scholarly journals Zoledronic acid promotes osteoclasts ferroptosis by inhibiting FBXO9-mediated p53 ubiquitination and degradation

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e12510
Author(s):  
Xingzhou Qu ◽  
Zhaoqi Sun ◽  
Yang Wang ◽  
Hui Shan Ong
Keyword(s):  
Gene Expression ◽  
Zoledronic Acid ◽  
Cell Viability ◽  
Cell Model ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Underlying Mechanism ◽  
Cell Counting ◽  
Venn Diagram

Bisphosphonates (BPs)-related osteonecrosis of jaw (BRONJ) is a severe complication of the long-term administration of BPs. The development of BRONJ is associated with the cell death of osteoclasts, but the underlying mechanism remains unclear. In the current study, the role of Zoledronic acid (ZA), a kind of bisphosphonates, in suppressing the growth of osteoclasts was investigated and its underlying mechanism was explored. The role of ZA in regulating osteoclasts function was evaluated in the RANKL-induced cell model. Cell viability was assessed by cell counting kit-8 (CCK-8) assay and fluorescein diacetate (FDA)-staining. We confirmed that ZA treatment suppressed cell viability of osteoclasts. Furthermore, ZA treatment led to osteoclasts death by facilitating osteoclasts ferroptosis, as evidenced by increased Fe2+, ROS, and malonyldialdehyde (MDA) level, and decreased glutathione peroxidase 4 (GPX4) and glutathione (GSH) level. Next, the gene expression profiles of alendronate- and risedronate-treated osteoclasts were obtained from Gene Expression Omnibus (GEO) dataset, and 18 differentially expressed genes were identified using venn diagram analysis. Among these 18 genes, the expression of F-box protein 9 (FBXO9) was inhibited by ZA treatment. Knockdown of FBXO9 resulted in osteoclasts ferroptosis. More important, FBXO9 overexpression repressed the effect of ZA on regulating osteoclasts ferroptosis. Mechanistically, FBXO9 interacted with p53 and decreased the protein stability of p53. Collectively, our study showed that ZA induced osteoclast cells ferroptosis by triggering FBXO9-mediated p53 ubiquitination and degradation.

Simulated microgravity using the Random Positioning Machine inhibits differentiation and alters gene expression profiles of 2T3 preosteoblasts

2005 ◽  
Vol 288 (6) ◽  
pp. C1211-C1221 ◽  
Author(s):  
Steven J. Pardo ◽  
Mamta J. Patel ◽  
Michelle C. Sykes ◽  
Manu O. Platt ◽  
Nolan L. Boyd ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alkaline Phosphatase ◽  
Bone Loss ◽  
Simulated Microgravity ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Underlying Mechanism ◽  
Bone Biology ◽  
Random Positioning Machine

Exposure to microgravity causes bone loss in humans, and the underlying mechanism is thought to be at least partially due to a decrease in bone formation by osteoblasts. In the present study, we examined the hypothesis that microgravity changes osteoblast gene expression profiles, resulting in bone loss. For this study, we developed an in vitro system that simulates microgravity using the Random Positioning Machine (RPM) to study the effects of microgravity on 2T3 preosteoblast cells grown in gas-permeable culture disks. Exposure of 2T3 cells to simulated microgravity using the RPM for up to 9 days significantly inhibited alkaline phosphatase activity, recapitulating a bone loss response that occurs in real microgravity conditions without altering cell proliferation and shape. Next, we performed DNA microarray analysis to determine the gene expression profile of 2T3 cells exposed to 3 days of simulated microgravity. Among 10,000 genes examined using the microarray, 88 were downregulated and 52 were upregulated significantly more than twofold using simulated microgravity compared with the static 1-g condition. We then verified the microarray data for some of the genes relevant in bone biology using real-time PCR assays and immunoblotting. We confirmed that microgravity downregulated levels of alkaline phosphatase, runt-related transcription factor 2, osteomodulin, and parathyroid hormone receptor 1 mRNA; upregulated cathepsin K mRNA; and did not significantly affect bone morphogenic protein 4 and cystatin C protein levels. The identification of gravisensitive genes provides useful insight that may lead to further hypotheses regarding their roles in not only microgravity-induced bone loss but also the general patient population with similar pathological conditions, such as osteoporosis.

scholarly journals Comparative Integrated Omics Analysis of the Hfq Regulon in Bordetella pertussis

2019 ◽  
Vol 20 (12) ◽  
pp. 3073 ◽  
Author(s):  
Ana Dienstbier ◽  
Fabian Amman ◽  
Daniel Štipl ◽  
Denisa Petráčková ◽  
Branislav Večerek
Keyword(s):  
Gene Expression ◽  
Bordetella Pertussis ◽  
Transcriptional Control ◽  
Whooping Cough ◽  
Expression Profiles ◽  
Bacterial Pathogen ◽  
Gene Expression Profiles ◽  
Control Of Gene Expression ◽  
Proteomic Data

Bordetella pertussis is a Gram-negative strictly human pathogen of the respiratory tract and the etiological agent of whooping cough (pertussis). Previously, we have shown that RNA chaperone Hfq is required for virulence of B. pertussis. Furthermore, microarray analysis revealed that a large number of genes are affected by the lack of Hfq. This study represents the first attempt to characterize the Hfq regulon in bacterial pathogen using an integrative omics approach. Gene expression profiles were analyzed by RNA-seq and protein amounts in cell-associated and cell-free fractions were determined by LC-MS/MS technique. Comparative analysis of transcriptomic and proteomic data revealed solid correlation (r2 = 0.4) considering the role of Hfq in post-transcriptional control of gene expression. Importantly, our study confirms and further enlightens the role of Hfq in pathogenicity of B. pertussis as it shows that Δhfq strain displays strongly impaired secretion of substrates of Type III secretion system (T3SS) and substantially reduced resistance to serum killing. On the other hand, significantly increased production of proteins implicated in transport of important metabolites and essential nutrients observed in the mutant seems to compensate for the physiological defect introduced by the deletion of the hfq gene.

scholarly journals THE ROLE OF TRANSCRIPTOMICS: PHYSIOLOGICAL EQUIVALENCE BASED ON GENE EXPRESSION PROFILES

2017 ◽  
Vol 5 (0) ◽  
pp. 21-35 ◽  
Author(s):  
Shiori Miura ◽  
Takehiro Himaki ◽  
Junko Takahashi ◽  
Hitoshi Iwahashi
Keyword(s):  
Gene Expression ◽  
Expression Profiles ◽  
Gene Expression Profiles

Gene expression profiles predict the possible regulatory role of OPN-mediated signaling pathways in rat liver regeneration

Gene ◽  
2016 ◽  
Vol 576 (2) ◽  
pp. 782-790 ◽  
Author(s):  
Gaiping Wang ◽  
Shasha Chen ◽  
Congcong Zhao ◽  
Xiaofang Li ◽  
Ling Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Liver Regeneration ◽  
Signaling Pathways ◽  
Rat Liver ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Regulatory Role ◽  
Rat Liver Regeneration

Overexpression of BRE in Pediatric MLL-Rearranged Acute Myeloid Leukemia Associated with t(9;11)(p22;q23).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3471-3471
Author(s):  
Brian Balgobind ◽  
C. Michel Zwaan ◽  
Susan T.C.J.M. Arentsen-Peters ◽  
Dirk Reinhardt ◽  
Ursula Creutzig ◽  
...  
Keyword(s):  
Gene Expression ◽  
Myeloid Leukemia ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Apoptotic Effect ◽  
The Mean ◽  
Pediatric Aml ◽  
Acute Myeloid

Abstract Abstract 3471 Poster Board III-359 One important cytogenetic subgroup of pediatric acute myeloid leukemia (AML) is characterized by translocations of chromosome 11q23, which accounts for 15 to 20% of all cases with an evaluable chromosome analysis. In most of these cases, the mixed lineage leukemia (MLL) gene is involved. More than 50 fusion translocation partners of the MLL gene have been identified and outcome differs by translocation partner, suggesting differences in the biological background. So far these biological differences have not been unravelled. Therefore, we investigated the gene expression profiles of MLL-rearranged subgroups in pediatric AML in order to discover and identify the role of differentially expressed genes. Affymetrix Human Genome U133 plus 2.0 microarrays were used to generate gene expression profiles of 257 pediatric AML cases, which included 21 pediatric AML cases with t(9;11)(p22;q23) and 33 with other MLL-rearrangements. With these profiles, we were able to identify a specific gene expression signature for t(9;11)(p22;q23) using an empirical Bayes linear regression model (Bioconductor package: Limma). This signature was mainly determined by overexpression of the BRE (brain and reproductive organ-expressed) gene. The mean average VSN normalized expression for BRE in the t(9;11)(p22;q23) subgroup was 3.7-fold higher compared with that in other MLL-rearranged cases (p<0.001). Validation by RQ-PCR confirmed this higher expression in t(9;11)(p22;q23) cases (p<0.001). In addition, we confirmed that overexpression of BRE was predominantly found in t(9;11)(p22;q23) in an independent gene expression profile cohort (Ross et al, Blood 2002). Remarkably, MLL-rearranged cases with a BRE expression higher than the mean expression showed a significant better 3 year disease free survival than MLL-rearranged cases with a lower expression (80±13% vs. 30±10%, p=0.02). Previously, overexpression of BRE has been described in hepatocellular carcinomas (HCC) (Chang et al., Oncogene 2008) and an anti-apoptotic effect was described. We transfected BRE in the monomac-1 cell line, which harbors a t(9;11)(p22;q23). We did not find a proliferative advantage for BRE overexpression using a BrDU-assay nor changes in drug sensitivity, indicating that the anti-apoptotic effect as described for HCC in vivo could not be confirmed in vitro in AML. In conclusion, overexpression of the BRE gene is predominantly involved in pediatric MLL-rearranged AML with t(9;11)(p22;q23). Moreover, high expression of BRE showed a favorable prognosis. We did not find any influence of BRE expression on cell proliferation or apoptosis in vitro. This indicates that further studies involving the role of the MLL-fusion protein on BRE transcription are necessary to unravel the leukemogenic role in pediatric AML. Disclosures No relevant conflicts of interest to declare.

scholarly journals Revisit the Cellular Transmission and Emerging Techniques in Understanding the Mechanisms of Proteinopathies

2021 ◽  
Vol 15 ◽  
Author(s):  
Jinwen Jiang ◽  
Yu Liu ◽  
Qihui Wu
Keyword(s):  
Gene Expression ◽  
Nervous System ◽  
Single Cell ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Molecular Taxonomy ◽  
Gene Expression Profiles ◽  
Underlying Mechanism ◽  
Signal Pathways ◽  
Parkinson’S Diseases

Alzheimer’s and Parkinson’s diseases (AD and PD) are amongst top of the prevalent neurodegenerative disease. One-third of PD patients are diagnosed with dementia, a pre-symptom of AD, but the underlying mechanism is elusive. Amyloid beta (Aβ) and α-synuclein are two of the most investigated proteins, whose pathological aggregation and spreading are crucial to the pathogenesis of AD and PD, respectively. Transcriptomic studies of the mammalian central nervous system shed light on gene expression profiles at molecular levels, regarding the complexity of neuronal morphologies and electrophysiological inputs/outputs. In the last decade, the booming of the single-cell RNA sequencing technique helped to understand gene expression patterns, alternative splicing, novel transcripts, and signal pathways in the nervous system at single-cell levels, providing insight for molecular taxonomy and mechanistic targets of the degenerative nervous system. Here, we re-visited the cell-cell transmission mechanisms of Aβ and α-synuclein in mediating disease propagation, and summarized recent single-cell transcriptome sequencing from different perspectives and discussed its understanding of neurodegenerative diseases.

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