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Viswanathan G, Hughes EJ, Gan M, Xet-Mull AM, Alexander G, Swain-Lenz D, Liu Q, Tobin DM. Granuloma Dual RNA-Seq Reveals Composite Transcriptional Programs Driven by Neutrophils and Necrosis within Tuberculous Granulomas. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.04.26.650783. [PMID: 40391323 PMCID: PMC12087985 DOI: 10.1101/2025.04.26.650783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/21/2025]
Abstract
Mycobacterial granulomas lie at the center of tuberculosis (TB) pathogenesis and represent a unique niche where infecting bacteria survive in nutrient-restricted conditions and in the face of a host immune response. The granuloma's necrotic core, where bacteria reside extracellularly in humans, is difficult to assess in many experimentally tractable models. Here, using necrotic mycobacterial granulomas in adult zebrafish, we develop dual RNA-seq across different host genotypes to identify the transcriptional alterations that enable bacteria to survive within this key microenvironment. Through pharmacological and genetic interventions, we find that neutrophils within mature, necrotic granulomas promote bacterial growth, in part through upregulation of the bacterial devR regulon. We identify conserved suites of bacterial transcriptional programs induced only in the context of this unique necrotic extracellular niche, including bacterial modules related to K + transport and rpf genes. Analysis of Mycobacterium tuberculosis strains across diverse lineages and human populations suggests that granuloma-specific transcriptional modules are targets for bacterial genetic adaptation in the context of human infection. Summary sentence Dual host-pathogen transcriptional profiling defines granuloma-specific programs during mycobacterial infection.
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Qian Z, Li Z, Peng X, Mao Y, Mao X, Li J. Annexin A: Cell Death, Inflammation, and Translational Medicine. J Inflamm Res 2025; 18:5655-5672. [PMID: 40309306 PMCID: PMC12042829 DOI: 10.2147/jir.s511439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Accepted: 04/07/2025] [Indexed: 05/02/2025] Open
Abstract
The annexin superfamily proteins, a family of calcium-dependent phospholipid-binding proteins, are involved in a variety of Ca²+-regulated membrane events. Annexin A, expressed in vertebrates, has been implicated in a variety of regulated cell death (RCD) pathways, including apoptosis, autophagy, pyroptosis, ferroptosis, and neutrophil extracellular trap-induced cell death (NETosis). Given that inflammation is a key driver of cell death, the roles of Annexin A in inflammation have been extensively studied. In this review, we discuss the regulatory roles of Annexin A in RCD and inflammation, the development of related targeted therapies in translational medicine, and the application of animal models to study these processes. We also analyze current challenges and discuss future directions for improved diagnostic and therapeutic strategies.
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Affiliation(s)
- Zibing Qian
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, 730000, People’s Republic of China
| | - Ziyi Li
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, 730000, People’s Republic of China
| | - Xuebin Peng
- Department of Infectious Disease, The First Hospital of Lanzhou University, Lanzhou, Gansu, 730000, People’s Republic of China
| | - Yongwu Mao
- Department of Infectious Disease, The First Hospital of Lanzhou University, Lanzhou, Gansu, 730000, People’s Republic of China
| | - Xiaorong Mao
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, 730000, People’s Republic of China
- Department of Infectious Disease, The First Hospital of Lanzhou University, Lanzhou, Gansu, 730000, People’s Republic of China
| | - Junfeng Li
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, 730000, People’s Republic of China
- Institute of Infectious Diseases, The First Hospital of Lanzhou University, Lanzhou, Gansu, 730000, People’s Republic of China
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Rahimi-Farsi N, Bostanian F, Shahbazi T, Shamsinejad FS, Bolideei M, Mohseni P, Zangooie A, Boustani F, Shoorei H. Novel oncogenes and tumor suppressor genes in Hepatocellular Carcinoma: Carcinogenesis, progression, and therapeutic targets. Gene 2025; 941:149229. [PMID: 39800198 DOI: 10.1016/j.gene.2025.149229] [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: 03/27/2024] [Revised: 10/21/2024] [Accepted: 01/07/2025] [Indexed: 01/15/2025]
Abstract
Hepatocellular carcinoma (HCC) is the primary malignancy affecting the liver and the leading cause of mortality among individuals with cirrhosis. This complex disease is associated with various risk factors, including environmental, pathological, and genetic influences, which dysregulate gene expression crucial for the cell cycle and cellular/molecular pathways. The disruption of the balance between tumor suppressors and proto-oncogenes amplifies the pathogenic cascade. Given its predilection for diseased or cirrhotic livers and late-stage diagnosis, HCC prognosis is typically poor. Current therapies offer limited benefits, with conventional non-specific cytotoxic agents exhibiting suboptimal efficacy. However, molecularly targeted therapies have emerged as a promising avenue, leveraging the strategic inhibition of carcinogenic molecules to provide heightened specificity and potency compared to cytotoxic chemotherapy. Several clinical trials have demonstrated promising outcomes in advanced HCC with targeted pharmacotherapies. Many genes have been implicated in HCC pathogenesis, underscoring the need to elucidate their molecular functions and roles. This has profound implications for early HCC prognostication via biomarkers and for identifying therapeutic targets to impede neoplastic progression. Notably, evidence highlights the pivotal roles of oncogenes and tumor suppressors in HCC pathophysiology. This discourse examines the potential involvement of ABL1, Annexins, FAK, FOX, and KIF as candidate oncogenes, contrasted with SORBS2, HPCAL1, PCDH10, PLAC8, and CXXC5 as plausible tumor suppressors. Their signaling cascades and relevance to HCC prognosis and progression are delineated to identify targets for improving HCC diagnosis, prognostication, and therapy.
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Affiliation(s)
| | | | - Taha Shahbazi
- Neurosurgery Research Group (NRG), Razi Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Mansoor Bolideei
- Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Parvin Mohseni
- Department of Pathobiology, Faculty of Veterinary Medicine, Shahid Bahonar University of Kerman, Kerman, Iran
| | - Alireza Zangooie
- Student Research Committee, Birjand University of Medical Sciences, Birjand, Iran; Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farnaz Boustani
- Clinical Research Development Unit of Tabriz Valiasr Hospital, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Hamed Shoorei
- Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; Clinical Research Development Unit of Tabriz Valiasr Hospital, Tabriz University of Medical Sciences, Tabriz, Iran; Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran.
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Lee SM, Yoon SJ, Park KW, Kim A, Kim HJ, Jung N, Jang H, Seeley WW, Kim Y, Moon SY, Kim E, the Longitudinal study of Early onset dementia And Family members (LEAF) investigators. Semantic variant primary progressive aphasia with ANXA11 p.D40G. Alzheimers Dement 2025; 21:e14566. [PMID: 40042459 PMCID: PMC11881632 DOI: 10.1002/alz.14566] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 12/27/2024] [Accepted: 12/28/2024] [Indexed: 05/13/2025]
Abstract
INTRODUCTION Pathogenic variants of annexin A11 (ANXA11) have been identified in patients with amyotrophic lateral sclerosis (ALS) with or without frontotemporal dementia (FTD). We explored ANXA11 pathogenic variants in a Korean FTD cohort to investigate the prevalence and the role of ANXA11 variation in FTD. METHODS We used next-generation sequencing (NGS) to search for pathogenic variants in ANXA11 in two nationwide FTD cohorts in Korea. RESULTS We identified a pathogenic variant in ANXA11, c.119A > G (p.D40G), in six patients with semantic variant primary progressive aphasia (svPPA), representing 5.5% of the svPPA cohort (6/109), and representing 2.3% of the FTD cohort overall (6/259). Only one patient later developed features suggestive of ALS. DISCUSSION This study links a rare variant in ANXA11 to a sporadic clinical syndrome in which specific TAR DNA-binding protein-43 (TDP-43) forms an obligate co-fibril with annexin A11. The variant, p.D40G, lies within the N-terminal portion of annexin A11's TDP-43 type C interacting domain, suggesting that genetic variation in that region may promote co-fibrillization. HIGHLIGHTS The pathogenic variant of annexin A11 (ANXA11I) is linked to frontotemporal dementia (FTD) syndrome. ANXA11 (p.D40G) may be one of the possible genetic causes of semantic variant primary progressive aphasia (svPPA). ANXA11 (p.D40G) may enhance heteromeric amyloid filaments of annexin A11 and TDP-43, promoting frontotemporal lobar degeneration with TAR DNA-binding protein-43 (TDP-43) inclusions (FTLD-TDP) type C.
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Affiliation(s)
- Sun Min Lee
- Department of NeurologyAjou University School of MedicineSuwonSouth Korea
| | - Soo Jin Yoon
- Department of NeurologyDaejeon Eulji Medical CenterEulji UniversityDaejeonSouth Korea
| | - Kyung Won Park
- Department of NeurologyDong‐A Medical CenterDong‐A University College of MedicineBusanSouth Korea
| | - Ahro Kim
- Department of NeurologyUlsan University HospitalUniversity of Ulsan College of MedicineUlsanSouth Korea
| | - Hee Jin Kim
- Department of NeurologySamsung Medical CenterSungkyunkwan University School of MedicineSeoulSouth Korea
| | - Na‐Yeon Jung
- Department of NeurologyPusan National University Yangsan HospitalResearch Institute for Convergence of Biomedical Science and TechnologyYangsanSouth Korea
| | - Hyemin Jang
- Department of NeurologySeoul National University HospitalSeoulSouth Korea
| | - William W. Seeley
- Memory and Aging CenterDepartment of NeurologyUniversity of California, San FranciscoSan FranciscoCaliforniaUSA
- Department of PathologyUniversity of California, San FranciscoSan FranciscoCaliforniaUSA
| | - Young‐Eun Kim
- Department of Laboratory MedicineHanyang University College of MedicineSeoulSouth Korea
| | - So Young Moon
- Department of NeurologyAjou University School of MedicineSuwonSouth Korea
| | - Eun‐Joo Kim
- Department of NeurologyPusan National University HospitalPusan National University School of Medicine and Medical Research InstituteBusanSouth Korea
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Nassan M, Ayala IA, Sloan J, Bonfitto A, Stark B, Song S, Naymik M, Geula C, Gefen T, Barbieri E, Piras IS, Mesulam MM, Huentelman MJ. The genetics of TDP43-Type-C neurodegeneration: a whole genome sequencing study. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.01.25.25320561. [PMID: 39973992 PMCID: PMC11839009 DOI: 10.1101/2025.01.25.25320561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
Frontotemporal lobar degeneration-TDP Type C (TDP-C) is a unique neurodegenerative disease that starts by attacking the anterior temporal lobe leading to language and/or behavioral syndromes. Current literature on the genetic associations of TDP-C, which we have reviewed here, is uneven and lacks a discernible corpus of robust findings. In our study, we completed genome wide hypothesis-free analyses utilizing artificial Intelligence (AI) to identify rare and common variants associated with TDP-C. We then investigated ANXA11 and TARDBP in a hypothesis-driven analysis, since it was recently shown that TDP-43 and Annexin A11 co-aggregate in all TDP-C cases. 1) Whole genome sequencing was completed to identify pathogenic rare variants prioritized with Illumina's AI-based Emedgene software on 37 confirmed or probable TDP-C cases from the Northwestern-University Cohort. 2) A genome wide association study was then completed to identify common variants associated with TDP-C cases vs 290 controls. 3) Next, common and rare variants in TARDBP, and ANXA11 were investigated in TDP-C vs controls. These analyses identified novel genetic associations between FIG4 , UBQLN2 , INPP5A , and ANXA11 with TDP-C. Of these FIG4, UBQLN2 and ANXA11 have been associated previously with Amyotrophic lateral sclerosis (ALS). To further assess the observed potential genetic overlap between ALS and TDP-C, we leveraged Mendelian randomization (MR) to assess if the ALS genetic load is associated with TDP-C risk, and found evidence supporting this association. The genetic association of ANXA11 with TDP-C is particularly interesting in view of the recently discovered role of Annexin A11 in forming heterodimers with TDP-43 in all abnormal precipitates, a feature not found in TDP-A or TDP-B, which have no similar predilection for the anterior temporal lobe. In addition to the observed overlap between ALS genetics/ genetic load and TDP-C, it is worth mentioning that FIG4, INPP5A and ANXA11 have been implicated in the inositol metabolism pathway, a feature that remains to be elucidated mechanistically. Our TDP-C genetic literature review identified a surprising paucity of neuropathologically confirmed cases in published investigations. Nonetheless, the literature offers support for some of our findings and reemphasizes the absence of dominant or major pathogenic genes for TDP-C, another feature that sets this neuropathologic entity apart from TDP-A and TDP-B.
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Marchica V, Biasetti L, Barnard J, Li S, Nikolaou N, Frosch MP, Lucente DE, Eldaief M, King A, Fanto M, Troakes C, Houart C, Smith BN. Annexin A11 mutations are associated with nuclear envelope dysfunction in vivo and in human tissues. Brain 2025; 148:276-290. [PMID: 38989900 PMCID: PMC11706284 DOI: 10.1093/brain/awae226] [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: 11/24/2023] [Revised: 05/04/2024] [Accepted: 05/20/2024] [Indexed: 07/12/2024] Open
Abstract
Annexin A11 mutations are a rare cause of amyotrophic lateral sclerosis (ALS), wherein replicated protein variants P36R, G38R, D40G and D40Y are located in a small helix within the long, disordered N-terminus. To elucidate disease mechanisms, we characterized the phenotypes induced by a genetic loss-of-function and by misexpression of G38R and D40G in vivo. Loss of Annexin A11 results in a low-penetrant behavioural phenotype and aberrant axonal morphology in zebrafish homozygous knockout larvae, which is rescued by human wild-type Annexin A11. Both Annexin A11 knockout/down and ALS variants trigger nuclear dysfunction characterized by Lamin B2 mislocalization. The Lamin B2 signature also presented in anterior horn, spinal cord neurons from post-mortem ALS ± frontotemporal dementia patient tissue possessing G38R and D40G protein variants. These findings suggest mutant Annexin A11 acts as a dominant negative, revealing a potential early nucleopathy highlighting nuclear envelope abnormalities preceding behavioural abnormality in animal models.
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Affiliation(s)
- Valentina Marchica
- Department of Basic and Clinical Neuroscience, Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 9RX, UK
- Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology and Neuroscience, Guy’s Campus, King’s College London, London SE1 1UL, UK
| | - Luca Biasetti
- Department of Basic and Clinical Neuroscience, Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 9RX, UK
| | - Jodi Barnard
- Department of Basic and Clinical Neuroscience, Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 9RX, UK
| | - Shujing Li
- Department of Basic and Clinical Neuroscience, Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 9RX, UK
| | - Nikolas Nikolaou
- Living Systems Institute, University of Exeter, Stocker Road, Exeter EX4 4QD, UK
| | - Matthew P Frosch
- Mass General Institute for Neurodegenerative Diseases, B114-2700, Charlestown, MA 02129, USA
- C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Diane E Lucente
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Mark Eldaief
- Mass General Institute for Neurodegenerative Diseases, B114-2700, Charlestown, MA 02129, USA
| | - Andrew King
- Department of Basic and Clinical Neuroscience, Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 9RX, UK
- London Neurodegenerative Diseases Brain Bank, SGDP Centre, PO65, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK
| | - Manolis Fanto
- Department of Basic and Clinical Neuroscience, Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 9RX, UK
| | - Claire Troakes
- Department of Basic and Clinical Neuroscience, Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 9RX, UK
- London Neurodegenerative Diseases Brain Bank, SGDP Centre, PO65, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK
| | - Corinne Houart
- Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology and Neuroscience, Guy’s Campus, King’s College London, London SE1 1UL, UK
| | - Bradley N Smith
- Department of Basic and Clinical Neuroscience, Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 9RX, UK
- Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology and Neuroscience, Guy’s Campus, King’s College London, London SE1 1UL, UK
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Radenković N, Milutinović M, Nikodijević D, Jovankić J, Jurišić V. Sample Preparation of Adherent Cell Lines for Flow Cytometry: Protocol Optimization-Our Experience with SW-480 colorectal cancer cell line. Indian J Clin Biochem 2025; 40:74-79. [PMID: 39835228 PMCID: PMC11741975 DOI: 10.1007/s12291-023-01161-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 10/30/2023] [Indexed: 01/22/2025]
Abstract
The most common method for detection of apoptosis is flow cytometry. In previously published studies there are some uncertainties and problems about the preparation of adherent cell lines for analysis. Thus, the aim of this study is to determine and describe how preparing the sample of SW-480 cells in two different ways affects the reliability of the results. In Protocol 1 the total cell number, cells in flow media and cells which adhere, were used, while in Protocol 2 the medium was removed after cell incubation and only the adherent cells were used. Results show statistically significant changes in percentages of different cell types (viable, apoptosis, and necrosis) between two different protocols. Protocol 2, where the first medium with dead cells were removed and only the cells that were attached to the bottom were used for analysis, give better cell viability in the control sample. Removing the medium is especially recommended for long-term treatments, where the cells consume nutrients and, due to lack, initiate apoptosis. After 72 h, spontaneous apoptosis is detectable in control cells and indicates low viability of the control sample, while in treated cells by proapoptotic substances, together with induced apoptosis leads to cumulative or synergistic effects.
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Affiliation(s)
- Nikola Radenković
- Faculty of Science, Department of Biology and Ecology, University of Kragujevac, Radoja Domanovića 12, Kragujevac, 34000 Serbia
| | - Milena Milutinović
- Faculty of Science, Department of Biology and Ecology, University of Kragujevac, Radoja Domanovića 12, Kragujevac, 34000 Serbia
| | - Danijela Nikodijević
- Faculty of Science, Department of Biology and Ecology, University of Kragujevac, Radoja Domanovića 12, Kragujevac, 34000 Serbia
| | - Jovana Jovankić
- Faculty of Science, Department of Biology and Ecology, University of Kragujevac, Radoja Domanovića 12, Kragujevac, 34000 Serbia
| | - Vladimir Jurišić
- Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, Kragujevac, 34000 Serbia
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Khullar S, Huang X, Ramesh R, Svaren J, Wang D. NetREm: Network Regression Embeddings reveal cell-type transcription factor coordination for gene regulation. BIOINFORMATICS ADVANCES 2024; 5:vbae206. [PMID: 40260118 PMCID: PMC12011367 DOI: 10.1093/bioadv/vbae206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 10/22/2024] [Accepted: 12/18/2024] [Indexed: 04/23/2025]
Abstract
Motivation Transcription factor (TF) coordination plays a key role in gene regulation via direct and/or indirect protein-protein interactions (PPIs) and co-binding to regulatory elements on DNA. Single-cell technologies facilitate gene expression measurement for individual cells and cell-type identification, yet the connection between TF-TF coordination and target gene (TG) regulation of various cell types remains unclear. Results To address this, we introduce our innovative computational approach, Network Regression Embeddings (NetREm), to reveal cell-type TF-TF coordination activities for TG regulation. NetREm leverages network-constrained regularization, using prior knowledge of PPIs among TFs, to analyze single-cell gene expression data, uncovering cell-type coordinating TFs and identifying revolutionary TF-TG candidate regulatory network links. NetREm's performance is validated using simulation studies and benchmarked across several datasets in humans, mice, yeast. Further, we showcase NetREm's ability to prioritize valid novel human TF-TF coordination links in 9 peripheral blood mononuclear and 42 immune cell sub-types. We apply NetREm to examine cell-type networks in central and peripheral nerve systems (e.g. neuronal, glial, Schwann cells) and in Alzheimer's disease versus Controls. Top predictions are validated with experimental data from rat, mouse, and human models. Additional functional genomics data helps link genetic variants to our TF-TG regulatory and TF-TF coordination networks. Availability and implementation https://github.com/SaniyaKhullar/NetREm.
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Affiliation(s)
- Saniya Khullar
- Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, United States
- Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI 53076, United States
| | - Xiang Huang
- Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, United States
| | - Raghu Ramesh
- Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, United States
- Comparative Biomedical Sciences Training Program, University of Wisconsin-Madison, Madison, WI 53706, United States
| | - John Svaren
- Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, United States
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, United States
| | - Daifeng Wang
- Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, United States
- Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI 53076, United States
- Department of Computer Sciences, University of Wisconsin-Madison, Madison, WI 53706, United States
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Liao SY, Fingerlin T, Maier L. Genetic predisposition to sarcoidosis. J Autoimmun 2024; 149:103122. [PMID: 37865580 DOI: 10.1016/j.jaut.2023.103122] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 10/04/2023] [Indexed: 10/23/2023]
Abstract
Sarcoidosis is a complex systemic disease with clinical heterogeneity based on varying phenotypes and natural history. The detailed etiology of sarcoidosis remains unknown, but genetic predisposition as well as environmental exposures play a significant role in disease pathogenesis. We performed a comprehensive review of germline genetic (DNA) and transcriptomic (RNA) studies of sarcoidosis, including both previous studies and more recent findings. In this review, we provide an assessment of the following: genetic variants in sarcoidosis susceptibility and phenotypes, ancestry- and sex-specific genetic variants in sarcoidosis, shared genetic architecture between sarcoidosis and other diseases, and gene-environment interactions in sarcoidosis. We also highlight the unmet needs in sarcoidosis genetic studies, including the pressing requirement to include diverse populations and have consistent definitions of phenotypes in the sarcoidosis research community to help advance the application of genetic predisposition to sarcoidosis disease risk and manifestations.
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Affiliation(s)
- Shu-Yi Liao
- National Jewish Health, Department of Medicine, Denver, CO, USA; University of Colorado Anschutz Medical Campus, Department of Medicine, Aurora, CO, USA; Colorado School of Public Health, University of Colorado Denver - Anschutz Medical Campus, Aurora, CO, USA
| | - Tasha Fingerlin
- National Jewish Health, Department of Medicine, Denver, CO, USA; University of Colorado Anschutz Medical Campus, Department of Medicine, Aurora, CO, USA; Colorado School of Public Health, University of Colorado Denver - Anschutz Medical Campus, Aurora, CO, USA; National Jewish Health, Department of Immunology and Genomic Medicine, Denver, CO, USA
| | - Lisa Maier
- National Jewish Health, Department of Medicine, Denver, CO, USA; University of Colorado Anschutz Medical Campus, Department of Medicine, Aurora, CO, USA; Colorado School of Public Health, University of Colorado Denver - Anschutz Medical Campus, Aurora, CO, USA.
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Ramezani F, Takhshid MA, Abuei H, Farhadi A, Mosleh-Shirazi MA, Ramezani P. Combined Effects of Annexin A5 Overexpression, 5-Fluorouracil Treatment, and Irradiation on Cell Viability of Caski Cervical Cancer Cell Line. Reprod Sci 2024; 31:2654-2666. [PMID: 38811453 DOI: 10.1007/s43032-024-01575-y] [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: 01/23/2024] [Accepted: 04/22/2024] [Indexed: 05/31/2024]
Abstract
Cervical cancer is the fourth leading cause of cancer deaths in women globally. Combining gene therapy with chemo- and radiotherapy may improve cervical cancer treatment outcomes. This study evaluated the effects of Annexin A5(ANXA5) overexpression alongside 5-fluorouracil (5-FU) and irradiation on the viability of CaSki cervical squamous cell carcinoma (SCC) cells. pAdenoVator-CMV-ANXA5-IRES-GFP-plasmid and mock plasmid were transfected into CaSki cells using calcium-phosphate. Seventy-two hours post-transfection, GFP expression was quantified by fluorescence microscopy and flow cytometry to evaluate transfection efficiency. ANXA5 overexpression was confirmed via qPCR. Twenty-four hours post-transfection, cells received a single dose of 8 Gy and were treated with 1 and 2 µg/ml of 5-FU (IC50 = 2.783 µg/ml). Cell viability, apoptosis, cell cycle stage, and Bcl-2 and Bax gene expression were assessed via MTT, annexin V/7-AAD, PI staining, and qPCR assays, respectively. ANXA5 was overexpressed 31.5-fold compared to control (p < 0.0001). MTT assays showed ANXA5 overexpression dose-dependently reduced CaSki cell viability (p < 0.001). IC50 of 5-FU was reduced from 2.783 μg/mL to 1.794 μg/mL when combined with ANXA5 overexpression. Additive effects on cell death were observed for ANXA5 plus 5-FU or irradiation versus ANXA5 alone. Apoptosis assays indicated combinatorial treatment increased CaSki cell apoptosis over ANXA5 alone. Cell cycle analysis revealed ANXA5 arrested cell cycle at G1/S phases; the percentage of cells in the S phase further rose with combination treatment. Finally, combination therapy significantly decreased Bcl-2 expression and increased Bax versus control (p < 0.001). Altogether, ANXA5 overexpression alongside 5-FU and irradiation may improve cervical squamous cell carcinoma (SCC) treatment efficacy. Further, in vivo investigations are warranted to confirm these in vitro results.
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Affiliation(s)
- Faezeh Ramezani
- Division of Medical Biotechnology, Department of Medical Laboratory Sciences, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Ali Takhshid
- Division of Medical Biotechnology, Department of Medical Laboratory Sciences, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran.
- School of Paramedical Sciences, Diagnostic Laboratory Sciences and Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Haniyeh Abuei
- Division of Medical Biotechnology, Department of Medical Laboratory Sciences, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ali Farhadi
- Division of Medical Biotechnology, Department of Medical Laboratory Sciences, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
- School of Paramedical Sciences, Diagnostic Laboratory Sciences and Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Amin Mosleh-Shirazi
- Ionizing and Non-Ionizing Radiation Protection Research Center (INIRPRC), School of Paramedical Sciences, Shiraz University of Medical Sciences, Meshkinfam St, Shiraz, Iran
- Physics Unit, Department of Radio-Oncology, School of Medicine, Shiraz University of Medical Sciences, Namazi Teaching Hospital, Namazi Square, Shiraz, Iran
| | - Pouya Ramezani
- Division of Medical Biotechnology, Department of Medical Laboratory Sciences, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
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11
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Bączek K, Piotrowski WJ. Lung fibrosis in sarcoidosis. Is there a place for antifibrotics? Front Pharmacol 2024; 15:1445923. [PMID: 39281278 PMCID: PMC11392764 DOI: 10.3389/fphar.2024.1445923] [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] [Received: 06/08/2024] [Accepted: 08/22/2024] [Indexed: 09/18/2024] Open
Abstract
Sarcoidosis, an enigmatic disease with unknown etiology, is characterized by inflammation and the potential involvement of various organs, predominantly the lungs and intrathoracic lymph nodes. Non-caseating granulomas can resolve spontaneously in approximately 60% of cases within 2-3 years. However, sarcoidosis-related mortality has increased. Lung fibrosis, affecting up to 20% of sarcoidosis patients, stands out as a primary cause of mortality. Traditionally, fibrosis is viewed because of prolonged inflammation, necessitating anti-inflammatory treatment with systemic steroids, immunosuppressants, and anti-TNF agents to manage the disease. The recent introduction of antifibrotic drugs such as nintedanib and pirfenidone offers new avenues for treating fibrotic sarcoidosis. Nintedanib, effective in idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-related interstitial lung disease (SSc-ILD), has shown promise in patients with various progressive fibrosing interstitial lung diseases (PF-ILD), including those with sarcoidosis. Pirfenidone, also effective in IPF, has demonstrated potential in managing fibrotic sarcoidosis, though results have been inconclusive due to limited participant numbers in studies. This review explores the theoretical and empirical evidence supporting the use of antifibrotics in sarcoidosis, weighing the benefits and drawbacks. While antifibrotics offer a potential therapeutic approach, further randomized controlled trials are essential to determine their efficacy in fibrotic sarcoidosis. Addressing fibrosis as a continuum of chronic inflammation, the role of antifibrotics in managing sarcoidosis remains an area requiring more in-depth research to improve patient outcomes and advance treatment paradigms.
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Affiliation(s)
- Karol Bączek
- Department of Pneumology, Medical University of Łódź, Łódź, Poland
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12
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Yin JH, Horzmann KA. Embryonic Zebrafish as a Model for Investigating the Interaction between Environmental Pollutants and Neurodegenerative Disorders. Biomedicines 2024; 12:1559. [PMID: 39062132 PMCID: PMC11275083 DOI: 10.3390/biomedicines12071559] [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: 06/10/2024] [Revised: 07/08/2024] [Accepted: 07/11/2024] [Indexed: 07/28/2024] Open
Abstract
Environmental pollutants have been linked to neurotoxicity and are proposed to contribute to neurodegenerative disorders. The zebrafish model provides a high-throughput platform for large-scale chemical screening and toxicity assessment and is widely accepted as an important animal model for the investigation of neurodegenerative disorders. Although recent studies explore the roles of environmental pollutants in neurodegenerative disorders in zebrafish models, current knowledge of the mechanisms of environmentally induced neurodegenerative disorders is relatively complex and overlapping. This review primarily discusses utilizing embryonic zebrafish as the model to investigate environmental pollutants-related neurodegenerative disease. We also review current applicable approaches and important biomarkers to unravel the underlying mechanism of environmentally related neurodegenerative disorders. We found embryonic zebrafish to be a powerful tool that provides a platform for evaluating neurotoxicity triggered by environmentally relevant concentrations of neurotoxic compounds. Additionally, using variable approaches to assess neurotoxicity in the embryonic zebrafish allows researchers to have insights into the complex interaction between environmental pollutants and neurodegenerative disorders and, ultimately, an understanding of the underlying mechanisms related to environmental toxicants.
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Affiliation(s)
| | - Katharine A. Horzmann
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA;
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13
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Lee MJ, de los Rios Kobara I, Barnard TR, Vales Torres X, Tobin NH, Ferbas KG, Rimoin AW, Yang OO, Aldrovandi GM, Wilk AJ, Fulcher JA, Blish CA. NK Cell-Monocyte Cross-talk Underlies NK Cell Activation in Severe COVID-19. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 212:1693-1705. [PMID: 38578283 PMCID: PMC11102029 DOI: 10.4049/jimmunol.2300731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 03/13/2024] [Indexed: 04/06/2024]
Abstract
NK cells in the peripheral blood of severe COVID-19 patients exhibit a unique profile characterized by activation and dysfunction. Previous studies have identified soluble factors, including type I IFN and TGF-β, that underlie this dysregulation. However, the role of cell-cell interactions in modulating NK cell function during COVID-19 remains unclear. To address this question, we combined cell-cell communication analysis on existing single-cell RNA sequencing data with in vitro primary cell coculture experiments to dissect the mechanisms underlying NK cell dysfunction in COVID-19. We found that NK cells are predicted to interact most strongly with monocytes and that this occurs via both soluble factors and direct interactions. To validate these findings, we performed in vitro cocultures in which NK cells from healthy human donors were incubated with monocytes from COVID-19+ or healthy donors. Coculture of healthy NK cells with monocytes from COVID-19 patients recapitulated aspects of the NK cell phenotype observed in severe COVID-19, including decreased expression of NKG2D, increased expression of activation markers, and increased proliferation. When these experiments were performed in a Transwell setting, we found that only CD56bright CD16- NK cells were activated in the presence of severe COVID-19 patient monocytes. O-link analysis of supernatants from Transwell cocultures revealed that cultures containing severe COVID-19 patient monocytes had significantly elevated levels of proinflammatory cytokines and chemokines, as well as TGF-β. Collectively, these results demonstrate that interactions between NK cells and monocytes in the peripheral blood of COVID-19 patients contribute to NK cell activation and dysfunction in severe COVID-19.
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Affiliation(s)
- Madeline J. Lee
- Department of Medicine, Stanford University School of Medicine, Palo Alto, CA
- Stanford Immunology Program, Stanford University School of Medicine, Palo Alto, CA
| | - Izumi de los Rios Kobara
- Department of Medicine, Stanford University School of Medicine, Palo Alto, CA
- Stanford Immunology Program, Stanford University School of Medicine, Palo Alto, CA
| | - Trisha R. Barnard
- Department of Medicine, Stanford University School of Medicine, Palo Alto, CA
| | - Xariana Vales Torres
- Department of Medicine, Stanford University School of Medicine, Palo Alto, CA
- Stanford Immunology Program, Stanford University School of Medicine, Palo Alto, CA
| | - Nicole H. Tobin
- Division of Infectious Diseases, Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Kathie G. Ferbas
- Division of Infectious Diseases, Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Anne W. Rimoin
- Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA
| | - Otto O. Yang
- Division of Infectious Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Grace M. Aldrovandi
- Division of Infectious Diseases, Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Aaron J. Wilk
- Department of Medicine, Stanford University School of Medicine, Palo Alto, CA
- Stanford Medical Scientist Training Program, Stanford University School of Medicine, Palo Alto, CA
| | - Jennifer A. Fulcher
- Division of Infectious Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Catherine A. Blish
- Department of Medicine, Stanford University School of Medicine, Palo Alto, CA
- Chan Zuckerberg Biohub, San Francisco, CA
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14
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Khullar S, Huang X, Ramesh R, Svaren J, Wang D. NetREm: Network Regression Embeddings reveal cell-type transcription factor coordination for gene regulation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.10.25.563769. [PMID: 37961577 PMCID: PMC10634989 DOI: 10.1101/2023.10.25.563769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2023]
Abstract
Transcription factor (TF) coordination plays a key role in target gene (TG) regulation via protein-protein interactions (PPIs) and DNA co-binding to regulatory elements. Single-cell technologies facilitate gene expression measurement for individual cells and cell-type identification, yet the connection between TF coordination and TG regulation of various cell types remains unclear. To address this, we have developed a novel computational approach, Network Regression Embeddings (NetREm), to reveal cell-type TF-TF coordination activities for TG regulation. NetREm leverages network-constrained regularization using prior knowledge of direct and/or indirect PPIs among TFs to analyze single-cell gene expression data. We test NetREm by simulation data and benchmark its performance in 4 real-world applications that have gold standard TF-TG networks available: mouse (mESCs) and simulated human (hESCs) embryonic stem (ESCs), human hematopoietic stem (HSCs), and mouse dendritic (mDCs) cells. Further, we use NetREm to prioritize valid novel TF-TF coordination links in human Peripheral Blood Mononuclear cell (PBMC) sub-types. We apply NetREm to analyze various cell types in both central (CNS) and peripheral (PNS) nerve system (NS) (e.g. neuronal, glial, Schwann cells (SCs)) as well as in Alzheimers disease (AD). Our findings uncover cell-type coordinating TFs and identify new TF-TG candidate links. We validate our top predictions using Cut&Run and knockout loss-of-function expression data in rat/mouse models and compare results with additional functional genomic data, including expression quantitative trait loci (eQTL) and Genome-Wide Association Studies (GWAS) to link genetic variants (single nucleotide polymorphisms (SNPs)) to TF coordination.
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15
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Upton C, Healey J, Rothnie AJ, Goddard AD. Insights into membrane interactions and their therapeutic potential. Arch Biochem Biophys 2024; 755:109939. [PMID: 38387829 DOI: 10.1016/j.abb.2024.109939] [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: 11/01/2023] [Revised: 01/31/2024] [Accepted: 02/19/2024] [Indexed: 02/24/2024]
Abstract
Recent research into membrane interactions has uncovered a diverse range of therapeutic opportunities through the bioengineering of human and non-human macromolecules. Although the majority of this research is focussed on fundamental developments, emerging studies are showcasing promising new technologies to combat conditions such as cancer, Alzheimer's and inflammatory and immune-based disease, utilising the alteration of bacteriophage, adenovirus, bacterial toxins, type 6 secretion systems, annexins, mitochondrial antiviral signalling proteins and bacterial nano-syringes. To advance the field further, each of these opportunities need to be better understood, and the therapeutic models need to be further optimised. Here, we summarise the knowledge and insights into several membrane interactions and detail their current and potential uses therapeutically.
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Affiliation(s)
- Calum Upton
- School of Biosciences, Health & Life Science, Aston University, Birmingham, B4 7ET, UK
| | - Joseph Healey
- Nanosyrinx, The Venture Centre, University of Warwick Science Park, Coventry, CV4 7EZ, UK
| | - Alice J Rothnie
- School of Biosciences, Health & Life Science, Aston University, Birmingham, B4 7ET, UK
| | - Alan D Goddard
- School of Biosciences, Health & Life Science, Aston University, Birmingham, B4 7ET, UK.
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16
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Becker A, Filipp M, Lantz C, Glinton K, Thorp EB. HIF-1α is Required to Differentiate the Neonatal Macrophage Secretome from Adults. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.04.24.591000. [PMID: 38712137 PMCID: PMC11071477 DOI: 10.1101/2024.04.24.591000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2024]
Abstract
The immune response to stress diverges with age, with neonatal macrophages implicated in tissue regeneration versus tissue scarring and maladaptive inflammation in adults. Integral to the macrophage stress response is the recognition of hypoxia and pathogen-associated molecular patterns (PAMPs), which are often coupled. The age-specific, cell-intrinsic nature of this stress response remains vague. To uncover age-defined divergences in macrophage crosstalk potential after exposure to hypoxia and PAMPs, we interrogated the secreted proteomes of neonatal versus adult macrophages via non-biased mass spectrometry. Through this approach, we newly identified age-specific signatures in the secretomes of neonatal versus adult macrophages in response to hypoxia and the prototypical PAMP, lipopolysaccharide (LPS). Neonatal macrophages polarized to an anti-inflammatory, regenerative phenotype protective against apoptosis and oxidative stress, dependent on hypoxia inducible transcription factor-1α ( HIF-1α). In contrast, adult macrophages adopted a pro-inflammatory, glycolytic phenotypic signature consistent with pathogen killing. Taken together, these data uncover fundamental age and HIF-1α dependent macrophage programs that may be targeted to calibrate the innate immune response during stress and inflammation.
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17
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Lozano-Iturbe V, Blanco-Agudín N, Vázquez-Espinosa E, Fernández-Vega I, Merayo-Lloves J, Vazquez F, Girón RM, Quirós LM. The Binding of Pseudomonas aeruginosa to Cystic Fibrosis Bronchial Epithelial Model Cells Alters the Composition of the Exosomes They Produce Compared to Healthy Control Cells. Int J Mol Sci 2024; 25:895. [PMID: 38255969 PMCID: PMC10815301 DOI: 10.3390/ijms25020895] [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: 12/05/2023] [Revised: 01/05/2024] [Accepted: 01/09/2024] [Indexed: 01/24/2024] Open
Abstract
Cystic fibrosis (CF) is a genetic disease that causes dehydration of the surface of the airways, increasing lung infections, most frequently caused by Pseudomonas aeruginosa. Exosomes are nanovesicles released by cells that play an essential role in intercellular communication, although their role during bacterial infections is not well understood. In this article, we analyze the alterations in exosomes produced by healthy bronchial epithelial and cystic fibrosis cell lines caused by the interaction with P. aeruginosa. The proteomic study detected alterations in 30% of the species analyzed. In healthy cells, they mainly involve proteins related to the extracellular matrix, cytoskeleton, and various catabolic enzymes. In CF, proteins related to the cytoskeleton and matrix, in addition to the proteasome. These differences could be related to the inflammatory response. A study of miRNAs detected alterations in 18% of the species analyzed. The prediction of their potential biological targets identified 7149 genes, regulated by up to 7 different miRNAs. The identification of their functions showed that they preferentially affected molecules involved in binding and catalytic activities, although with differences between cell types. In conclusion, this study shows differences in exosomes between CF and healthy cells that could be involved in the response to infection.
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Affiliation(s)
- Víctor Lozano-Iturbe
- Department of Functional Biology, University of Oviedo, 33006 Oviedo, Spain; (V.L.-I.); (N.B.-A.); (F.V.)
- Instituto Universitario Fernández-Vega, Fundación de Investigación Oftalmológica, University of Oviedo, 33012 Oviedo, Spain; (I.F.-V.); (J.M.-L.)
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
| | - Noelia Blanco-Agudín
- Department of Functional Biology, University of Oviedo, 33006 Oviedo, Spain; (V.L.-I.); (N.B.-A.); (F.V.)
- Instituto Universitario Fernández-Vega, Fundación de Investigación Oftalmológica, University of Oviedo, 33012 Oviedo, Spain; (I.F.-V.); (J.M.-L.)
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
| | - Emma Vázquez-Espinosa
- Pneumology Service, Institute for Health Research (IP), Hospital Universitario de La Princesa, 28006 Madrid, Spain;
| | - Iván Fernández-Vega
- Instituto Universitario Fernández-Vega, Fundación de Investigación Oftalmológica, University of Oviedo, 33012 Oviedo, Spain; (I.F.-V.); (J.M.-L.)
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
- Department of Pathology, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain
| | - Jesús Merayo-Lloves
- Instituto Universitario Fernández-Vega, Fundación de Investigación Oftalmológica, University of Oviedo, 33012 Oviedo, Spain; (I.F.-V.); (J.M.-L.)
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
| | - Fernando Vazquez
- Department of Functional Biology, University of Oviedo, 33006 Oviedo, Spain; (V.L.-I.); (N.B.-A.); (F.V.)
- Instituto Universitario Fernández-Vega, Fundación de Investigación Oftalmológica, University of Oviedo, 33012 Oviedo, Spain; (I.F.-V.); (J.M.-L.)
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
- Department of Microbiology, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain
| | - Rosa M. Girón
- Pneumology Service, Institute for Health Research (IP), Hospital Universitario de La Princesa, 28006 Madrid, Spain;
| | - Luis M. Quirós
- Department of Functional Biology, University of Oviedo, 33006 Oviedo, Spain; (V.L.-I.); (N.B.-A.); (F.V.)
- Instituto Universitario Fernández-Vega, Fundación de Investigación Oftalmológica, University of Oviedo, 33012 Oviedo, Spain; (I.F.-V.); (J.M.-L.)
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
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18
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Jamwal S, Jena MK, Tyagi N, Kancharla S, Kolli P, Mandadapu G, Kumar S, Mohanty AK. Proteomic Approaches to Unravel the Molecular Dynamics of Early Pregnancy in Farm Animals: An In-Depth Review. J Dev Biol 2023; 12:2. [PMID: 38248867 PMCID: PMC10801625 DOI: 10.3390/jdb12010002] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 12/22/2023] [Accepted: 12/28/2023] [Indexed: 01/23/2024] Open
Abstract
Infertility is a major problem in farm animals, which has a negative economic effect on farm industries. Infertility can be defined as the inability of animals to achieve a successful pregnancy. Early pregnancy is crucial to establish a successful pregnancy, and it is reported that 70-80% and 20-30% of total embryonic loss occur in cattle and pigs, respectively, during the first month of pregnancy. The advanced high-throughput proteomics techniques provide valuable tools for in-depth understanding of the implantation process in farm animals. In the present review, our goal was to compile, assess, and integrate the latest proteomic research on farm animals, specifically focused on female reproduction, which involves endometrial tissues, uterine fluids, oviductal fluids, and microRNAs. The series of studies has provided in-depth insights into the events of the implantation process by unfolding the molecular landscape of the uterine tract. The discussed data are related to pregnant vs. non-pregnant animals, pregnancy vs. oestrous cycle, different days of the early pregnancy phase, and animals with uterine infections affecting reproduction health. Some of the studies have utilized non-invasive methods and in vitro models to decipher the molecular events of embryo-maternal interaction. The proteomics data are valuable sources for discovering biomarkers for infertility in ruminants and new regulatory pathways governing embryo-uterine interaction, endometrium receptivity, and embryonic development. Here, we envisage that the identified protein signatures can serve as potential therapeutic targets and biomarkers to develop new therapeutics against pregnancy diseases.
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Affiliation(s)
- Shradha Jamwal
- Proteomics and Structural Biology Lab, Animal Biotechnology Centre, National Dairy Research Institute, Karnal 132001, Haryana, India; (S.J.); (N.T.); (S.K.)
| | - Manoj Kumar Jena
- Department of Biotechnology, School of Bioengineering and Biosciences, Lovely Professional University, Phagwara 144411, Punjab, India;
| | - Nikunj Tyagi
- Proteomics and Structural Biology Lab, Animal Biotechnology Centre, National Dairy Research Institute, Karnal 132001, Haryana, India; (S.J.); (N.T.); (S.K.)
| | - Sudhakar Kancharla
- Devansh Lab Werks, 234 Aquarius Drive, Homewood, AL 35209, USA; (S.K.); (G.M.)
| | - Prachetha Kolli
- Microgen Health Inc., 14225 Sullyfield Cir Suite E, Chantilly, VA 20151, USA;
| | - Gowtham Mandadapu
- Devansh Lab Werks, 234 Aquarius Drive, Homewood, AL 35209, USA; (S.K.); (G.M.)
| | - Sudarshan Kumar
- Proteomics and Structural Biology Lab, Animal Biotechnology Centre, National Dairy Research Institute, Karnal 132001, Haryana, India; (S.J.); (N.T.); (S.K.)
| | - Ashok Kumar Mohanty
- ICAR–Central Institute for Research on Cattle, Meerut Cantt 250001, Uttar Pradesh, India
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19
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Cralley AL, Erickson C, Schaid TR, Hallas W, Thielen O, Mitra S, Stafford P, Hom P, Silliman C, Cohen MJ, Moore EE, D'Alessandro A, Hansen KC. The proteomic and metabolomic signatures of isolated and polytrauma traumatic brain injury. Am J Surg 2023; 226:790-797. [PMID: 37541795 DOI: 10.1016/j.amjsurg.2023.07.040] [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: 03/22/2023] [Revised: 07/02/2023] [Accepted: 07/27/2023] [Indexed: 08/06/2023]
Abstract
BACKGROUND The interactions of polytrauma, shock, and traumatic brain injury (TBI) on thromboinflammatory responses remain unclear and warrant investigation as we strive towards personalized medicine in trauma. We hypothesized that comprehensive omics characterization of plasma would identify unique metabolic and thromboinflammatory pathways following TBI. METHODS Patients were categorized as TBI vs Non-TBI, and stratified into Polytrauma or minimally injured. Discovery 'omics was employed to quantify the top differently expressed proteins and metabolites of TBI and Non-TBI patient groups. RESULTS TBI compared to Non-TBI showed gene enrichment in coagulation/complement cascades and neuronal markers. TBI was associated with elevation in glycolytic metabolites and conjugated bile acids. Division into isolated TBI vs polytrauma showed further distinction of proteomic and metabolomic signatures. CONCLUSION Identified mediators involving in neural inflammation, blood brain barrier disruption, and bile acid building leading to TBI associated coagulopathy offer suggestions for follow up mechanistic studies to target personalized interventions.
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Affiliation(s)
| | - Chris Erickson
- Department of Proteomics and Metabolomics, University of Colorado, Aurora, CO, USA
| | - Terry R Schaid
- Department of Surgery, University of Colorado, Aurora, CO, USA
| | - William Hallas
- Department of Surgery, University of Colorado, Aurora, CO, USA
| | - Otto Thielen
- Department of Surgery, University of Colorado, Aurora, CO, USA
| | | | | | - Patrick Hom
- Department of Surgery, University of Colorado, Aurora, CO, USA
| | - Christopher Silliman
- Vitalant Research Institute, Denver, CO, USA; Department of Pediatrics, University of Colorado, Aurora, CO, USA
| | | | - Ernest E Moore
- Department of Surgery, University of Colorado, Aurora, CO, USA; Ernest E. Moore Shock Trauma Center at Denver Health Medical Center Surgery, Aurora, CO, USA
| | - Angelo D'Alessandro
- Department of Proteomics and Metabolomics, University of Colorado, Aurora, CO, USA
| | - Kirk C Hansen
- Department of Proteomics and Metabolomics, University of Colorado, Aurora, CO, USA
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20
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Bandyopadhyay D, Mirsaeidi MS. Sarcoidosis-associated pulmonary fibrosis: joining the dots. Eur Respir Rev 2023; 32:230085. [PMID: 37758275 PMCID: PMC10523156 DOI: 10.1183/16000617.0085-2023] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 08/10/2023] [Indexed: 09/30/2023] Open
Abstract
Sarcoidosis is a multisystem granulomatous disorder of unknown aetiology. A minority of patients with sarcoidosis develop sarcoidosis-associated pulmonary fibrosis (SAPF), which may become progressive. Genetic profiles differ between patients with progressive and self-limiting disease. The mechanisms of fibrosis in SAPF are not fully understood, but SAPF is likely a distinct clinicopathological entity, rather than a continuum of acute inflammatory sarcoidosis. Risk factors for the development of SAPF have been identified; however, at present, it is not possible to make a robust prediction of risk for an individual patient. The bulk of fibrotic abnormalities in SAPF are located in the upper and middle zones of the lungs. A greater extent of SAPF on imaging is associated with a worse prognosis. Patients with SAPF are typically treated with corticosteroids, second-line agents such as methotrexate or azathioprine, or third-line agents such as tumour necrosis factor inhibitors. The antifibrotic drug nintedanib is an approved treatment for slowing the decline in lung function in patients with progressive fibrosing interstitial lung diseases, but more evidence is needed to assess its efficacy in SAPF. The management of patients with SAPF should include the identification and treatment of complications such as bronchiectasis and pulmonary hypertension. Further research is needed into the mechanisms underlying SAPF and biomarkers that predict its clinical course.
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Affiliation(s)
| | - Mehdi S Mirsaeidi
- Division of Pulmonary and Critical Care, University of Florida, Jacksonville, FL, USA
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21
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Asif H, Ribeiro Neto M, Culver D. Pulmonary fibrosis in sarcoidosis. SARCOIDOSIS, VASCULITIS, AND DIFFUSE LUNG DISEASES : OFFICIAL JOURNAL OF WASOG 2023; 40:e2023027. [PMID: 37712364 PMCID: PMC10540713 DOI: 10.36141/svdld.v40i3.14830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Accepted: 07/06/2023] [Indexed: 09/16/2023]
Abstract
Sarcoidosis may progress to pulmonary fibrosis in 5% of patients with significantly increased mortality. Histopathology shows fibrosis in a lymphangitic pattern surrounding the granulomas. Th1 to Th2 shift in environment along with angiogenesis is implicated in exuberant fibrosis. Clinical features include dyspnea, cough, and frequently with pulmonary function tests showing a mixed ventilatory defect with severely decreased diffusion capacity of carbon monoxide. Serologic markers including soluble interleukin 2 receptor, chitotriosidase and kern von den lunges 6, and chemokine ligand 18 are elevated and implicated in progression of disease. CT imaging shows fibrosis along bronchovascular bundles with reticulations, traction bronchiectasis and honeycombing predominantly in the upper and central distribution. Complications include sarcoidosis-associated pulmonary hypertension (SAPH) and chronic pulmonary aspergillosis. Treatment involves glucocorticoids and steroid-sparing agents in the presence of active granulomas. Anti-fibrotic agents such as pirfenidone and nintedanib have been shown to slow down pulmonary function decline in randomized clinical trials involving sarcoidosis-associated pulmonary fibrosis. Transplant workup is indicated in New York Heart Association class III or IV with similar success rates as in other lung transplant patients.
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Affiliation(s)
- Huda Asif
- University of South Florida, FL, USA .
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22
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Lindsay S, Bartolotti L, Li Y. Interactions and conformational changes of annexin A2/p11 heterotetramer models on a membrane: a molecular dynamics study. J Biomol Struct Dyn 2023; 42:10342-10351. [PMID: 37705315 PMCID: PMC11611455 DOI: 10.1080/07391102.2023.2256877] [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: 06/09/2023] [Accepted: 09/04/2023] [Indexed: 09/15/2023]
Abstract
Ca2+-dependent membrane-binding by the Annexin A2/p11 heterotetramer (A2t) plays an important role in various biological processes including fibrinogen activation and exocytosis in neuroendocrine cells. Two models where A2t associates with a single membrane surface were generated and used to perform molecular dynamics simulations. The first model mimics initial A2t-membrane binding through both Annexin A2 (A2) subunits of A2t (TS model) while the second model mimics A2t-binding through a single A2 subunit (OS model). Conformational changes were summarized using principal component analysis (PCA), simulation snapshots, and distance plots from the simulations. The full TS model, including the p11 dimer, fully associates with the membrane adopting a stable structure with little conformational variation as evidence by PCA. The unassociated subunits of the OS model moved toward the membrane. The molecular mechanics/Generalized-Born surface area (MMGBSA) method was applied to investigate the energetics of the models. The MMGBSA results demonstrated that R63 of p11 was the primary contributor to the p11-membrane interaction. The TS model results were both consistent with those found in the literature and provide novel insights about the specific residues driving the A2t-membrane interaction. Additionally, it represents the most complete model of A2t on the membrane surface available.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Samuel Lindsay
- Department of Chemistry, East Carolina University, Greenville, North Carolina 27858, USA
| | - Libero Bartolotti
- Department of Chemistry, East Carolina University, Greenville, North Carolina 27858, USA
| | - Yumin Li
- Department of Chemistry, East Carolina University, Greenville, North Carolina 27858, USA
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Lu C, Zhan Y, Jiang Y, Liao J, Qiu Z. Exosome-derived ANXA9 functions as an oncogene in breast cancer. J Pathol Clin Res 2023; 9:378-390. [PMID: 37294149 PMCID: PMC10397375 DOI: 10.1002/cjp2.334] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 05/05/2023] [Accepted: 05/24/2023] [Indexed: 06/10/2023]
Abstract
Breast cancer (BCA) is one of the most prevalent cancers among women. Emerging evidence has revealed that Annexin A-9 (ANXA9) plays a crucial function in the development of some cancers. Notably, ANXA9 has been reported to be a new prognostic biomarker for gastric and colorectal cancers. However, its expression and biological function in BCA have not yet been investigated. Using online bioinformatics tools such as TIMER, GEPIA, HPA, and UALCAN, we predicted ANXA9 expression and its correlation with the clinicopathological characteristics of BCA patients. RT-qPCR and western blot were utilized to measure ANXA9 mRNA and ANXA9 protein expression in BCA patient tissues and cells. BCA-derived exosomes were identified by transmission electron microscopy. Functional assays were employed to evaluate the biological role of ANXA9 in BCA cell proliferation, migration, invasion, and apoptosis. A tumor xenograft in vivo model was utilized to assess the role of ANXA9 in tumor growth in mice. Bioinformatics and functional screening analysis revealed that ANXA9 was highly expressed in BCA patient tissues, with median ANXA9 expression 1.5- to 2-fold higher than in normal tissues (p < 0.05). RT-qPCR confirmed that ANXA9 expression in BCA tissues was around 1.5-fold higher than the adjacent normal tissues (p < 0.001). ANXA9 expression in different subtypes of BCA also showed a difference, and ANXA9 was found to be mostly significantly upregulated in luminal BCA relative to normal tissues or other histological subtypes (p < 0.001). Moreover, ANXA9 expression was elevated in different races, ages, clinical stages, node metastasis status, and menopause status groups relative to the normal group (p < 0.001). Furthermore, ANXA9 was found to be secreted by BCA tissue-derived exosomes and its expression was upregulated 1- to 7-fold in BCA cells treated with exosomes (p < 0.001), while its expression in MCF10A cells was not significantly altered by treatment with exosomes (p > 0.05). ANXA9 silencing induced a significant decrease of around 30% in the colony number of BCA cells (p < 0.01). The number of migrated and invaded BCA cells also decreased by around 65 and 68%, respectively, after silencing ANXA9 (p < 0.01). Tumor size was significantly reduced (nearly half) in the LV-sh-ANXA9 group relative to the LV-NC group in the xenograft model (p < 0.01), suggesting that ANXA9 silencing repressed tumor progression in BCA progression in vitro and in vivo. In conclusion, exosome-derived ANXA9 functions as an oncogene that facilitates the proliferation, migration, and invasiveness of BCA cells and enhances tumor growth in BCA development, which may provide a new prognostic and therapeutic biomarker for BCA patients.
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Affiliation(s)
- Cuiping Lu
- Department of Medical OncologyLongyan First Affiliated Hospital of Fujian Medical UniversityLongyanFujianPR China
| | - Ying Zhan
- Department of Medical OncologyLongyan First Affiliated Hospital of Fujian Medical UniversityLongyanFujianPR China
| | - Yunshan Jiang
- Department of Medical OncologyLongyan First Affiliated Hospital of Fujian Medical UniversityLongyanFujianPR China
| | - Jianrong Liao
- Department of Medical OncologyLongyan First Affiliated Hospital of Fujian Medical UniversityLongyanFujianPR China
| | - Zidan Qiu
- Department of Medical OncologyLongyan First Affiliated Hospital of Fujian Medical UniversityLongyanFujianPR China
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Pejchinovski I, Turkkan S, Pejchinovski M. Recent Advances of Proteomics in Management of Acute Kidney Injury. Diagnostics (Basel) 2023; 13:2648. [PMID: 37627907 PMCID: PMC10453063 DOI: 10.3390/diagnostics13162648] [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: 06/28/2023] [Revised: 07/31/2023] [Accepted: 08/03/2023] [Indexed: 08/27/2023] Open
Abstract
Acute Kidney Injury (AKI) is currently recognized as a life-threatening disease, leading to an exponential increase in morbidity and mortality worldwide. At present, AKI is characterized by a significant increase in serum creatinine (SCr) levels, typically followed by a sudden drop in glomerulus filtration rate (GFR). Changes in urine output are usually associated with the renal inability to excrete urea and other nitrogenous waste products, causing extracellular volume and electrolyte imbalances. Several molecular mechanisms were proposed to be affiliated with AKI development and progression, ultimately involving renal epithelium tubular cell-cycle arrest, inflammation, mitochondrial dysfunction, the inability to recover and regenerate proximal tubules, and impaired endothelial function. Diagnosis and prognosis using state-of-the-art clinical markers are often late and provide poor outcomes at disease onset. Inappropriate clinical assessment is a strong disease contributor, actively driving progression towards end stage renal disease (ESRD). Proteins, as the main functional and structural unit of the cell, provide the opportunity to monitor the disease on a molecular level. Changes in the proteomic profiles are pivotal for the expression of molecular pathways and disease pathogenesis. Introduction of highly-sensitive and innovative technology enabled the discovery of novel biomarkers for improved risk stratification, better and more cost-effective medical care for the ill patients and advanced personalized medicine. In line with those strategies, this review provides and discusses the latest findings of proteomic-based biomarkers and their prospective clinical application for AKI management.
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Affiliation(s)
- Ilinka Pejchinovski
- Department of Quality Assurance, Nikkiso Europe GmbH, 30885 Langenhagen, Germany; (I.P.); (S.T.)
| | - Sibel Turkkan
- Department of Quality Assurance, Nikkiso Europe GmbH, 30885 Langenhagen, Germany; (I.P.); (S.T.)
| | - Martin Pejchinovski
- Department of Analytical Instruments Group, Thermo Fisher Scientific, 82110 Germering, Germany
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Ferreira AAG, Desplan C. An Atlas of the Developing Drosophila Visual System Glia and Subcellular mRNA Localization of Transcripts in Single Cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.06.552169. [PMID: 37609218 PMCID: PMC10441313 DOI: 10.1101/2023.08.06.552169] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/24/2023]
Abstract
Glial cells are essential for proper nervous system development and function. To understand glial development and function, we comprehensively annotated glial cells in a single-cell mRNA-sequencing (scRNAseq) atlas of the developing Drosophila visual system. This allowed us to study their developmental trajectories, from larval to adult stages, and to understand how specific types of glia diversify during development. For example, neuropil glia that are initially transcriptionally similar in larvae, split into ensheathing and astrocyte-like glia during pupal stages. Other glial types, such as chiasm glia change gradually during development without splitting into two cell types. The analysis of scRNA-seq allowed us to discover that the transcriptome of glial cell bodies can be distinguished from that of their broken processes. The processes contain distinct enriched mRNAs that were validated in vivo. Therefore, we have identified most glial types in the developing optic lobe and devised a computational approach to identify mRNA species that are localized to cell bodies or cellular processes.
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Affiliation(s)
| | - Claude Desplan
- Department of Biology, New York University, New York, NY, USA
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Su Q, Baker L, Emery S, Balan B, Ansell B, Tichkule S, Mueller I, Svärd SG, Jex A. Transcriptomic analysis of albendazole resistance in human diarrheal parasite Giardia duodenalis. INTERNATIONAL JOURNAL FOR PARASITOLOGY: DRUGS AND DRUG RESISTANCE 2023; 22:9-19. [PMID: 37004489 PMCID: PMC10111952 DOI: 10.1016/j.ijpddr.2023.03.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 03/09/2023] [Accepted: 03/21/2023] [Indexed: 04/03/2023]
Abstract
Benzimidazole-2-carbamates (BZ, e.g., albendazole; ALB), which bind β-tubulin to disrupt microtubule polymerization, are one of two primary compound classes used to treat giardiasis. In most parasitic nematodes and fungi, BZ-resistance is caused by β-tubulin mutations and its molecular mode of action (MOA) is well studied. In contrast, in Giardia duodenalis BZ MOA or resistance is less well understood, may involve target-specific and broader impacts including cellular damage and oxidative stress, and its underlying cause is not clearly determined. Previously, we identified acquisition of a single nucleotide polymorphism, E198K, in β-tubulin in ALB-resistant (ALB-R) G. duodenalis WB-1B relative to ALB-sensitive (ALB-S) parental controls. E198K is linked to BZ-resistance in fungi and its allelic frequency correlated with the magnitude of BZ-resistance in G. duodenalis WB-1B. Here, we undertook detailed transcriptomic comparisons of these ALB-S and ALB-R G. duodenalis WB-1B cultures. The primary transcriptional changes with ALB-R in G. duodenalis WB-1B indicated increased protein degradation and turnover, and up-regulation of tubulin, and related genes, associated with the adhesive disc and basal bodies. These findings are consistent with previous observations noting focused disintegration of the disc and associated structures in Giardia duodenalis upon ALB exposure. We also saw transcriptional changes with ALB-R in G. duodenalis WB-1B consistent with prior observations of a shift from glycolysis to arginine metabolism for ATP production and possible changes to aspects of the vesicular trafficking system that require further investigation. Finally, we saw mixed transcriptional changes associated with DNA repair and oxidative stress responses in the G. duodenalis WB-1B line. These changes may be indicative of a role for H2O2 degradation in ALB-R, as has been observed in other G. duodenalis cell cultures. However, they were below the transcriptional fold-change threshold (log2FC > 1) typically employed in transcriptomic analyses and appear to be contradicted in ALB-R G. duodenalis WB-1B by down-regulation of the NAD scavenging and conversion pathways required to support these stress pathways and up-regulation of many highly oxidation sensitive iron-sulphur (FeS) cluster based metabolic enzymes.
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Stephani L, Rahayu P, Retnoningrum D, Suhartono MT, Rachmawati H, Tjandrawinata RR. Purification and proteomic analysis of potent fibrinolytic enzymes extracted from Lumbricus rubellus. Proteome Sci 2023; 21:8. [PMID: 37158880 PMCID: PMC10165752 DOI: 10.1186/s12953-023-00206-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 04/16/2023] [Indexed: 05/10/2023] Open
Abstract
BACKGROUND Lumbrokinase derived from earthworms, Lumbricus rubellus is known to have fibrinolytic enzymes that have potential as therapeutic drugs due to its ability to dissolve fibrin. The current study is aimed to purify the Lumbrokinase from L. rubellus and identify its protein component. METHODS Water extract of local earthworm Lumbricus rubellus revealed several proteins. Therefore, to identify its protein component, purification through HiPrep DEAE fast flow and proteomic analysis were conducted prior to identifications. A combination of two-dimension gel electrophoresis (2DE) and electrospray ionization mass spectrometry analysis was used to identify the purified fractions. RESULTS The purified fractions contain five protein bands, namely F25-1, F25-2, F85-1, F85-2, and F85-3, which displayed strong fibrinogenolytic activity. F25 fractions showed fibrinogenolytic activity of 974.85 U/mg, while F85 fractions showed higher activity of 1,484.11 U/mg. Fractions F85-1, F85-2, and F85-3 showed molecular weights of 42.6 kDa, 27.03 kDa, and 14 kDa, respectively and were identified as Lumbrokinase iso-enzymes. CONCLUSION This preliminary study indicates that the F25 and F85 fractions are similar to published fibrinolytic protease-1 and lumbrokinase, respectively, in terms of their amino acid sequence.
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Affiliation(s)
- Laurentia Stephani
- Biopharmaceutical Technology Division, Research Innovation and Invention, Dexa Laboratories of Biomolecular Sciences, PT Dexa Medica, Kawasan Industri Jababeka II, Industri Selatan V Block PP No. 7, Cikarang, 17550, Indonesia
| | - Puji Rahayu
- Biopharmaceutical Technology Division, Research Innovation and Invention, Dexa Laboratories of Biomolecular Sciences, PT Dexa Medica, Kawasan Industri Jababeka II, Industri Selatan V Block PP No. 7, Cikarang, 17550, Indonesia
| | - Debbie Retnoningrum
- Research Group of Pharmaceutics, School of Pharmacy, Bandung Institute of Technology, Bandung, Indonesia
| | - Maggy Thenawidjaja Suhartono
- Department of Food Science and Technology, Bogor Agricultural University, Fateta Building, Kampus IPB Darmaga, Bogor, Indonesia
| | - Heni Rachmawati
- Research Group of Pharmaceutics, School of Pharmacy, Bandung Institute of Technology, Bandung, Indonesia
| | - Raymond R Tjandrawinata
- Biopharmaceutical Technology Division, Research Innovation and Invention, Dexa Laboratories of Biomolecular Sciences, PT Dexa Medica, Kawasan Industri Jababeka II, Industri Selatan V Block PP No. 7, Cikarang, 17550, Indonesia.
- Faculty of Biotechnology, Atma Jaya Catholic University of Indonesia, Jalan Raya Cisauk-Lapan No. 10, Tangerang, 15345, Indonesia.
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Arcanjo C, Frelon S, Armant O, Camoin L, Audebert S, Camilleri V, Cavalié I, Adam-Guillermin C, Gagnaire B. Insights into the modes of action of tritium on the early-life stages of zebrafish, Danio rerio, using transcriptomic and proteomic analyses. JOURNAL OF ENVIRONMENTAL RADIOACTIVITY 2023; 261:107141. [PMID: 36878054 DOI: 10.1016/j.jenvrad.2023.107141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 01/29/2023] [Accepted: 02/17/2023] [Indexed: 06/18/2023]
Abstract
In the environment, populations are exposed to different kinds of ionizing radiation. Little is known about their modes of action on non-human species, and whether or not they are similar for alpha, beta and gamma radiations, considered as the reference. In this context, tritium effects (beta emitter) under the form of tritiated water (HTO) were investigated in zebrafish, a common model in toxicology and ecotoxicology with a fully sequenced genome. Experiments were conducted on early life stages, considered to be highly sensitive to pollutants, by exposing eggs to 0.4 mGy/h of HTO until 10 days post fertilization. Tritium internalization was quantified, and effects were investigated using a combined approach of transcriptomic and proteomic analyses. Results highlighted similarities in the biological pathways affected by HTO by both techniques, such as defence response, muscle integrity and contraction, and potential visual alterations. These results correlated well with previous data obtained on earlier developmental stages (1 and 4 dpf). Interestingly, HTO effects were partly overlapping those obtained after gamma irradiation, underlying potential common modes of action. This study, therefore, brought a body of evidence on the effects of HTO observed at the molecular level on zebrafish larvae. Further studies could investigate if the effects persist in adult organisms.
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Affiliation(s)
- Caroline Arcanjo
- Institut de Radioprotection et de Sureté Nucléaire (IRSN), PSE-ENV/SRTE/LECO, Cadarache, Saint-Paul-lez-Durance, 13115, France
| | - Sandrine Frelon
- Institut de Radioprotection et de Sureté Nucléaire (IRSN), PSE-ENV/SRTE/LECO, Cadarache, Saint-Paul-lez-Durance, 13115, France
| | - Olivier Armant
- Institut de Radioprotection et de Sureté Nucléaire (IRSN), PSE-ENV/SRTE/LECO, Cadarache, Saint-Paul-lez-Durance, 13115, France
| | - Luc Camoin
- Aix-Marseille Univ., CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille Proteomics, Marseille, France
| | - Stéphane Audebert
- Aix-Marseille Univ., CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille Proteomics, Marseille, France
| | - Virginie Camilleri
- Institut de Radioprotection et de Sureté Nucléaire (IRSN), PSE-ENV/SRTE/LECO, Cadarache, Saint-Paul-lez-Durance, 13115, France
| | - Isabelle Cavalié
- Institut de Radioprotection et de Sureté Nucléaire (IRSN), PSE-ENV/SRTE/LECO, Cadarache, Saint-Paul-lez-Durance, 13115, France
| | - Christelle Adam-Guillermin
- Institut de Radioprotection et de Sureté Nucléaire (IRSN), PSE-SANTE/SDOS/LMDN, Cadarache, Saint-Paul-lez-Durance, 13115, France
| | - Beatrice Gagnaire
- Institut de Radioprotection et de Sureté Nucléaire (IRSN), PSE-ENV/SRTE/LECO, Cadarache, Saint-Paul-lez-Durance, 13115, France.
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Li J, Wang L, Zhang X, Wen X, Wei X, Qin Q, Wang S. Grouper annexin A2 affects RGNNV by regulating the host immune response. FISH & SHELLFISH IMMUNOLOGY 2023; 137:108771. [PMID: 37100308 DOI: 10.1016/j.fsi.2023.108771] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Revised: 04/07/2023] [Accepted: 04/24/2023] [Indexed: 05/07/2023]
Abstract
Annexin A2 (AnxA2) is ubiquitous in vertebrates and has been identified as a multifunctional protein participating in a series of biological processes, such as endocytosis, exocytosis, signal transduction, transcription regulation, and immune responses. However, the function of AnxA2 in fish during virus infection still remains unknown. In this study, we identified and characterized AnxA2 (EcAnxA2) in Epinephelus coioides. EcAnxA2 encoded a 338 amino acids protein with four identical annexin superfamily conserved domains, which shared high identity with other AnxA2 of different species. EcAnxA2 was widely expressed in different tissues of healthy groupers, and its expression was significantly increased in grouper spleen cells infected with red-spotted grouper nervous necrosis virus (RGNNV). Subcellular locatio n analyses showed that EcAnxA2 diffusely distributed in the cytoplasm. After RGNNV infection, the spatial distribution of EcAnxA2 was unaltered, and a few EcAnxA2 co-localized with RGNNV during the late stage of infection. Furthermore, overexpression of EcAnxA2 significantly increased RGNNV infection, and knockdown of EcAnxA2 reduced RGNNV infection. In addition, overexpressed EcAnxA2 reduced the transcription of interferon (IFN)-related and inflammatory factors, including IFN regulatory factor 7 (IRF7), IFN stimulating gene 15 (ISG15), melanoma differentiation related gene 5 (MDA5), MAX interactor 1 (Mxi1) laboratory of genetics and physiology 2 (LGP2), IFN induced 35 kDa protein (IFP35), tumor necrosis factor receptor-associated factor 6 (TRAF6) and interleukin 6 (IL-6). The transcription of these genes was up-regulated when EcAnxA2 was inhibited by siRNA. Taken together, our results showed that EcAnxA2 affected RGNNV infection by down-regulating the host immune response in groupers, which provided new insights into the roles of AnxA2 in fish during virus infection.
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Affiliation(s)
- Junrong Li
- Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, China
| | - Liqun Wang
- Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, China
| | - Xinyue Zhang
- Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, China
| | - Xiaozhi Wen
- Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, China
| | - Xinyan Wei
- Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, China
| | - Qiwei Qin
- Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, 510642, China; Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266000, China.
| | - Shaowen Wang
- Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, China.
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Bhar A, Chakraborty A, Roy A. The captivating role of calcium in plant-microbe interaction. FRONTIERS IN PLANT SCIENCE 2023; 14:1138252. [PMID: 36938033 PMCID: PMC10020633 DOI: 10.3389/fpls.2023.1138252] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 02/16/2023] [Indexed: 06/18/2023]
Abstract
Plant immune response is fascinating due to the complete absence of a humoral system. The adaptive immune response in plants relies on the intracellular orchestration of signalling molecules or intermediates associated with transcriptional reprogramming. Plant disease response phenomena largely depend on pathogen recognition, signal perception, and intracellular signal transduction. The pathogens possess specific pathogen-associated molecular patterns (PAMP) or microbe-associated molecular patterns (MAMP), which are first identified by pattern recognition receptors (PRRs) of host plants for successful infection. After successful pathogen recognition, the defence response is initiated within plants. The first line of non-specific defence response is called PAMP-triggered immunity (PTI), followed by the specific robust signalling is called effector-triggered immunity (ETI). Calcium plays a crucial role in both PTI and ETI. The biphasic induction of reactive oxygen species (ROS) is inevitable in any plant-microbe interaction. Calcium ions play crucial roles in the initial oxidative burst and ROS induction. Different pathogens can induce calcium accumulation in the cytosol ([Ca2+]Cyt), called calcium signatures. These calcium signatures further control the diverse defence-responsive proteins in the intracellular milieu. These calcium signatures then activate calcium-dependent protein kinases (CDPKs), calcium calmodulins (CaMs), calcineurin B-like proteins (CBLs), etc., to impart intricate defence signalling within the cell. Decoding this calcium ionic map is imperative to unveil any plant microbe interplay and modulate defence-responsive pathways. Hence, the present review is unique in developing concepts of calcium signature in plants and their subsequent decoding mechanism. This review also intends to articulate early sensing of calcium oscillation, signalling events, and comprehensive mechanistic roles of calcium within plants during pathogenic ingression. This will accumulate and summarize the exciting roles of calcium ions in plant immunity and provide the foundation for future research.
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Affiliation(s)
- Anirban Bhar
- Post Graduate Department of Botany, Ramakrishna Mission Vivekananda Centenary College, Kolkata, India
| | - Amrita Chakraborty
- Faculty of Forestry and Wood Sciences, Czech University of Life Sciences, Prague, Czech Republic
| | - Amit Roy
- Faculty of Forestry and Wood Sciences, Czech University of Life Sciences, Prague, Czech Republic
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Abo Al Hayja M, Kullberg S, Eklund A, Padyukov L, Grunewald J, Rivera NV. Functional link between sarcoidosis-associated gene variants and quantitative levels of bronchoalveolar lavage fluid cell types. Front Med (Lausanne) 2023; 10:1061654. [PMID: 36824606 PMCID: PMC9941743 DOI: 10.3389/fmed.2023.1061654] [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: 10/04/2022] [Accepted: 01/11/2023] [Indexed: 02/09/2023] Open
Abstract
Background Sarcoidosis is an inflammatory disease that affects multiple organs. Cell analysis from bronchoalveolar lavage fluid (BALF) is a valuable tool in the diagnostic workup and differential diagnosis of sarcoidosis. Besides the expansion of lymphocyte expression-specific receptor segments (Vα2.3 and Vβ22) in some patients with certain HLA types, the relation between sarcoidosis susceptibility and BAL cell populations' quantitative levels is not well-understood. Methods Quantitative levels defined by cell concentrations of BAL cells and CD4+/CD8+ ratio were evaluated together with genetic variants associated with sarcoidosis in 692 patients with extensive clinical data. Genetic variants associated with clinical phenotypes, Löfgren's syndrome (LS) and non-Löfgren's syndrome (non-LS), were examined separately. An association test via linear regression using an additive model adjusted for sex, age, and correlated cell type was applied. To infer the biological function of genetic associations, enrichment analysis of expression quantitative trait (eQTLs) across publicly available eQTL databases was conducted. Results Multiple genetic variants associated with sarcoidosis were significantly associated with quantitative levels of BAL cells. Specifically, LS genetic variants, mainly from the HLA locus, were associated with quantitative levels of BAL macrophages, lymphocytes, CD3+ cells, CD4+ cells, CD8+ cells, CD4+/CD8+ ratio, neutrophils, basophils, and eosinophils. Non-LS genetic variants were associated with quantitative levels of BAL macrophages, CD8+ cells, basophils, and eosinophils. eQTL enrichment revealed an influence of sarcoidosis-associated SNPs and regulation of gene expression in the lung, blood, and immune cells. Conclusion Genetic variants associated with sarcoidosis are likely to modulate quantitative levels of BAL cell types and may regulate gene expression in immune cell populations. Thus, the role of sarcoidosis-associated gene-variants may be to influence cellular phenotypes underlying the disease immunopathology.
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Affiliation(s)
- Muntasir Abo Al Hayja
- Division of Respiratory Medicine, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Susanna Kullberg
- Division of Respiratory Medicine, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Anders Eklund
- Division of Respiratory Medicine, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Leonid Padyukov
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden,Center of Molecular Medicine (CMM), Karolinska Institutet, Stockholm, Sweden
| | - Johan Grunewald
- Division of Respiratory Medicine, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden,Center of Molecular Medicine (CMM), Karolinska Institutet, Stockholm, Sweden
| | - Natalia V. Rivera
- Division of Respiratory Medicine, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden,Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden,Center of Molecular Medicine (CMM), Karolinska Institutet, Stockholm, Sweden,*Correspondence: Natalia V. Rivera, ✉
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Lotfollahi M, Rybakov S, Hrovatin K, Hediyeh-Zadeh S, Talavera-López C, Misharin AV, Theis FJ. Biologically informed deep learning to query gene programs in single-cell atlases. Nat Cell Biol 2023; 25:337-350. [PMID: 36732632 PMCID: PMC9928587 DOI: 10.1038/s41556-022-01072-x] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 12/08/2022] [Indexed: 02/04/2023]
Abstract
The increasing availability of large-scale single-cell atlases has enabled the detailed description of cell states. In parallel, advances in deep learning allow rapid analysis of newly generated query datasets by mapping them into reference atlases. However, existing data transformations learned to map query data are not easily explainable using biologically known concepts such as genes or pathways. Here we propose expiMap, a biologically informed deep-learning architecture that enables single-cell reference mapping. ExpiMap learns to map cells into biologically understandable components representing known 'gene programs'. The activity of each cell for a gene program is learned while simultaneously refining them and learning de novo programs. We show that expiMap compares favourably to existing methods while bringing an additional layer of interpretability to integrative single-cell analysis. Furthermore, we demonstrate its applicability to analyse single-cell perturbation responses in different tissues and species and resolve responses of patients who have coronavirus disease 2019 to different treatments across cell types.
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Affiliation(s)
- Mohammad Lotfollahi
- Institute of Computational Biology, Helmholtz Center Munich, Munich, Germany
- Wellcome Sanger Institute, Cambridge, UK
| | - Sergei Rybakov
- Institute of Computational Biology, Helmholtz Center Munich, Munich, Germany
- Department of Mathematics, Technical University of Munich, Munich, Germany
| | - Karin Hrovatin
- Institute of Computational Biology, Helmholtz Center Munich, Munich, Germany
- TUM School of Life Sciences Weihenstephan, Technical University of Munich, Munich, Germany
| | - Soroor Hediyeh-Zadeh
- Institute of Computational Biology, Helmholtz Center Munich, Munich, Germany
- Bioinformatics Division, WEHI, Melbourne, Victoria, Australia
| | - Carlos Talavera-López
- Institute of Computational Biology, Helmholtz Center Munich, Munich, Germany
- Division of Infectious Diseases and Tropical Medicine, Ludwig-Maximilian-Universität Klinikum, Munich, Germany
| | - Alexander V Misharin
- Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Fabian J Theis
- Institute of Computational Biology, Helmholtz Center Munich, Munich, Germany.
- Wellcome Sanger Institute, Cambridge, UK.
- Department of Mathematics, Technical University of Munich, Munich, Germany.
- TUM School of Life Sciences Weihenstephan, Technical University of Munich, Munich, Germany.
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Zhang X, Xing M, Ma Y, Zhang Z, Qiu C, Wang X, Zhao Z, Ji Z, Zhang JY. Oridonin Induces Apoptosis in Esophageal Squamous Cell Carcinoma by Inhibiting Cytoskeletal Protein LASP1 and PDLIM1. Molecules 2023; 28:805. [PMID: 36677861 PMCID: PMC9862004 DOI: 10.3390/molecules28020805] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2022] [Revised: 01/07/2023] [Accepted: 01/09/2023] [Indexed: 01/15/2023] Open
Abstract
Esophageal squamous cell carcinoma is a severe malignancy for its high mortality and poor prognosis. Mainstay chemotherapies cause serious side effects for their ways of inducing cell death. Oridonin is the main bioactive constituent from natural plants that has anticancer ability and weak side effects. The proteomics method is efficient to understand the anticancer mechanism. However, proteins identified by proteomics aimed at understanding oridonin's anticancer mechanism is seldom overlapped by different groups. This study used proteomics based on two-dimensional electrophoresis sodium dodecyl sulfate-polyacrylamide gel electrophoresis (2-DE SDS-PAGE) integrated with mass spectrometry and Gene Set Enrichment Analysis (GSEA) to understand the anticancer mechanism of oridonin on esophageal squamous cell carcinoma (ESCC). The results showed that oridonin induced ESCC cell death via apoptosis by decreasing the protein expression of LASP1 and PDLIM1.
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Affiliation(s)
- Xiaojun Zhang
- Department of Biological Sciences & Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX 79968, USA
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, China
| | - Mengtao Xing
- Department of Biological Sciences & Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX 79968, USA
| | - Yangcheng Ma
- Department of Biological Sciences & Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX 79968, USA
| | - Zhuangli Zhang
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, China
| | - Cuipeng Qiu
- Department of Biological Sciences & Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX 79968, USA
| | - Xiao Wang
- Department of Biological Sciences & Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX 79968, USA
| | - Zhihong Zhao
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, China
| | - Zhenyu Ji
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, China
| | - Jian-Ying Zhang
- Department of Biological Sciences & Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX 79968, USA
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Jayaswamy PK, Vijaykrishnaraj M, Patil P, Alexander LM, Kellarai A, Shetty P. Implicative role of epidermal growth factor receptor and its associated signaling partners in the pathogenesis of Alzheimer's disease. Ageing Res Rev 2023; 83:101791. [PMID: 36403890 DOI: 10.1016/j.arr.2022.101791] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 11/12/2022] [Accepted: 11/13/2022] [Indexed: 11/18/2022]
Abstract
Epidermal growth factor receptor (EGFR) plays a pivotal role in early brain development, although its expression pattern declines in accordance with the maturation of the active nervous system. However, recurrence of EGFR expression in brain cells takes place during neural functioning decline and brain atrophy in order to maintain the homeostatic neuronal pool. As a consequence, neurotoxic lesions such as amyloid beta fragment (Aβ1-42) formed during the alternative splicing of amyloid precursor protein in Alzheimer's disease (AD) elevate the expression of EGFR. This inappropriate peptide deposition on EGFR results in the sustained phosphorylation of the downstream signaling axis, leading to extensive Aβ1-42 production and tau phosphorylation as subsequent pathogenesis. Recent reports convey that the pathophysiology of AD is correlated with EGFR and its associated membrane receptor complex molecules. One such family of molecules is the annexin superfamily, which has synergistic relationships with EGFR and is known for membrane-bound signaling that contributes to a variety of inflammatory responses. Besides, Galectin-3, tissue-type activated plasminogen activator, and many more, which lineate the secretion of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-18) result in severe neuronal loss. Altogether, we emphasized the perspectives of cellular senescence up-regulated by EGFR and its associated membrane receptor molecules in the pathogenesis of AD as a target for a therapeutical alternative to intervene in AD.
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Affiliation(s)
- Pavan K Jayaswamy
- Central Research Laboratory, KS. Hegde Medical Academy, Nitte (Deemed to be University), Deralakatte, Mangalore 575018, Karnataka, India
| | - M Vijaykrishnaraj
- Central Research Laboratory, KS. Hegde Medical Academy, Nitte (Deemed to be University), Deralakatte, Mangalore 575018, Karnataka, India
| | - Prakash Patil
- Central Research Laboratory, KS. Hegde Medical Academy, Nitte (Deemed to be University), Deralakatte, Mangalore 575018, Karnataka, India
| | - Lobo Manuel Alexander
- Department of Neurology, KS. Hegde Medical Academy, Nitte (Deemed to be University), Deralakatte, Mangalore 575018, Karnataka, India
| | - Adithi Kellarai
- Department of General Medicine, KS. Hegde Medical Academy, Nitte (Deemed to be University), Deralakatte, Mangalore 575018, Karnataka, India
| | - Praveenkumar Shetty
- Central Research Laboratory, KS. Hegde Medical Academy, Nitte (Deemed to be University), Deralakatte, Mangalore 575018, Karnataka, India; Department of Biochemistry, K.S. Hegde Medical Academy, Nitte (Deemed to be University), Deralakatte, Mangalore 575018, Karnataka, India.
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35
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Zhao M, Shao F, Yu D, Zhang J, Liu Z, Ma J, Xia P, Wang S. Maturation and specialization of group 2 innate lymphoid cells through the lung-gut axis. Nat Commun 2022; 13:7600. [PMID: 36494354 PMCID: PMC9734379 DOI: 10.1038/s41467-022-35347-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 11/29/2022] [Indexed: 12/13/2022] Open
Abstract
Innate lymphoid cells (ILC) are abundant in mucosal tissues. They serve critical functions in anti-pathogen response and tissue homeostasis. However, the heterogenous composition of ILCs in mucosal sites and their various maturation trajectories are less well known. In this study, we characterize ILC types and functions from both the lung and the small intestine, and identify their tissue-specific markers. We find that ILC2s residing in the lung express CCR2, whereas intestinal ILC2s express CCR4. Through the use of CCR2 and CCR4 reporter mice, we show that ILC2s undergo translocation via the lung-gut axis upon IL-33 treatment. This trajectory of ILC2s is also observed at the postnatal stage. Allergen-induced activation of lung ILC2s affects the homeostasis of gut ILC2s. Together, our findings implicate that ILCs display tissue-specific features in both the lung and gut, and ILC2s mature along the lung-gut axis in particular homeostatic and inflammatory conditions.
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Affiliation(s)
- Min Zhao
- grid.9227.e0000000119573309CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, 100101 Beijing, China
| | - Fei Shao
- grid.9227.e0000000119573309CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, 100101 Beijing, China ,grid.410726.60000 0004 1797 8419University of Chinese Academy of Sciences, Beijing, 100049 China
| | - Dou Yu
- grid.9227.e0000000119573309CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, 100101 Beijing, China ,grid.410726.60000 0004 1797 8419University of Chinese Academy of Sciences, Beijing, 100049 China
| | - Jiaqi Zhang
- grid.9227.e0000000119573309CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, 100101 Beijing, China ,grid.410726.60000 0004 1797 8419University of Chinese Academy of Sciences, Beijing, 100049 China
| | - Zhen Liu
- grid.9227.e0000000119573309CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, 100101 Beijing, China ,grid.410726.60000 0004 1797 8419University of Chinese Academy of Sciences, Beijing, 100049 China
| | - Jiangwen Ma
- grid.9227.e0000000119573309CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, 100101 Beijing, China ,grid.410726.60000 0004 1797 8419University of Chinese Academy of Sciences, Beijing, 100049 China
| | - Pengyan Xia
- grid.11135.370000 0001 2256 9319Department of Immunology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Peking University, Beijing, China
| | - Shuo Wang
- grid.9227.e0000000119573309CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, 100101 Beijing, China ,grid.410726.60000 0004 1797 8419University of Chinese Academy of Sciences, Beijing, 100049 China
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36
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Proteomic Profiling of Intra-Islet Features Reveals Substructure-Specific Protein Signatures. Mol Cell Proteomics 2022; 21:100426. [PMID: 36244662 PMCID: PMC9706166 DOI: 10.1016/j.mcpro.2022.100426] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 08/30/2022] [Accepted: 09/04/2022] [Indexed: 11/11/2022] Open
Abstract
Despite their diminutive size, islets of Langerhans play a large role in maintaining systemic energy balance in the body. New technologies have enabled us to go from studying the whole pancreas to isolated whole islets, to partial islet sections, and now to islet substructures isolated from within the islet. Using a microfluidic nanodroplet-based proteomics platform coupled with laser capture microdissection and field asymmetric waveform ion mobility spectrometry, we present an in-depth investigation of protein profiles specific to features within the islet. These features include the islet-acinar interface vascular tissue, inner islet vasculature, isolated endocrine cells, whole islet with vasculature, and acinar tissue from around the islet. Compared to interface vasculature, unique protein signatures observed in the inner vasculature indicate increased innervation and intra-islet neuron-like crosstalk. We also demonstrate the utility of these data for identifying localized structure-specific drug-target interactions using existing protein/drug binding databases.
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37
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Peck AB, Ambrus JL. A Temporal Comparative RNA Transcriptome Profile of the Annexin Gene Family in the Salivary versus Lacrimal Glands of the Sjögren's Syndrome-Susceptible C57BL/6.NOD- Aec1Aec2 Mouse. Int J Mol Sci 2022; 23:11709. [PMID: 36233010 PMCID: PMC9570365 DOI: 10.3390/ijms231911709] [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: 08/17/2022] [Revised: 09/29/2022] [Accepted: 09/29/2022] [Indexed: 11/29/2022] Open
Abstract
A generally accepted hypothesis for the initial activation of an immune or autoimmune response argues that alarmins are released from injured, dying and/or activated immune cells, and these products complex with receptors that activate signal transduction pathways and recruit immune cells to the site of injury where the recruited cells are stimulated to initiate immune and/or cellular repair responses. While there are multiple diverse families of alarmins such as interleukins (IL), heat-shock proteins (HSP), Toll-like receptors (TLR), plus individual molecular entities such as Galectin-3, Calreticulin, Thymosin, alpha-Defensin-1, RAGE, and Interferon-1, one phylogenetically conserved family are the Annexin proteins known to promote an extensive range of biomolecular and cellular products that can directly and indirectly regulate inflammation and immune activities. For the present report, we examined the temporal expression profiles of the 12 mammalian annexin genes (Anxa1-11 and Anxa13), applying our temporal genome-wide transcriptome analyses of ex vivo salivary and lacrimal glands from our C57BL/6.NOD-Aec1Aec2 mouse model of Sjögren's Syndrome (SS), a human autoimmune disease characterized primarily by severe dry mouth and dry eye symptoms. Results indicate that annexin genes Anax1-7 and -11 exhibited upregulated expressions and the initial timing for these upregulations occurred as early as 8 weeks of age and prior to any covert signs of a SS-like disease. While the profiles of the two glands were similar, they were not identical, suggesting the possibility that the SS-like disease may not be uniform in the two glands. Nevertheless, this early pre-clinical and concomitant upregulated expression of this specific set of alarmins within the immune-targeted organs represents a potential target for identifying the pre-clinical stage in human SS as well, a fact that would clearly impact future interventions and therapeutic strategies.
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Affiliation(s)
- Ammon B Peck
- Department of Infectious Diseases and Immunology, College of Veterinary Medicine, University of Florida, P.O. Box 100125, Gainesville, FL 32610, USA
| | - Julian L Ambrus
- Division of Allergy, Immunology and Rheumatology, SUNY Buffalo School of Medicine, 875 Ellicott Street, Buffalo, NY 14203, USA
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38
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Prieto-Fernández L, Menéndez ST, Otero-Rosales M, Montoro-Jiménez I, Hermida-Prado F, García-Pedrero JM, Álvarez-Teijeiro S. Pathobiological functions and clinical implications of annexin dysregulation in human cancers. Front Cell Dev Biol 2022; 10:1009908. [PMID: 36247003 PMCID: PMC9554710 DOI: 10.3389/fcell.2022.1009908] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 08/29/2022] [Indexed: 11/13/2022] Open
Abstract
Annexins are an extensive superfamily of structurally related calcium- and phospholipid-binding proteins, largely conserved and widely distributed among species. Twelve human annexins have been identified, referred to as Annexin A1-13 (A12 remains as of yet unassigned), whose genes are spread throughout the genome on eight different chromosomes. According to their distinct tissue distribution and subcellular localization, annexins have been functionally implicated in a variety of biological processes relevant to both physiological and pathological conditions. Dysregulation of annexin expression patterns and functions has been revealed as a common feature in multiple cancers, thereby emerging as potential biomarkers and molecular targets for clinical application. Nevertheless, translation of this knowledge to the clinic requires in-depth functional and mechanistic characterization of dysregulated annexins for each individual cancer type, since each protein exhibits varying expression levels and phenotypic specificity depending on the tumor types. This review specifically and thoroughly examines the current knowledge on annexin dysfunctions in carcinogenesis. Hence, available data on expression levels, mechanism of action and pathophysiological effects of Annexin A1-13 among different cancers will be dissected, also further discussing future perspectives for potential applications as biomarkers for early diagnosis, prognosis and molecular-targeted therapies. Special attention is devoted to head and neck cancers (HNC), a complex and heterogeneous group of aggressive malignancies, often lately diagnosed, with high mortality, and scarce therapeutic options.
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Affiliation(s)
- Llara Prieto-Fernández
- Department of Otolaryngology, Hospital Universitario Central de Asturias and Instituto de Investigación Sanitaria Del Principado de Asturias (ISPA), Instituto Universitario de Oncología Del Principado de Asturias (IUOPA), University of Oviedo, Oviedo, Spain
- CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
| | - Sofía T. Menéndez
- Department of Otolaryngology, Hospital Universitario Central de Asturias and Instituto de Investigación Sanitaria Del Principado de Asturias (ISPA), Instituto Universitario de Oncología Del Principado de Asturias (IUOPA), University of Oviedo, Oviedo, Spain
- CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
| | - María Otero-Rosales
- Department of Otolaryngology, Hospital Universitario Central de Asturias and Instituto de Investigación Sanitaria Del Principado de Asturias (ISPA), Instituto Universitario de Oncología Del Principado de Asturias (IUOPA), University of Oviedo, Oviedo, Spain
| | - Irene Montoro-Jiménez
- Department of Otolaryngology, Hospital Universitario Central de Asturias and Instituto de Investigación Sanitaria Del Principado de Asturias (ISPA), Instituto Universitario de Oncología Del Principado de Asturias (IUOPA), University of Oviedo, Oviedo, Spain
- CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
| | - Francisco Hermida-Prado
- Department of Otolaryngology, Hospital Universitario Central de Asturias and Instituto de Investigación Sanitaria Del Principado de Asturias (ISPA), Instituto Universitario de Oncología Del Principado de Asturias (IUOPA), University of Oviedo, Oviedo, Spain
- CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
| | - Juana M. García-Pedrero
- Department of Otolaryngology, Hospital Universitario Central de Asturias and Instituto de Investigación Sanitaria Del Principado de Asturias (ISPA), Instituto Universitario de Oncología Del Principado de Asturias (IUOPA), University of Oviedo, Oviedo, Spain
- CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
| | - Saúl Álvarez-Teijeiro
- Department of Otolaryngology, Hospital Universitario Central de Asturias and Instituto de Investigación Sanitaria Del Principado de Asturias (ISPA), Instituto Universitario de Oncología Del Principado de Asturias (IUOPA), University of Oviedo, Oviedo, Spain
- CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
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Yang MH, Li WY, Wu CF, Lee YC, Chen AYN, Tyan YC, Chen YMA. Reversal of High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease by Metformin Combined with PGG, an Inducer of Glycine N-Methyltransferase. Int J Mol Sci 2022; 23:ijms231710072. [PMID: 36077467 PMCID: PMC9456083 DOI: 10.3390/ijms231710072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 08/27/2022] [Accepted: 08/29/2022] [Indexed: 11/16/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver-related morbidities and mortality, and no effective drug treatment currently exists. We aimed to develop a novel treatment strategy to induce the expression of glycine N-methyltransferase (GNMT), which is an important enzyme regulating S-adenosylmethionine metabolism whose expression is downregulated in patients with NAFLD. Because 1,2,3,4,6-pentagalloyl glucose (PGG) is a GNMT inducer, and metformin was shown to upregulate liver mitochondrial GNMT protein expression, the effect of PGG and metformin was evaluated. Biochemical analysis, histopathological examination, immunohistochemical staining, reverse transcription-quantitative PCR (RT-qPCR), Western blotting (WB), proteomic analysis and Seahorse XF Cell Mito Stress Test were performed. The high-fat diet (HFD)-induced NAFLD mice were treated with PGG and metformin. Combination of PGG and metformin nearly completely reversed weight gain, elevation of serum aminotransferases, and hepatic steatosis and steatohepatitis. In addition, the downregulated GNMT expression in liver tissues of HFD-induced NAFLD mice was restored. The GNMT expression was further confirmed by RT-qPCR and WB analysis using both in vitro and in vivo systems. In addition, PGG treatment was shown to increase oxygen consumption rate (OCR) maximum capacity in a dose-dependent manner, and was capable of rescuing the suppression of mitochondrial OCR induced by metformin. Proteomic analysis identified increased expression of glutathione S-transferase mu 4 (GSTM4), heat shock protein 72 (HSP72), pyruvate carboxylase (PYC) and 40S ribosomal protein S28 (RS28) in the metformin plus PGG treatment group. Our findings show that GNMT expression plays an important role in the pathogenesis of NAFLD, and combination of an inducer of GNMT and metformin can be of therapeutic potential for patients with NAFLD.
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Affiliation(s)
- Ming-Hui Yang
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan
- Center of General Education, Shu-Zen Junior College of Medicine and Management, Kaohsiung 821, Taiwan
| | - Wei-You Li
- Laboratory of Important Infectious Diseases and Cancer, Graduate Institute of Biomedical and Pharmacological Science, School of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan
| | - Ching-Fen Wu
- Department of Veterinary Medicine, National Chiayi University, Chiayi City 600, Taiwan
| | - Yi-Ching Lee
- Laboratory of Important Infectious Diseases and Cancer, Graduate Institute of Biomedical and Pharmacological Science, School of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan
| | - Allan Yi-Nan Chen
- School of Medicine, University of California, Davis, Sacramento, CA 95817, USA
| | - Yu-Chang Tyan
- Department of Medical Imaging and Radiological Sciences, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Nuclear Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
- Graduate Institute of Animal Vaccine Technology, College of Veterinary Medicine, National Pingtung University of Science and Technology, Pingtung 912, Taiwan
- School of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Research Center for Precision Environmental Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung 804, Taiwan
- Correspondence: (Y.-C.T.); (Y.-M.A.C.)
| | - Yi-Ming Arthur Chen
- Laboratory of Important Infectious Diseases and Cancer, Graduate Institute of Biomedical and Pharmacological Science, School of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli County 350, Taiwan
- Correspondence: (Y.-C.T.); (Y.-M.A.C.)
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Inhibitory role of Annexin A1 in pathological bone resorption and therapeutic implications in periprosthetic osteolysis. Nat Commun 2022; 13:3919. [PMID: 35798730 PMCID: PMC9262976 DOI: 10.1038/s41467-022-31646-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 06/20/2022] [Indexed: 12/26/2022] Open
Abstract
There is currently no therapy available for periprosthetic osteolysis, the most common cause of arthroplasty failure. Here, the role of AnxA1 in periprosthetic osteolysis and potential therapeutics were investigated. Reducing the expression of AnxA1 in calvarial tissue was found to be associated with increased osteolytic lesions and the osteolytic lesions induced by debris implantation were more severe in AnxA1-defecient mice than in wild-type mice. AnxA1 inhibits the differentiation of osteoclasts through suppressing NFκB signaling and promoting the PPAR-γ pathway. Administration of N-terminal-AnxA1 (Ac2-26 peptide) onto calvariae significantly reduced osteolytic lesions triggered by wear debris. These therapeutic effects were abrogated in mice that had received the PPAR-γ antagonist, suggesting that the AnxA1/PPAR-γ axis has an inhibitory role in osteolysis. The administration of Ac2–26 suppressed osteolysis induced by TNF-α and RANKL injections in mice. These findings indicate that AnxA1 is a potential therapeutic agent for the treatment of periprosthetic osteolysis. Periprosthetic osteolysis is a cause of arthroplasty failure without available therapies. Here the authors show that Annexin A1 (AnxA1) is involved in in periprosthetic osteolysis and exerts potential therapeutic effects through suppressing NFκB signaling and promoting the PPAR-γ pathway resulting in inhibition of inflammation and osteoclasts differentiation induced by wear debris.
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Zhao J, Chang L, Tu J, Sun B, Wei X. Evaluation of Annexins Family as Potential Biomarker for Predicting Progression and Prognosis in Clear Renal Cell Carcinoma. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2022; 2022:8748434. [PMID: 39290334 PMCID: PMC11407897 DOI: 10.1155/2022/8748434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Revised: 04/23/2022] [Accepted: 04/26/2022] [Indexed: 09/19/2024]
Abstract
Background Annexins family (ANXAs), as a Ca2+-dependent phospholipid-binding protein superfamily, participates in a wide variety of biological activities and has been reported to be dysregulated in numerous types of human cancers. Evidence from cell lines and human tissues indicates that ANAXs are involved in kidney clear renal cell carcinoma (KIRC) tumorigenesis. However, their prognostic value and expression pattern associated with KIRC remain to be elucidated. Methods We visited public databases, including ONCOMINE, Gene Expression Profiling Interactive Analysis (GEPIA), Kaplan-Meier plotter, cBioPortal, and GeneMANIA, to conduct comprehensive bioinformatics analysis and tried to detect basic relationships between each Annexins family member and KIRC. Results We found that the expression level of ANXA1/2/4/5/6/7/8/13 in clear renal cell carcinoma tissue was higher than that in the kidney tissue, while the expression level of ANXA3/9/11 in the former was lower than that in the latter. The expression level of ANXA7/8/13 is related to the stage of the tumour. Survival analysis using the Kaplan-Meier plotter database showed that a high transcription level of ANXA2/5/8/10 is related to a low overall survival rate (OS) in predicting KIRC patients. In contrast, high ANXA3/4/7/9/11/13 levels are associated with a high OS in these patients. Conclusions Our study implies that ANXA4/8/13 are potential targets of precision therapy for patients with KIRC and that ANXA2/5/8/10 are new biomarkers for the prognosis of KIRC.
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Affiliation(s)
- Jiyu Zhao
- Department of Urology, ChuiYangLiu Hospital Affiliated to Tsinghua University, 100021 Beijing, China
| | - Luchen Chang
- Department of Diagnostic and Therapeutic Ultrasonography, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, 300060 Tianjin, China
| | - Jianping Tu
- Department of Urology, The Third Hospital of Xiamen, 361199 Xiamen, Fujian, China
| | - Bei Sun
- Department of Outpatient Office, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, 300060 Tianjin, China
| | - Xi Wei
- Department of Diagnostic and Therapeutic Ultrasonography, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, 300060 Tianjin, China
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Yan Z, Cheng X, Wang T, Hong X, Shao G, Fu C. Therapeutic potential for targeting Annexin A1 in fibrotic diseases. Genes Dis 2022; 9:1493-1505. [PMID: 36157506 PMCID: PMC9485289 DOI: 10.1016/j.gendis.2022.05.038] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Accepted: 05/30/2022] [Indexed: 11/23/2022] Open
Abstract
Annexin A1, a well-known endogenous anti-inflammatory mediator, plays a critical role in a variety of pathological processes. Fibrosis is described by a failure of tissue regeneration and contributes to the development of many diseases. Accumulating evidence supports that Annexin A1 participates in the progression of tissue fibrosis. However, the fundamental mechanisms by which Annexin A1 regulates fibrosis remain elusive, and even the functions of Annexin A1 in fibrotic diseases are still paradoxical. This review focuses on the roles of Annexin A1 in the development of fibrosis of lung, liver, heart, and other tissues, with emphasis on the therapy potential of Annexin A1 in fibrosis, and presents future research interests and directions in fibrotic diseases.
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Annexin in Taenia crassiceps ORF Strain is Localized in the Osmoregulatory System. Acta Parasitol 2022; 67:827-834. [PMID: 35113341 DOI: 10.1007/s11686-022-00526-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 01/18/2022] [Indexed: 11/01/2022]
Abstract
PURPOSE Annexins are proteins with important roles in parasites, some of which are related to excretion-secretion processes, protein traffic, and microvesicle functionality. The participation of annexins in osmoregulation has been reported in tapeworms, including Taenia solium. This study aimed to investigate the localization and expression of annexin in cysticerci of Taenia crassiceps, used as a model of cysticercosis. METHODS We used an antibody made with a protein, previously employed on Schistosoma bovis, to detect annexin in T. crassiceps proteins extracts used Western blot assay. The histological distribution of annexin was studied with immunofluorescence and confocal microscopy. RESULTS The antibody against annexin recognized a band at a molecular weight of 40.9 kDa. The histological distribution of annexin showed that the protein is mainly localized in the tegument and the protonephridia ducts. CONCLUSION In our study, annexin was detected at a molecular weight similar to that described for Schistosoma bovis. In addition, its principal localization entailed structures of the osmoregulatory system one of the most important by the survival of the parasites. This confirms and solidifies previous reports concerning the role of annexins in T. crassiceps and this will be interesting by the development of new compounds against this protein.
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ANXA11 rs1049550 Associates with Löfgren’s Syndrome and Chronic Sarcoidosis Patients. Cells 2022; 11:cells11091557. [PMID: 35563867 PMCID: PMC9101321 DOI: 10.3390/cells11091557] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 04/19/2022] [Accepted: 04/26/2022] [Indexed: 02/04/2023] Open
Abstract
Sarcoidosis is an immune mediated granulomatous disease commonly affecting the lungs. Genome wide association studies identified many genomic regions that are shared among multiple immune mediated diseases. However, ANXA11 gene polymorphism rs1049550 is exclusively associated with sarcoidosis, making it a key gene of interest for sarcoidosis disease pathogenesis. However, sarcoidosis is a heterogeneous disease and contradictory findings for ANXA11 have been reported for disease phenotypes. We performed a case–control association study to investigate if ANXA11 associates with benign (Löfgren’s syndrome (LS)) or chronic sarcoidosis and performed a meta-analysis on previously reported findings. A total of 262 sarcoidosis patients, of which 149 had LS and 113 chronic sarcoidosis, and 363 controls were genotyped for rs1049550. Meta-analysis included allele findings for rs1049550 from 6 additional studies. We found a significantly lower T allele frequency in sarcoidosis patients than in healthy controls (0.30 vs. 0.41, respectively, odds ratio (OR) 0.61, 95% confidence interval (CI) 0.48–0.77, p = 3 × 10−5). In LS the T allele frequency of 0.33, and in chronic sarcoidosis the T allele frequency of 0.26 were significantly lower than in healthy controls (OR 0.69, 95% CI 0.52–0.92, p = 0.01 and OR 0.51, 95% CI 0.36–0.70, p = 4 × 10−5, respectively). Meta-analysis including previously published European, African American and Asian cohorts confirmed the association of rs1049550 with sarcoidosis and resulted in a pooled OR of 0.70 (CI 0.66–0.75, p = 3.58 × 10−29). Presence of the T allele of rs1049550 in ANXA11 is protective for sarcoidosis, including benign and chronic phenotypes of the disease.
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Hoare R, Shahin K, McLean K, Adams A, K. D. Thompson. Skin mucus proteins of rainbow trout (Oncorhynchus mykiss) in response to mucosal vaccination and challenge with Flavobacterium psychrophilum. JOURNAL OF FISH DISEASES 2022; 45:491-495. [PMID: 34905629 PMCID: PMC9299601 DOI: 10.1111/jfd.13562] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 11/06/2021] [Accepted: 11/10/2021] [Indexed: 11/07/2023]
Affiliation(s)
- R. Hoare
- Institute of AquacultureUniversity of StirlingStirlingUK
| | - K. Shahin
- Institute of AquacultureUniversity of StirlingStirlingUK
- Aquatic Animal Diseases LaboratoryAquaculture DivisionNational Institute of Oceanography and FisheriesSuezEgypt
| | - K. McLean
- Moredun Research InstitutePenicuikUK
| | - A. Adams
- Institute of AquacultureUniversity of StirlingStirlingUK
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Shao YY, Kuo HY, Jeng YM, Wu YM, Wang HP, Hsu C, Hsu CH, Hsu HC, Cheng AL, Lin ZZ. Association of annexin A10 expression with poor prognosis of intrahepatic cholangiocarcinoma. BMC Cancer 2022; 22:219. [PMID: 35227227 PMCID: PMC8883661 DOI: 10.1186/s12885-022-09288-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 02/09/2022] [Indexed: 12/26/2022] Open
Abstract
Background Annexin A10 expression influences the prognosis of several gastrointestinal cancers. We explored the association of annexin A10 expression with the overall survival (OS) of patients who underwent curative surgery for cholangiocarcinoma. Methods Patients who underwent curative surgery for cholangiocarcinoma (except gallbladder cancer) and had pathological stage T1-3N0M0 disease were enrolled. Annexin A10 expression was examined by performing immunohistochemical staining. Patient demographics and survival outcome data were retrieved from medical records. Results In total, 185 patients were enrolled. The primary tumor location was intrahepatic and extrahepatic (including the perihilar region) for 89% and 11% of patients, respectively. Positive annexin A10 staining was detected for 61 (33%) patients and associated with extrahepatic or perihilar cholangiocarcinoma (p = 0.001) and lower histological grade (p < 0.001). Patients with positive annexin A10 staining exhibited significantly poorer survival relative to patients with negative staining results (median OS, 2.5 vs. 4.9 years, p = 0.025). In the multivariate analysis adjusting for age, sex, tumor location, tumor grade, hepatitis infection, and disease stage, positive annexin A10 remained an independent predictor of poor OS (hazard ratio 1.572, p = 0.034). In the subgroup analysis, the association between annexin A10 and prognosis was restricted to intrahepatic cholangiocarcinoma. Among patients with intrahepatic cholangiocarcinoma, patients with positive annexin A10 staining exhibited significantly poorer survival compared with patients with negative annexin A10 staining (median OS, 2.3 vs. 4.9 years, p = 0.008). Conclusion Positive annexin A10 expression was associated with poor prognosis of intrahepatic cholangiocarcinoma.
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Affiliation(s)
- Yu-Yun Shao
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.,Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan
| | - Hung-Yang Kuo
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.,Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan
| | - Yung-Ming Jeng
- Department of Pathology and Graduate Institute of Pathology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yao-Ming Wu
- Department of Surgery, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Hsiu-Po Wang
- Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Chiun Hsu
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.,Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan
| | - Chih-Hung Hsu
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.,Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan
| | - Hey-Chi Hsu
- Department of Pathology and Graduate Institute of Pathology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Ann-Lii Cheng
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.,Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Zhong-Zhe Lin
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan. .,Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan. .,Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
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Chatzigoulas A, Cournia Z. Predicting protein–membrane interfaces of peripheral membrane proteins using ensemble machine learning. Brief Bioinform 2022; 23:6527274. [PMID: 35152294 PMCID: PMC8921665 DOI: 10.1093/bib/bbab518] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 10/23/2021] [Accepted: 11/12/2021] [Indexed: 12/13/2022] Open
Abstract
Abstract
Abnormal protein–membrane attachment is involved in deregulated cellular pathways and in disease. Therefore, the possibility to modulate protein–membrane interactions represents a new promising therapeutic strategy for peripheral membrane proteins that have been considered so far undruggable. A major obstacle in this drug design strategy is that the membrane-binding domains of peripheral membrane proteins are usually unknown. The development of fast and efficient algorithms predicting the protein–membrane interface would shed light into the accessibility of membrane–protein interfaces by drug-like molecules. Herein, we describe an ensemble machine learning methodology and algorithm for predicting membrane-penetrating amino acids. We utilize available experimental data from the literature for training 21 machine learning classifiers and meta-classifiers. Evaluation of the best ensemble classifier model accuracy yields a macro-averaged F1 score = 0.92 and a Matthews correlation coefficient = 0.84 for predicting correctly membrane-penetrating amino acids on unknown proteins of a validation set. The python code for predicting protein–membrane interfaces of peripheral membrane proteins is available at https://github.com/zoecournia/DREAMM.
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Affiliation(s)
- Alexios Chatzigoulas
- Biomedical Research Foundation, Academy of Athens, 4 Soranou Ephessiou, 11527 Athens, Greece
- Department of Informatics and Telecommunications, National and Kapodistrian University of Athens, 15784 Athens, Greece
| | - Zoe Cournia
- Biomedical Research Foundation, Academy of Athens, 4 Soranou Ephessiou, 11527 Athens, Greece
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Ramezani S, Parkhideh A, Bhattacharya PK, Farach-Carson MC, Harrington DA. Beyond Colonoscopy: Exploring New Cell Surface Biomarkers for Detection of Early, Heterogenous Colorectal Lesions. Front Oncol 2021; 11:657701. [PMID: 34290978 PMCID: PMC8287259 DOI: 10.3389/fonc.2021.657701] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Accepted: 04/09/2021] [Indexed: 01/10/2023] Open
Abstract
Colorectal cancer (CRC) is the third leading cause of cancer-related deaths among both men and women in the United States. Early detection and surgical removal of high-risk lesions in the colon can prevent disease from developing and spreading. Despite implementation of programs aimed at early detection, screening colonoscopies fail to detect a fraction of potentially aggressive colorectal lesions because of their location or nonobvious morphology. Optical colonoscopies, while highly effective, rely on direct visualization to detect changes on the surface mucosa that are consistent with dysplasia. Recent advances in endoscopy techniques and molecular imaging permit microscale visualization of the colonic mucosa. These technologies can be combined with various molecular probes that recognize and target heterogenous lesion surfaces to achieve early, real-time, and potentially non-invasive, detection of pre-cancerous lesions. The primary goal of this review is to contextualize existing and emergent CRC surface biomarkers and assess each’s potential as a candidate marker for early marker-based detection of CRC lesions. CRC markers that we include were stratified by the level of support gleaned from peer-reviewed publications, abstracts, and databases of both CRC and other cancers. The selected biomarkers, accessible on the cell surface and preferably on the luminal surface of the colon tissue, are organized into three categories: (1) established biomarkers (those with considerable data and high confidence), (2) emerging biomarkers (those with increasing research interest but with less supporting data), and (3) novel candidates (those with very recent data, and/or supportive evidence from other tissue systems). We also present an overview of recent advances in imaging techniques useful for visual detection of surface biomarkers, and discuss the ease with which these methods can be combined with microscopic visualization.
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Affiliation(s)
- Saleh Ramezani
- Department of Diagnostic and Biomedical Sciences, The University of Texas Health Science Center at Houston, School of Dentistry, Houston, TX, United States.,Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.,MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, United States
| | - Arianna Parkhideh
- MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, United States.,Department of Anthropology, Washington University in St. Louis, St. Louis, MO, United States
| | - Pratip K Bhattacharya
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.,MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, United States
| | - Mary C Farach-Carson
- Department of Diagnostic and Biomedical Sciences, The University of Texas Health Science Center at Houston, School of Dentistry, Houston, TX, United States.,MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, United States.,Departments of BioSciences and Bioengineering, Rice University, Houston, TX, United States
| | - Daniel A Harrington
- Department of Diagnostic and Biomedical Sciences, The University of Texas Health Science Center at Houston, School of Dentistry, Houston, TX, United States.,MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, United States.,Departments of BioSciences and Bioengineering, Rice University, Houston, TX, United States
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ANXA2 Facilitates Enterovirus 71 Infection by Interacting with 3D Polymerase and PI4KB to Assist the Assembly of Replication Organelles. Virol Sin 2021; 36:1387-1399. [PMID: 34196914 DOI: 10.1007/s12250-021-00417-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Accepted: 04/27/2021] [Indexed: 10/21/2022] Open
Abstract
Similar to that of other enteroviruses, the replication of enterovirus 71 (EV71) occurs on rearranged membranous structures called replication organelles (ROs). Phosphatidylinositol 4-kinase III (PI4KB), which is required by enteroviruses for RO formation, yields phosphatidylinositol-4-phosphate (PI4P) on ROs. PI4P then binds and induces conformational changes in the RNA-dependent RNA polymerase (RdRp) to modulate RdRp activity. Here, we targeted 3D polymerase, the core enzyme of EV71 ROs, and found that the host factor Annexin A2 (ANXA2) can interact with 3D polymerase and promote the replication of EV71. Then, an experiment showed that the annexin domain of ANXA2, which possesses membrane-binding capacity, mediates the interaction of ANXA2 with EV71 3D polymerase. Further research showed that ANXA2 is localized on ROs and interacts with PI4KB. Overexpression of ANXA2 stimulated the formation of PI4P, and the level of PI4P was decreased in ANXA2-knockout cells. Furthermore, ANXA2, PI4KB, and 3D were shown to be localized to the viral RNA replication site, where they form a higher-order protein complex, and the presence of ANXA2 promoted the PI4KB-3D interaction. Altogether, our data provide new insight into the role of ANXA2 in facilitating formation of the EV71 RNA replication complex.
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Li W, Hu X, Li Y, Song K. Cytotoxicity and growth-inhibiting activity of Astragalus polysaccharides against breast cancer via the regulation of EGFR and ANXA1. J Nat Med 2021; 75:854-870. [PMID: 34043154 DOI: 10.1007/s11418-021-01525-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 05/03/2021] [Indexed: 12/17/2022]
Abstract
Astragalus polysaccharide (APS) has been frequently used as an adjuvant agent responsible for its immunoregulatory activity to enhance efficacy and reduce toxicity of chemotherapy used in the management of breast cancer. However, the other synergism mechanism of APS remains unclear. This study was performed to evaluate the potential targets and possible mechanism behind APS in vivo direct anti-tumor activity on breast cancer. Multiple biological detections were conducted to investigate the protein and mRNA expression levels of key targets. In total, 116 down-regulated and 73 up-regulated differential expressed genes (DEGs) were examined from 7 gene expression datasets. Top ten hub genes were obtained in four typical protein-protein interaction (PPI) network of DEGs involved in each specific biological process (BP, cell cycle, cell proliferation, cell apoptosis and death) that was related to inhibitory activity of APS in vitro against breast cancer cell lines. Four common DEGs (EGFR, ANXA1, KIF14 and IGF1) were further identified in the above four BP-PPI networks, among which EGFR and ANXA1 were the hub genes that were potentially linked to the progression of breast cancer. The results of biological detections indicated that the expression of EGFR in breast cancer cells was down-regulated, while the expression of ANXA1 was markedly increased in response to APS. In conclusion, the present study may provide potential molecular therapeutic targets and a new insight into the mechanism of APS against breast cancer.
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Affiliation(s)
- Wenfang Li
- School of Life Science and Technology, Weifang Medical University, Weifang, 261053, China
| | - Xueyan Hu
- State Key Laboratory of Fine Chemicals, Dalian R&D Center for Stem Cell and Tissue Engineering, Dalian University of Technology, Dalian, 116024, China
| | - Yanjie Li
- School of Pharmacy, Weifang Medical University, Weifang, 261053, China
| | - Kedong Song
- State Key Laboratory of Fine Chemicals, Dalian R&D Center for Stem Cell and Tissue Engineering, Dalian University of Technology, Dalian, 116024, China.
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