University of Technology, Hangzhou, Zhejiang, 310032, PR China
| | - Yuanchen Chen
- Key Laboratory of Microbial Technology for Industrial Pollution Control of Zhejiang Province, College of Environment, Zhejiang University of Technology, Hangzhou, Zhejiang, 310032, PR China
| | - Yifan Jiang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, PR China; Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310003, PR China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310003, PR China
| | - Keyi Du
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, PR China; Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310003, PR China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310003, PR China
| | - Diyu Chen
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, PR China; Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310003, PR China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310003, PR China
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, PR China; Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310003, PR China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310003, PR China
| | - Linping Cao
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, PR China; Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310003, PR China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310003, PR China.
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18
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Wang Y, Yao M, Li C, Yang K, Qin X, Xu L, Shi S, Yu C, Meng X, Xie C. Targeting ST8SIA6-AS1 counteracts KRAS G12C inhibitor resistance through abolishing the reciprocal activation of PLK1/c-Myc signaling. Exp Hematol Oncol 2023; 12:105. [PMID: 38104151 PMCID: PMC10724920 DOI: 10.1186/s40164-023-00466-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 12/03/2023] [Indexed: 12/19/2023] Open
Abstract
BACKGROUND KRASG12C inhibitors (KRASG12Ci) AMG510 and MRTX849 have shown promising efficacy in clinical trials and been approved for the treatment of KRASG12C-mutant cancers. However, the emergence of therapy-related drug resistance limits their long-term potential. This study aimed to identify the critical mediators and develop overcoming strategies. METHODS By using RNA sequencing, RT-qPCR and immunoblotting, we identified and validated the upregulation of c-Myc activity and the amplification of the long noncoding RNA ST8SIA6-AS1 in KRASG12Ci-resistant cells. The regulatory axis ST8SIA6-AS1/Polo-like kinase 1 (PLK1)/c-Myc was investigated by bioinformatics, RNA fluorescence in situ hybridization, RNA immunoprecipitation, RNA pull-down and chromatin immunoprecipitation. Gain/loss-of-function assays, cell viability assay, xenograft models, and IHC staining were conducted to evaluate the anti-cancer effects of co-inhibition of ST8SIA6-AS1/PLK1 pathway and KRAS both in vitro and in vivo. RESULTS KRASG12Ci sustainably decreased c-Myc levels in responsive cell lines but not in cell lines with intrinsic or acquired resistance to KRASG12Ci. PLK1 activation contributed to this ERK-independent c-Myc stability, which in turn directly induced PLK1 transcription, forming a positive feedback loop and conferring resistance to KRASG12Ci. ST8SIA6-AS1 was found significantly upregulated in resistant cells and facilitated the proliferation of KRASG12C-mutant cancers. ST8SIA6-AS1 bound to Aurora kinase A (Aurora A)/PLK1 and promoted Aurora A-mediated PLK1 phosphorylation. Concurrent targeting of KRAS and ST8SIA6-AS1/PLK1 signaling suppressed both ERK-dependent and -independent c-Myc expression, synergistically led to cell death and tumor regression and overcame KRASG12Ci resistance. CONCLUSIONS Our study deciphers that the axis of ST8SIA6-AS1/PLK1/c-Myc confers both intrinsic and acquired resistance to KRASG12Ci and represents a promising therapeutic target for combination strategies with KRASG12Ci in the treatment of KRASG12C-mutant cancers.
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Affiliation(s)
- Yafang Wang
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, People's Republic of China
| | - Mingyue Yao
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, People's Republic of China
- Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC (Anhui Provincial Hospital), University of Science and Technology of China, Hefei, Anhui, China
- Drug Discovery and Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, People's Republic of China
| | - Cheng Li
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, People's Republic of China
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
| | - Kexin Yang
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
- Lingang Laboratory, 319 Yueyang Road, Shanghai, 200031, China
| | - Xiaolong Qin
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, People's Republic of China
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
| | - Lansong Xu
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, People's Republic of China
- Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC (Anhui Provincial Hospital), University of Science and Technology of China, Hefei, Anhui, China
- Drug Discovery and Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, People's Republic of China
| | - Shangxuan Shi
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, People's Republic of China
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
| | - Chengcheng Yu
- Drug Discovery and Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, People's Republic of China
- Lingang Laboratory, 319 Yueyang Road, Shanghai, 200031, China
| | - Xiangjun Meng
- Gastroenterology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200001, China
- China Center for Digestive Diseases Research and Clinical Translation of Shanghai Jiao Tong University, Shanghai, 200001, China
- China Shanghai Key Laboratory of Gut Microecology and Associated Major Diseases Research, Shanghai, 200001, China
| | - Chengying Xie
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, People's Republic of China.
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
- Lingang Laboratory, 319 Yueyang Road, Shanghai, 200031, China.
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19
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Becker CJ, Cigliola V, Gillotay P, Rich A, De Simone A, Han Y, Di Talia S, Poss KD. In toto imaging of glial JNK signaling during larval zebrafish spinal cord regeneration. Development 2023; 150:dev202076. [PMID: 37997694 PMCID: PMC10753585 DOI: 10.1242/dev.202076] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 11/09/2023] [Indexed: 11/25/2023]
Abstract
Identification of signaling events that contribute to innate spinal cord regeneration in zebrafish can uncover new targets for modulating injury responses of the mammalian central nervous system. Using a chemical screen, we identify JNK signaling as a necessary regulator of glial cell cycling and tissue bridging during spinal cord regeneration in larval zebrafish. With a kinase translocation reporter, we visualize and quantify JNK signaling dynamics at single-cell resolution in glial cell populations in developing larvae and during injury-induced regeneration. Glial JNK signaling is patterned in time and space during development and regeneration, decreasing globally as the tissue matures and increasing in the rostral cord stump upon transection injury. Thus, dynamic and regional regulation of JNK signaling help to direct glial cell behaviors during innate spinal cord regeneration.
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Affiliation(s)
- Clayton J. Becker
- Duke Regeneration Center and Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA
| | - Valentina Cigliola
- Duke Regeneration Center and Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA
- Université Côte d’Azur, Inserm, CNRS, Institut de Biologie Valrose, 06100 Nice, France
| | - Pierre Gillotay
- Duke Regeneration Center and Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA
| | - Ashley Rich
- Duke Regeneration Center and Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA
| | - Alessandro De Simone
- Department of Genetics and Evolution, University of Geneva, 1211 Geneva, Switzerland
| | - Yanchao Han
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Suzhou Medical College, Soochow University, Suzhou, 215006 Jiangsu, China
| | - Stefano Di Talia
- Duke Regeneration Center and Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA
| | - Kenneth D. Poss
- Duke Regeneration Center and Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA
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20
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Li Y, Johnson JP, Yang Y, Yu D, Kubo H, Berretta RM, Wang T, Zhang X, Foster M, Yu J, Tilley DG, Houser SR, Chen X. Effects of maternal hypothyroidism on postnatal cardiomyocyte proliferation and cardiac disease responses of the progeny. Am J Physiol Heart Circ Physiol 2023; 325:H702-H719. [PMID: 37539452 PMCID: PMC10659327 DOI: 10.1152/ajpheart.00320.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 07/31/2023] [Accepted: 08/01/2023] [Indexed: 08/05/2023]
Abstract
Maternal hypothyroidism (MH) could adversely affect the cardiac disease responses of the progeny. This study tested the hypothesis that MH reduces early postnatal cardiomyocyte (CM) proliferation so that the adult heart of MH progeny has a smaller number of larger cardiac myocytes, which imparts adverse cardiac disease responses following injury. Thyroidectomy (TX) was used to establish MH. The progeny from mice that underwent sham or TX surgery were termed Ctrl (control) or MH (maternal hypothyroidism) progeny, respectively. MH progeny had similar heart weight (HW) to body weight (BW) ratios and larger CM size consistent with fewer CMs at postnatal day 60 (P60) compared with Ctrl (control) progeny. MH progeny had lower numbers of EdU+, Ki67+, and phosphorylated histone H3 (PH3)+ CMs, which suggests they had a decreased CM proliferation in the postnatal timeframe. RNA-seq data showed that genes related to DNA replication were downregulated in P5 MH hearts, including bone morphogenetic protein 10 (Bmp10). Both in vivo and in vitro studies showed Bmp10 treatment increased CM proliferation. After transverse aortic constriction (TAC), the MH progeny had more severe cardiac pathological remodeling compared with the Ctrl progeny. Thyroid hormone (T4) treatment for MH mothers preserved their progeny's postnatal CM proliferation capacity and prevented excessive pathological remodeling after TAC. Our results suggest that CM proliferation during early postnatal development was significantly reduced in MH progeny, resulting in fewer CMs with hypertrophy in adulthood. These changes were associated with more severe cardiac disease responses after pressure overload.NEW & NOTEWORTHY Our study shows that compared with Ctrl (control) progeny, the adult progeny of mothers who have MH (MH progeny) had fewer CMs. This reduction of CM numbers was associated with decreased postnatal CM proliferation. Gene expression studies showed a reduced expression of Bmp10 in MH progeny. Bmp10 has been linked to myocyte proliferation. In vivo and in vitro studies showed that Bmp10 treatment of MH progeny and their myocytes could increase CM proliferation. Differences in CM number and size in adult hearts of MH progeny were linked to more severe cardiac structural and functional remodeling after pressure overload. T4 (synthetic thyroxine) treatment of MH mothers during their pregnancy, prevented the reduction in CM number in their progeny and the adverse response to disease stress.
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Affiliation(s)
- Yijia Li
- Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, United States
| | - Jaslyn P Johnson
- Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, United States
| | - Yijun Yang
- Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, United States
| | - Daohai Yu
- Department of Biomedical Education and Data Science, Center for Biostatistics and Epidemiology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, United States
| | - Hajime Kubo
- Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, United States
| | - Remus M Berretta
- Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, United States
| | - Tao Wang
- Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, United States
| | - Xiaoying Zhang
- Department of Cardiovascular Sciences, Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Cardiovascular Research Center, Philadelphia, Pennsylvania, United States
| | - Michael Foster
- Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, United States
| | - Jun Yu
- Department of Cardiovascular Sciences, Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, Cardiovascular Research Center, Philadelphia, Pennsylvania, United States
| | - Douglas G Tilley
- Department of Cardiovascular Sciences, Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Cardiovascular Research Center, Philadelphia, Pennsylvania, United States
| | - Steven R Houser
- Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, United States
| | - Xiongwen Chen
- Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, United States
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, People's Republic of China
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21
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Cai C, Luo Q, Jia L, Xia Y, Lan X, Wei X, Shi S, Liu Y, Wang Y, Xiong Z, Shi R, Huang C, Chen Z. TRIM67 Implicates in Regulating the Homeostasis and Synaptic Development of Mitral Cells in the Olfactory Bulb. Int J Mol Sci 2023; 24:13439. [PMID: 37686246 PMCID: PMC10487898 DOI: 10.3390/ijms241713439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Revised: 08/28/2023] [Accepted: 08/28/2023] [Indexed: 09/10/2023] Open
Abstract
In recent years, olfactory dysfunction has attracted increasingly more attention as a hallmark symptom of neurodegenerative diseases (ND). Deeply understanding the molecular basis underlying the development of the olfactory bulb (OB) will provide important insights for ND studies and treatments. Now, with a genetic knockout mouse model, we show that TRIM67, a new member of the tripartite motif (TRIM) protein family, plays an important role in regulating the proliferation and development of mitral cells in the OB. TRIM67 is abundantly expressed in the mitral cell layer of the OB. The genetic deletion of TRIM67 in mice leads to excessive proliferation of mitral cells in the OB and defects in its synaptic development, resulting in reduced olfactory function in mice. Finally, we show that TRIM67 may achieve its effect on mitral cells by regulating the Semaphorin 7A/Plexin C1 (Sema7A/PlxnC1) signaling pathway.
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Affiliation(s)
- Chunyu Cai
- Laboratory of Experimental Animal Disease Model, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (C.C.); (Q.L.); (L.J.); (Y.X.); (X.L.); (X.W.); (S.S.); (Y.L.); (Y.W.); (Z.X.)
| | - Qihui Luo
- Laboratory of Experimental Animal Disease Model, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (C.C.); (Q.L.); (L.J.); (Y.X.); (X.L.); (X.W.); (S.S.); (Y.L.); (Y.W.); (Z.X.)
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Chengdu 611130, China
| | - Lanlan Jia
- Laboratory of Experimental Animal Disease Model, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (C.C.); (Q.L.); (L.J.); (Y.X.); (X.L.); (X.W.); (S.S.); (Y.L.); (Y.W.); (Z.X.)
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Chengdu 611130, China
| | - Yu Xia
- Laboratory of Experimental Animal Disease Model, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (C.C.); (Q.L.); (L.J.); (Y.X.); (X.L.); (X.W.); (S.S.); (Y.L.); (Y.W.); (Z.X.)
| | - Xinting Lan
- Laboratory of Experimental Animal Disease Model, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (C.C.); (Q.L.); (L.J.); (Y.X.); (X.L.); (X.W.); (S.S.); (Y.L.); (Y.W.); (Z.X.)
| | - Xiaoli Wei
- Laboratory of Experimental Animal Disease Model, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (C.C.); (Q.L.); (L.J.); (Y.X.); (X.L.); (X.W.); (S.S.); (Y.L.); (Y.W.); (Z.X.)
| | - Shuai Shi
- Laboratory of Experimental Animal Disease Model, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (C.C.); (Q.L.); (L.J.); (Y.X.); (X.L.); (X.W.); (S.S.); (Y.L.); (Y.W.); (Z.X.)
| | - Yucong Liu
- Laboratory of Experimental Animal Disease Model, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (C.C.); (Q.L.); (L.J.); (Y.X.); (X.L.); (X.W.); (S.S.); (Y.L.); (Y.W.); (Z.X.)
| | - Yao Wang
- Laboratory of Experimental Animal Disease Model, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (C.C.); (Q.L.); (L.J.); (Y.X.); (X.L.); (X.W.); (S.S.); (Y.L.); (Y.W.); (Z.X.)
| | - Zongliang Xiong
- Laboratory of Experimental Animal Disease Model, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (C.C.); (Q.L.); (L.J.); (Y.X.); (X.L.); (X.W.); (S.S.); (Y.L.); (Y.W.); (Z.X.)
| | - Riyi Shi
- Center for Paralysis Research, Department of Basic Medical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907, USA;
| | - Chao Huang
- Laboratory of Experimental Animal Disease Model, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (C.C.); (Q.L.); (L.J.); (Y.X.); (X.L.); (X.W.); (S.S.); (Y.L.); (Y.W.); (Z.X.)
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Chengdu 611130, China
| | - Zhengli Chen
- Laboratory of Experimental Animal Disease Model, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (C.C.); (Q.L.); (L.J.); (Y.X.); (X.L.); (X.W.); (S.S.); (Y.L.); (Y.W.); (Z.X.)
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Chengdu 611130, China
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22
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Wang XP, Sun SP, Li YX, Wang L, Dong DJ, Wang JX, Zhao XF. 20-hydroxyecdysone reprograms amino acid metabolism to support the metamorphic development of Helicoverpa armigera. Cell Rep 2023; 42:112644. [PMID: 37310862 DOI: 10.1016/j.celrep.2023.112644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 04/16/2023] [Accepted: 05/27/2023] [Indexed: 06/15/2023] Open
Abstract
Amino acid metabolism is regulated according to nutrient conditions; however, the mechanism is not fully understood. Using the holometabolous insect cotton bollworm (Helicoverpa armigera) as a model, we report that hemolymph metabolites are greatly changed from the feeding larvae to the wandering larvae and to pupae. Arginine, alpha-ketoglutarate (α-KG), and glutamate (Glu) are identified as marker metabolites of feeding larvae, wandering larvae, and pupae, respectively. Arginine level is decreased by 20-hydroxyecdysone (20E) regulation via repression of argininosuccinate synthetase (Ass) expression and upregulation of arginase (Arg) expression during metamorphosis. α-KG is transformed from Glu by glutamate dehydrogenase (GDH) in larval midgut, which is repressed by 20E. The α-KG is then transformed to Glu by GDH-like in pupal fat body, which is upregulated by 20E. Thus, 20E reprogrammed amino acid metabolism during metamorphosis by regulating gene expression in a stage- and tissue-specific manner to support insect metamorphic development.
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Affiliation(s)
- Xiao-Pei Wang
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Qingdao 266237, China
| | - Shu-Peng Sun
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Qingdao 266237, China
| | - Yan-Xue Li
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Qingdao 266237, China
| | - Lin Wang
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Qingdao 266237, China
| | - Du-Juan Dong
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Qingdao 266237, China
| | - Jin-Xing Wang
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Qingdao 266237, China
| | - Xiao-Fan Zhao
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Qingdao 266237, China.
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23
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Kar A, Sable M, A A, Jena SK, Tripathy PR, Gaikwad M. An Immunohistochemical Study of Proliferation of Human Fetal Heart Cardiomyocyte With Phospho-Histone H3 Antibody. Cureus 2023; 15:e41159. [PMID: 37525760 PMCID: PMC10387164 DOI: 10.7759/cureus.41159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/29/2023] [Indexed: 08/02/2023] Open
Abstract
The rapid proliferation of cardiomyocytes in mammals occurs during fetal life. But in postnatal life, this capacity of proliferation is reduced or lost as they exit the cell cycle. However, the cardiomyocytes don't show the same activity for different species. In human fetuses or in adult life, the capacity of the proliferation of cardiomyocytes and their response to an injury are not understood yet. In this study, we have done an immunohistochemical study using phospho-histone H3 (PHH3) to observe human fetal cardiomyocytes' proliferative activity. The heart specimens from the fetal autopsy of spontaneously aborted and stillborn human fetuses were subjected to immunohistochemical study using PHH3 antibody, and comparison between the PHH3 index (number of PHH3 positive cells per 1000 number of cardiomyocytes/high power field [HPF]) of myocardial regions was done using appropriate statistical tests. A total of 17 fetal hearts were included in our study. In the left ventricle, right ventricle, right atrium, and interventricular septum, the PHH3 index of myocardium was significantly higher over the pericardial region (p-value 0.002, p-value <0.001, <0.001, and 0.009 respectively) as compared to the region of over the endocardium and the middle part of the myocardium. The PHH3 index of the pericardial region of the left ventricle was significantly correlated with the maximum thickness of the left ventricle.
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Affiliation(s)
- Arundhati Kar
- Anatomy, Institute of Medical Sciences (IMS) and SUM Hospital, Bhubaneswar, IND
| | - Mukund Sable
- Pathology and Laboratory Medicine, All India Institute of Medical Sciences, Bhubaneswar, Bhubaneswar, IND
| | - Anbarasan A
- Cytogenetics, Christian Medical College (CMC) Vellore, Vellore, IND
| | - Saubhagya K Jena
- Obstetrics and Gyenacology, All India Institute of Medical Sciences, Bhubaneswar, Bhubaneswar, IND
| | - Prabhas R Tripathy
- Anatomy, All India Institute of Medical Sciences, Bhubaneswar, Bhubaneswar, IND
| | - Manisha Gaikwad
- Anatomy, All India Institute of Medical Sciences, Bhubaneswar, Bhubaneswar, IND
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El Mir J, Fedou S, Thézé N, Morice‐Picard F, Cario M, Fayyad‐Kazan H, Thiébaud P, Rezvani H. Xenopus: An in vivo model for studying skin response to ultraviolet B irradiation. Dev Growth Differ 2023; 65:194-202. [PMID: 36880984 PMCID: PMC11520974 DOI: 10.1111/dgd.12848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Revised: 02/25/2023] [Accepted: 02/27/2023] [Indexed: 03/08/2023]
Abstract
Ultraviolet B (UVB) in sunlight cause skin damage, ranging from wrinkles to photoaging and skin cancer. UVB can affect genomic DNA by creating cyclobutane pyrimidine dimers (CPDs) and pyrimidine-pyrimidine (6-4) photoproducts (6-4PPs). These lesions are mainly repaired by the nucleotide excision repair (NER) system and by photolyase enzymes that are activated by blue light. Our main goal was to validate the use of Xenopus laevis as an in vivo model system for investigating the impact of UVB on skin physiology. The mRNA expression levels of xpc and six other genes of the NER system and CPD/6-4PP photolyases were found at all stages of embryonic development and in all adult tissues tested. When examining Xenopus embryos at different time points after UVB irradiation, we observed a gradual decrease in CPD levels and an increased number of apoptotic cells, together with an epidermal thickening and an increased dendricity of melanocytes. We observed a quick removal of CPDs when embryos are exposed to blue light versus in the dark, confirming the efficient activation of photolyases. A decrease in the number of apoptotic cells and an accelerated return to normal proliferation rate was noted in blue light-exposed embryos compared with their control counterparts. Overall, a gradual decrease in CPD levels, detection of apoptotic cells, thickening of epidermis, and increased dendricity of melanocytes, emulate human skin responses to UVB and support Xenopus as an appropriate and alternative model for such studies.
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Affiliation(s)
| | | | | | - Fanny Morice‐Picard
- University Bordeaux, Inserm, BRICBordeauxFrance
- Department of Dermatology and Pediatric Dermatology, National Reference Centre for Rare DisordersHôpital des Enfants Pellegrin, Centre Hospitalier Universitaire de BordeauxBordeauxFrance
| | - Muriel Cario
- University Bordeaux, Inserm, BRICBordeauxFrance
- Aquiderm, University of BordeauxBordeauxFrance
| | - Hussein Fayyad‐Kazan
- Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences ILebanese UniversityHadathLebanon
| | | | - Hamid‐Reza Rezvani
- University Bordeaux, Inserm, BRICBordeauxFrance
- Aquiderm, University of BordeauxBordeauxFrance
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25
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Gellisch M, Bablok M, Divvela SSK, Morosan-Puopolo G, Brand-Saberi B. Systemic Prenatal Stress Exposure through Corticosterone Application Adversely Affects Avian Embryonic Skin Development. BIOLOGY 2023; 12:biology12050656. [PMID: 37237470 DOI: 10.3390/biology12050656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 04/23/2023] [Accepted: 04/24/2023] [Indexed: 05/28/2023]
Abstract
Prenatal stress exposure is considered a risk factor for developmental deficits and postnatal behavioral disorders. While the effect of glucocorticoid-associated prenatal stress exposure has been comprehensively studied in many organ systems, there is a lack of in-depth embryological investigations regarding the effects of stress on the integumentary system. To approach this, we employed the avian embryo as a model organism and investigated the effects of systemic pathologically-elevated glucocorticoid exposure on the development of the integumentary system. After standardized corticosterone injections on embryonic day 6, we compared the stress-exposed embryos with a control cohort, using histological and immunohistochemical analyses as well as in situ hybridization. The overarching developmental deficits observed in the stress-exposed embryos were reflected through downregulation of both vimentin as well as fibronectin. In addition, a deficient composition in the different skin layers became apparent, which could be linked to a reduced expression of Dermo-1 along with significantly reduced proliferation rates. An impairment of skin appendage formation could be demonstrated by diminished expression of Sonic hedgehog. These results contribute to a more profound understanding of prenatal stress causing severe deficits in the integumentary system of developing organisms.
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Affiliation(s)
- Morris Gellisch
- Department of Anatomy and Molecular Embryology, Institute of Anatomy, Medical Faculty, Ruhr University Bochum, 44801 Bochum, Germany
| | - Martin Bablok
- Department of Anatomy and Molecular Embryology, Institute of Anatomy, Medical Faculty, Ruhr University Bochum, 44801 Bochum, Germany
| | - Satya Srirama Karthik Divvela
- Department of Anatomy and Molecular Embryology, Institute of Anatomy, Medical Faculty, Ruhr University Bochum, 44801 Bochum, Germany
| | - Gabriela Morosan-Puopolo
- Department of Anatomy and Molecular Embryology, Institute of Anatomy, Medical Faculty, Ruhr University Bochum, 44801 Bochum, Germany
| | - Beate Brand-Saberi
- Department of Anatomy and Molecular Embryology, Institute of Anatomy, Medical Faculty, Ruhr University Bochum, 44801 Bochum, Germany
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26
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Luo J, Lu C, Chen Y, Wu X, Zhu C, Cui W, Yu S, Li N, Pan Y, Zhao W, Yang Q, Yang X. Nuclear translocation of cGAS orchestrates VEGF-A-mediated angiogenesis. Cell Rep 2023; 42:112328. [PMID: 37027305 DOI: 10.1016/j.celrep.2023.112328] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Revised: 12/20/2022] [Accepted: 03/17/2023] [Indexed: 04/08/2023] Open
Abstract
Cyclic GMP-AMP synthase (cGAS) senses cytosolic incoming DNA and consequently activates stimulator of interferon response cGAMP interactor 1 (STING) to mount immune response. Here, we show nuclear cGAS could regulate VEGF-A-mediated angiogenesis in an immune-independent manner. We found VEGF-A stimulation induces cGAS nuclear translocation via importin-β pathway. Moreover, nuclear cGAS subsequently regulates miR-212-5p-ARPC3 cascade to modulate VEGF-A-mediated angiogenesis through affecting cytoskeletal dynamics and VEGFR2 trafficking from trans-Golgi network (TGN) to plasma membrane via a regulatory feedback loop. In contrast, cGAS deficiency remarkably impairs VEGF-A-mediated angiogenesis in vivo and in vitro. Furthermore, we found strong association between the expression of nuclear cGAS and VEGF-A, and the malignancy and prognosis in malignant glioma, suggesting that nuclear cGAS might play important roles in human pathology. Collectively, our findings illustrated the function of cGAS in angiogenesis other than immune surveillance, which might be a potential therapeutic target for pathological angiogenesis-related diseases.
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Affiliation(s)
- Juanjuan Luo
- Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Chunjiao Lu
- Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Yang Chen
- Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Xuewei Wu
- Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Chenchen Zhu
- Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Wei Cui
- College of Life Science and Biopharmaceutical of Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China
| | - Shicang Yu
- Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Ningning Li
- The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong 518107, China
| | - Yihang Pan
- The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong 518107, China
| | - Weijiang Zhao
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Qingkai Yang
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning 116044, China.
| | - Xiaojun Yang
- Shantou University Medical College, Shantou, Guangdong 515041, China.
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27
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Ghassib I, Zhang H, Qi S, Moshen R, Mishina Y, Bellido T, Liu F. Off-target activity of the 8 kb Dmp1-Cre results in the deletion of Tsc1 gene in mouse intestinal mesenchyme. Transgenic Res 2023; 32:135-141. [PMID: 36547785 DOI: 10.1007/s11248-022-00332-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 12/09/2022] [Indexed: 12/24/2022]
Abstract
The Dmp1-Cre mouse, expressing Cre from an 8-kb DNA fragment of the mouse Dmp1 gene, is a common tool to study gene functions in osteocytes. Here we report that the deletion of Tsc1 (TSC complex subunit 1) by 8 kb Dmp1-Cre causes rectal prolapse in mice. Histological examination shows the presence of colon polyps in Tsc1-deficient mice in association with significantly larger colon and narrower lumen, which recapitulates the common polyps pathology in Tuberous Sclerosis, an autosomal dominant disorder caused by mutations in either TSC1 or TSC2. The intestine in Tsc1-deficient mice is also enlarged with the presence of taller villi. Using the Ai14 reporter mice that express a red fluorescence protein upon Cre recombination, we show that 8 kb Dmp1-Cre activity is evident in portion of the mesenchyme of the colon and small intestine. Lastly, our data show that Tsc1 deletion by Dmp1-Cre leads to an increased proliferation in the mesenchyme of colon, which at least partly contributes to the polyps pathology seen in this mouse model and is likely a contributing factor of the polyps in Tuberous Sclerosis.
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Affiliation(s)
- Iya Ghassib
- Department of Biologic and Materials Sciences & Prosthodontics, School of Dentistry, University of Michigan, 1011 N University Ave, Ann Arbor, MI, 48109, USA
| | - Honghao Zhang
- Department of Biologic and Materials Sciences & Prosthodontics, School of Dentistry, University of Michigan, 1011 N University Ave, Ann Arbor, MI, 48109, USA
| | - Shuqun Qi
- Department of Biologic and Materials Sciences & Prosthodontics, School of Dentistry, University of Michigan, 1011 N University Ave, Ann Arbor, MI, 48109, USA
| | - Rawan Moshen
- Department of Biologic and Materials Sciences & Prosthodontics, School of Dentistry, University of Michigan, 1011 N University Ave, Ann Arbor, MI, 48109, USA
| | - Yuji Mishina
- Department of Biologic and Materials Sciences & Prosthodontics, School of Dentistry, University of Michigan, 1011 N University Ave, Ann Arbor, MI, 48109, USA
| | - Teresita Bellido
- Department of Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Fei Liu
- Department of Biologic and Materials Sciences & Prosthodontics, School of Dentistry, University of Michigan, 1011 N University Ave, Ann Arbor, MI, 48109, USA.
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28
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Iwasa K, Yamagishi A, Yamamoto S, Haruta C, Maruyama K, Yoshikawa K. GPR137 Inhibits Cell Proliferation and Promotes Neuronal Differentiation in the Neuro2a Cells. Neurochem Res 2023; 48:996-1008. [PMID: 36436172 PMCID: PMC9922245 DOI: 10.1007/s11064-022-03833-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 11/08/2022] [Accepted: 11/19/2022] [Indexed: 11/28/2022]
Abstract
The orphan receptor, G protein-coupled receptor 137 (GPR137), is an integral membrane protein involved in several types of cancer. GPR137 is expressed ubiquitously, including in the central nervous system (CNS). We established a GPR137 knockout (KO) neuro2A cell line to analyze GPR137 function in neuronal cells. KO cells were generated by genome editing using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 and cultured as single cells by limited dilution. Rescue cells were then constructed to re-express GPR137 in GPR137 KO neuro2A cells using an expression vector with an EF1-alpha promoter. GPR137 KO cells increased cellular proliferation and decreased neurite outgrowth (i.e., a lower level of neuronal differentiation). Furthermore, GPR137 KO cells exhibited increased expression of a cell cycle regulator, cyclin D1, and decreased expression of a neuronal differentiation marker, NeuroD1. Additionally, GPR137 KO cells exhibited lower expression levels of the neurite outgrowth markers STAT3 and GAP43. These phenotypes were all abrogated in the rescue cells. In conclusion, GPR137 deletion increased cellular proliferation and decreased neuronal differentiation, suggesting that GPR137 promotes cell cycle exit and neuronal differentiation in neuro2A cells. Regulation of neuronal differentiation by GPR137 could be vital to constructing neuronal structure during brain development.
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Affiliation(s)
- Kensuke Iwasa
- Department of Pharmacology, Faculty of Medicine, Saitama Medical University, 38 Moro-Hongo, Moroyama-Machi, Iruma-Gun, Saitama, 350-0495, Japan
| | - Anzu Yamagishi
- Department of Pharmacology, Faculty of Medicine, Saitama Medical University, 38 Moro-Hongo, Moroyama-Machi, Iruma-Gun, Saitama, 350-0495, Japan
| | - Shinji Yamamoto
- Department of Pharmacology, Faculty of Medicine, Saitama Medical University, 38 Moro-Hongo, Moroyama-Machi, Iruma-Gun, Saitama, 350-0495, Japan
| | - Chikara Haruta
- Department of Pharmacology, Faculty of Medicine, Saitama Medical University, 38 Moro-Hongo, Moroyama-Machi, Iruma-Gun, Saitama, 350-0495, Japan
| | - Kei Maruyama
- Department of Pharmacology, Faculty of Medicine, Saitama Medical University, 38 Moro-Hongo, Moroyama-Machi, Iruma-Gun, Saitama, 350-0495, Japan
| | - Keisuke Yoshikawa
- Department of Pharmacology, Faculty of Medicine, Saitama Medical University, 38 Moro-Hongo, Moroyama-Machi, Iruma-Gun, Saitama, 350-0495, Japan.
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29
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Ibrahim A, Toss MS, Makhlouf S, Miligy IM, Minhas F, Rakha EA. Improving mitotic cell counting accuracy and efficiency using phosphohistone-H3 (PHH3) antibody counterstained with haematoxylin and eosin as part of breast cancer grading. Histopathology 2023; 82:393-406. [PMID: 36349500 PMCID: PMC10100421 DOI: 10.1111/his.14837] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 10/08/2022] [Accepted: 11/05/2022] [Indexed: 11/11/2022]
Abstract
BACKGROUND Mitotic count in breast cancer is an important prognostic marker. Unfortunately, substantial inter- and intraobserver variation exists when pathologists manually count mitotic figures. To alleviate this problem, we developed a new technique incorporating both haematoxylin and eosin (H&E) and phosphorylated histone H3 (PHH3), a marker highly specific to mitotic figures, and compared it to visual scoring of mitotic figures using H&E only. METHODS Two full-face sections from 97 cases were cut, one stained with H&E only, and the other was stained with PHH3 and counterstained with H&E (PHH3-H&E). Counting mitoses using PHH3-H&E was compared to traditional mitoses scoring using H&E in terms of reproducibility, scoring time, and the ability to detect mitosis hotspots. We assessed the agreement between manual and image analysis-assisted scoring of mitotic figures using H&E and PHH3-H&E-stained cells. The diagnostic performance of PHH3 in detecting mitotic figures in terms of sensitivity and specificity was measured. Finally, PHH3 replaced the mitosis score in a multivariate analysis to assess its significance. RESULTS Pathologists detected significantly higher mitotic figures using the PHH3-H&E (median ± SD, 20 ± 33) compared with H&E alone (median ± SD, 16 ± 25), P < 0.001. The concordance between pathologists in identifying mitotic figures was highest when using the dual PHH3-H&E technique; in addition, it highlighted mitotic figures at low power, allowing better agreement on choosing the hotspot area (k = 0.842) in comparison with standard H&E (k = 0.625). A better agreement between image analysis-assisted software and the human eye was observed for PHH3-stained mitotic figures. When the mitosis score was replaced with PHH3 in a Cox regression model with other grade components, PHH3 was an independent predictor of survival (hazard ratio [HR] 5.66, 95% confidence interval [CI] 1.92-16.69; P = 0.002), and even showed a more significant association with breast cancer-specific survival (BCSS) than mitosis (HR 3.63, 95% CI 1.49-8.86; P = 0.005) and Ki67 (P = 0.27). CONCLUSION Using PHH3-H&E-stained slides can reliably be used in routine scoring of mitotic figures and integrating both techniques will compensate for each other's limitations and improve diagnostic accuracy, quality, and precision.
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Affiliation(s)
- Asmaa Ibrahim
- Academic Unit for Translational Medical Sciences, School of Medicine, University of Nottingham Biodiscovery Institute, University Park, Nottingham, UK.,Histopathology department, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Michael S Toss
- Academic Unit for Translational Medical Sciences, School of Medicine, University of Nottingham Biodiscovery Institute, University Park, Nottingham, UK
| | - Shorouk Makhlouf
- Academic Unit for Translational Medical Sciences, School of Medicine, University of Nottingham Biodiscovery Institute, University Park, Nottingham, UK.,Department of Pathology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Islam M Miligy
- Histopathology department, Faculty of Medicine, Menoufia University, Shebin El Kom, Egypt.,Histopathology department, School of Medicine, University of Nottingham, Nottingham, UK
| | - Fayyaz Minhas
- Department of Computer Science, University of Warwick, Coventry, UK
| | - Emad A Rakha
- Academic Unit for Translational Medical Sciences, School of Medicine, University of Nottingham Biodiscovery Institute, University Park, Nottingham, UK.,Histopathology department, Faculty of Medicine, Menoufia University, Shebin El Kom, Egypt.,Histopathology department, School of Medicine, University of Nottingham, Nottingham, UK
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30
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SCGN deficiency is a risk factor for autism spectrum disorder. Signal Transduct Target Ther 2023; 8:3. [PMID: 36588101 PMCID: PMC9806109 DOI: 10.1038/s41392-022-01225-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 09/15/2022] [Accepted: 09/30/2022] [Indexed: 01/03/2023] Open
Abstract
Autism spectrum disorder (ASD) affects 1-2% of all children and poses a great social and economic challenge for the globe. As a highly heterogeneous neurodevelopmental disorder, the development of its treatment is extremely challenging. Multiple pathways have been linked to the pathogenesis of ASD, including signaling involved in synaptic function, oxytocinergic activities, immune homeostasis, chromatin modifications, and mitochondrial functions. Here, we identify secretagogin (SCGN), a regulator of synaptic transmission, as a new risk gene for ASD. Two heterozygous loss-of-function mutations in SCGN are presented in ASD probands. Deletion of Scgn in zebrafish or mice leads to autism-like behaviors and impairs brain development. Mechanistically, Scgn deficiency disrupts the oxytocin signaling and abnormally activates inflammation in both animal models. Both ASD probands carrying Scgn mutations also show reduced oxytocin levels. Importantly, we demonstrate that the administration of oxytocin and anti-inflammatory drugs can attenuate ASD-associated defects caused by SCGN deficiency. Altogether, we identify a convergence between a potential autism genetic risk factor SCGN, and the pathological deregulation in oxytocinergic signaling and immune responses, providing potential treatment for ASD patients suffering from SCGN deficiency. Our study also indicates that it is critical to identify and stratify ASD patient populations based on their disease mechanisms, which could greatly enhance therapeutic success.
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31
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Chen S, Gao Y, Chen F, Wang TB. ANLN Serves as an Oncogene in Bladder Urothelial Carcinoma via Activating JNK Signaling Pathway. Urol Int 2023; 107:310-320. [PMID: 35504258 DOI: 10.1159/000524204] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 03/05/2022] [Indexed: 12/19/2022]
Abstract
INTRODUCTION To understand the significance of ANLN (anillin, actin-binding protein)-mediated c-Jun N-terminal kinase (JNK) signal pathway on the progression of bladder urothelial carcinoma (BLCA). METHODS The Cancer Genome Atlas (TCGA) database was utilized to perform the clinical significance of ANLN in BLCA. Then, ANLN expression was determined in human normal primary bladder epithelial cells (BdEC) and BLCA cells. Later, ANLN knockdown was performed in BLCA cells, where the expression of MAPK8, MAPK9, and p-JNK/JNK was detected. BLCA cells were divided into the Mock, siNC, siANLN, SP600125 (a selective JNK inhibitor), and ANLN + SP600125 group, followed by measurements of real-time quantitative polymerase chain reaction, 3-4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide, Annexin V-FITC/PI, Wound-healing, Transwell, and immunofluorescence assays. RESULTS ANLN was upregulated in the BLCA tissues, which showed a relation with the stage of patients. Besides, BLCA patients with high expression of ANLN had a worse prognosis than those with low expression of ANLN. Besides, the expression of ANLN in the BLCA tissues was positively correlated with MAPK8 and MAPK9. SP600125 suppressed the JNK signal pathway, reduced the proliferation, and increased BLCA cell apoptosis, with the reductions in the invasion and migration and the upregulation of phospho-histone H3 Ser-10 (pHH3), which was abolished by the overexpression of ANLN. CONCLUSION ANLN, as an oncogene of BLCA, may associate with the activation of JNK signal pathway. Inhibiting ANLN could deactivate the JNK signal pathway, thereby suppressing the proliferation, invasion, and migration while promoting the apoptosis of BLCA cells.
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Affiliation(s)
- Sheng Chen
- Department of Urology, Renmin Hospital, Hubei University of Medicine, Shiyan, China
| | - Yi Gao
- Department of Urology, Renmin Hospital, Hubei University of Medicine, Shiyan, China
| | - Fei Chen
- Department of Cardiology, Renmin Hospital, Hubei University of Medicine, Shiyan, China
| | - Tian-Bao Wang
- Department of Urology, Renmin Hospital, Hubei University of Medicine, Shiyan, China
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Weng W, Hong J, Owusu-Ansah KG, Chen B, Zheng S, Jiang D. Pralatrexate mediates effective killing of gemcitabine-resistant pancreatic cancer: role of mTOR/4E-BP1 signal pathway. Heliyon 2022; 8:e12064. [PMID: 36544829 PMCID: PMC9761725 DOI: 10.1016/j.heliyon.2022.e12064] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 11/07/2022] [Accepted: 11/25/2022] [Indexed: 12/12/2022] Open
Abstract
Gemcitabine is the first-line chemotherapeutic agent for pancreatic cancer. However, gemcitabine-resistance frequently leads to poor prognosis. Exploring new chemotherapeutic agents is important for patients with gemcitabine-resistant pancreatic cancer. In this study, we established a new acquired gemcitabine-resistant pancreatic cancer cell line BxPC-GEM-20 from parental BxPC-3. We found that pralatrexate significantly inhibited the growth of BxPC-GEM-20. The half-maximal inhibitory concentration of pralatrexate on BxPC-GEM-20 cell was about 3.43 ± 0.25 nM. Pralatrexate was found to effectively inhibit the clonal growth of BxPC-GEM-20 cell. Additionally, pralatrexate at 20 mg/kg had an excellent tumor inhibitory effect with an inhibitory rate of 76.92% in vivo. This pralatrexate therapy showed good safety profile that with little to no additional influence on the hepatic, renal function as well as body weight changes in nude mice. Pralatrexate was confirmed to prevent cells from entering the G2/M phase, leading to the promotion of apoptosis and autophagy. Further analysis demonstrated that the reduced phosphorylation of mTOR played a significant role in the tumor cell damage caused by pralatrexate. Pralatrexate effectively inhibited the mTOR/4E-BP1 pathway. Activation of mTOR pathway can further obstruct the repressive effect of pralatrexate on gemcitabine-resistant pancreatic cancer. In summary, pralatrexate induces effective inhibition of gemcitabine-resistant pancreatic cancer. This may lead to the expansion of pralatrexate's application and offer benefit to gemcitabine-resistant pancreatic cancer patients in the future.
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Affiliation(s)
- Wanwen Weng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China,NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China,Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China,Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Zhejiang Province, Hangzhou 310003, China,Department of Nuclear Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jiawei Hong
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China,NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China,Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China,Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Zhejiang Province, Hangzhou 310003, China
| | - Kwabena G. Owusu-Ansah
- Department of Internal Medicine, St. Elizabeth Youngstown Hospital, Youngstown, OH, USA,Department of Medicine, Northeastern Ohio Medical University, Rootstown, OH, USA
| | - Bingjie Chen
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China,NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China,Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China,Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Zhejiang Province, Hangzhou 310003, China
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China,NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China,Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China,Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Zhejiang Province, Hangzhou 310003, China,Corresponding author.
| | - Donghai Jiang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China,NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China,Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China,Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Zhejiang Province, Hangzhou 310003, China,Corresponding author.
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Roy S, Saha S, Dhar D, Chakraborty P, Singha Roy K, Mukherjee C, Gupta A, Bhattacharyya S, Roy A, Sengupta S, Roychoudhury S, Nath S. Molecular crosstalk between CUEDC2 and ERα influences the clinical outcome by regulating mitosis in breast cancer. Cancer Gene Ther 2022; 29:1697-1706. [PMID: 35732909 DOI: 10.1038/s41417-022-00494-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 05/13/2022] [Accepted: 06/08/2022] [Indexed: 02/04/2023]
Abstract
Development of endocrine resistance in hormone-receptor-positive (HR+ve) subtype and lack of definitive target in triple-negative subtype challenge breast cancer management. Contributing to such endocrine resistance is a protein called CUEDC2. It degrades hormone receptors, estrogen receptor-α (ERα) and progesterone receptor. Higher level of CUEDC2 in ERα+ve breast cancer corresponded to poorer disease prognosis. It additionally influences mitotic progression. However, the crosstalk of these two CUEDC2-driven functions in the outcome of breast cancer remained elusive. We showed that CUEDC2 degrades ERα during mitosis, utilising the mitotic-ubiquitination-machinery. We elucidated the importance of mitosis-specific phosphorylation of CUEDC2 in this process. Furthermore, upregulated CUEDC2 overrode mitotic arrest, increasing aneuploidy. Finally, recruiting a prospective cohort of breast cancer, we found significantly upregulated CUEDC2 in HR-ve cases. Moreover, individuals with higher CUEDC2 levels showed a poorer progression-free-survival. Together, our data confirmed that CUEDC2 up-regulation renders ERα+ve malignancies to behave essentially as HR-ve tumors with the prevalence of aneuploidy. This study finds CUEDC2 as a potential prognostic marker and a therapeutic target in the clinical management of breast cancer.
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Affiliation(s)
- Stuti Roy
- Department of Basic and Translational Research, Saroj Gupta Cancer Centre and Research Institute, Thakurpukur, Kolkata, India
| | - Suryendu Saha
- Department of Basic and Translational Research, Saroj Gupta Cancer Centre and Research Institute, Thakurpukur, Kolkata, India
| | - Debanil Dhar
- Department of Basic and Translational Research, Saroj Gupta Cancer Centre and Research Institute, Thakurpukur, Kolkata, India
| | - Puja Chakraborty
- Department of Basic and Translational Research, Saroj Gupta Cancer Centre and Research Institute, Thakurpukur, Kolkata, India
| | - Kumar Singha Roy
- Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | | | - Arnab Gupta
- Department of Surgery, Saroj Gupta Cancer Centre and Research Institute, Thakurpukur, Kolkata, India
| | - Samir Bhattacharyya
- Department of Surgery, Saroj Gupta Cancer Centre and Research Institute, Thakurpukur, Kolkata, India
| | - Anup Roy
- Department of Pathology, Nil Ratan Sircar Medical College and Hospital, Kolkata, India
| | | | - Susanta Roychoudhury
- Department of Basic and Translational Research, Saroj Gupta Cancer Centre and Research Institute, Thakurpukur, Kolkata, India.,CSIR-Indian Institute of Chemical Biology, CN-06, CN Block, Sector V, Kolkata, India
| | - Somsubhra Nath
- Department of Basic and Translational Research, Saroj Gupta Cancer Centre and Research Institute, Thakurpukur, Kolkata, India.
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Insulin-like Growth Factor 2 Promotes Tissue-Specific Cell Growth, Proliferation and Survival during Development of Helicoverpa armigera. Cells 2022; 11:cells11111799. [PMID: 35681494 PMCID: PMC9180042 DOI: 10.3390/cells11111799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 05/24/2022] [Accepted: 05/25/2022] [Indexed: 11/19/2022] Open
Abstract
During development, cells constantly undergo fate choices by differentiating, proliferating, and dying as part of tissue remodeling. However, we only begin to understand the mechanisms of these different fate choices. Here, we took the lepidopteran insect Helicoverpa armigera, the cotton bollworm, as a model to reveal that insulin-like growth factor 2 (IGF-2-like) prevented cell death by promoting cell growth and proliferation. Tissue remodeling occurs during insect metamorphosis from larva to adult under regulation by 20-hydroxyecdysone (20E), a steroid hormone. An unknown insulin-like peptide in the genome of H. armigera was identified as IGF-2-like by sequence analysis using human IGFs. The expression of Igf-2-like was upregulated by 20E. IGF-2-like was localized in the imaginal midgut during tissue remodeling, but not in larval midgut that located nearby. IGF-2-like spread through the fat body during fat body remodeling. Cell proliferation was detected in the imaginal midgut and some fat body cells expressing IGF-2-like. Apoptosis was detected in the larval midgut and some fat body cells that did not express IGF-2-like, suggesting the IGF-2-like was required for cell survival, and IGF-2-like and apoptosis were exclusive, pointing to a survival requirement. Knockdown of Igf-2-like resulted in repression of growth and proliferation of the imaginal midgut and fat body. Our results suggested that IGF-2-like promotes cell growth and proliferation in imaginal tissues, promoting cell death avoidance and survival of imaginal cells during tissue remodeling. It will be interesting to determine whether the mechanism of action of steroid hormones on insulin growth factors is conserved in other species.
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35
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Baek KI, Chang SS, Chang CC, Roustaei M, Ding Y, Wang Y, Chen J, O'Donnell R, Chen H, Ashby JW, Xu X, Mack JJ, Cavallero S, Roper M, Hsiai TK. Vascular Injury in the Zebrafish Tail Modulates Blood Flow and Peak Wall Shear Stress to Restore Embryonic Circular Network. Front Cardiovasc Med 2022; 9:841101. [PMID: 35369301 PMCID: PMC8971683 DOI: 10.3389/fcvm.2022.841101] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 02/21/2022] [Indexed: 12/16/2022] Open
Abstract
Mechano-responsive signaling pathways enable blood vessels within a connected network to structurally adapt to partition of blood flow between organ systems. Wall shear stress (WSS) modulates endothelial cell proliferation and arteriovenous specification. Here, we study vascular regeneration in a zebrafish model by using tail amputation to disrupt the embryonic circulatory loop (ECL) at 3 days post fertilization (dpf). We observed a local increase in blood flow and peak WSS in the Segmental Artery (SeA) immediately adjacent to the amputation site. By manipulating blood flow and WSS via changes in blood viscosity and myocardial contractility, we show that the angiogenic Notch-ephrinb2 cascade is hemodynamically activated in the SeA to guide arteriogenesis and network reconnection. Taken together, ECL amputation induces changes in microvascular topology to partition blood flow and increase WSS-mediated Notch-ephrinb2 pathway, promoting new vascular arterial loop formation and restoring microcirculation.
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Affiliation(s)
- Kyung In Baek
- Department of Medicine and Bioengineering, University of California, Los Angeles, Los Angeles, CA, United States
| | - Shyr-Shea Chang
- Department of Mathematics, University of California, Los Angeles, Los Angeles, CA, United States
- Center for Studies in Physics and Biology, The Rockefeller University, New York, NY, United States
- Developmental Biology Program, Sloan Kettering Institute, New York, NY, United States
| | - Chih-Chiang Chang
- Department of Medicine and Bioengineering, University of California, Los Angeles, Los Angeles, CA, United States
| | - Mehrdad Roustaei
- Department of Medicine and Bioengineering, University of California, Los Angeles, Los Angeles, CA, United States
| | - Yichen Ding
- Department of Medicine and Bioengineering, University of California, Los Angeles, Los Angeles, CA, United States
| | - Yixuan Wang
- Department of Mathematics, University of California, Los Angeles, Los Angeles, CA, United States
| | - Justin Chen
- Department of Medicine and Bioengineering, University of California, Los Angeles, Los Angeles, CA, United States
| | - Ryan O'Donnell
- Department of Medicine and Bioengineering, University of California, Los Angeles, Los Angeles, CA, United States
| | - Hong Chen
- Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States
| | - Julianne W. Ashby
- Division of Cardiology, Department of Medicine, School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Xiaolei Xu
- Zebrafish Genetics, Mayo Clinic, Rochester, MN, United States
| | - Julia J. Mack
- Division of Cardiology, Department of Medicine, School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Susana Cavallero
- Division of Cardiology, Department of Medicine, School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
- Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, United States
| | - Marcus Roper
- Department of Mathematics, University of California, Los Angeles, Los Angeles, CA, United States
| | - Tzung K. Hsiai
- Department of Medicine and Bioengineering, University of California, Los Angeles, Los Angeles, CA, United States
- Division of Cardiology, Department of Medicine, School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
- Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, United States
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36
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Shcheglova E, Blaszczyk K, Borowiak M. Mitogen Synergy: An Emerging Route to Boosting Human Beta Cell Proliferation. Front Cell Dev Biol 2022; 9:734597. [PMID: 35155441 PMCID: PMC8829426 DOI: 10.3389/fcell.2021.734597] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 08/24/2021] [Indexed: 12/11/2022] Open
Abstract
Decreased number and function of beta cells are a key aspect of diabetes mellitus (diabetes), a disease that remains an onerous global health problem. Means of restoring beta cell mass are urgently being sought as a potential cure for diabetes. Several strategies, such as de novo beta cell derivation via pluripotent stem cell differentiation or mature somatic cell transdifferentiation, have yielded promising results. Beta cell expansion is another promising strategy, rendered challenging by the very low proliferative capacity of beta cells. Many effective mitogens have been identified in rodents, but the vast majority do not have similar mitogenic effects in human beta cells. Extensive research has led to the identification of several human beta cell mitogens, but their efficacy and specificity remain insufficient. An approach based on the simultaneous application of several mitogens has recently emerged and can yield human beta cell proliferation rates of up to 8%. Here, we discuss recent advances in restoration of the beta cell population, focusing on mitogen synergy, and the contribution of RNA-sequencing (RNA-seq) to accelerating the elucidation of signaling pathways in proliferating beta cells and the discovery of novel mitogens. Together, these approaches have taken beta cell research up a level, bringing us closer to a cure for diabetes.
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Affiliation(s)
- Ekaterina Shcheglova
- Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznań, Poland
| | - Katarzyna Blaszczyk
- Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznań, Poland
| | - Malgorzata Borowiak
- Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznań, Poland
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States
- *Correspondence: Malgorzata Borowiak, ;
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37
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Tang SY, Zhou PJ, Meng Y, Zeng FR, Deng GT. Gastric cancer: An epigenetic view. World J Gastrointest Oncol 2022; 14:90-109. [PMID: 35116105 PMCID: PMC8790429 DOI: 10.4251/wjgo.v14.i1.90] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 05/17/2021] [Accepted: 12/23/2021] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) poses a serious threat worldwide with unfavorable prognosis mainly due to late diagnosis and limited therapies. Therefore, precise molecular classification and search for potential targets are required for diagnosis and treatment, as GC is complicated and heterogeneous in nature. Accumulating evidence indicates that epigenetics plays a vital role in gastric carcinogenesis and progression, including histone modifications, DNA methylation and non-coding RNAs. Epigenetic biomarkers and drugs are currently under intensive evaluations to ensure efficient clinical utility in GC. In this review, key epigenetic alterations and related functions and mechanisms are summarized in GC. We focus on integration of existing epigenetic findings in GC for the bench-to-bedside translation of some pivotal epigenetic alterations into clinical practice and also describe the vacant field waiting for investigation.
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Affiliation(s)
- Si-Yuan Tang
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Pei-Jun Zhou
- Cancer Research Institute, School of Basic Medicine Science, Central South University, School of Basic Medicine Science, Central South University 410008, Hunan Province, China
| | - Yu Meng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Fu-Rong Zeng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Guang-Tong Deng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
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38
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Wang Y, Sun Q, Geng R, Liu H, Yuan F, Xu Y, Qi Y, Jiang H, Chen Q, Liu B. Notch intracellular domain regulates glioblastoma proliferation through the Notch1 signaling pathway. Oncol Lett 2021; 21:303. [PMID: 33732379 PMCID: PMC7905607 DOI: 10.3892/ol.2021.12564] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Accepted: 11/24/2020] [Indexed: 12/15/2022] Open
Abstract
Notch intracellular domain (NICD), also known as the activated form of Notch1 is closely associated with cell differentiation and tumor invasion. However, the role of NICD in glioblastoma (GBM) proliferation and the underlying regulatory mechanism remains unclear. The present study aimed to investigate the expression of NICD and Notch1 downstream gene HES5 in human GBM and normal brain samples and to further detect the effect of NICD on human GBM cell proliferation. For this purpose, western blotting and immunohistochemical staining were performed to analyze the expression of NICD in human GBM tissues, while western blotting and reverse-transcription quantitative PCR experiments were used to analyze the expression of Hes5 in human GBM tissues. A Flag-NICD vector was used to overexpress NICD in U87 cells and compound E and small interfering (si) Notch1 were used to downregulate NICD. Cellular proliferation curves were generated and BrdU assays performed to evaluate the proliferation of U87 cells. The results demonstrated that compared with normal brain tissues, the level of NICD protein in human GBM tissues was upregulated and the protein and mRNA levels of Hes5 were also upregulated in GBM tissues indicating that the Notch1 signaling pathway is activated in GBM. Overexpression of NICD promoted the proliferation of U87 cells in vitro while downregulation of NICD by treatment with compound E or siNotch1 suppressed the proliferation of U87 cells in vitro. In conclusion, NICD was upregulated in human GBM and NICD promoted GBM proliferation via the Notch1 signaling pathway. NICD may be a potential diagnostic marker and therapeutic target for GBM treatment.
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Affiliation(s)
- Yixuan Wang
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.,Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Qian Sun
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.,Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Rongxin Geng
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.,Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Hao Liu
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.,Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Fan'en Yuan
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.,Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Yang Xu
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.,Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Yangzhi Qi
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.,Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Hongxiang Jiang
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.,Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Qianxue Chen
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.,Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Baohui Liu
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.,Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
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Abdellatif AM. Structure of the Eurasian moorhen spleen: A comprehensive study using gross anatomy, light, and transmission electron microscopy. Microsc Res Tech 2021; 84:1696-1709. [PMID: 33576559 DOI: 10.1002/jemt.23728] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 01/08/2021] [Accepted: 01/27/2021] [Indexed: 11/09/2022]
Abstract
The spleen is the largest secondary lymphoid organ with major roles in the removal of blood-borne antigens. The Eurasian moorhen is a wild aquatic bird that revealed the adaptation to harsh environmental conditions. Information regarding the structural features of moorhen's spleen is lacking. The present study aimed to describe the composition of moorhen's spleen using anatomical dissection, histology, histochemistry, immunohistochemistry, and transmission electron microscopy. The spleen appeared as a brownish red sickle-shaped organ close to the proventriculus and gizzard. The splenic capsule was very thin, and the trabeculae were poorly developed. The white pulp formed of the periarteriolar lymphoid sheath, lymphoid follicles, and periellipsoidal lymphatic sheath. The red pulp composed of sinusoids and cords and contained various types of blood cells. Blood vessels were observed within the splenic capsule and inside the parenchyma. Notably, penicillar capillaries (PCs) appeared branched and surrounded by well-developed ellipsoids. Direct connections were observed between PCs and splenic sinusoids suggesting a closed type of circulation. Ultrastructurally, intercellular spaces and vascular channels were evident in the wall of PCs. Ellipsoid-associated cells, lymphocytes, monocytes, and heterophils were observed within splenic ellipsoids. Ellipsoids were thus suggested as a crucial component of moorhen's spleen. Numerous MafB-immunoreactive (IR) macrophages were seen within the red pulp. Splenic cords contained the highest number of PHH3-IR cells, while CCASP3-IR cells were exclusive to follicles of the white pulp. In conclusion, the structure of moorhen's spleen revealed species-specific features. The findings of the present study could help to improve the immunity of domestic birds.
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Affiliation(s)
- Ahmed M Abdellatif
- Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt
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40
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Hacking SM, Sajjan S, Lee L, Ziemba Y, Angert M, Yang Y, Jin C, Chavarria H, Kataria N, Jain S, Nasim M. Potential Pitfalls in Diagnostic Digital Image Analysis: Experience with Ki-67 and PHH3 in Gastrointestinal Neuroendocrine Tumors. Pathol Res Pract 2020; 216:152753. [DOI: 10.1016/j.prp.2019.152753] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 11/11/2019] [Accepted: 11/17/2019] [Indexed: 11/28/2022]
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41
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Leonel ECR, Campos SGP, Bedolo CMB, Guerra LHA, Vilamaior PSL, Calmon MF, Rahal P, Amorim CA, Taboga SR. Perinatal exposure to bisphenol A impacts in the mammary gland morphology of adult Mongolian gerbils. Exp Mol Pathol 2020; 113:104374. [PMID: 31917966 DOI: 10.1016/j.yexmp.2020.104374] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 10/07/2019] [Accepted: 01/04/2020] [Indexed: 12/31/2022]
Abstract
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.
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Affiliation(s)
- Ellen Cristina Rivas Leonel
- Department of Biology, Institute of Biosciences, Humanities and Exact Sciences, São Paulo State University (UNESP), Rua Cristóvão Colombo 2265, Jardim Nazareth, 15054-000 São José do Rio Preto, São Paulo, Brazil
| | - Silvana Gisele Pegorin Campos
- Federal University of São João del Rei, Campus Centro Oeste Dona Lindu, Avenida Sebastião Gonçalves Coelho, 400, Bairro Chanadour, 35501-296 Divinópolis, Minas Gerais, Brazil
| | - Carolina Marques Baraldi Bedolo
- Department of Biology, Institute of Biosciences, Humanities and Exact Sciences, São Paulo State University (UNESP), Rua Cristóvão Colombo 2265, Jardim Nazareth, 15054-000 São José do Rio Preto, São Paulo, Brazil
| | - Luiz Henrique Alves Guerra
- Department of Biology, Institute of Biosciences, Humanities and Exact Sciences, São Paulo State University (UNESP), Rua Cristóvão Colombo 2265, Jardim Nazareth, 15054-000 São José do Rio Preto, São Paulo, Brazil
| | - Patrícia Simone Leite Vilamaior
- Department of Biology, Institute of Biosciences, Humanities and Exact Sciences, São Paulo State University (UNESP), Rua Cristóvão Colombo 2265, Jardim Nazareth, 15054-000 São José do Rio Preto, São Paulo, Brazil
| | - Marilia Freitas Calmon
- Department of Biology, Institute of Biosciences, Humanities and Exact Sciences, São Paulo State University (UNESP), Rua Cristóvão Colombo 2265, Jardim Nazareth, 15054-000 São José do Rio Preto, São Paulo, Brazil
| | - Paula Rahal
- Department of Biology, Institute of Biosciences, Humanities and Exact Sciences, São Paulo State University (UNESP), Rua Cristóvão Colombo 2265, Jardim Nazareth, 15054-000 São José do Rio Preto, São Paulo, Brazil
| | - Christiani Andrade Amorim
- Laboratory of Gynecology, Institute of Experimental and Clinique Research, Université Catholique de Louvain (UCL), Avenue Mounier 52, bte B1.52.02, 1200 Brussels, Belgium
| | - Sebastião Roberto Taboga
- Department of Biology, Institute of Biosciences, Humanities and Exact Sciences, São Paulo State University (UNESP), Rua Cristóvão Colombo 2265, Jardim Nazareth, 15054-000 São José do Rio Preto, São Paulo, Brazil.
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Tumor Budding in Colorectal Carcinoma Showing a Paradoxical Mitotic Index (Via PHH3) With Possible Association to the Tumor Stromal Microenvironment. Appl Immunohistochem Mol Morphol 2019; 28:627-634. [PMID: 31567276 DOI: 10.1097/pai.0000000000000805] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Colorectal carcinomas (CC) are one of the most commonly diagnosed malignancies. Tumor budding (the histologic process of dissociation that occurs at the invasive margin of colorectal cancer), has significant prognostic implications, in that higher tumor budding is associated with adverse histopathologic and clinical outcomes. Because of this prognostic significance, more research is needed to further understand the pathologic and immunohistochemical (IHC) associations pertaining to this important prognostic variable. In this study, we will further evaluate selective clinopathologic and IHC variables with possible association to tumor budding. DESIGN A total of 234 cases of CC diagnosed in our health system were retrospectively reviewed and routine hematoxylin and eosin-stained slides of these cases were collected. A representative slide for tumor budding was selected per case and selective IHC staining was performed. Clinicopathologic data were collected for each case and analyzed in relation to tumor budding scores. In exploratory analyses, tumor budding scores per individual investigator and consensus tumor budding scores were compared with selected IHC stains (MLH1, PMS2, and PHH3) as well as numerous clinicopathologic variables. RESULTS We found a paradoxical association between tumor budding and mitosis score using PHH3 immunostaining in univariate and multivariable analysis. Furthermore, patients with intact nuclear expression for MLH1 and/or PMS2 are more likely to have higher tumor budding compared with patients with lost expression. For multivariable analysis, the following covariates were significantly associated with higher tumor budding: the presence of lymphovascular invasion, higher pathologic tumor stage, and finally infiltrating border was more likely to be associated with higher tumor budding compared with cases with a pushing border. Regarding nonmucinous versus mucinous CC, nonmucinous adenocarcinoma (MCA) was more likely to be associated with higher tumor budding compared with MCA. CONCLUSION Numerous clinicopathologic variables were found to be associated with tumor budding including lymphovascular invasion, tumor stage, infiltrating tumor border, non-MCA was more likely to be associated with higher tumor budding compared with MCA, possibly related to MUC-2 and MSI. Furthermore, regarding the paradoxical association between tumor budding and mitosis score using a PHH3 immunostaining (high tumor budding having lower mitosis), this is possibly related to the tumoral stomal microenvironment and cancer associated fibroblasts. An idea for a future study would be to look at the maturity of cancer-associated fibroblasts (immature vs. mature) and the tumoral stroma microenvironment, with regards to markers of tumor aggressiveness such as mitosis. In addition, we found that patients with intact nuclear expression for MLH1 and/or PMS2 were more likely to have higher tumor budding compared with patients with lost expression, possibly related to mismatch repair CC's not being as reliant on tumor budding. Future research will hopefully concede further insight into the variables that affect tumor budding, especially regarding the tumoral microenvironment and variations between different patient populations, inclusive of patients lacking activity of the mismatch repair. Ultimately, this will allow for better prognostic information, and more precise treatment modalities.
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Evaluation of phospho-histone H3 in Asian triple-negative breast cancer using multiplex immunofluorescence. Breast Cancer Res Treat 2019; 178:295-305. [PMID: 31410680 DOI: 10.1007/s10549-019-05396-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Accepted: 08/04/2019] [Indexed: 12/22/2022]
Abstract
PURPOSE We used multiplex immunofluorescence (mIF) to determine whether mitotic rate represents an independent prognostic marker in triple-negative breast cancer (TNBC). Secondary aims were to confirm the prognostic significance of immune cells in TNBC, and to investigate the relationship between immune cells and proliferating tumour cells. METHODS A retrospective Asian cohort of 298 patients with TNBC diagnosed from 2003 to 2015 at the Singapore General Hospital was used in the present study. Formalin-fixed, paraffin-embedded breast cancer samples were analysed on tissue microarrays using mIF, which combined phospho-histone H3 (pHH3) expression with cytokeratin (CK) and leukocyte common antigen (CD45) expression to identify tumour and immune cells, respectively. RESULTS Multivariate analysis showed that a high pHH3 index was associated with significantly improved overall survival (OS; p = 0.004), but this was not significantly associated with disease-free survival (DFS; p = 0.22). Similarly, multivariate analysis also revealed that a pHH3 positive count of > 1 cell per high-power field in the malignant epithelial compartment was an independent favourable prognostic marker for OS (p = 0.033) but not for DFS (p = 0.250). Furthermore, a high CD45 index was an independent favourable prognostic marker for DFS (p = 0.018), and there was a significant positive correlation between CD45 and pHH3 index (Spearman rank correlation coefficient, 0.250; p < 0.001). CONCLUSIONS Mitotic rates as determined by pHH3 expression in epithelial cells are significantly associated with improved survival in TNBC. mIF analysis of pHH3 in combination with CK and CD45 could help clinicians in prognosticating patients with TNBC.
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Starodubtseva NL, Brzhozovskiy AG, Bugrova AE, Kononikhin AS, Indeykina MI, Gusakov KI, Chagovets VV, Nazarova NM, Frankevich VE, Sukhikh GT, Nikolaev EN. Label-free cervicovaginal fluid proteome profiling reflects the cervix neoplastic transformation. JOURNAL OF MASS SPECTROMETRY : JMS 2019; 54:693-703. [PMID: 31116903 DOI: 10.1002/jms.4374] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 05/08/2019] [Accepted: 05/12/2019] [Indexed: 06/09/2023]
Abstract
Cervicovaginal fluid (CVF) is a valuable source of clinical information about the female reproductive tract in both nonpregnant and pregnant women. The aim of this study is to specify the CVF proteome at different stages of cervix neoplastic transformation by label-free quantitation approach based on liquid chromatography tandem mass spectrometry (LC-MS/MS) method. The proteome composition of CVF from 40 women of reproductive age with human papillomavirus (HPV)-associated cervix neoplastic transformation (low-grade squamous intraepithelial lesion [LSIL], high-grade squamous intraepithelial lesion [HSIL], and CANCER) was investigated. Hierarchical clustering and principal component analysis (PCA) of the proteomic data obtained by a label-free quantitation approach show the distribution of the sample set between four major clusters (no intraepithelial lesion or malignancy [NILM], LSIL, HSIL and CANCER) depending on the form of cervical lesion. Multisample ANOVA with subsequent Welch's t test resulted in 117 that changed significantly across the four clinical stages, including 27 proteins significantly changed in cervical cancer. Some of them were indicated as promising biomarkers previously (ACTN4, VTN, ANXA1, CAP1, ANXA2, and MUC5B). CVF proteomic data from the discovery stage were analyzed by the partial least squares-discriminant analysis (PLS-DA) method to build a statistical model, allowing to differentiate severe dysplasia (HSIL and CANCER) from the mild/normal stage (NILM and LSIL), and receiver operating characteristic (ROC) area under the curve (AUC) were obtained on an independent set of 33 samples. The sensitivity of the model was 77%, and the specificity was 94%; AUC was equal to 0.87. CVF proteome proved to be reflect the stage of cervical epithelium neoplastic process.
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Affiliation(s)
- Natalia L Starodubtseva
- System Biology Department, V. I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of Ministry of Healthcare of Russian Federation, Moscow, Russia
- Laboratory of Ion and Molecular Physics, Moscow Institute of Physics and Technology, Moscow, Russia
| | - Alexander G Brzhozovskiy
- System Biology Department, V. I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of Ministry of Healthcare of Russian Federation, Moscow, Russia
| | - Anna E Bugrova
- System Biology Department, V. I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of Ministry of Healthcare of Russian Federation, Moscow, Russia
- Emanuel Institute for Biochemical Physics, Russian Academy of Sciences, Moscow, Russia
| | - Alexey S Kononikhin
- Laboratory of Ion and Molecular Physics, V.L. Talrose Institute for Energy Problems of Chemical Physics, N.N. Semenov Federal Center of Chemical Physics, Russian Academy of Sciences, Moscow, Russia
- Laboratory of Mass Specrometry, Skolkovo Institute of Science and Technology, Moscow, Russia
| | - Maria I Indeykina
- Laboratory of Ion and Molecular Physics, Moscow Institute of Physics and Technology, Moscow, Russia
- Emanuel Institute for Biochemical Physics, Russian Academy of Sciences, Moscow, Russia
| | - Kiril I Gusakov
- System Biology Department, V. I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of Ministry of Healthcare of Russian Federation, Moscow, Russia
| | - Vitaliy V Chagovets
- System Biology Department, V. I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of Ministry of Healthcare of Russian Federation, Moscow, Russia
| | - Niso M Nazarova
- System Biology Department, V. I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of Ministry of Healthcare of Russian Federation, Moscow, Russia
| | - Vladimir E Frankevich
- System Biology Department, V. I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of Ministry of Healthcare of Russian Federation, Moscow, Russia
| | - Gennady T Sukhikh
- System Biology Department, V. I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of Ministry of Healthcare of Russian Federation, Moscow, Russia
| | - Eugene N Nikolaev
- Laboratory of Ion and Molecular Physics, V.L. Talrose Institute for Energy Problems of Chemical Physics, N.N. Semenov Federal Center of Chemical Physics, Russian Academy of Sciences, Moscow, Russia
- Laboratory of Mass Specrometry, Skolkovo Institute of Science and Technology, Moscow, Russia
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The correlation between phosphorylated Histone H3 (PHH3) and p-STAT3 in Meningiomas. Clin Neurol Neurosurg 2019; 178:46-50. [DOI: 10.1016/j.clineuro.2019.01.016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Revised: 12/19/2018] [Accepted: 01/24/2019] [Indexed: 12/26/2022]
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Léger H, Santana E, Leu NA, Smith ET, Beltran WA, Aguirre GD, Luca FC. Ndr kinases regulate retinal interneuron proliferation and homeostasis. Sci Rep 2018; 8:12544. [PMID: 30135513 PMCID: PMC6105603 DOI: 10.1038/s41598-018-30492-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2018] [Accepted: 08/01/2018] [Indexed: 12/31/2022] Open
Abstract
Ndr2/Stk38l encodes a protein kinase associated with the Hippo tumor suppressor pathway and is mutated in a naturally-occurring canine early retinal degeneration (erd). To elucidate the retinal functions of Ndr2 and its paralog Ndr1/Stk38, we generated Ndr1 and Ndr2 single knockout mice. Although retinal lamination appeared normal in these mice, Ndr deletion caused a subset of Pax6-positive amacrine cells to proliferate in differentiated retinas, while concurrently decreasing the number of GABAergic, HuD and Pax6-positive amacrine cells. Retinal transcriptome analyses revealed that Ndr2 deletion increased expression of neuronal stress genes and decreased expression of synaptic organization genes. Consistent with the latter, Ndr deletion dramatically reduced levels of Aak1, an Ndr substrate that regulates vesicle trafficking. Our findings indicate that Ndr kinases are important regulators of amacrine and photoreceptor cells and suggest that Ndr kinases inhibit the proliferation of a subset of terminally differentiated cells and modulate interneuron synapse function via Aak1.
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Affiliation(s)
- Hélène Léger
- Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, United States
| | - Evelyn Santana
- Division of Experimental Retinal Therapies, Department of Clinical Sciences and Advanced Medicine, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, United States
| | - N Adrian Leu
- Center for Animal Transgenesis and Germ Cell Research, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, United States
| | - Eliot T Smith
- Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, United States
| | - William A Beltran
- Division of Experimental Retinal Therapies, Department of Clinical Sciences and Advanced Medicine, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, United States
| | - Gustavo D Aguirre
- Division of Experimental Retinal Therapies, Department of Clinical Sciences and Advanced Medicine, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, United States
| | - Francis C Luca
- Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, United States.
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