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PMC11277330_p8
|
PMC11277330
|
sec[1]/sec[1]/p[0]
|
2.2. DEG Analysis Supports Survival Results
| 4.195313 |
biomedical
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Study
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We performed differential expression gene (DEG) analysis by comparing the low survival group with the high survival group and observed that our results support our survival analysis results. As a result of our DEG analysis, we found that 398, 192, and 425 genes were upregulated in the TCGA dataset, CGGA_693 dataset, and CGGA_325 dataset, respectively ( Figure 2 (A.3)). We compared the upregulated gene groups from each dataset using a hypergeometric test and found that they were significantly overlapped . In total, 60 genes were upregulated (URPGs) in at least two datasets. We did not consider downregulated genes since the TCGA and CGGA_693 datasets did not show a significant overlap in terms of downregulated genes. When we compared the UPGs using a hypergeometric test, we found that they were significantly overlapped, supporting the consistency of our DEG and survival results . We then performed Gene Ontology (GO) enrichment analysis using the upregulated genes to further reveal the associated functions and found that strongly exposed immune systems responses to cancer, including macrophage activation and leukocyte activation. We also found that the cell migration process was significantly enriched. This suggests that the extracellular matrix organization may be rearranged due to the cancer cell infiltration ( Figure 3 (B.1)). KEGG pathway functional enrichment analysis showed that only one pathway was altered: ECM-receptor interaction, which is a well-known alteration in GBM .
|
[
"Ali Kaynar",
"Mehmet Ozcan",
"Xiangyu Li",
"Hasan Turkez",
"Cheng Zhang",
"Mathias Uhlén",
"Saeed Shoaie",
"Adil Mardinoglu"
] |
https://doi.org/10.3390/ijms25147868
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
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PMC11277330_p9
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PMC11277330
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sec[1]/sec[2]/p[0]
|
2.3. WGCNA Identify Mostly Connected Genes in GBM
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We performed weighted gene co-expression network analysis (WGCNA) to identify the modules correlating with the disease outcome, like survival. After performing WGCNA on three cohorts separately, we found 22, 11, and 25 gene modules from the TCGA, CGGA_325, and CGGA_693 datasets, respectively. Modules from the three cohorts were compared with each other to evaluate their overlap using the hypergeometric test. We observed significant overlap over the cohorts represented using the Jaccard Index . We used each module as a “node” to visualize significantly overlapping modules in Cytoscape. “Edge” represents a significant overlap between the two nodes. Some modules, like C2.M_1, were significantly connected with 11 modules over the three datasets . Functional enrichment analysis showed that this module related to important biological processes like cell morphogenesis, collagen metabolic process, cell differentiation, cytokine production angiogenesis, and extracellular matrix organization. To narrow down our results by evaluating the survival outcomes in the network centrality of modules, we compared UPGs with each module over three datasets by using the hypergeometric test . We obtained six modules, one from CGGA_325, two from CGGA_693, and three from TCGA, that significantly overlapped with the UPGs from three cohorts, and defined them as prognostic modules hereafter ( Figure 2 (D.1)). Module genes and comparative analysis outcomes from the WGCNA are presented in Supplementary File SB .
|
[
"Ali Kaynar",
"Mehmet Ozcan",
"Xiangyu Li",
"Hasan Turkez",
"Cheng Zhang",
"Mathias Uhlén",
"Saeed Shoaie",
"Adil Mardinoglu"
] |
https://doi.org/10.3390/ijms25147868
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
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PMC11277330_p10
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PMC11277330
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sec[1]/sec[3]/p[0]
|
2.4. Discovery of Target Genes for Effective Treatment of GBM
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In GBM research, it is preferable to inhibit the target genes since the activation of genes in the brain is relatively more challenging. The UPGs were pointed out as suitable candidates since their expression increases when the patients’ survival decreases. The expression pattern of these target genes over the human body, including the human brain, was obtained from the Human Protein Atlas (HPA) portal (data from the HPA database are available in Supplementary File SB ). The goal was to identify the genes within the UPGs that are either brain-specific or brain-elevated. The main idea behind this is that when we knock out the selected gene, it should not affect the other tissues severely. This analysis revealed 13 genes that are brain-elevated compared to other tissues and 1 brain-specific gene, yielding a total of 14 target genes that were identified as suitable candidates ( Table 1 ).
|
[
"Ali Kaynar",
"Mehmet Ozcan",
"Xiangyu Li",
"Hasan Turkez",
"Cheng Zhang",
"Mathias Uhlén",
"Saeed Shoaie",
"Adil Mardinoglu"
] |
https://doi.org/10.3390/ijms25147868
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
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PMC11277330_p11
|
PMC11277330
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sec[1]/sec[3]/p[1]
|
2.4. Discovery of Target Genes for Effective Treatment of GBM
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The essentiality scores of these genes were obtained from the Dependency Map (DepMap) ( Table S3 ), with a preference for those with scores close to −0.5. Among these 14 target genes, we focused on 4 genes, CHST2, GLIS3, GNA12 , and MT1F , since the T-drug database contains drug-target information for these genes. After analysing the available data, we determined that CHST2 is the most promising candidate, since CHST2 is present in prognostic modules ( Figure 2 (D.1)) and, according to the DepMap gene effect plot ( Table S3 ), it may be a potentially essential gene. In addition, the expression level of CHST2 was higher in the GBM samples than in the control group according to TCGA data, and CHST2 was considered as an UPG in the CGGA_325 and TCGA cohorts . CHST2 , known as carbohydrate sulfotransferase 2, encodes an enzyme responsible for the sulfation of complex carbohydrates. CHST2 primarily has a role in keratan sulfate (KS) and chondroitin sulfate (CS). CHST2 impacts heparan sulfate (HS) production by connecting with HS6ST1 , which has a primary role in HS production. In addition to HS6ST1, B4GALT1 also altered the gene responsible for HS production. CHST2, CHSY1 , and CHPF , which are members of UPGs, are responsible for the production of CS.
|
[
"Ali Kaynar",
"Mehmet Ozcan",
"Xiangyu Li",
"Hasan Turkez",
"Cheng Zhang",
"Mathias Uhlén",
"Saeed Shoaie",
"Adil Mardinoglu"
] |
https://doi.org/10.3390/ijms25147868
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277330_p12
|
PMC11277330
|
sec[1]/sec[3]/p[2]
|
2.4. Discovery of Target Genes for Effective Treatment of GBM
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On the other hand, DRAXIN , which plays a role in neurite formation and axon guidance, has the potential to be a target gene since it is a brain-specific gene. But DRAXIN was found in non-prognostic modules, and its gene effect was graphically skewed to the positive according to the DepMap gene effect plot.
|
[
"Ali Kaynar",
"Mehmet Ozcan",
"Xiangyu Li",
"Hasan Turkez",
"Cheng Zhang",
"Mathias Uhlén",
"Saeed Shoaie",
"Adil Mardinoglu"
] |
https://doi.org/10.3390/ijms25147868
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
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en
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PMC11277330_p13
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PMC11277330
|
sec[1]/sec[4]/p[0]
|
2.5. Drug Repositioning for Treatment of the GBM
| 4.15625 |
biomedical
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Study
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We identified potential drug candidates for the treatment of GBM based on a drug repositioning approach . This involved searching for target genes in the T-Drug database and integrating data on the transcriptional response to shRNA knockdown and chemical perturbation based on Connectivity Map (CMAP). We focused on CHST2 , an enzyme involved in keratan sulphate and heparan sulphate metabolism. Our analysis followed the flowchart outlined in Figure 5 . We searched available drugs that might be effective against CHST2 in the T-Drug database. Potential drugs were identified by searching the T-Drug database for substances that have an inhibitory effect on CHST2 . Of the top 25 drugs ( Table S1 ) identified in this way, 2 were selected for further analysis based on their known target genes: carbinoxamine, which targets the HRH1 gene, and WZ-4002, which targets the EGFR (also known as ERBB1 ) and ERBB2 genes ( Table S2 ). We found that CHST2 and the well-known target genes of the proposed drugs, HRH1 , and EGFR/ERBB2 , were co-expressed in the GBM tumours as shown in iNetModels . When we investigated the interactive properties of HRH1 vs. CHST2 , there was no interaction in the brain’s cortex region in a healthy state. Similarly, we did not see any interaction between CHST2 and EGFR/ERBB2 in the healthy brain in the cortex region.
|
[
"Ali Kaynar",
"Mehmet Ozcan",
"Xiangyu Li",
"Hasan Turkez",
"Cheng Zhang",
"Mathias Uhlén",
"Saeed Shoaie",
"Adil Mardinoglu"
] |
https://doi.org/10.3390/ijms25147868
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277330_p14
|
PMC11277330
|
sec[1]/sec[4]/p[1]
|
2.5. Drug Repositioning for Treatment of the GBM
| 3.628906 |
biomedical
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Hence, we found that CHST2 and well-known target genes of WZ-4002 were significantly co-expressed in the GBM. Some significantly altered genes that have functional roles in GAG metabolism were then examined using the iNetModels database .
|
[
"Ali Kaynar",
"Mehmet Ozcan",
"Xiangyu Li",
"Hasan Turkez",
"Cheng Zhang",
"Mathias Uhlén",
"Saeed Shoaie",
"Adil Mardinoglu"
] |
https://doi.org/10.3390/ijms25147868
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
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PMC11277330_p15
|
PMC11277330
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sec[1]/sec[5]/p[0]
|
2.6. In Vitro Validation of Drug Candidate
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The U-138 MG brain glioblastoma cancer cell line was used to evaluate the effect of the drug candidates on the cell viability and the protein expression of CHST2 . Before determining the application doses, different concentrations of WZ-4002 and carbinoxamine were applied to U-138 MG, and cell viabilities were examined using MTT . According to the cell viability results, while the application of WZ-4002 at 10 μM reduced cell viability by approximately 50%, no toxic effect of carbinoxamine was observed. Therefore, concentrations of 5 and 10 μM for WZ-4002 and a higher concentration of 20 μM for carbinoxamine were applied to observe their potential effects on U-138 MG cells. After the treatments of cells with the drug candidates, the expression level of CHST2 was measured via Western blot. We found that 5 and 10 µM WZ-4002 treatments decreased the CHST2 expression level depending on the dose, while 20 µM Carbinoxamine was not as effective as WZ-4002 . Moreover, we found that WZ-4002 slightly decreased the expression of EGFR . In parallel to Western blot analysis results, 10 µM WZ-4002 treatment significantly ( p ≤ 0.001) reduced the cell viability by 50%, while Carbinoxamine treatment was not effective on the cell viability . In addition, we performed the wound healing assay to demonstrate the effect of the drugs on the migration of the cells . The results of the wound healing assay indicated that the treatment of 10 µM WZ-4002 completely blocked the cell migration and the treatment of 5 µM WZ-4002 slowed down. However, we observed that the wound scarring was closed in the carbinoxamine-treated cells as in the control at the end of two days. In summary, the efficacy of WZ-4002 as a drug candidate was validated by Western blot analysis as well as cell viability and wound healing assays in vitro.
|
[
"Ali Kaynar",
"Mehmet Ozcan",
"Xiangyu Li",
"Hasan Turkez",
"Cheng Zhang",
"Mathias Uhlén",
"Saeed Shoaie",
"Adil Mardinoglu"
] |
https://doi.org/10.3390/ijms25147868
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277330_p16
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PMC11277330
|
sec[2]/p[0]
|
3. Discussion
| 4.566406 |
biomedical
|
Study
|
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GBM is an exceptionally aggressive and lethal brain cancer, marked by disrupted cell proliferation, angiogenesis, and the invasion of adjacent tissues. This malignancy involves aberrant endothelial cell proliferation, modified vascular permeability, and the formation of new blood vessels by tumour cells . In our study, we identified WZ-4002 as a promising drug candidate for GBM treatment. WZ-4002 is a third-generation EGFR inhibitor, belonging to the ERBB family of four transmembrane tyrosine receptor kinases: EGFR, ERBB2, ERBB3 , and ERBB4 . This receptor family is crucial in various cellular processes, including cell survival. The dimerization of ERBB family members triggers downstream cell signalling cascades following 3D structural alterations that allow certain agents to bind to their extracellular domain. Activating the ERBB family leads to the stimulation of key pathways such as the MAPK pathway, STAT3 signalling, and the PI3K–Akt pathway, which are primarily associated with cell proliferation and tumour cell survival . The activation of the MAPK pathway promotes gene transcription activities controlling cell proliferation, cell migration, and angiogenesis. Conversely, the PI3K–Akt pathway activation governs vital cellular functions like anti-apoptotic activity, cell survival, and cell cycle regulation . The ERBB family, crucial in cancer cell biology, is a target for various anticancer agents, including monoclonal antibodies, small-molecule tyrosine kinase inhibitors (TKIs), antibody-drug conjugates (ADCs), peptide-based inhibitors, immunotoxins, and heat-shock protein inhibitors. Regarding the ERBB family, a range of inhibitors has been tailored to its unique aspects. Monoclonal antibodies, such as cetuximab, panitumumab, and trastuzumab, specifically target the ERBB family to impede cancer cell proliferation to prevent EGFR activation by obstructing its extracellular domain from binding with growth factors. A monoclonal antibody, necitumumab, specifically approved for squamous cell lung cancer , similarly inhibits EGFR activation. In the field of small-molecule TKIs, drugs like erlotinib, gefitinib, lapatinib, and osimertinib inhibit EGFR’s tyrosine kinase domain . In our initial screening, erlotinib and lapatinib were identified among the larger list ( Supplementary File SB ) of candidate drugs. Both of these drugs are well-established tyrosine kinase inhibitors with known efficacy in targeting EGFR and ERBB2 pathways. Given their mechanisms of action and our preliminary findings, it is plausible that erlotinib and lapatinib could also modulate the CHST2 and its adjacent networks. Innovative approaches such as antibody-drug conjugates (ADCs), which consist of a monoclonal antibody, and a cytotoxic drug, such as gemtuzumab ozogamicin, and peptide-based inhibitors, broaden therapeutic strategies . Another notable example of EGFR family modulation involves heat shock protein 90 ( HSP90 ), which regulates the stability of ERBB2 . HSP90B1 , a member of the HSP90 family, plays a role in sustaining cancer cell survival by facilitating ERBB2-dependent downstream signalling pathways. The inhibition of ERBB2 signalling has been shown to disrupt cell cycle progression and hinder angiogenesis, demonstrating its potential as a therapeutic target in cancer treatment.
|
[
"Ali Kaynar",
"Mehmet Ozcan",
"Xiangyu Li",
"Hasan Turkez",
"Cheng Zhang",
"Mathias Uhlén",
"Saeed Shoaie",
"Adil Mardinoglu"
] |
https://doi.org/10.3390/ijms25147868
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11277330_p17
|
PMC11277330
|
sec[2]/p[1]
|
3. Discussion
| 4.300781 |
biomedical
|
Study
|
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The ECM, one of the major altered biological processes in GBM, is a complex network of proteins and carbohydrates that surrounds and supports cells. ECM plays a critical role in the development and progression of GBM because of the crosstalk between the tumour cells and the microenvironment, which can influence the behaviour of cancer cells. Proteoglycans, essential components of the ECM, consist of a core protein containing GAG that plays a critical role in cross-talking. Altered proteoglycan content could promote tumour progression, invasion, and tumour growth . The main components of the ECM in GBM consist of hyaluronic acid and some protein families such as tenascin, fibulin 3, and fibronectin . Some members of the protein families involved in the formation and functioning of the ECM are in our prognostic gene pool, including TNC, FN1 , and FBLIM1 , which has changed significantly. A crucial gene in hyaluronic acid synthesis, a member of the ECM component, is HAS2 , a member of UPGs and URPGs. ECM remodelling, regarding conditions such as cancer or brain injury, is accomplished by tightly regulated production and degradation of ECM components . In this study, we observed that genes related to important biological events in cancer, such as cell survival, cell adhesion, cell proliferation, angiogenesis, ECM organization, and signal transduction, have been significantly altered . In this context, our results have been verified based on the literature.
|
[
"Ali Kaynar",
"Mehmet Ozcan",
"Xiangyu Li",
"Hasan Turkez",
"Cheng Zhang",
"Mathias Uhlén",
"Saeed Shoaie",
"Adil Mardinoglu"
] |
https://doi.org/10.3390/ijms25147868
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277330_p18
|
PMC11277330
|
sec[2]/p[2]
|
3. Discussion
| 4.109375 |
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Study
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GAGs have a crucial role in such biological functions, including ECM modulation, cell proliferation, and immune control. Altered GAGs profiles can be used as a biomarker for the early detection of several cancer types . When we analysed the altered biological process and KEGG pathway results, we observed that the GAGs and GAG-related proteoglycan processes were significantly altered. The expression level of the key genes, which have a critical role in GAGs and the proteoglycan process, was increased in line with the decreased survival time. Hypothetically, we found that increased GAGs and proteoglycan levels were significantly correlated with the survival of the patients. Our analysis indicated that the genes involved in the GAGs production process, especially our target gene CHST2 , have a prognostic profile. Several studies have shown that GAGs, including HS, KS, and CS, have an important role in the cancer process .
|
[
"Ali Kaynar",
"Mehmet Ozcan",
"Xiangyu Li",
"Hasan Turkez",
"Cheng Zhang",
"Mathias Uhlén",
"Saeed Shoaie",
"Adil Mardinoglu"
] |
https://doi.org/10.3390/ijms25147868
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277330_p19
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PMC11277330
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sec[2]/p[3]
|
3. Discussion
| 4.339844 |
biomedical
|
Study
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One of the UPGs and URPGs in our results is HBEGF , which is an important gene for the cell survival downstream signalling pathway, including MAPK/ERK, PI3K/AKT, and JAK/STAT. HBEGF binds to EGFR and activates EGFR-dependent signalling . Another gene significantly altered in our study is STC1 , which regulates the migration and invasion of GBM cells by interacting TGF-β/SMAD4 signalling cascade . On the other hand, CAV1 negatively regulates TGF-β/SMAD4 signalling by mediated internalization of TβRI, a TGF-β receptor . In another carcinogenesis-related pathway, the Hedgehog (HH) pathway, related genes were significantly altered based on our analysis. The HH pathway altered via ligand-independent changes like PTCH1 (downregulated) mutation and SMO (UPGs) mutation. The HH pathway was also altered via paracrine ligand-dependent alteration that stroma cells provoke tumour cells via IL6, VEGF, IGF , and WNT alteration, resulting in HH alteration via PTCH1 and SMO , as well as reverse-paracrine ligand-dependent alteration via stroma cells, inducing tumour cell via PTCH1 . In our study, IGF binding protein family members IGFBP4, IGFBP5, and IGFBP6, which are involved in tumorigenesis, as well as genes including WNT5A , DKK1, DRAXIN and IGFBP4 , which are involved in the WNT pathway, were significantly altered.
|
[
"Ali Kaynar",
"Mehmet Ozcan",
"Xiangyu Li",
"Hasan Turkez",
"Cheng Zhang",
"Mathias Uhlén",
"Saeed Shoaie",
"Adil Mardinoglu"
] |
https://doi.org/10.3390/ijms25147868
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277330_p20
|
PMC11277330
|
sec[2]/p[4]
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3. Discussion
| 4.488281 |
biomedical
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Study
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GBM cells cause alterations in cytokines’ expression, composed of glycoproteins and polypeptides, and interact with tumour-associated macrophages (TAM) to suppress the anti-tumour immune response. STAT3 is active in GBM, and its expression level correlates with patients’ survival outcomes . STAT3 mediate interferon ( IFN ) and IL6 , affecting the JAK downstream signalling in GBM. CXCL10 expression level increases the tumour cell. GBM formation is enhanced by TNF-α secretion, which leads to LIF upregulation . Cytokine activation may induce sulfotransferase, including CHST2 overexpression in some circumstances .
|
[
"Ali Kaynar",
"Mehmet Ozcan",
"Xiangyu Li",
"Hasan Turkez",
"Cheng Zhang",
"Mathias Uhlén",
"Saeed Shoaie",
"Adil Mardinoglu"
] |
https://doi.org/10.3390/ijms25147868
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277330_p21
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3. Discussion
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Our research utilized various system biology approaches to investigate genes with potential roles in GBM. Among these, EFEMP2 , identified from the UPGs (upregulated prognostic genes) pool, stands out due to its significant function in molecular cancer mechanisms. This gene is notably interconnected with CHST2 and ERBB2 within the C1.M_4 module, which also includes other synergistically effective genes, highlighting their common properties. EFEMP2 also appears in the T.M_2 and C2.M_10 modules, demonstrating significant overlaps with the UPGs pool, further underscoring its prognostic relevance. EFEMP2 (EGF-containing fibulin-like extracellular matrix protein 2) is crucial in shaping the tumour microenvironment, markedly influencing overall survival and tumour-associated macrophage dynamics in glioma . As a fibulin family member with EGF-like calcium-binding domains, EFEMP2 is essential for cellular architecture and signalling within tumours and may influence glycosaminoglycan metabolism. In aggressive conditions like GBM, EFEMP2 ′s high expression correlates with poorer patient outcomes. Its prognostic ability is reinforced by its association with a spectrum of macrophage activation states—from typical polarizations to an M0-like continuum—thus impacting immune responses within the tumour . EFEMP2 ′s pivotal interactions with the EGFR play a significant role in oncogenic pathways. By binding directly to EGFR , it activates the EGFR/ERK1/2/c-Jun signalling pathway, promoting tumour cell proliferation and migration while also upregulating PD-L1 expression, which aids in immune evasion .
|
[
"Ali Kaynar",
"Mehmet Ozcan",
"Xiangyu Li",
"Hasan Turkez",
"Cheng Zhang",
"Mathias Uhlén",
"Saeed Shoaie",
"Adil Mardinoglu"
] |
https://doi.org/10.3390/ijms25147868
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999993 |
PMC11277330_p22
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3. Discussion
| 4.035156 |
biomedical
|
Study
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[
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Based on the literature on the above-mentioned genes and their relationships with CHST2 within the network, we found that CHST2 and its close neighbours could be considered a drug target for developing effective treatment strategies for GBM. Our in vitro experiments showed that targeting GAGs metabolism with the here-identified drug candidate, WZ-4002, results in decreased cell viability.
|
[
"Ali Kaynar",
"Mehmet Ozcan",
"Xiangyu Li",
"Hasan Turkez",
"Cheng Zhang",
"Mathias Uhlén",
"Saeed Shoaie",
"Adil Mardinoglu"
] |
https://doi.org/10.3390/ijms25147868
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277330_p23
|
PMC11277330
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sec[2]/p[7]
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3. Discussion
| 4.203125 |
biomedical
|
Study
|
[
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Our study, utilizing system biology approaches, including DEG analysis, co-expression network analysis, survival analysis, and in vitro validation, highlights the potential role of CHST2 and other genes in GBM treatment. We identified promising drug candidates such as WZ-4002, an EGFR inhibitor, which targets crucial genes and their adjacent networks, including ERBB2 and EFEMP2 . Future studies should explore combinations of drug treatments targeting multiple network nodes to enhance therapeutic efficacy and address issues of drug resistance. Delving deeper into the role of CHST2 in tumour biology through expanded datasets and integrative approaches could significantly improve GBM treatment strategies. Despite the promising clues, our study’s limitations stem from heterogeneity and may not fully account for the sample heterogeneity that could affect gene expression profiles. The complexity of signalling pathways and their interactions call for larger, more comprehensive datasets to accurately decipher the intricate dynamics of CHST2 and other relevant genes in tumour biology. Future work should also consider integrating single-cell data and other omics layers to refine our understanding and overcome the current dataset limitations.
|
[
"Ali Kaynar",
"Mehmet Ozcan",
"Xiangyu Li",
"Hasan Turkez",
"Cheng Zhang",
"Mathias Uhlén",
"Saeed Shoaie",
"Adil Mardinoglu"
] |
https://doi.org/10.3390/ijms25147868
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999993 |
PMC11277330_p24
|
PMC11277330
|
sec[3]/sec[0]/p[0]
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4.1. Data Acquisition and Pre-Processing
| 4.148438 |
biomedical
|
Study
|
[
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We retrieved the global gene expression profiling data (RNA-seq dataset) of the GBM patients recruited in the TCGA project from the Genomic Data Commons (GDC) platform . The dataset includes global mRNA expression levels of all protein-coding genes (Transcript Per Million (TPM) and STAR read count) and clinical information for 174 tumour samples and 5 control samples from adjacent normal tissues. We removed duplicate samples that had low purity scores according to the clinical information. In total, we screened RNA-seq data of 149 tumour samples obtained from primary solid tumour tissue samples and well-recorded clinical information, including survival time and day to the last follow-up recording. Protein-coding genes were selected depending on the embedded information in the dataset as a “protein_coding”. The dataset was downloaded on the RStudio platform using the TCGAbiolinks R package . The gene expression profiles (expression data from STAR + RSEM FPKM value and STAR read counts) and clinical information of the other two datasets, CGGA_693 and CGGA_325 , were collected from the Chinese Glioma Genome Atlas (CGGA) . The RNA-seq data of normal control samples, with a sample size of 20, were also obtained from the same database by downloading the CGGA_RNAseq_Control dataset. We screened all samples of GBM and kept only primary tumour solid tissue samples and well-recorded clinical information, including survival time. After pre-processing, we included 133 and 85 samples for CGGA_693 and CGGA_325 in our analysis, respectively (detailed sample information can be found in Supplementary File SB ). In each cohort, genes with a mean expression value < 1 were considered as unexpressed, and they were excluded from the data to reduce the noise. After removing the lowly expressed genes, 14,552, 13,298, and 13,121 genes remained for the TCGA dataset, CGGA_693 dataset, and CGGA_325 dataset, respectively . The sample distribution of the datasets is presented in Figures S10–S12 . The analysis was performed using RStudio (R version 4.1.0).
|
[
"Ali Kaynar",
"Mehmet Ozcan",
"Xiangyu Li",
"Hasan Turkez",
"Cheng Zhang",
"Mathias Uhlén",
"Saeed Shoaie",
"Adil Mardinoglu"
] |
https://doi.org/10.3390/ijms25147868
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277330_p25
|
PMC11277330
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sec[3]/sec[1]/p[0]
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4.2. Survival Analysis
| 4.082031 |
biomedical
|
Study
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The univariate Cox regression model was used to evaluate the relationship between the gene expression levels and patients’ survival outcomes, and the hazard ratio of each gene was calculated. Genes with p -value < 0.05 were identified as prognostic genes based on survival analysis. If a gene’s high expression was correlated with the poor survival outcomes of GBM patients, this gene was defined as an unfavourable prognostic gene; otherwise, it was defined as a favourable prognostic gene. Favourable and unfavourable genes were determined by performing the same analysis for the three cohorts independently. In addition, a pairwise comparison was performed for the prognostic genes by hypergeometric analysis. Unfavourable or favourable genes that were significant in at least two datasets were combined to form an unfavourable prognostic gene pool (UPGs) or favourable prognostic gene pool (FPGs), respectively ( Supplementary File SB ). All analyses were performed using the R package “survival”.
|
[
"Ali Kaynar",
"Mehmet Ozcan",
"Xiangyu Li",
"Hasan Turkez",
"Cheng Zhang",
"Mathias Uhlén",
"Saeed Shoaie",
"Adil Mardinoglu"
] |
https://doi.org/10.3390/ijms25147868
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277330_p26
|
PMC11277330
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sec[3]/sec[2]/p[0]
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4.3. DEG Analysis
| 4.050781 |
biomedical
|
Study
|
[
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] |
In the DEG analysis, we used the gene count values of each sample selected from each dataset. In the survival analysis, count values in the selected samples were used, and lowly expressed genes were removed from the data. Finally, the obtained data were used in the DEG analysis. The samples were sorted according to the number of survival days, and two groups were formed, namely genes associated with high survival and low survival. The quantile degrees of the data were considered when creating the high survival and low survival groups: the first quantile was chosen as 0.33, and the second quantile as 0.66. Samples with survival values lower than the first quantile were classified as low survival. Conversely, samples with a survival value greater than the second quantile were grouped as high survival. The high survival group was chosen as the reference and compared with the low survival group. The same procedure was performed for the three datasets, separately. Results with p -values < 0.01 were considered as significant. DEG analysis was performed using the R package “DESeq2” in the R platform .
|
[
"Ali Kaynar",
"Mehmet Ozcan",
"Xiangyu Li",
"Hasan Turkez",
"Cheng Zhang",
"Mathias Uhlén",
"Saeed Shoaie",
"Adil Mardinoglu"
] |
https://doi.org/10.3390/ijms25147868
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277330_p27
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PMC11277330
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sec[3]/sec[3]/p[0]
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4.4. Co-Expression Network Analysis
| 4.085938 |
biomedical
|
Study
|
[
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[
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] |
In this study, we used weighted gene co-expression network analysis (WGCNA) by employing a series of correlations to identify the sets of co-expressed genes in each dataset. We used count data as input from the GBM samples. We performed Pearson’s correlation matrices for all pairwise genes and constructed a weighted adjacency matrix using a power function that incorporated both the Pearson correlation and adjacency between each gene pair.
|
[
"Ali Kaynar",
"Mehmet Ozcan",
"Xiangyu Li",
"Hasan Turkez",
"Cheng Zhang",
"Mathias Uhlén",
"Saeed Shoaie",
"Adil Mardinoglu"
] |
https://doi.org/10.3390/ijms25147868
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277330_p28
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PMC11277330
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sec[3]/sec[3]/p[1]
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4.4. Co-Expression Network Analysis
| 4.140625 |
biomedical
|
Study
|
[
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[
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] |
Before constructing the adjacency matrix, we removed some genes with low standard deviation. Accordingly, the cut-off value of the dataset to determine the low standard deviation was 0.25,0.35, and 0.3 for the datasets TCGA, CGGA_693, and CGGA_325, respectively. The power parameter, which controlled the strength of the correlations, was optimized for each cohort to achieve a scale-free topology fit (R 2 ), and the cut-off was selected as 0.85. We set the power parameters as 12, 13, and 11 for TCGA, CGG_325, and CGGA_693, respectively . We then converted the adjacency matrix into a topological overlap matrix (TOM) to determine the connectivity of each gene in the network. Following this, we generated a TOM dissimilarity matrix. Modules were identified using the dynamic tree-cut selecting method as a hybrid, following numeric labels converted into colours. Eigengenes were calculated, and modules were merged with similar expression profiles. To summarise, the hierarchical clustering analysis was performed on the TOM to identify the groups of genes with a similar expression pattern. A minimum group size of 20 genes was used as a threshold for the dendrogram .
|
[
"Ali Kaynar",
"Mehmet Ozcan",
"Xiangyu Li",
"Hasan Turkez",
"Cheng Zhang",
"Mathias Uhlén",
"Saeed Shoaie",
"Adil Mardinoglu"
] |
https://doi.org/10.3390/ijms25147868
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277330_p29
|
PMC11277330
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sec[3]/sec[4]/p[0]
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4.5. Functional Enrichment Analysis
| 4.039063 |
biomedical
|
Study
|
[
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[
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] |
GO term lists were retrieved from Ensembl Biomart from Ensembl Release 106 using the “getBM” function. We obtained the GO terms using the “enrichGO” function of “clusterProfiler”, an R package, to analyse the functional enrichment of the DEGs. GO terms with Benjamini–Hochberg-adjusted p -values <0.05 were determined to be statistically significant. We obtained the KEGG pathway terms using the “enrichKEGG” function of “clusterProfiler”, an R package, for pathway enrichment analysis of DEGs. KEGG pathway terms with Benjamini–Hochberg-adjusted p -values <0.05 were determined as statistically significant.
|
[
"Ali Kaynar",
"Mehmet Ozcan",
"Xiangyu Li",
"Hasan Turkez",
"Cheng Zhang",
"Mathias Uhlén",
"Saeed Shoaie",
"Adil Mardinoglu"
] |
https://doi.org/10.3390/ijms25147868
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277330_p30
|
PMC11277330
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sec[3]/sec[5]/p[0]
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4.6. Drug Target Identification
| 4.105469 |
biomedical
|
Study
|
[
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[
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] |
Since unfavourable genes are associated with the poor survival of GBM patients, knockout of these genes could theoretically kill cancer cells or reduce proliferation. Further, genes showing high expression in the brain based on the data in the Human Protein Atlas were compared with UPGs. As a result, 13 overlapped genes were identified as brain elevated, and one was identified as brain-specific ( Table 1 ). These genes were selected as a candidate drug target pool. In addition, essential scores of these genes were searched from the Dependency Map (DepMap) portal to investigate the perturbation effects. A lower gene score indicates that this gene has more potent effects on tumour cell proliferation after CRISPR-Cas9 or RNA interference knockout. In most cases, a gene with an essential score less than −0.5 means that the cells may grow more slowly when the gene is knocked out.
|
[
"Ali Kaynar",
"Mehmet Ozcan",
"Xiangyu Li",
"Hasan Turkez",
"Cheng Zhang",
"Mathias Uhlén",
"Saeed Shoaie",
"Adil Mardinoglu"
] |
https://doi.org/10.3390/ijms25147868
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277330_p31
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PMC11277330
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4.7. Drug Repositioning
| 4.195313 |
biomedical
|
Study
|
[
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[
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] |
In our previous study, we proposed a drug repositioning method based on the similarity analysis of the transcriptomics signature profiles of human cells treated with drugs and genetic perturbations. We hypothesised that the inhibitory effect of a drug on the expression of a target gene can be inferred if the drug causes a perturbation in the gene expression landscape of tumour cells (in this case), similar to the effect of shRNA-mediated knockdown of the target gene. The approach for drug repositioning comprises four steps: construction of the drug-shRNA matrix, optimization of the matrix, identification of the top 1% of drug candidates, and selection of the most potent drugs for each target gene . Based on this drug repositioning approach, we constructed a web tool named T-Drug , in which users can freely query a specific gene or drug. T-Drug provides a ranked list of predicted gene-drug associations based on the confidence scores. Based on the results, we sorted the candidate drugs in descending order in the number of hit cells, short for “Num Hit Cells”. The first 25 drugs were selected as candidate drugs. Then, drugs and their well-known target gene information (compoundinfo_beta.txt) were downloaded from CMAP to evaluate the relationship between the candidate genes and selected drugs. Next, we examined the interaction between the CHST2 and the well-known target genes using the iNetModels 2.0 and investigated how candidate drugs can potentially modulate it and its neighbouring genes.
|
[
"Ali Kaynar",
"Mehmet Ozcan",
"Xiangyu Li",
"Hasan Turkez",
"Cheng Zhang",
"Mathias Uhlén",
"Saeed Shoaie",
"Adil Mardinoglu"
] |
https://doi.org/10.3390/ijms25147868
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277330_p32
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PMC11277330
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4.8. Cell Culture and Drug Treatment
| 4.09375 |
biomedical
|
Study
|
[
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[
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] |
The U-138 MG cells were maintained in Dulbecco’s Modified Eagle Medium supplemented with 10% fetal bovine serum (FBS) and 1% penicillin/streptomycin (P/S) solution in a humidified incubator with 5% CO 2 at 37 °C. For the drug treatments, 2.5 × 10 5 cells were seeded to per well in a 6-well plate. After 24 h of cell seeding, cells were treated with the WZ-4002 and Carbinoxamine dissolved in 0.1% Dimethyl sulfoxide for two days.
|
[
"Ali Kaynar",
"Mehmet Ozcan",
"Xiangyu Li",
"Hasan Turkez",
"Cheng Zhang",
"Mathias Uhlén",
"Saeed Shoaie",
"Adil Mardinoglu"
] |
https://doi.org/10.3390/ijms25147868
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277330_p33
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PMC11277330
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4.9. Western Blot Analysis
| 4.171875 |
biomedical
|
Study
|
[
0.99951171875,
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[
0.9970703125,
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0.0004868507385253906,
0.00011116266250610352
] |
After the drug treatments for 2 days, the cells were washed with phosphate-buffered saline (PBS) and lysed with CelLytic M lysis buffer containing protease inhibitors . The cell lysates were centrifuged at 12,000 rpm and +4 °C for 10 min, and then supernatants were collected. Protein Assay Dye Reagent was used for the determination of protein concentration. The absorbance of the proteins was measured spectrophotometrically at 595 nm by a microplate reader (Hidex Sense Beta Plus). Protein electrophoresis was performed using Mini-PROTEAN ® TGX TM Precast Gels , and then the proteins were transferred to a Trans-Blot Turbo Mini 0.2 um PVDF Transfer Packs membrane using the Trans-Blot ® Turbo TM Transfer System (Bio-Rad). The membrane was blocked with 5% skim milk for 30 min at 4 °C with gentle rocking. After blocking, the membrane was treated with the primary antibodies: Anti-CHST2 , Anti-EGFR and Anti-Beta actin as a loading control, overnight at 4 °C on a rocking platform. After the treatment of primary antibodies, the membrane was washed three times with TBS-T buffer . Then, Goat anti-Rabbit IgG-HRP was treated as the secondary antibody for 30 min at 4 °C with gentle rocking. The protein bands on the membrane were revealed using enhanced chemiluminescence substrate and detected with ImageQuant™ LAS 500 (GE Healthcare, Medison, WI, USA).
|
[
"Ali Kaynar",
"Mehmet Ozcan",
"Xiangyu Li",
"Hasan Turkez",
"Cheng Zhang",
"Mathias Uhlén",
"Saeed Shoaie",
"Adil Mardinoglu"
] |
https://doi.org/10.3390/ijms25147868
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11277330_p34
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PMC11277330
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sec[3]/sec[9]/p[0]
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4.10. Cell Viability Assay
| 4.121094 |
biomedical
|
Study
|
[
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[
0.9990234375,
0.0004050731658935547,
0.0003674030303955078,
0.00008183717727661133
] |
The cytotoxic effects of the drugs on the U-138 MG cell line were tested by MTT (Thiazolyl Blue Tetrazolium Bromide) analysis. Therein, 1 × 10 4 cells were seeded to per well in a 96-well plate in 100 µL of DMEM, 10% FBS and 1% P/S. After 24 h of cell seeding, different concentrations of the drugs were treated on the cells for two days. After the incubation period, 5 mg/mL MTT solution in PBS (10 µL) was added to each well. After 2 h, MTT solutions were removed from the wells. Then, 100 μL of DMSO was added and mixed to dissolve the formazan crystals. Cell viability was analysed by measuring the absorbance of the dissolved formazan at a wavelength of 570 nm.
|
[
"Ali Kaynar",
"Mehmet Ozcan",
"Xiangyu Li",
"Hasan Turkez",
"Cheng Zhang",
"Mathias Uhlén",
"Saeed Shoaie",
"Adil Mardinoglu"
] |
https://doi.org/10.3390/ijms25147868
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277330_p35
|
PMC11277330
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sec[3]/sec[10]/p[0]
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4.11. Wound Healing Assay
| 4.105469 |
biomedical
|
Study
|
[
0.99951171875,
0.00026416778564453125,
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[
0.99951171875,
0.00035190582275390625,
0.00025844573974609375,
0.00006371736526489258
] |
To investigate the effects of the selected candidate drugs on cell migration using U-138 MG cells, a wound healing assay was performed. Therein, 1 × 10 5 cells were seeded into 24-well plates for each well and grown until 95–100% confluent. After the medium was removed, a linear wound was created using a 200 μL pipette tip, and the image was recorded at the time point of day 0. Cells were washed with PBS, and the drugs were treated in DMEM containing 2% FBS. Then, images of the wound surfaces were recorded after one and two days by the ZOE Fluorescent Cell Imager (Bio-Rad, Hercules, CA, USA).
|
[
"Ali Kaynar",
"Mehmet Ozcan",
"Xiangyu Li",
"Hasan Turkez",
"Cheng Zhang",
"Mathias Uhlén",
"Saeed Shoaie",
"Adil Mardinoglu"
] |
https://doi.org/10.3390/ijms25147868
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277330_p36
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5. Conclusions
| 4.128906 |
biomedical
|
Study
|
[
0.99951171875,
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[
0.99853515625,
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0.00011157989501953125
] |
In conclusion, our study introduces a drug repositioning method grounded in mRNA expression profiling, aimed at developing alternative therapeutic strategies for GBM. This approach facilitated the identification of CHST2 as a gene with altered expression linked to patient survival outcomes. Subsequently, we pinpointed disease-related hub genes through network topology and co-expression network analysis. The impact of drug perturbation on these selected genes was assessed through in vitro experiments, leading to the identification of WZ-4002 as an effective drug for modulating CHST2 . Our findings suggest that this methodology offers a promising, cost-effective avenue for expediting drug development.
|
[
"Ali Kaynar",
"Mehmet Ozcan",
"Xiangyu Li",
"Hasan Turkez",
"Cheng Zhang",
"Mathias Uhlén",
"Saeed Shoaie",
"Adil Mardinoglu"
] |
https://doi.org/10.3390/ijms25147868
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277342_p0
|
PMC11277342
|
sec[0]/p[0]
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1. Introduction
| 4.332031 |
biomedical
|
Study
|
[
0.9990234375,
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[
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The trace metals iron (Fe), copper (Cu), zinc (Zn), and manganese (Mn) are essential for cellular metabolism in living organisms , being involved in amino acid, lipid, protein, and carbohydrate metabolism . They act as structural cofactors for proteins and nucleic acids, and are essential for oxygen transport, neurotransmitter synthesis, nucleic acid repair, and construction of the extracellular matrix , as well as cellular respiration and transcription . Despite their importance, the transition metals Cu 2+/+ , Fe 3+/2+ , and Mn 3+/2+ can participate in electron transfer reactions, which can result in damage to structural cellular components, potentially inducing cell death . To this, intra and extracellular systems are equipped with different mechanisms that ensure their uptake, storage, and distribution to their respective targets.
|
[
"Adriana Fontes",
"Adrian T. Jauch",
"Judith Sailer",
"Jonas Engler",
"Anabela Marisa Azul",
"Hans Zischka"
] |
https://doi.org/10.3390/ijms25147880
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277342_p1
|
PMC11277342
|
sec[0]/p[1]
|
1. Introduction
| 3.935547 |
biomedical
|
Review
|
[
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[
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Intoxications caused by transition metals may have their origins in air, water, or soil contamination and agriculture (namely, resulting from the use of fertilizers and pesticides). Other anthropogenic activities, like mining and smelting, can also be a source of metal intoxication in humans . Genetic conditions and aging represent further circumstances that may contribute to the accumulation of transition metals in tissues such as liver and brain; the latter being of substantial concern with respect to neurodegenerative diseases . Metal imbalances in the body have also been associated with conditions like cardiovascular disease , metabolic syndrome , cancer , inflammatory bowel disease , and even depression and anxiety .
|
[
"Adriana Fontes",
"Adrian T. Jauch",
"Judith Sailer",
"Jonas Engler",
"Anabela Marisa Azul",
"Hans Zischka"
] |
https://doi.org/10.3390/ijms25147880
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277342_p2
|
PMC11277342
|
sec[0]/p[2]
|
1. Introduction
| 4.109375 |
biomedical
|
Study
|
[
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[
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A more recent concern is the increased adoption of food supplements in diets . Augustsson and co-workers demonstrated a considerable variability in the amount of metals in 138 supplements, with discrepancies between the declared versus measured content ranging from 50% to 150%. This included a large spam concentration for Zn 2+ , Cu 2+/+ , Fe 3+/2+ , and Mn 3+/2+ in supplements, with P95/P5 ratios (P95 percentile to P5 percentile ratio) of 40.000-, 19.000-, 16.000-, and 18.000-fold, respectively. This results in values above the tolerable daily intake (TDI), namely, 10% for copper and 50% for iron, manganese, and zinc, in both normal and underweight women and children (3–6 years old), according to the European Food Safety Authority (EFSA), the US Environmental Protection Agency, the Dutch RIVM, and the National Institute of Public Health and the Environment .
|
[
"Adriana Fontes",
"Adrian T. Jauch",
"Judith Sailer",
"Jonas Engler",
"Anabela Marisa Azul",
"Hans Zischka"
] |
https://doi.org/10.3390/ijms25147880
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277342_p3
|
PMC11277342
|
sec[0]/p[3]
|
1. Introduction
| 4.128906 |
biomedical
|
Review
|
[
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[
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Transition metal intoxications at the cellular level may arise from the interaction with proteins in different cellular pathways, which cause changes in enzymatic activities, in protein structure, or even lead to the misplacement of other metals that are important co-factors for different enzymes. Currently, the main therapeutic approach to treating metal intoxication is the use of chelators that can, with limitations, remove metals from the body. The use of natural antioxidants has proven beneficial effects in alleviating the consequences of metal toxicity, such as oxidative stress, particularly in pre-clinical studies. This review provides an overview about the essential transition metals’ (Fe 3+/2+ , Zn 2+ , Cu 2+/+ , and Mn 3+/2+ ) metabolism, the toxic consequences derived from metal overload, current treatments, and paths towards novel complementary therapies.
|
[
"Adriana Fontes",
"Adrian T. Jauch",
"Judith Sailer",
"Jonas Engler",
"Anabela Marisa Azul",
"Hans Zischka"
] |
https://doi.org/10.3390/ijms25147880
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277342_p4
|
PMC11277342
|
sec[1]/sec[0]/p[0]
|
2.1. Iron (Fe)
| 4.621094 |
biomedical
|
Study
|
[
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Iron enters the body via dietary sources in two major forms: heme and nonheme iron. The bioavailability of heme-Fe 2+ from meat, fish, and poultry is around 20–40%, while non-heme-Fe 3+ present in vegetables, fruits, and cereals has a lower bioavailability of ca. 15% . Iron absorption can be hindered by other metals (calcium and zinc), phytates, polyphenols, and proteins such as conglycinin, present in soybeans , but is augmented by vitamin C, which enhances the absorption of the nonheme form. Besides its ability to reduce Fe 3+ for cellular uptake, thereby increasing its bioavailability, vitamin C also stimulates ferritin synthesis and the transferrin (Tf)-dependent Fe 3+ uptake . Otherwise, Fe 3+ reduction is mostly performed by ferrireductase duodenal cytochrome b (DCYTB)/six transmembrane epithelial antigen of the prostate (STEAP), allowing Fe 2+ uptake via the divalent metal transporter 1 (DMT1), while heme-Fe 2+ is transported by the heme carrier protein 1 (HCP1) into enterocytes .
|
[
"Adriana Fontes",
"Adrian T. Jauch",
"Judith Sailer",
"Jonas Engler",
"Anabela Marisa Azul",
"Hans Zischka"
] |
https://doi.org/10.3390/ijms25147880
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277342_p5
|
PMC11277342
|
sec[1]/sec[0]/p[1]
|
2.1. Iron (Fe)
| 4.492188 |
biomedical
|
Study
|
[
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[
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From there, Fe 2+ is either stored in ferritin, which can accommodate up to 4500 atoms in its ferric form (Fe 3+ ), or released into the portal vein via ferroportin-1 (FPN1), which may be repressed by hepcidin . Iron can also be exported from the intestine via HCP1, followed by Tf binding and subsequent transport in plasma. From the diet, around 1–2 mg/day are absorbed, while roughly the same amount is lost via enterocyte and skin desquamation, hemorrhages, and parasitic infections . The major Fe 3+/2+ portion is present in erythrocytes (2–2.3 g) that are recycled in the spleen, releasing Fe 3+ to be bound to Tf (~4 mg). Around 1 g of Fe 3+ is stored in hepatocyte ferritin, while 150 mg are found in the bone marrow . Iron is essential for hemoglobin synthesis, oxygen transport, biosynthesis of collagen, myelin, neurotransmitters, and several components of the mitochondrial electron transport chain .
|
[
"Adriana Fontes",
"Adrian T. Jauch",
"Judith Sailer",
"Jonas Engler",
"Anabela Marisa Azul",
"Hans Zischka"
] |
https://doi.org/10.3390/ijms25147880
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277342_p6
|
PMC11277342
|
sec[1]/sec[0]/p[2]
|
2.1. Iron (Fe)
| 4.285156 |
biomedical
|
Study
|
[
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[
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These essential Fe-dependent metabolic functions appear evident from numerous studies, for example, linking obesity to iron deficiency . Interestingly, this linkage cannot be attributed solely to a lower dietary iron uptake due to general malnutrition but rather may be explained by reduced iron absorption due to increased hepcidin levels in obese individuals . Increased hepcidin expression appears to be linked to inflammation in adipose tissue, greatly mediated by interleukin 6 (IL-6) . Hepcidin levels are also controlled by the gut hormone leptin , which is commonly dysregulated in obese individuals. This notion is further supported by the observation that serum concentrations of Fe 3+/2+ and Tf were negatively associated with leptin. This association was found in individuals with a body mass index (BMI) below 30 kg/m 2 .
|
[
"Adriana Fontes",
"Adrian T. Jauch",
"Judith Sailer",
"Jonas Engler",
"Anabela Marisa Azul",
"Hans Zischka"
] |
https://doi.org/10.3390/ijms25147880
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11277342_p7
|
PMC11277342
|
sec[1]/sec[0]/p[3]
|
2.1. Iron (Fe)
| 4.15625 |
biomedical
|
Study
|
[
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[
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Conversely, the excess of iron can lead to health problems as well, especially because of the lack of a physiologic excretion route. A consequence of the gradual increase in Fe 3+/2+ in the body is the aggravation of anemia as a result of lower Fe 3+/2+ absorption in the gut , with its accumulation in the liver and heart, further worsening the course of liver diseases and other chronic conditions such as metabolic and cardiovascular diseases . Higher intake of heme-Fe 2+ was also associated with a higher risk of type 2 diabetes mellitus in humans . In the brain, excess Fe 3+/2+ was found in the substantia nigra of patients with Parkinson’s disease , and its accumulation was associated with tau accumulation and amyloid-β aggregation in patients with Alzheimer disease .
|
[
"Adriana Fontes",
"Adrian T. Jauch",
"Judith Sailer",
"Jonas Engler",
"Anabela Marisa Azul",
"Hans Zischka"
] |
https://doi.org/10.3390/ijms25147880
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277342_p8
|
PMC11277342
|
sec[1]/sec[0]/p[4]
|
2.1. Iron (Fe)
| 4.734375 |
biomedical
|
Review
|
[
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[
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The most predominant Fe 3+/2+ overload disorder is hereditary hemochromatosis, with an incidence of 1:220–250 individuals, most commonly observed in populations of northern European origin . Different types of hemochromatosis are known and relate to different disease severity levels. The most common type is linked to mutations in the homeostatic iron regulator (HFE), followed by mutations in hemojuvelin (HJV), hepcidin, transferrin 2 receptor (TfR2), and FPN1 . If such gene mutations negatively affect hepcidin synthesis (e.g., HJV), circulatory iron can rapidly reach high levels , causing an early onset of disease (first–second decade of life) that impacts different organs such as the heart and the endocrine glands. In the cases where HFE is mutated, a milder late-onset phenotype arises . Transferrin saturation is observed in patients with hemochromatosis, with a later increase in serum ferritin, which indicates iron accumulation in tissues. The most common symptoms include fatigue, malaise, arthralgia, and hepatomegaly. Together with high serum ferritin levels, patients might develop liver fibrosis, which can progress to liver cirrhosis and hepatocellular carcinoma . Thalassemia syndrome also correlates with Fe 3+/2+ overload due to ineffective erythropoiesis that is caused by mutations in α- or β-globin genes .
|
[
"Adriana Fontes",
"Adrian T. Jauch",
"Judith Sailer",
"Jonas Engler",
"Anabela Marisa Azul",
"Hans Zischka"
] |
https://doi.org/10.3390/ijms25147880
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277342_p9
|
PMC11277342
|
sec[1]/sec[0]/p[5]
|
2.1. Iron (Fe)
| 4.152344 |
biomedical
|
Review
|
[
0.99755859375,
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[
0.032440185546875,
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The typical treatments for Fe 3+/2+ overload are phlebotomy, whereby blood is taken weekly (around 500 mL), and chelation therapy. The three chelating agents approved by the US Food and Drug Administration (FDA) are deferoxamine (DFO), deferiprone, and deferasirox. Side effects of these chelators are retinopathy and auditory toxicity, neutropenia and agranulocytosis, gastrointestinal issues, and liver and kidney toxicity, respectively . New treatments for Fe 3+/2+ overload conditions include the development of hepcidin mimetics or agonists that may lead to novel treatments for hereditary hemochromatosis, β-thalassemia, and other diseases of Fe 3+/2+ excess . With proven positive effects in pre-clinical studies, and with a phase I clinical trial in healthy individuals, the ferroportin inhibitor vamifeport is currently being studied as a new potential therapy .
|
[
"Adriana Fontes",
"Adrian T. Jauch",
"Judith Sailer",
"Jonas Engler",
"Anabela Marisa Azul",
"Hans Zischka"
] |
https://doi.org/10.3390/ijms25147880
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277342_p10
|
PMC11277342
|
sec[1]/sec[1]/p[0]
|
2.2. Zinc (Zn)
| 4.027344 |
biomedical
|
Study
|
[
0.9990234375,
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[
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The total amount of zinc (Zn) in an average adult is around 2.5 g (70 kg), with its major portion present in the musculoskeletal system (49.5%), followed by bone (36.7%), skin (4.2%), liver (3.4%), blood (1.5%), and brain (0.6%) . In plasma, Zn 2+ binds predominantly to albumin, α-macroglobulin, and Tf. Intracellularly, its majority is stored in Zn +2 -binding proteins in the cytosol .
|
[
"Adriana Fontes",
"Adrian T. Jauch",
"Judith Sailer",
"Jonas Engler",
"Anabela Marisa Azul",
"Hans Zischka"
] |
https://doi.org/10.3390/ijms25147880
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277342_p11
|
PMC11277342
|
sec[1]/sec[1]/p[1]
|
2.2. Zinc (Zn)
| 3.964844 |
biomedical
|
Study
|
[
0.9990234375,
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[
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Zinc absorption in the intestine is highly regulated, and typically 16% to 50% of Zn 2+ present in the diet is taken up systemically, depending on individual requirements . A meat-based diet promotes Zn 2+ absorption, while the presence of other metals (calcium and Fe 3+/2+ ) or phytates (source of phosphorus in seeds and plants, which form pH-dependent complexes with Zn 2+ ) can hinder its absorption .
|
[
"Adriana Fontes",
"Adrian T. Jauch",
"Judith Sailer",
"Jonas Engler",
"Anabela Marisa Azul",
"Hans Zischka"
] |
https://doi.org/10.3390/ijms25147880
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277342_p12
|
PMC11277342
|
sec[1]/sec[1]/p[2]
|
2.2. Zinc (Zn)
| 4.746094 |
biomedical
|
Study
|
[
0.99853515625,
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[
0.67578125,
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Since there is no body compartment dedicated to Zn 2+ storage, the metal needs to be constantly replenished from food, thus the balance between absorption and excretion is tightly controlled. Zinc loss occurs mainly via fecal and urinary excretion, menstrual flow in women, and semen in men, as well as loss through hair and nails, and skin desquamation . Zinc homeostasis is maintained between Zn transporters (ZnT-) and the Zrt-, Irt-like protein family (ZIP), as well as metallothioneins (MTs), whose expression is induced by Zn +2 via the metal regulatory transcription factor 1 (MTF-1). At the enterocyte level, ZIP4 transports Zn 2+ from the intestinal lumen, either to bind cytosolic MT for storage, or to be further transported to vesicles and ER by ZnTs. At the basolateral side, ZnT-1 exports Zn 2+ into the bloodstream, while ZIP5/ZIP14 may import Zn 2+ back into the cytosol . Zinc is a co-factor for over 300 proteins, participating in a multitude of physiological processes in the cell. It is involved in signal transduction for endocrine regulation, systemic growth, response to infection and inflammation, and cytokine production, as well as for gene regulation responsible for synaptic plasticity and neuronal death, mood, and memory regulation .
|
[
"Adriana Fontes",
"Adrian T. Jauch",
"Judith Sailer",
"Jonas Engler",
"Anabela Marisa Azul",
"Hans Zischka"
] |
https://doi.org/10.3390/ijms25147880
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277342_p13
|
PMC11277342
|
sec[1]/sec[1]/p[3]
|
2.2. Zinc (Zn)
| 4.542969 |
biomedical
|
Review
|
[
0.99609375,
0.0016937255859375,
0.0020427703857421875
] |
[
0.1319580078125,
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] |
Zinc also guides different metabolic functions that regulate obesity and diabetes . It is involved in insulin secretion and subsequent action in peripheral tissues. It also modulates the absorption of long-chain polyunsaturated fatty acids levels through its action in fatty acid absorption in the intestine and subsequent desaturation. Furthermore, Zn 2+ is important in the assembly and clearance of chylomicrons and lipoproteins . In ob/ob mice, an animal model for obesity, Zn 2+ concentrations were shown to be reduced in various tissues , and intestinal Zn 2+ absorption was slightly increased . Nonetheless, zinc and its supplementation as therapy in obesity is controversial. Zinc has been shown to increase body fat content and aggravate obesity in genetically obese and dietary-induced obese mice . Moreover, zinc plasma levels were found to be directly correlated with abdominal adiposity and liver fat , as well as with the risk of metabolic syndrome in patients, together with copper and iron . Also, studies with zinc supplementation in high-fat diet (HFD)-fed mice have reported different results. Bolatimi and co-workers showed that zinc supplementation in HFD-fed mice did not improve glucose handling, hepatic steatosis, or overall diet induced-liver injury (plasma transaminases) , whereas Qi et al. observed that zinc supplementation promoted glucose absorption, reduced lipid deposition, improved HFD-induced liver injury, and regulated energy metabolism . In patients with obesity, Khorsandi et al. demonstrated a beneficial effect on body weight and, more recently, Bashandy et al. reported that zinc nanoparticles reduced body weight, BMI, and leptin concentrations in an obese mouse model through a decrease in inflammation, insulin resistance, and Fe 2+ cardiac content, along with an increase in cardiac-reduced glutathione (GSH) and Cu + /Zn 2+ superoxide dismutase (SOD1) . Zinc supplementation was also found to have beneficial health effects in reducing the risk of digestive tract cancers and diabetes in adults .
|
[
"Adriana Fontes",
"Adrian T. Jauch",
"Judith Sailer",
"Jonas Engler",
"Anabela Marisa Azul",
"Hans Zischka"
] |
https://doi.org/10.3390/ijms25147880
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11277342_p14
|
PMC11277342
|
sec[1]/sec[1]/p[4]
|
2.2. Zinc (Zn)
| 4.300781 |
biomedical
|
Study
|
[
0.99951171875,
0.00020825862884521484,
0.00014531612396240234
] |
[
0.99072265625,
0.0004911422729492188,
0.00839996337890625,
0.00015461444854736328
] |
In the brain, high-dose Zn 2+ supplementation (60 ppm in water) in mice has been shown to induce hippocampal Zn 2+ deficiency. While being mechanistically unclear at present, this caused a deficit of synaptic releasable Zn 2+ , possibly leading to the inhibition of brain-derived neurotrophic factor (BDNF) signaling, resulting in learning and memory deficits . In Alzheimer’s patients, an increase in Zn 2+ abundance in the brain is associated with the accumulation of the amyloid β-peptide and disease severity . In bipolar disorder, in contrast, elevated serum Zn 2+ levels were observed in clinically stable patients . Thus, with respect to brain damage, both Zn deficiency and excess appear to be detrimental.
|
[
"Adriana Fontes",
"Adrian T. Jauch",
"Judith Sailer",
"Jonas Engler",
"Anabela Marisa Azul",
"Hans Zischka"
] |
https://doi.org/10.3390/ijms25147880
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277342_p15
|
PMC11277342
|
sec[1]/sec[1]/p[5]
|
2.2. Zinc (Zn)
| 4.371094 |
biomedical
|
Review
|
[
0.99365234375,
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] |
[
0.032135009765625,
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Zinc intoxication in humans is mostly due to acute, short-term exposure to Zn 2+ salts, often by attempted suicide, leading to severe gastrointestinal and pancreatic damage . Exposure to toxic industrial fumes containing Zn oxide may temporarily impair lung function; contact with Zn 2+ -containing products may provoke skin reactions; and highly concentrated Zn sulfate solutions (20%) may cause ocular damage . Chronic and sub-chronic Zn 2+ exposure is often related to unsupervised and/or long-term supplementation. In the intestine, Zn 2+ related up-regulation of MTs leads to MT-Cu binding which causes decreased Cu + absorption . In this scenario, Cu deficiency can be responsible for the development of anemia and neurological problems . Zinc intoxication can be treated using Zn chelators such as calcium disodium edetate (CaNa 2 EDTA) or diethylentriamene pentaacetate (DTPA). To directly target the symptoms of Zn 2+ intoxication, antiemetics, proton pump inhibitors (PPIs) and/or H2-blockers are administered in the case of oral ingestion. A whole-bowel irrigation can also be performed if significant gut burden is observed. Intoxication by inhalation is treated with antipyretics, oral hydration, and nonsteroidal anti-inflammatory drugs. Chronic Zn 2+ exposure is primarily treated with Cu sulfate and/or Zn chelators in more severe cases .
|
[
"Adriana Fontes",
"Adrian T. Jauch",
"Judith Sailer",
"Jonas Engler",
"Anabela Marisa Azul",
"Hans Zischka"
] |
https://doi.org/10.3390/ijms25147880
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277342_p16
|
PMC11277342
|
sec[1]/sec[2]/p[0]
|
2.3. Copper (Cu)
| 4.753906 |
biomedical
|
Study
|
[
0.9990234375,
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0.0004699230194091797
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[
0.90869140625,
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0.08831787109375,
0.0005793571472167969
] |
Copper (Cu) is taken up by the diet, with a daily average intake of around 1 mg, and a bioavailability of 65% to 70% . The body Cu 2+/+ content can be around 100 mg, mainly distributed amongst the liver (≈ 10 mg), muscle (≈ 28 mg), and bone tissue (≈ 46 mg) . Copper is an essential enzymatic co-factor, and approximately 54 Cu-binding proteins have been identified , with the most important/studied cuproenzymes being cytochrome c oxidase (CCO), tyrosinase, dopamine-β-hydroxylase, amine oxidase, lysyl oxidase, SOD1, hephaestin, and ceruloplasmin (Cp). These enzymes are fundamental in different metabolic pathways, such as cellular respiration, melanin synthesis, dopamine conversion, oxidoreductase activity, and Fe 3+/2+ metabolism . The balance between Cu + uptake, distribution, and excretion is well accomplished by the body, crucially involving the intestine and liver. Copper is mainly taken up via nutrition, at the proximal part of the intestine, where it is reduced by a specific family of metalloreductases, the STEAP proteins, and transported by the high-affinity copper transporter 1 (CTR1). Other transporters, like DMT1, or the low-affinity copper transporter 2 (CTR2), have been suggested to have a role in Cu + uptake as well; however, their exact mechanisms remain unclear .
|
[
"Adriana Fontes",
"Adrian T. Jauch",
"Judith Sailer",
"Jonas Engler",
"Anabela Marisa Azul",
"Hans Zischka"
] |
https://doi.org/10.3390/ijms25147880
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11277342_p17
|
PMC11277342
|
sec[1]/sec[2]/p[1]
|
2.3. Copper (Cu)
| 4.800781 |
biomedical
|
Study
|
[
0.99853515625,
0.0006494522094726562,
0.0005788803100585938
] |
[
0.9609375,
0.007259368896484375,
0.031158447265625,
0.0006785392761230469
] |
For distribution throughout the body, Cu + is first delivered via ATPase copper transporting alpha (ATP7A) from the enterocytes to the portal vein, where it binds to serum proteins, such as macroglobulin and albumin, or amino acids like histidine (His) . Afterwards, Cu + enters the liver via CTR1 . Intracellular Cu + binding and transfer amongst Cu-dependent proteins is regulated based on a gradient of increasing Cu-binding affinity . Such “Cu-chaperones” bind Cu + and transport them either to cytosolic enzymes or transporters that deliver Cu + to different enzymes in the cellular organelles . For instance, antioxidant protein 1 (ATOX1) is responsible for the transport of Cu + to ATP7A and ATPase copper-transporting beta (ATP7B) in the trans-Golgi network (TGN). There, apo-Cp can bind up to six Cu + atoms, turning into holo-Cp, that is responsible for the Cu + distribution to other tissues . Ceruloplasmin is considered a main copper distributor to other organs in the body, together with serum albumin, α-2-macroglobulin, and His-containing proteins . Also, ATOX1 is responsible for transferring Cu + to the nucleus or to secretory pathways via ATP7B. The copper chaperone for SOD1 (CCS) distributes Cu + to SOD1 in the cytosol and mitochondria, while a myriad of other different proteins (Cox17, Cox11, Sco1, and Sco2) are responsible for Cu + delivery to CCO into mitochondria .
|
[
"Adriana Fontes",
"Adrian T. Jauch",
"Judith Sailer",
"Jonas Engler",
"Anabela Marisa Azul",
"Hans Zischka"
] |
https://doi.org/10.3390/ijms25147880
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277342_p18
|
PMC11277342
|
sec[1]/sec[2]/p[2]
|
2.3. Copper (Cu)
| 4.296875 |
biomedical
|
Study
|
[
0.99951171875,
0.0002073049545288086,
0.0003604888916015625
] |
[
0.9697265625,
0.0269927978515625,
0.0029506683349609375,
0.0003178119659423828
] |
In a scenario of copper excess, Cu-ATPases (ATP7A and ATP7B) increase Cu + transport to the secretory pathways to be incorporated into cuproenzymes or translocate from the TGN to the vesicular compartment for Cu + excretion . Daily, and under physiological conditions, the bile transports around 0.6–6 mg Cu + into the gastrointestinal tract (GIT), with saliva and gastric and pancreatic juices accounting for 0.8 mg, and duodenal secretions accounting for 0.16 mg Cu + . Through the fecal route, 0.6–1.6 mg Cu + is eliminated, whereas only 0.05 mg are excreted via the urine .
|
[
"Adriana Fontes",
"Adrian T. Jauch",
"Judith Sailer",
"Jonas Engler",
"Anabela Marisa Azul",
"Hans Zischka"
] |
https://doi.org/10.3390/ijms25147880
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277342_p19
|
PMC11277342
|
sec[1]/sec[2]/p[3]
|
2.3. Copper (Cu)
| 4.203125 |
biomedical
|
Review
|
[
0.99853515625,
0.0009522438049316406,
0.0004551410675048828
] |
[
0.11328125,
0.0282440185546875,
0.8564453125,
0.0019102096557617188
] |
Copper excess can lead to various diseases, most prominently Wilson’s disease (WD), a rare autosomal recessive inherited metabolic disorder characterized by the pathological accumulation of Cu + due to mutations in the ATP7B gene , resulting in hepatic, neurologic, and/or psychiatric symptoms . The treatment of WD involves chelator agents (D-penicillamine and trientine) and zinc salts, aiming at avoidance of Cu + overload and its symptoms . In addition to WD, Indian childhood cirrhosis and idiopathic copper toxicosis are also characterized by Cu + excess, which are caused by a synergy of an autosomal-recessive inherited defect in Cu + metabolism and excess dietary Cu + intake .
|
[
"Adriana Fontes",
"Adrian T. Jauch",
"Judith Sailer",
"Jonas Engler",
"Anabela Marisa Azul",
"Hans Zischka"
] |
https://doi.org/10.3390/ijms25147880
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277342_p20
|
PMC11277342
|
sec[1]/sec[2]/p[4]
|
2.3. Copper (Cu)
| 3.886719 |
biomedical
|
Other
|
[
0.99169921875,
0.007541656494140625,
0.0006961822509765625
] |
[
0.0254669189453125,
0.8828125,
0.08612060546875,
0.005512237548828125
] |
Acute effects of excess Cu 2+ ingestion in humans include GIT symptoms such as nausea or abdominal pain, vomiting, and diarrhea . In more critical situations, the symptoms can progress to hepatic necrosis, neurological diseases, renal failure, and hematological and cardiovascular disorders . These cases are frequently associated with attempted suicide , and the treatment may rely on chelators, such as D-Penicillamine, dimercaprol, ethylenediaminetetraacetic acid (EDTA), and 2,3-dimercaptopropane-sulfonate. Therapy may also include gastric lavage, vasoactive and antiemetic drugs, and hemodialysis .
|
[
"Adriana Fontes",
"Adrian T. Jauch",
"Judith Sailer",
"Jonas Engler",
"Anabela Marisa Azul",
"Hans Zischka"
] |
https://doi.org/10.3390/ijms25147880
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11277342_p21
|
PMC11277342
|
sec[1]/sec[2]/p[5]
|
2.3. Copper (Cu)
| 4.1875 |
biomedical
|
Study
|
[
0.9990234375,
0.00040340423583984375,
0.0005397796630859375
] |
[
0.72509765625,
0.0008406639099121094,
0.273681640625,
0.0004057884216308594
] |
Chronic copper toxicity has also been documented in patients with renal failure receiving dialysis via copper tubing , upon exposure to pesticides containing copper , and in patients receiving intravenous total parenteral nutrition for long time periods . Altered Cu + levels have also been implicated in metabolic syndrome. Both low and high dietary intake have been proposed to increase the risk of developing obesity, referred to as a U-shaped association . In a cross-sectional study, Bulka et al. found a positive correlation between serum Cu + levels and abdominal obesity , which is supported by Fan et al. and Övermöhle et al., who showed a strong positive association between Cu + serum levels and obesity in children and adolescents . In general, the risk for the development of metabolic syndrome has been attributed to higher serum copper levels . Furthermore, urine copper was demonstrated to positively correlate with lipid accumulation products and the visceral adiposity-, body roundness-, conicity-, body adiposity-, and abdominal volume indices .
|
[
"Adriana Fontes",
"Adrian T. Jauch",
"Judith Sailer",
"Jonas Engler",
"Anabela Marisa Azul",
"Hans Zischka"
] |
https://doi.org/10.3390/ijms25147880
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277342_p22
|
PMC11277342
|
sec[1]/sec[3]/p[0]
|
2.4. Manganese (Mn)
| 4.3125 |
biomedical
|
Study
|
[
0.99951171875,
0.00025653839111328125,
0.0003399848937988281
] |
[
0.9267578125,
0.018890380859375,
0.05389404296875,
0.0005044937133789062
] |
The recommended oral intake of manganese (Mn) for adult men is 2.3 mg/day, and for adult women is 1.8 mg/day. The upper tolerable intake in adults is 11 mg/day, with toxicity being observed above 40 mg/day. Manganese can enter the body via absorption in the GIT tract (3% to 5% of ingested Mn 3+/2+ is further taken up, depending on the individual status), through the lungs after exposure to Mn-rich environments, as happens near smelters, or after dermal contact. Manganese also has the particularity of having 11 known oxidative states, ranging from −3 to +7, with Mn 3+/2+ as the most physiologically relevant states . In the gut, Mn 2+ is transported via DMT1, ZIPs (most prominently ZIP8 and ZIP14), and calcium channels. Manganese can also be absorbed as Mn +3 , bound to Tf, via the transferrin receptor .
|
[
"Adriana Fontes",
"Adrian T. Jauch",
"Judith Sailer",
"Jonas Engler",
"Anabela Marisa Azul",
"Hans Zischka"
] |
https://doi.org/10.3390/ijms25147880
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277342_p23
|
PMC11277342
|
sec[1]/sec[3]/p[1]
|
2.4. Manganese (Mn)
| 4.640625 |
biomedical
|
Study
|
[
0.99951171875,
0.0002884864807128906,
0.0002505779266357422
] |
[
0.9814453125,
0.0018796920776367188,
0.0165557861328125,
0.00026869773864746094
] |
For the basolateral transport in the intestine, it shares Fe +2 and Zn 2+ transporters such as ferroportin and zinc transporter 10 (Znt10) . Importantly, it is documented that Fe status influences Mn 3+/2+ metabolism, since they share both intestinal importers and exporters . In the human body, the amount of Mn 3+/2+ is around 10–20 mg, and its metabolism is highly dependent on the liver, where it accumulates and can be excreted via the bile (3.6 mg/day) . In blood, its concentration can range from 1.6 to 62.5 μg/L, depending on age, ethnicity, and gender . Manganese accumulates non-uniformly in the brain (5.32 to 14.03 μg/g wet weight), namely in the striatum, globus pallidus, substantia nigra, and hypothalamic nuclei . This essential trace element is involved in the synthesis and activation of various enzymes, regulation of glucose and lipid metabolism and acts as a cofactor for enzymes like arginase, glutamine synthase, and manganese superoxide dismutase (MnSOD) . The metalloenzyme MnSOD is localized in the mitochondria and is one of the most important antioxidant components in the cell. This enzyme catalyzes the dismutation of superoxide in hydrogen peroxide, which is further degraded by catalase (CAT) to form water and oxygen .
|
[
"Adriana Fontes",
"Adrian T. Jauch",
"Judith Sailer",
"Jonas Engler",
"Anabela Marisa Azul",
"Hans Zischka"
] |
https://doi.org/10.3390/ijms25147880
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11277342_p24
|
PMC11277342
|
sec[1]/sec[3]/p[2]
|
2.4. Manganese (Mn)
| 4.121094 |
biomedical
|
Study
|
[
0.99951171875,
0.00024247169494628906,
0.0002579689025878906
] |
[
0.7734375,
0.0016498565673828125,
0.2242431640625,
0.00046634674072265625
] |
Manganese imbalance, particularly Mn 2+ excess (hypermanganesemia), has been associated with neurological and behavioral defects as well as diseases such as Parkinson’s disease (PD) and manganism , and reproductive and respiratory problems in both humans and animals . Manganese dyshomeostasis has also recently been implicated in metabolic syndrome . Higher dietary Mn 3+/2+ intake has been shown to increase the risk of developing metabolic syndrome ; elevated blood levels of Mn 2+ were shown to correlate with increased visceral adipose tissue ; and urinary manganese was positively associated with metabolic syndrome in Asian women .
|
[
"Adriana Fontes",
"Adrian T. Jauch",
"Judith Sailer",
"Jonas Engler",
"Anabela Marisa Azul",
"Hans Zischka"
] |
https://doi.org/10.3390/ijms25147880
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277342_p25
|
PMC11277342
|
sec[1]/sec[3]/p[3]
|
2.4. Manganese (Mn)
| 4.3125 |
biomedical
|
Review
|
[
0.99853515625,
0.0008540153503417969,
0.0005068778991699219
] |
[
0.182861328125,
0.00733184814453125,
0.80859375,
0.001155853271484375
] |
On one hand, as an important co-factor for MnSOD, its deficiency can lead to mitochondrial dysfunction due to a decreased capacity for reactive oxygen species (ROS) scavenging. On the other hand, being a highly reactive element, in excess, it can cause an increase in ROS production, ultimately damaging mitochondria . Manganese intoxication can occur in individuals with chronic liver disease due to the failure of its hepatic clearance, and upon prolonged total parenteral nutrition, where excessive Mn 2+ amounts bypass the hepatic filter and enter the bloodstream . Furthermore, occupational exposure to excess Mn 7+/3− poses a risk for factory workers, miners, and welders . Other human activities can expose individuals to high Mn 7+/3− , including the use of fungicides, medical imaging contrast agents and water purification agents, the combustion of gasoline, and Mn-containing emissions from contaminated soil, dust, and plants near roadways. Treatment for Mn 3+/2+ intoxication is based on chelation therapy with EDTA and, in some cases, administration of Fe 3+/2+ can be used in combination with chelators . In Chinese patients, para-amino salicylic acid (PAS) proved to be a promising treatment for severe Mn intoxication .
|
[
"Adriana Fontes",
"Adrian T. Jauch",
"Judith Sailer",
"Jonas Engler",
"Anabela Marisa Azul",
"Hans Zischka"
] |
https://doi.org/10.3390/ijms25147880
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11277342_p26
|
PMC11277342
|
sec[2]/p[0]
|
3. Essential Transition Metals and Oxidative Stress
| 3.962891 |
biomedical
|
Study
|
[
0.99951171875,
0.00023090839385986328,
0.0004165172576904297
] |
[
0.626953125,
0.291748046875,
0.0804443359375,
0.0008769035339355469
] |
Metal toxicity has been linked to oxidative stress . In cells, the generation of ROS is a physiologic mechanism derived from the utilization of oxygen by different metabolic reactions . In response, the antioxidant enzymes control the harmful effects of ROS , which may also lead to DNA damage, lipid peroxidation, mitochondrial dysfunction, and cell death .
|
[
"Adriana Fontes",
"Adrian T. Jauch",
"Judith Sailer",
"Jonas Engler",
"Anabela Marisa Azul",
"Hans Zischka"
] |
https://doi.org/10.3390/ijms25147880
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277342_p27
|
PMC11277342
|
sec[2]/p[1]
|
3. Essential Transition Metals and Oxidative Stress
| 4.421875 |
biomedical
|
Study
|
[
0.99951171875,
0.0002472400665283203,
0.0001456737518310547
] |
[
0.9921875,
0.0005478858947753906,
0.00690460205078125,
0.0001964569091796875
] |
The labile Fe 2+ pool can be present in different cellular compartments, such as cytosol, mitochondria, and lysosomes, and prompts the participation of the metal in reactions of oxidation and reduction, which can catalyze the formation of hydroxyl radicals (OH) from hydrogen peroxide via the Fenton and Haber/Weiss reactions . Iron overload was shown to cause oxidative stress in skeletal muscles, delayed muscle regeneration, decreased expression of myoblast differentiation markers, and decreased phosphorylation of MAPK signaling pathways in a mouse model of cardiotoxin-induced muscle regeneration . An increase in ROS, as well as decreased insulin signaling, was observed upon iron treatment of mouse hepatocytes . Additionally, oxidative stress related to iron toxicity was implicated in neurodegeneration , kidney injury , and delayed spinal cord regeneration .
|
[
"Adriana Fontes",
"Adrian T. Jauch",
"Judith Sailer",
"Jonas Engler",
"Anabela Marisa Azul",
"Hans Zischka"
] |
https://doi.org/10.3390/ijms25147880
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277342_p28
|
PMC11277342
|
sec[2]/p[2]
|
3. Essential Transition Metals and Oxidative Stress
| 4.210938 |
biomedical
|
Study
|
[
0.99951171875,
0.00018739700317382812,
0.00017952919006347656
] |
[
0.9931640625,
0.00031495094299316406,
0.006320953369140625,
0.00010943412780761719
] |
In mitochondria, biogenesis of Fe-sulfur cluster proteins, which are fundamental for their function, are highly sensitive to an increase in ROS and Fe 3+/2+ levels . To this end, it is not unforeseen that Fe-induced oxidative stress led to mitochondrial dysfunction in cardiac tissues. Chan and co-workers observed decreased mitochondrial function and increased oxidative stress in embryonic heart H9C2 cells, plus opening of the mitochondrial permeability transition pore in ventricular myocytes from mice treated with Fe 3+ /8-hydroxyquinoline. Furthermore, Gordan et al. described arrhythmias in ex-vivo mouse hearts, also upon treatment with Fe 3+ /8-hydroxyquinoline . A reduced respiratory capacity of hepatic mitochondria, together with an increase in ROS was observed by Volani and co-workers in mice fed with an Fe-enriched diet for two weeks .
|
[
"Adriana Fontes",
"Adrian T. Jauch",
"Judith Sailer",
"Jonas Engler",
"Anabela Marisa Azul",
"Hans Zischka"
] |
https://doi.org/10.3390/ijms25147880
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277342_p29
|
PMC11277342
|
sec[2]/p[3]
|
3. Essential Transition Metals and Oxidative Stress
| 4.390625 |
biomedical
|
Study
|
[
0.99951171875,
0.00022733211517333984,
0.00020062923431396484
] |
[
0.9931640625,
0.00047087669372558594,
0.00620269775390625,
0.00014221668243408203
] |
For Cu 2+/+ , in the case of an intracellular elevation of the metal, GSH and MTs bind it with high affinity , largely avoiding the involvement of non-bound Cu + in Fenton-based reactions. For a long time, oxidative stress was considered as the main mechanism of cellular damage in Cu-overload toxicity, as happens in WD. However, decreased activity of antioxidant enzymes, with increased lipid peroxidation and DNA damage were only observed at later stages of the disease, in both WD patients and animal models . Moreover, studies in yeast showed that free Cu + concentration is less than 10 −18 M, which corresponds to less than one free Cu + atom per cell, rendering the cellular free Cu + pool practically nonexistent . Therefore, even in copper stress conditions, the cellular response capacity towards Cu-related oxidative damage has proven efficient, at least in an early disease state .
|
[
"Adriana Fontes",
"Adrian T. Jauch",
"Judith Sailer",
"Jonas Engler",
"Anabela Marisa Azul",
"Hans Zischka"
] |
https://doi.org/10.3390/ijms25147880
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277342_p30
|
PMC11277342
|
sec[2]/p[4]
|
3. Essential Transition Metals and Oxidative Stress
| 4.441406 |
biomedical
|
Study
|
[
0.99951171875,
0.0003180503845214844,
0.00023865699768066406
] |
[
0.9970703125,
0.00028014183044433594,
0.002376556396484375,
0.0001239776611328125
] |
Mitochondria are indeed a preferential target for Cu + toxicity in cells. New evidence shows that specific proteins in the mitochondria could be targets for Cu + , namely thiol-rich or lipoylated proteins , resulting in proteotoxic stress and cell death . In a study by Borchard and co-workers, it was observed that mitochondria isolated from brain tissue were more sensitive to Cu + challenges in comparison to those from heart, kidney, and liver tissue. Mitochondria structural alterations were present upon in vitro treatments, with a Cu/GSH ratio of 1:10, i.e., at reducing conditions, thereby ruling out a Fenton chemistry-based mechanism of destruction. Interestingly, a significant emergence of ROS was only detected upon treatment with a Cu/GSH ratio of 5:10, which would hardly occur in vivo . Such results clearly argue for a thiol/protein-directed attack of Cu + as the toxic mechanism, and not for an undirected overwhelming oxidative stress via Cu-induced Fenton chemistry. Furthermore, other mechanisms for Cu-induced toxicity were described, such as the interference with cellular signaling pathways, like the mitogen-activated protein kinases (MAPKs) pathway , or the induction of apoptosis via the mitochondria apoptotic pathway .
|
[
"Adriana Fontes",
"Adrian T. Jauch",
"Judith Sailer",
"Jonas Engler",
"Anabela Marisa Azul",
"Hans Zischka"
] |
https://doi.org/10.3390/ijms25147880
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277342_p31
|
PMC11277342
|
sec[2]/p[5]
|
3. Essential Transition Metals and Oxidative Stress
| 4.738281 |
biomedical
|
Study
|
[
0.998046875,
0.0009407997131347656,
0.0008549690246582031
] |
[
0.9072265625,
0.001087188720703125,
0.09100341796875,
0.0006766319274902344
] |
In the case of Zn 2+ , although it is generally considered a redox-inert metal, it serves as a co-factor for several enzymes that participate in redox reactions, namely SOD1. It has a complex and important role in the oxidative stress balance in cells, both as an antioxidant and as a prooxidant . In the form of Zn 2+ , it can bind to and inhibit mitochondria complex I, III, and IV, which can result in decreased ATP production, increased mitochondrial membrane permeability transition (MPT), and ROS generation . Moreover, Zn 2+ overload can impact glycolysis by inhibition of glyceraldehyde 3-phosphate dehydrogenase (GAPDH), pyruvate kinase, and phosphofructokinase . Due to allosteric similarities, zinc can also compete for copper and iron binding sites, causing its misplacement in a scenario of Zn 2+ overload . Overall, excessive Zn 2+ directly affects several signaling pathways that ultimately lead to disruption of cellular homeostasis . Chen et al. reported that Zn sulfate elicited oxidative stress, decreased mitochondrial membrane potential and induced the activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) phosphorylation, lipid peroxidation, and DNA oxidation in human neuroblastoma cells . Slepchenko and co-workers also observed an increase in ROS upon zinc treatment in HeLa cells subjected to hypoxia. In this study, the inhibition of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity significantly decreased Zn-induced ROS, which led the authors to hypothesize that intracellular activation of this enzyme by zinc triggers mitochondrial ROS production . In agreement, Noh et al. showed that Zn 2+ overload induced NADPH oxidase activation in a protein kinase C (PKC)-dependent manner, possibly contributing to the increased generation of ROS in mouse cortical cultures . In a study by Pan et al., zinc was also shown to induce mitochondrial ROS, as well as decreased mitochondrial membrane potential in hypoxia-induced astrocytes .
|
[
"Adriana Fontes",
"Adrian T. Jauch",
"Judith Sailer",
"Jonas Engler",
"Anabela Marisa Azul",
"Hans Zischka"
] |
https://doi.org/10.3390/ijms25147880
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277342_p32
|
PMC11277342
|
sec[2]/p[6]
|
3. Essential Transition Metals and Oxidative Stress
| 4.40625 |
biomedical
|
Study
|
[
0.9990234375,
0.00037097930908203125,
0.00037384033203125
] |
[
0.97265625,
0.00048422813415527344,
0.026580810546875,
0.0002123117446899414
] |
Manganese, as an essential redox-active trace metal, has also been implicated in inducing oxidative stress in cellular systems. A time-dependent increase in intracellular ROS/reactive nitrogen species (RNS), decreased GSH content, and impaired mitochondria function was reported by Neely et al. in human-induced pluripotent stem cell-derived postmitotic mesencephalic dopamine neurons after treatment with MnCl 2 . Nuclear localization and subsequent binding of nuclear factor erythroid 2 (Nrf2) to the antioxidant-responsive element leading to heme oxygenase-1 (HO-1) was observed by Li and co-workers in rat catecholaminergic cells upon exposure to 300 μM MnCl 2 . In a study by Tan et al., increasing doses of MnSO 4 led to a decrease in SOD, glutathione peroxidase (GPx), and CAT activities, while the levels of malondialdehyde (MDA) were upregulated in rat adrenal pheochromocytoma-derived cells. Moreover, cell apoptosis was significantly increased, as shown by the significant decrease in B-cell lymphoma 2 (Bcl-2) and caspase-3 mRNA levels, while Bcl-2-associated X protein (Bax) mRNA levels increased . In addition, Liu and co-workers have also shown that Mn 2+ induced a significant increase in H 2 O 2 production in the mitochondria of rat microglia cells through suppression of complex II .
|
[
"Adriana Fontes",
"Adrian T. Jauch",
"Judith Sailer",
"Jonas Engler",
"Anabela Marisa Azul",
"Hans Zischka"
] |
https://doi.org/10.3390/ijms25147880
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277342_p33
|
PMC11277342
|
sec[3]/sec[0]/p[0]
|
4.1. Iron (Fe)
| 4.621094 |
biomedical
|
Study
|
[
0.99755859375,
0.001255035400390625,
0.00141143798828125
] |
[
0.591796875,
0.001735687255859375,
0.4052734375,
0.001018524169921875
] |
Iron is a redox-active essential transition metal that is indispensable for several biological processes, but can also induce oxidative stress when in excess . Rhee et al. showed that the DMT1 inhibitor and antioxidant ebselen prevented intracellular Fe 2+ uptake and decreased ROS production in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) subjected to Fe 3+/2+ overload. In humans, iron overload induced arrhythmia and contractile dysfunction, similarly to the effects observed in the cardiomyocytes . Natural flavonoids like quercetin (and some derivates), catechin, and rutin had a positive antioxidant effect on iron excess in human red blood cells. In this study by Cherrak et al., Fe 3+ and Zn 2+ had an enormous prooxidant effect (37% and 33% induced hemolysis, respectively), while treatment with the flavonoids had a pronounced antioxidant activity against iron, as measured by levels of hemolysate-reduced GSH and MDA, as well as CAT activity . Flavonoids have been repeatedly shown to protect against Fe toxicity, either by direct metal chelation or by scavenging of oxidant species . In pre-clinical models, depending on the compound, different effects were described. Wang and co-workers observed that treatment with myricetin reduced iron content and inhibited transferrin receptor 1 (TfR1) in human neuroblastoma cells, and significantly reversed scopolamine-induced cognitive deficits in a mouse model of Alzheimer’s disease . In two different studies, myricetin , present in tomatoes, oranges, nuts, berries, tea and red wine, significantly inhibited hepcidin expression in vitro and in vivo , thereby possibly preventing iron accumulation in the brain . Two different dithiolethiones (D3T and ACDT), present in cruciferous vegetables, exhibited antioxidant activity by activating Nrf2 transcription factor and upregulating GSH levels, which protected human glioblastoma cells (U-87) from Fe-induced toxicity. Furthermore, Kulkarni and co-workers showed that D3T and ACDT could upregulate the expression of Nrf2-mediated iron storage protein ferritin, resulting in a reduced total labile Fe 2+ pool, therefore preventing ferroptosis-induced cell death by erastin . Molinari et al. reported the combined action of lipoic acid , present in foods such as red meat, carrots, beets, spinach, broccoli and potatoes, and vitamin D to decrease intracellular iron content and ROS production in primary mouse astrocytes. Furthermore, p53 activity, amyloid precursor protein and SOD1 content was significantly reduced in comparison to the Fe-treated control .
|
[
"Adriana Fontes",
"Adrian T. Jauch",
"Judith Sailer",
"Jonas Engler",
"Anabela Marisa Azul",
"Hans Zischka"
] |
https://doi.org/10.3390/ijms25147880
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277342_p34
|
PMC11277342
|
sec[3]/sec[0]/p[1]
|
4.1. Iron (Fe)
| 4.230469 |
biomedical
|
Study
|
[
0.99853515625,
0.0007576942443847656,
0.0005855560302734375
] |
[
0.51611328125,
0.0014753341674804688,
0.48193359375,
0.0006546974182128906
] |
The amino acid taurine , enriched in shellfish, turkey and chicken, has an important role in aging, cardiovascular health, neuroprotection, and cellular function, as shown in murine models and humans in a detailed overview by Santulli et al. . The benefits of taurine are correlated with its capacity to act as an osmolyte, regulating cell volume and maintaining cell integrity; its antioxidant properties; and its role in calcium signaling and neurotransmission, as well as in bile acid metabolism . Zhang et al. also described the hepatoprotective properties of taurine in an iron-overload murine model . Quercetin , enriched in capers, is one of the most reported antioxidant compounds for Fe-overload treatment, with proven positive effects in iron depletion and oxidative stress in rats, mice, and human carcinoma cell lines . In thalassemia patients under DFO therapy, Sajadi et al. reported that 500 mg/day of quercetin for 12 weeks reduced high-sensitivity C-reactive protein, Fe content, ferritin and Tf saturation, and increased Tf levels in serum, in comparison to non-treated controls . Moreover, in thalassemia patients at risk of suffering from iron toxicity due to blood transfusions, treatment with a combination of DFO and silymarin from milk thistle for 9 months significantly decreased serum ferritin levels, serum Fe 3+/2+ , and total Fe-binding capacity, in comparison with the placebo group (DFO-alone). Serum hepcidin and soluble Tf were also significantly decreased in the silymarin-treated group, with improvement in overall liver function, in comparison to placebo .
|
[
"Adriana Fontes",
"Adrian T. Jauch",
"Judith Sailer",
"Jonas Engler",
"Anabela Marisa Azul",
"Hans Zischka"
] |
https://doi.org/10.3390/ijms25147880
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277342_p35
|
PMC11277342
|
sec[3]/sec[1]/p[0]
|
4.2. Zinc (Zn)
| 4.320313 |
biomedical
|
Study
|
[
0.9990234375,
0.0004203319549560547,
0.0004329681396484375
] |
[
0.8388671875,
0.0009169578552246094,
0.1600341796875,
0.00040459632873535156
] |
Zinc plays an important role in human health, and it has anti-oxidant and anti-inflammatory properties . In contrast to other essential transition metals, such as Fe 3+/2+ and Cu 2+/+ , few conditions are linked to Zn 2+ overload, whether the consequences are related to oxidative stress or not. Nonetheless, some studies have reported the potential of antioxidant therapies to ameliorate Zn-related toxicity. Deore and co-workers showed that administration of α-lipoic acid (15 mg/kg bw) for 15 days improved the levels of SOD, CAT, GSH and GPx, and decreased ROS in spleen and brain tissue of rats treated with zinc oxide nanoparticles (ZnONP), 100 mg/kg bw, for 28 days. Also, the augmented levels of tumor necrosis factor alpha (TNF-α) and interleukins (IL-1β, IL-4, and IL-6) were decreased in rat brain and spleen tissue upon α-lipoic acid treatment . An improvement of the cerebellum structure, together with reduced oxidative stress, e.g., MDA, GPx, and nitric oxide (NO) levels, autophagy (caspase 3, p53) and inflammatory response (IL-1, IL-6, TNF-α), was observed by Amer et al. after pre-treatment with curcumin (200 mg/kg diet), enriched in turmeric root, in rats exposed to ZnONP (5.6 mg/kg bw) for 28 days. However, no differences in brain Zn 2+ levels were observed upon pre-treatment . Other studies also reported reduced lipid peroxidation, improved oxidative defense systems (SOD and GPx), and reduced apoptosis in rats pre-treated with curcumin (200 mg/kg in the food) and afterwards exposed to ZnONP . The use of ZnONP in different applications such as cosmetics, electronics, and in the chemical and medical industry has raised concerns for its potential toxicity for various organisms, from algae and fish to humans. Particularly in mammalian cells, several studies have found that ROS play a key role in ZnONP toxicity , which further supports the use of antioxidants as a potential remedy.
|
[
"Adriana Fontes",
"Adrian T. Jauch",
"Judith Sailer",
"Jonas Engler",
"Anabela Marisa Azul",
"Hans Zischka"
] |
https://doi.org/10.3390/ijms25147880
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277342_p36
|
PMC11277342
|
sec[3]/sec[2]/p[0]
|
4.3. Copper (Cu)
| 4.464844 |
biomedical
|
Study
|
[
0.9990234375,
0.00041222572326660156,
0.00037169456481933594
] |
[
0.95849609375,
0.0006160736083984375,
0.040374755859375,
0.0002980232238769531
] |
In similarity to Fe 3+/2+ , Cu 2+/+ is also a redox-active essential transition metal that participates in different cellular processes, mostly mitochondrial ROS scavenging and oxidative phosphorylation, as well as different nuclear signaling pathways. Nevertheless, elevated Cu 2+/+ levels can be toxic and lead to proteotoxic stress and ultimately cell death. Several natural compounds have been investigated for their antioxidant properties in the context of Cu 2+/+ toxicity. A combination of bioactive antioxidant compounds (resveratrol, ferulic acid, phloretin, and tetrahydrocurcuminoids) , improved cellular viability, increased proliferation, and decreased total ROS emergence in human oral fibroblasts treated with CuCl 2 . Tamagno et al. further showed that the use of an antioxidant-rich pitaya fruit extract ameliorated Cu-induced toxicity in organisms like Caenorhabditis elegans by enhancing the antioxidant system . Treatment with this extract decreased the activity of acetylcholinesterase (AChE), lipid peroxidation, and the levels of SOD and CAT that were elevated upon Cu exposure . A concomitant treatment of the same pitaya extract with 0.7 mg/L Cu 2+ for four days in zebrafish decreased glutathione S-transferase (GST) and CAT activity in brain tissue, while SOD activity was increased. In gut tissue, GST activity was increased upon treatment, while CAT activity was also decreased, in comparison with zebrafish Cu-treated controls . The activity of AChE and δ-aminolevulinate dehydratase was increased in the brain, while the cortisol levels in the whole body were decreased upon co-treatment with the extract . Moreover, Azeez and co-workers reported that the treatment with vitamin E , in the presence of Cu-sulphate, improved body weight, GPx and GST activity, while decreasing H 2 O 2 and MDA levels in the liver of Clarias gariepinus (African catfish), in comparison with Cu-treated controls . A 21-day treatment with silymarin encapsulated in a liposomal formulation (0.5 mg/kg bw, twice daily) improved liver dysfunction and neurobehavioral abnormalities associated with Cu-toxicity in rats given Cu-sulphate (200 mg/kg bw daily) for 90 days .
|
[
"Adriana Fontes",
"Adrian T. Jauch",
"Judith Sailer",
"Jonas Engler",
"Anabela Marisa Azul",
"Hans Zischka"
] |
https://doi.org/10.3390/ijms25147880
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277342_p37
|
PMC11277342
|
sec[3]/sec[2]/p[1]
|
4.3. Copper (Cu)
| 4.144531 |
biomedical
|
Review
|
[
0.99658203125,
0.00142669677734375,
0.0018320083618164062
] |
[
0.07666015625,
0.0009093284606933594,
0.921875,
0.00040268898010253906
] |
In a widely used rat model for Cu-overload in LEC rats, therapeutic antioxidant strategies to improve liver damaged were reviewed by Zischka et al. . From the collected evidence, linolenic and linoleic acid supplemented in the diet for 10 weeks reduced the incidence of hepatitis and delayed its onset for one month. However, no effect was observed with regards to oxidative stress . In a study by Yamamoto et al., treatment with lipoic acid dose-dependently reduced liver damage and increased GPx, glutathione reductase (GR), and SOD1 activity, while decreasing lipid peroxidation. A decrease in Cu + and Fe 2+ content was also observed, but only in mitochondria . Kitamura and co-workers showed that N-acetylcysteine (NAC) had a positive effect in LEC rats by decreasing the Cu/Fe ratio, as well as liver and kidney damage. However, the authors hypothesized that this effect is most likely linked to metal chelation rather than ROS scavenging . Overall, most antioxidant therapies had only a mild effect in vivo, inducing some delay in the onset of hepatitis, but not reverting liver damage or oxidative stress .
|
[
"Adriana Fontes",
"Adrian T. Jauch",
"Judith Sailer",
"Jonas Engler",
"Anabela Marisa Azul",
"Hans Zischka"
] |
https://doi.org/10.3390/ijms25147880
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277342_p38
|
PMC11277342
|
sec[3]/sec[3]/p[0]
|
4.4. Manganese (Mn)
| 4.046875 |
biomedical
|
Study
|
[
0.99951171875,
0.00029468536376953125,
0.0003514289855957031
] |
[
0.58544921875,
0.005420684814453125,
0.40869140625,
0.0006527900695800781
] |
Manganese can induce oxidative stress in cells via H 2 O 2 production and disruption of different cellular functions such as mitochondria respiration and dopamine oxidation . This effect is particularly described for the brain, with Mn 2+ being associated with neurological problems that are currently attributed mostly to oxidative damage but also to the impairment of several neurotransmitter systems, especially dopaminergic, but also cholinergic and GABAergic . To this end, potential antioxidant therapies have been explored in the context of Mn toxicity.
|
[
"Adriana Fontes",
"Adrian T. Jauch",
"Judith Sailer",
"Jonas Engler",
"Anabela Marisa Azul",
"Hans Zischka"
] |
https://doi.org/10.3390/ijms25147880
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277342_p39
|
PMC11277342
|
sec[3]/sec[3]/p[1]
|
4.4. Manganese (Mn)
| 4.5 |
biomedical
|
Study
|
[
0.99853515625,
0.0007953643798828125,
0.0009121894836425781
] |
[
0.673828125,
0.0013799667358398438,
0.323974609375,
0.0006656646728515625
] |
Chtourou et al. observed the beneficial effects of the flavonoid silymarin against Mn-induced, radical-mediated cell death in murine neuroblastoma cells . Co-treatment with silymarin for 24 h improved cellular viability, reduced cellular H 2 O 2 levels, and improved MnSOD, SOD1, CAT, and GPx enzymatic activities . A methanolic extract of Acaí (most probably due to its anthocyanins) was reported by da Silva Santos et al. to reduce neurotoxicity in rat primary astrocytes by restoring the GSH/GSSG ratio and net glutamate uptake, and protecting the cell membranes from lipid peroxidation and Nrf2 activation by Mn-exposure. However, higher concentrations of the extract exacerbate the negative effects of Mn 2+ , further pointing to the importance of dosing . Stephenson and co-workers showed that pre-treatment with NAC or GSH reduces the DNA damage induced dose-dependently by Mn 2+ in human neuroblastoma cells . The natural flavonoid quercetin prevented Mn-induced oxidative stress in the hypothalamus, cerebrum, and cerebellum in the brains of rats, which was characterized by increased H 2 O 2 and MDA levels, and decreased antioxidant enzyme activity (measured SOD and CAT), with the animals presenting pronounced locomotor impairment and increased AChE activity . Moreover, Bahar et al. observed that pre-treatment with quercetin improved cellular viability and decreased ROS production and MDA levels, while increasing SOD, CAT, and GSH activity in human neuroblastoma cells treated with Mn 2+ . Furthermore, an improvement in mitochondrial function, and a decrease in apoptosis was observed in the cells. A reduction in inflammatory factors was also observed in both cells and rats treated with quercetin. Particularly in the animals, TNF-α, IL-1β, IL-6, and iNOS protein expression in the brain was reduced in comparison to Mn-treated controls. The mRNA levels of NF-kB and inducible nitric oxide synthase (iNOS) were reduced, while HO-1 and Nrf2 were increased in brain tissue, upon treatment. Lastly, quercetin treatment reduced the apoptotic marker expression in the rats, as observed by the decreased protein expression of Bax, cytochrome C, caspase 3, and poly(ADP-ribose)-polymerase 1 (PARP-1) in the brain . The neurohepatic protective effects of the carotenoid lycopene were studied by Lebda et al. in rats treated daily with Mn 2+ for 4 weeks, after 20-days of lycopene supplementation. No significant changes were observed in Mn 2+ content in the serum, liver, or brain tissue. But ALT, AST, AChE, and glucose levels were decreased in the serum of pretreated animals in comparison to Mn-treated controls . In the liver and brain, lipid peroxidation was decreased, while GSH, GST and CAT levels were increased as consequence of lycopene pretreatment. The amount of AChE in the brain was increased with Mn 2+ exposure, and further decreased with the therapeutic intervention . Cordova and co-workers explored the potential positive effects of the hydrophilic vitamin E analog Trolox on the central nervous system of rodents and cell cultures exposed to Mn 2+ . A concomitant addition of Trolox and Mn 2+ to rat pups (8 days old) decreased caspase activity and oxidative stress (by F2-isoprostrane quantification) in the striatum, while reversing the motor coordination deficits observed in the animals treated with Mn 2+ . The positive effects of Trolox and NAC were also observed by Marreilha et al. in immortalized rat brain microvessel endothelial cells exposed to Mn 2+ . Co-treatment with the antioxidants for 24 h improved Mn-induced loss of cell viability and reduced the content of thiol-rich proteins such as GSH . Milatovic and co-workers also reported the neuroprotective effect of Trolox pre-treatment in rats (primary cultures and in vivo treatment) against oxidative damage and ATP depletion caused by the presence of Mn 2+ . In humans, treatment for three and a half months with sodium para-aminosalicylic acid, 6 g/day, intravenously (4 days treatment, 3 days pause) significantly improved neurological issues such as tremor, muscular tension, difficulties with writing and speaking, and gait and grip capacity, amongst others, derived from chronic exposure to Mn 2+ .
|
[
"Adriana Fontes",
"Adrian T. Jauch",
"Judith Sailer",
"Jonas Engler",
"Anabela Marisa Azul",
"Hans Zischka"
] |
https://doi.org/10.3390/ijms25147880
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277342_p40
|
PMC11277342
|
sec[3]/sec[3]/p[2]
|
4.4. Manganese (Mn)
| 3.675781 |
biomedical
|
Review
|
[
0.9990234375,
0.0003437995910644531,
0.0007433891296386719
] |
[
0.1842041015625,
0.043792724609375,
0.77099609375,
0.0008368492126464844
] |
Table 1 summarizes the most relevant antioxidant compounds reported to ameliorate the oxidative damage caused by iron, copper, and manganese and their respective positive effects in pre-clinical and clinical studies, as described in the text.
|
[
"Adriana Fontes",
"Adrian T. Jauch",
"Judith Sailer",
"Jonas Engler",
"Anabela Marisa Azul",
"Hans Zischka"
] |
https://doi.org/10.3390/ijms25147880
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277342_p41
|
PMC11277342
|
sec[4]/p[0]
|
5. Conclusions
| 4.25 |
biomedical
|
Review
|
[
0.99609375,
0.0017337799072265625,
0.001972198486328125
] |
[
0.036346435546875,
0.0015153884887695312,
0.9619140625,
0.0003898143768310547
] |
Essential transition metals play key roles in cellular metabolism. As enzymatic co-factors, they interfere with lipid and glucose metabolism, mitochondrial function, transcription, protein synthesis, and cellular renewal processes, among others. However, excess caused by genetic mutations, environmental exposure, or over-supplementation can be detrimental and even fatal if untreated. Apart from traditional chelation therapies, the use of antioxidants as a treatment strategy for metal toxicity is supported by research that demonstrated its efficacy in alleviating oxidative damage. Nonetheless, such investigation was mostly done in pre-clinical models, with studies in humans showing the potential of antioxidant therapies almost nonexistent. The reason could be related to the high molecular complexity of metal-induced oxidative stress and the knowledge still lacking in terms of how transition metals, such as manganese, act. Moreover, most of the information available report beneficial effects of antioxidants before the metal insult, or as a co-treatment. The use of antioxidants as a treatment in the case of metal overload and toxicity needs to be thoroughly addressed in future studies.
|
[
"Adriana Fontes",
"Adrian T. Jauch",
"Judith Sailer",
"Jonas Engler",
"Anabela Marisa Azul",
"Hans Zischka"
] |
https://doi.org/10.3390/ijms25147880
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277342_p42
|
PMC11277342
|
sec[4]/p[1]
|
5. Conclusions
| 3.291016 |
biomedical
|
Other
|
[
0.998046875,
0.0007309913635253906,
0.0013933181762695312
] |
[
0.0360107421875,
0.85791015625,
0.1051025390625,
0.0012044906616210938
] |
A potentially promising approach could be the combination of antioxidants with chelating agents, addressing both metal overload and oxidative stress. Clearly, with the current rise of uncontrolled and unsupervised supplementation, as well as the increasing evidence of toxicity by these metals, more efficient therapeutic countermeasures need to be developed.
|
[
"Adriana Fontes",
"Adrian T. Jauch",
"Judith Sailer",
"Jonas Engler",
"Anabela Marisa Azul",
"Hans Zischka"
] |
https://doi.org/10.3390/ijms25147880
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277355_p0
|
PMC11277355
|
sec[0]/p[0]
|
1. Introduction
| 4.4375 |
biomedical
|
Study
|
[
0.9990234375,
0.0005998611450195312,
0.0003857612609863281
] |
[
0.7919921875,
0.0049285888671875,
0.2022705078125,
0.0006694793701171875
] |
Solid tumors are biologically complex structures with substantial intratumor heterogeneity that contain transformed cancer cells, supportive cells, and tumor-infiltrating cells . Also, tumor cells significantly differ in the potency to initiate and maintain tumor growth, with stem-like cancer cells exhibiting the highest self-renewal potency, responding rapidly and flexibly to environmental challenges and becoming a primary source of drug-resistant tumor cells . Stem cell-associated molecular features of cancer cells might be acquired by the bulk tumor cells, i.e., in response to exogenous stimuli. Later on, those cells may experience phases of transitions between stem-like and non-stem-like states without any additional genetic perturbations. This phenomenon of stemness acquisition and maintenance robustly contributes to cancer cell heterogeneity, ultimately warranting drug resistance and tumor relapse .
|
[
"Kacper Maciejewski",
"Marek Giers",
"Urszula Oleksiewicz",
"Patrycja Czerwinska"
] |
https://doi.org/10.3390/ijms25147841
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277355_p1
|
PMC11277355
|
sec[0]/p[1]
|
1. Introduction
| 4.296875 |
biomedical
|
Study
|
[
0.99853515625,
0.0006561279296875,
0.0006160736083984375
] |
[
0.5185546875,
0.0014791488647460938,
0.4794921875,
0.0005736351013183594
] |
Previous studies aimed to characterize the populations of cancer cells with stem-like properties (known as cancer stem cells, CSCs) in diverse tumor types, including breast , lung , liver , pancreatic , gliomas , melanomas , and many other tumors . The stem cell-associated molecular features of solid tumors, also known as cancer stemness, are essential for cancer progression . Hopefully, targeting factors that mediate cancer stemness might help overcome therapy resistance and improve clinical outcomes for cancer patients . The negative association of cancer stemness with antitumor immunity is an essential concern in designing therapeutic approaches. As reported by Miranda A. et al. , solid tumors that exhibit high stem cell-like molecular traits are significantly abrogated with immune cells, and cancer stemness confers immunosuppressive properties on tumors. Accordingly, immunologically cold microenvironments can arise due to the presence of stem cell-like cancer cells, suggesting that by inducing cancer cell differentiation (irreversibly disrupting cancer stemness), tumors might become more susceptible to immunotherapy .
|
[
"Kacper Maciejewski",
"Marek Giers",
"Urszula Oleksiewicz",
"Patrycja Czerwinska"
] |
https://doi.org/10.3390/ijms25147841
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277355_p2
|
PMC11277355
|
sec[0]/p[2]
|
1. Introduction
| 4.167969 |
biomedical
|
Study
|
[
0.99951171875,
0.0003371238708496094,
0.0002396106719970703
] |
[
0.85888671875,
0.001651763916015625,
0.13916015625,
0.00037789344787597656
] |
Epigenetic perturbations have a grounded role in mediating cancer development and progression, and at least partially, the dysregulation of epigenetic mechanisms facilitates the self-renewal of cancer cells . Our recent reports highlighted the involvement of several epigenetic factors in the acquisition of cancer dedifferentiation . As epigenetic mechanisms are highly reversible, they appear significantly responsible for cancer stemness acquisition or maintenance . Among other epigenetic factors, the components of histone-modifying machinery are potent therapeutic targets due to their enzymatic activity that could be blocked with specific small molecule inhibitors .
|
[
"Kacper Maciejewski",
"Marek Giers",
"Urszula Oleksiewicz",
"Patrycja Czerwinska"
] |
https://doi.org/10.3390/ijms25147841
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277355_p3
|
PMC11277355
|
sec[0]/p[3]
|
1. Introduction
| 4.242188 |
biomedical
|
Other
|
[
0.99853515625,
0.0007653236389160156,
0.0006885528564453125
] |
[
0.38720703125,
0.48779296875,
0.12274169921875,
0.00225830078125
] |
Histone deacetylases (HDACs), a class of enzymes that remove acetyl groups from ε-N-acetylated lysine residues on target proteins—being either histones or non-histone targets—act primarily as epigenetic regulators of gene expression by modulating chromatin compaction . Contrary to histone acetyltransferases (HATs), HDACs’ activity tightens the associations of histone tails with DNA and prevents the binding of transcription cofactors to DNA, resulting in gene repression.
|
[
"Kacper Maciejewski",
"Marek Giers",
"Urszula Oleksiewicz",
"Patrycja Czerwinska"
] |
https://doi.org/10.3390/ijms25147841
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277355_p4
|
PMC11277355
|
sec[0]/p[4]
|
1. Introduction
| 4.816406 |
biomedical
|
Study
|
[
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[
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There are 18 mammalian HDACs grouped into four distinct classes based on their sequence similarity, chemical structure, and cofactor dependency ( Table 1 ) . The class I HDAC group, which comprises HDAC1/2/3 8, is primarily localized in the nucleus and is ubiquitously expressed. On the other hand, class II (HDAC4/5/6/7/9/10) and class IV HDACs (HDAC11) can shuttle between the nucleus and cytoplasm and exhibit greater tissue-specific expression. All members of class I, II, and IV HDACs are zinc-dependent enzymes in contrast to class III HDACs (sirtuins), which constitute a structurally distinct subfamily that requires NAD+ to catalyze its activity . Class I HDACs show the most robust histone deacetylase activity, while the remaining classes prefer other substrates. The specificity of HDACs for regulating distinct expression profiles depends on the cell type and the different partner proteins typically expressed in that cell, in addition to the signaling context of the cell. Specifically, HDAC1 and HDAC2 are catalytic subunits of the Sin3, Mi-2/NurD, and CoREST complexes, whereas HDAC3 is mainly recruited by the N-CoR/SMRT complex (characterized in detail in ). HDAC8 has not been described as a member of any protein complex so far. As for class II HDAC proteins, the recruitment into the multi-protein corepressor complexes does not promote their deacetylase activity but, instead, seems to have a protein scaffold role . HDAC11, the only member of class IV HDACs, is the most recently discovered HDAC enzyme with a very short half-life (approx. 4 h), and a very efficient long-chain fatty acid deacylase activity .
|
[
"Kacper Maciejewski",
"Marek Giers",
"Urszula Oleksiewicz",
"Patrycja Czerwinska"
] |
https://doi.org/10.3390/ijms25147841
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277355_p5
|
PMC11277355
|
sec[0]/p[5]
|
1. Introduction
| 4.066406 |
biomedical
|
Study
|
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Existing studies on the role of HDACs in facilitating cancer stem cell-like properties primarily focus on designating the involvement of one/several HDAC member(s) in one tested tumor type and do not allow for a broader perspective and a direct comparison of HDACs’ relation to tumor dedifferentiation. Here, we investigated the relationship between the expression of all HDACs and cancer stemness across various solid tumor types. We utilized data primarily from TCGA along with several free and open-access bioinformatic tools such as GEPIA2, TISIDB, GSCA, Enrichr, and GSEA, leveraging the idea of deriving new meaningful findings only from already existing tools and publicly available datasets.
|
[
"Kacper Maciejewski",
"Marek Giers",
"Urszula Oleksiewicz",
"Patrycja Czerwinska"
] |
https://doi.org/10.3390/ijms25147841
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277355_p6
|
PMC11277355
|
sec[0]/p[6]
|
1. Introduction
| 4.074219 |
biomedical
|
Study
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[
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[
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Our findings represent the first comprehensive analysis, revealing robust and versatile associations between specific members of the HDAC family, cancer dedifferentiation, and the anti-tumor immune status within solid tumors. Our data strongly suggest that by targeting specific HDAC members, we may be able to render stem cell-like cancer cells more susceptible to immunotherapy.
|
[
"Kacper Maciejewski",
"Marek Giers",
"Urszula Oleksiewicz",
"Patrycja Czerwinska"
] |
https://doi.org/10.3390/ijms25147841
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277355_p7
|
PMC11277355
|
sec[1]/sec[0]/p[0]
|
2.1. The Expression of HDAC Family Members in Tumor and Normal Adjacent Tissues and the Association with Cancer Patients’ Survival
| 4.136719 |
biomedical
|
Study
|
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Firstly, we analyzed the differential expression of all histone deacetylase (HDAC) gene family members in malignant tissues of selected solid tumors ( Table 2 ), relative to adjacent normal tissues using the TCGA and GTEx data , respectively . We observed a significant upregulation of class I HDACs (HDAC1/2/3/8) in malignant tissues regardless of the tumor type. On the other hand, class IIA and IIB HDACs (HDAC4/5/7/9 and HDAC6/10, respectively) exhibit both up- and downregulation in tumors depending on the tumor type. Similarly, class III HDACs (sirtuins) and the only member of class IV (HDAC11) are differentially expressed in malignant tissues with prevalent upregulation across TCGA tumor types.
|
[
"Kacper Maciejewski",
"Marek Giers",
"Urszula Oleksiewicz",
"Patrycja Czerwinska"
] |
https://doi.org/10.3390/ijms25147841
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277355_p8
|
PMC11277355
|
sec[1]/sec[0]/p[1]
|
2.1. The Expression of HDAC Family Members in Tumor and Normal Adjacent Tissues and the Association with Cancer Patients’ Survival
| 4.101563 |
biomedical
|
Study
|
[
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As shown in Figure S1 , mutations of HDAC family members occur occasionally in selected studies when combined. They ranged from 1% up to 3% of total profiled samples for each gene, with the highest fraction of altered samples present in KIRC for HDAC3 (amplification in 13.94% of cases) and in PRAD for HDAC2 (deep deletion in 13.03% of cases). The expression of HDAC genes differs across solid tumors and does not exhibit particular co-expression patterns .
|
[
"Kacper Maciejewski",
"Marek Giers",
"Urszula Oleksiewicz",
"Patrycja Czerwinska"
] |
https://doi.org/10.3390/ijms25147841
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11277355_p9
|
PMC11277355
|
sec[1]/sec[0]/p[2]
|
2.1. The Expression of HDAC Family Members in Tumor and Normal Adjacent Tissues and the Association with Cancer Patients’ Survival
| 4.175781 |
biomedical
|
Study
|
[
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Also, the expression of HDAC family members is scarcely correlated with patients’ outcomes in TCGA data, and few significant associations are strictly tumor-dependent and do not exhibit any consistent pattern within HDAC classes . The expression of HDAC members in tumors like KIRC and PAAD is correlated with only better prognosis wherever the trend is statistically significant for either overall survival (OS) or disease-free survival (DFS). On the other hand, tumors like LIHC, LUSC, PRAD, CEST, and STAD present opposite trends, being correlated with only worse prognoses. However, when using the Prognoscan platform —an extensive collection of publicly available cancer microarray datasets with clinical annotation—we observed that when statistically significant, the higher expression of class I HDAC members is predominantly associated with worse survival. In contrast, the upregulation of class IIA HDAC proteins correlates with better prognosis . As for class IIA, class III, and class IV HDACs’ expression, the associations with overall survival are gene-specific and do not follow any particular trend.
|
[
"Kacper Maciejewski",
"Marek Giers",
"Urszula Oleksiewicz",
"Patrycja Czerwinska"
] |
https://doi.org/10.3390/ijms25147841
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277355_p10
|
PMC11277355
|
sec[1]/sec[1]/p[0]
|
2.2. The Expression of HDAC Family Members Is Associated with Clinicopathological Features of TCGA Solid Tumors in a Cancer-Dependent and Gene-Specific Manner
| 4.082031 |
biomedical
|
Study
|
[
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[
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Next, we studied correlations between the expression of each HDAC family member and clinical features like staging and grading for every solid tumor, wherever such data were available in the TCGA database. As presented in Figure 3 , HDAC family members’ expressions correlate with tumor stage or tumor grade in a cancer-dependent and gene-specific manner and do not follow any specific trends, even within each HDAC family class. It is worth noticing that the expression of HDAC1, HDAC2, and HDAC3 (all members of class I) significantly correlates with TGCT’s staging most robustly among all correlations in a positive manner .
|
[
"Kacper Maciejewski",
"Marek Giers",
"Urszula Oleksiewicz",
"Patrycja Czerwinska"
] |
https://doi.org/10.3390/ijms25147841
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277355_p11
|
PMC11277355
|
sec[1]/sec[1]/p[1]
|
2.2. The Expression of HDAC Family Members Is Associated with Clinicopathological Features of TCGA Solid Tumors in a Cancer-Dependent and Gene-Specific Manner
| 4.089844 |
biomedical
|
Study
|
[
0.99951171875,
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[
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We further explored the associations between HDAC family gene expression and clinicopathological features by comparing patients with low and high expressions of specific genes (with 25th and 75th percentiles as cut-offs, respectively). We found statistically significant associations between the expression of multiple HDAC family members and TNM classifiers (i.e., tumor size, lymph node, and metastasis status) in several solid tumors . For example, the expression of HDAC2/3/7/10 and SIRT2/3/6/7 associates with tumor size in BRCA, the level of HDAC4/5/8/10/11 and SIRT1/5/7 associates with tumor size in KIRC, and the upregulation of HDAC2/4/6/7 and SIRT1/2/6 associates with tumor size in LUAD.
|
[
"Kacper Maciejewski",
"Marek Giers",
"Urszula Oleksiewicz",
"Patrycja Czerwinska"
] |
https://doi.org/10.3390/ijms25147841
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277355_p12
|
PMC11277355
|
sec[1]/sec[1]/p[2]
|
2.2. The Expression of HDAC Family Members Is Associated with Clinicopathological Features of TCGA Solid Tumors in a Cancer-Dependent and Gene-Specific Manner
| 4.152344 |
biomedical
|
Study
|
[
0.99951171875,
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[
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While tumor size differs between high- and low-expression groups for many HDAC members in many tumors, KIRC is the only one in which the expression of nine HDAC family members, HDAC1/5/8/10/11 and SIRT1/5/6/7, is associated with metastasis. Interestingly, a low expression of HDAC11 was associated with advanced disease status in KIRP, which complies with a statistically significant negative correlation between HDAC11 expression and both staging and grading in this tumor.
|
[
"Kacper Maciejewski",
"Marek Giers",
"Urszula Oleksiewicz",
"Patrycja Czerwinska"
] |
https://doi.org/10.3390/ijms25147841
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277355_p13
|
PMC11277355
|
sec[1]/sec[2]/p[0]
|
2.3. Class I HDAC Family Members Correlate Positively, While Class IIA HDAC Genes Correlate Negatively with Cancer Stemness across TCGA Solid Tumors
| 4.1875 |
biomedical
|
Study
|
[
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As previously reported, solid tumors display distinct levels of cancer stemness . Here, we analyzed the association between the expression of HDAC family members and the level of tumor stemness, quantified with the transcriptome-based stemness index-mRNA-SI, as previously defined by Malta T. et al. . We further validated our results with additional stem cell-derived gene signatures . As presented in Figure 4 and Figure 5 A, class I HDAC family members correlate positively, while class IIA HDAC genes correlate negatively with cancer stemness across TCGA solid tumors, with the most robust and most consistent associations observed for BLCA, BRCA, COAD (or effectively COADREAD), HNSC, LIHC, LUAD, LUSC, OV, PRAD, and STAD . Specifically, HDAC2 (member of class I) and HDAC7 (member of class IIA) genes show the highest correlations across studied solid tumors, exhibiting statistically significant opposite trends for all the applied stemness indices. We observed only minor exceptions for HDAC7 in HNSC, LUAD, LUSC, and OV, where correlation is statistically significant for at least one of the applied stemness indices . For HDAC2 and HDAC7 genes, the opposite statistically significant correlation trend is not observable in the case of LIHC, PRAD, and SARC.
|
[
"Kacper Maciejewski",
"Marek Giers",
"Urszula Oleksiewicz",
"Patrycja Czerwinska"
] |
https://doi.org/10.3390/ijms25147841
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277355_p14
|
PMC11277355
|
sec[1]/sec[2]/p[1]
|
2.3. Class I HDAC Family Members Correlate Positively, While Class IIA HDAC Genes Correlate Negatively with Cancer Stemness across TCGA Solid Tumors
| 4.277344 |
biomedical
|
Study
|
[
0.99951171875,
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[
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] |
Previously, Malta et al. have found a strong association between the mRNA-SI and known clinical and molecular features of TCGA BRCA tumors, demonstrating that the basal subtype, known to exhibit an aggressive phenotype associated with an undifferentiated state, displays the highest levels of mRNA-SI. Therefore, we analyzed the expression of class I and class IIA HDAC members in individual TCGA BRCA samples stratified by molecular subtype (PAM50). We observed a significant upregulation of HDAC2 in highly dedifferentiated basal and HER2+ subtypes, in contrast to other class I HDAC members, which exhibit equable expression patterns across BRCA subtypes. On the other hand, HDAC7 was significantly overexpressed in less aggressive luminal A and luminal B BRCA subtypes , distinguishing from the expression profiles of other class IIA HDAC members. When testing the level of individual pluripotency markers’ expressions (namely OCT4 (POU5F1), SOX2, NANOG, and MYC) in highly stem cell-like TGCT tumors, we observed significant positive associations with class I HDAC members, with the most robust ones for HDAC2 . This further supports our first observation that HDAC2 is strongly associated with cancer stemness.
|
[
"Kacper Maciejewski",
"Marek Giers",
"Urszula Oleksiewicz",
"Patrycja Czerwinska"
] |
https://doi.org/10.3390/ijms25147841
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277355_p15
|
PMC11277355
|
sec[1]/sec[2]/p[2]
|
2.3. Class I HDAC Family Members Correlate Positively, While Class IIA HDAC Genes Correlate Negatively with Cancer Stemness across TCGA Solid Tumors
| 3.367188 |
biomedical
|
Study
|
[
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[
0.99560546875,
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0.00010633468627929688
] |
As HDAC2 and HDAC7 genes are observed to present the purest correlation trends with stemness indices in previously selected tumors, they were used as representative members of class I and class IIA for the subsequent analyses.
|
[
"Kacper Maciejewski",
"Marek Giers",
"Urszula Oleksiewicz",
"Patrycja Czerwinska"
] |
https://doi.org/10.3390/ijms25147841
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277355_p16
|
PMC11277355
|
sec[1]/sec[2]/p[3]
|
2.3. Class I HDAC Family Members Correlate Positively, While Class IIA HDAC Genes Correlate Negatively with Cancer Stemness across TCGA Solid Tumors
| 4.109375 |
biomedical
|
Study
|
[
0.99951171875,
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[
0.99951171875,
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0.000055789947509765625
] |
We used the GSEA to compare the HDAC2 and HDAC7-associated transcriptome profiles with a priori-defined stemness-associated gene signatures like Muller Plurinet, Wong ESC, Kim Myc, and Assou ESC, as previously described . We confirmed significant enrichment of HDAC2-associated transcriptome profiles followed by significant depletion of HDAC7-related transcriptome profiles with stemness markers in all tested tumors. This strongly supports our first observation that HDAC2 is positively and HDAC7 is negatively correlated with tumor stemness.
|
[
"Kacper Maciejewski",
"Marek Giers",
"Urszula Oleksiewicz",
"Patrycja Czerwinska"
] |
https://doi.org/10.3390/ijms25147841
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277355_p17
|
PMC11277355
|
sec[1]/sec[2]/p[4]
|
2.3. Class I HDAC Family Members Correlate Positively, While Class IIA HDAC Genes Correlate Negatively with Cancer Stemness across TCGA Solid Tumors
| 4.113281 |
biomedical
|
Study
|
[
0.99951171875,
0.00019562244415283203,
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[
0.99951171875,
0.000202178955078125,
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0.00005364418029785156
] |
Further, using the Enrichr tool , we performed the enrichment analysis to detect potential targets for known transcription factors in the HDAC2-related or HDAC7-related gene expression profiles. We identified BMI1, MYC, NANOG, and OCT3/4 (POU5F1 gene) pluripotency markers as the most prominent transcription factors associated with HDAC2 gene expression, highly supporting HDAC2’s association with cancer stemness.
|
[
"Kacper Maciejewski",
"Marek Giers",
"Urszula Oleksiewicz",
"Patrycja Czerwinska"
] |
https://doi.org/10.3390/ijms25147841
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277355_p18
|
PMC11277355
|
sec[1]/sec[3]/p[0]
|
2.4. HDAC2-Associated Transcriptome Profiles Are Significantly Enriched with Stemness-Related Hallmarks of Cancer, While HDAC7-Associated Transcriptome Profiles Are Enriched with Immune-Related Terms
| 4.179688 |
biomedical
|
Study
|
[
0.99951171875,
0.0002377033233642578,
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[
0.99951171875,
0.0001621246337890625,
0.0004150867462158203,
0.00005644559860229492
] |
Cancer stemness is significantly negatively associated with tumor immunity, with high stem cell-like tumors exhibiting low infiltration levels and significant immunosuppressive microenvironments . It was unsurprising that HDAC2-associated transcriptome profiles were significantly depleted with immune-related signaling pathways or terms as determined with the GSEA using Hallmark’s collection of gene signatures . As shown in Figure 7 , the transcription profile associated with HDAC2 is highly enriched, while associated with HDAC7 is highly depleted with stemness-related terms like MYC targets, G2/M checkpoint, and E2F targets. These terms are statistically significant in all 11 selected solid tumors. On the other hand, the HDAC7 transcription profile is highly enriched with immune-related Hallmark terms, especially in SARC and HNSC.
|
[
"Kacper Maciejewski",
"Marek Giers",
"Urszula Oleksiewicz",
"Patrycja Czerwinska"
] |
https://doi.org/10.3390/ijms25147841
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277355_p19
|
PMC11277355
|
sec[1]/sec[3]/p[1]
|
2.4. HDAC2-Associated Transcriptome Profiles Are Significantly Enriched with Stemness-Related Hallmarks of Cancer, While HDAC7-Associated Transcriptome Profiles Are Enriched with Immune-Related Terms
| 4.125 |
biomedical
|
Study
|
[
0.99951171875,
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[
0.99951171875,
0.00015056133270263672,
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0.00005245208740234375
] |
Enrichment of systematically selected gene sets from GO Biological Process ontology collection (C5:BP, see Section 4.5 ) further confirmed our findings. As shown in Figure S8 , ontology processes having immune-related ancestors are significantly enriched in HDAC7-related transcriptome profiles in SARC and HNSC, and to a lesser extent in STAD. Albeit with no statistical significance, these processes also exhibit enrichment in other tumors: PRAD, LUSC, LIHC, OV, or BLCA. On the other hand, for HDAC2-associated transcriptome profiles, we observed a significant depletion of immune-related terms, which complies with previous findings. Processes with ancestors related to cell cycle, cell division, and DNA repair were highly enriched for HDAC2 while depleted for HDAC7. These processes were previously reported as associated with stem cell features .
|
[
"Kacper Maciejewski",
"Marek Giers",
"Urszula Oleksiewicz",
"Patrycja Czerwinska"
] |
https://doi.org/10.3390/ijms25147841
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277355_p20
|
PMC11277355
|
sec[1]/sec[3]/p[2]
|
2.4. HDAC2-Associated Transcriptome Profiles Are Significantly Enriched with Stemness-Related Hallmarks of Cancer, While HDAC7-Associated Transcriptome Profiles Are Enriched with Immune-Related Terms
| 4.21875 |
biomedical
|
Study
|
[
0.99951171875,
0.0002486705780029297,
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] |
[
0.9990234375,
0.00019431114196777344,
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] |
We performed additional validation through GSEA using curated gene sets from chemical and genetic perturbations collection (C2:CGP). We observed that HDAC2-related transcriptome profiles are significantly enriched across studied tumors with terms like DREAM targets, upregulation of epithelial–mesenchymal transition, G2/M cell cycle, E2F targets, EZH2 targets, and proliferation . In contrast, HDAC7-related transcriptome profiles are significantly depleted within these terms in the same tumors. In BRCA, LUAD, PRAD, and SARC, HDAC2—contrary to HDAC7—is associated with the enrichment of SOX2 and OCT4 targets. Conversely, the HDAC7 profile is enriched with immune-related terms like IL-4 signaling, differentiating of T cells, Th1 cell cytotoxicity, IFN-β targets, and IFN-γ response in HNSC and SARC. These observations support previous findings that HDAC2-associated transcriptome profiles are significantly enriched with stemness-related hallmarks of cancer, while HDAC7-associated transcriptome profiles are enriched with immune-related terms.
|
[
"Kacper Maciejewski",
"Marek Giers",
"Urszula Oleksiewicz",
"Patrycja Czerwinska"
] |
https://doi.org/10.3390/ijms25147841
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277355_p21
|
PMC11277355
|
sec[1]/sec[4]/p[0]
|
2.5. HDAC Expression Correlates with the Infiltration of Selected Immune Cell Subtypes, and HDAC7-High Expressing Tumors Exhibit Significant Upregulation of Distinct Chemoattractants
| 4.019531 |
biomedical
|
Study
|
[
0.99951171875,
0.00024628639221191406,
0.0002753734588623047
] |
[
0.99951171875,
0.00021851062774658203,
0.0004220008850097656,
0.000054717063903808594
] |
Next, we evaluated the tumor microenvironment concerning HDAC2 or HDAC7 expression in all tested tumor types. As presented in Figure 8 A and Figure S10 , the expression of HDAC2 correlates negatively with the leukocyte fraction and immune checkpoint molecules in most tumors, while HDAC7 is mostly positively associated.
|
[
"Kacper Maciejewski",
"Marek Giers",
"Urszula Oleksiewicz",
"Patrycja Czerwinska"
] |
https://doi.org/10.3390/ijms25147841
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277355_p22
|
PMC11277355
|
sec[1]/sec[4]/p[1]
|
2.5. HDAC Expression Correlates with the Infiltration of Selected Immune Cell Subtypes, and HDAC7-High Expressing Tumors Exhibit Significant Upregulation of Distinct Chemoattractants
| 4.097656 |
biomedical
|
Study
|
[
0.99951171875,
0.00022780895233154297,
0.000232696533203125
] |
[
0.99951171875,
0.00014650821685791016,
0.00035834312438964844,
0.00005060434341430664
] |
To validate the observation of HDAC-dependent tumor microenvironment, we employed the ESTIMATE tool and observed that the purity, immune, and stromal scores correlate highly positively with HDAC7 gene expression in selected solid tumors, except for OV and BLCA . On the other hand, we observed the opposite statistically significant correlation trend for HDAC2 expression in studied tumors, apart from LIHC. This confirms high immune infiltration and stroma presence in the tumor tissues associated with HDAC7-high and HDAC2-low expression. Low–high HDAC2/7 expression levels significantly differentiate the immune and stromal scores between patients in these groups . In other words, HDAC7-high and HDAC2-low patients have significantly higher tumor immune and stromal infiltration levels in many tumors.
|
[
"Kacper Maciejewski",
"Marek Giers",
"Urszula Oleksiewicz",
"Patrycja Czerwinska"
] |
https://doi.org/10.3390/ijms25147841
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277355_p23
|
PMC11277355
|
sec[1]/sec[4]/p[2]
|
2.5. HDAC Expression Correlates with the Infiltration of Selected Immune Cell Subtypes, and HDAC7-High Expressing Tumors Exhibit Significant Upregulation of Distinct Chemoattractants
| 4.25 |
biomedical
|
Study
|
[
0.99951171875,
0.00028228759765625,
0.000255584716796875
] |
[
0.9990234375,
0.0001589059829711914,
0.0005536079406738281,
0.00007277727127075195
] |
To further examine immune infiltration, we used the TIMER2.0 database and employed the xCELL algorithm of cell type quantification . Compared to the expression of HDAC2 in many studied tumors, we observed a greater number of significant positive correlations between HDAC7 expression and different immune subpopulation levels . This may suggest a strong positive relationship between HDAC7 and tumor infiltrating cells (TILs), especially considering CD4+ T cell populations whose levels generally correlate positively with HDAC7 expression and negatively with HDAC2 expression. Interestingly, myeloid-derived suppressor cells (whose level was evaluated through the TIDE algorithm ) strongly correlate with HDAC2 expression in all studied solid tumors, which is not observed for HDAC7. Furthermore, we looked at the levels of chemoattractants in all tested tumor types regarding HDAC2 or HDAC7 expression and observed that HDAC7 upregulation significantly associates with elevation of chemokines and their recognizing receptors. Moreover, HDAC7 expression is significantly associated with the promotion of inflammatory factors in all 11 tumors . In the case of HDAC2, we observed such an elevation in only BRCA, LIHC, and PRAD, while depletion in COAD and LUSC.
|
[
"Kacper Maciejewski",
"Marek Giers",
"Urszula Oleksiewicz",
"Patrycja Czerwinska"
] |
https://doi.org/10.3390/ijms25147841
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277355_p24
|
PMC11277355
|
sec[1]/sec[4]/p[3]
|
2.5. HDAC Expression Correlates with the Infiltration of Selected Immune Cell Subtypes, and HDAC7-High Expressing Tumors Exhibit Significant Upregulation of Distinct Chemoattractants
| 4.113281 |
biomedical
|
Study
|
[
0.99951171875,
0.0002818107604980469,
0.0003554821014404297
] |
[
0.99951171875,
0.00011497735977172852,
0.0003170967102050781,
0.00005054473876953125
] |
Finally, we compared the expression levels of HDAC2 and HDAC7 in studied tumors between patients with different transcriptome-based immune subtypes . As shown in Figure S14 , the median HDAC2 expression is generally lower in patients with immune subtypes C3 (inflammatory type) and C6 (TGF-b dominant type) relative to other subtypes in all tumors of interest besides (1) SARC, where the TGF-b dominant subtype features the highest relative expression of HDAC2 among all tumors, and (2) wherever no samples were classified as C6 subtype (OV, PRAD, READ, and LIHC). As shown in Figure S15 , differences in HDAC7 expression between patients with different immune subtypes are statistically significant for all tumors (except OV and COAD) and p -values are generally lower in comparison to HDAC2 differences in the same cancers. Interestingly, C3 and C6 subtypes are associated with higher HDAC7 expression than other immune subtypes in LUSC and STAD.
|
[
"Kacper Maciejewski",
"Marek Giers",
"Urszula Oleksiewicz",
"Patrycja Czerwinska"
] |
https://doi.org/10.3390/ijms25147841
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277355_p25
|
PMC11277355
|
sec[1]/sec[5]/p[0]
|
2.6. HDAC2/7 as Potential Biomarkers of Immunotherapy Response in Solid Tumors
| 4.109375 |
biomedical
|
Study
|
[
0.99951171875,
0.0002601146697998047,
0.00022077560424804688
] |
[
0.998046875,
0.0001919269561767578,
0.0015993118286132812,
0.0000699162483215332
] |
We searched the TIGER database to explore the differential expression of class I and class IIA HDACs between responders and non-responders to immunotherapy in different tumors . Among available studies, the only statistically significant difference between such patients was found in SKCM, where responders to combined anti-CTLA4+anti-PD1 therapy were characterized with lower HDAC2 expression than non-responders . Although differences are not statistically significant for other available studies, preliminary yet no definitive results suggest the possible potential of HDAC2 and HDAC7 as immunotherapy response biomarkers, which can be confirmed only if more samples are available. In the case of HDAC2, this regards anti-PD1 therapy against KIRC and STAD and anti-CTLA-4 therapy against SKCM . HDAC7 could eventually become a potential response biomarker in the case of KIRC anti-PD1 immunotherapy . As patient cohorts in this analysis are too small, we underline that these findings are only suggestive, indicating the possible and promising direction of further research. Additional analyses should also be included to definitely prove the HDAC2/7 associations with immune response. In particular, HDAC2/7 activity and protein levels should be measured, alongside their chromatin accessibility.
|
[
"Kacper Maciejewski",
"Marek Giers",
"Urszula Oleksiewicz",
"Patrycja Czerwinska"
] |
https://doi.org/10.3390/ijms25147841
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277355_p26
|
PMC11277355
|
sec[2]/p[0]
|
3. Discussion
| 4.425781 |
biomedical
|
Study
|
[
0.99951171875,
0.0005064010620117188,
0.0002028942108154297
] |
[
0.9951171875,
0.0004589557647705078,
0.004451751708984375,
0.00020766258239746094
] |
This is the first comprehensive report revealing the associations between HDAC family members, cancer stemness, and anti-tumor immune response across more than 20 types of solid tumors. Here, based on the transcriptomic, genomic, and clinical data from the TCGA database , Prognoscan platform , and TIGER database , and using several other bioinformatic tools , we demonstrated that the expression levels of class I and class II HDAC genes are related to cancer stemness and immunity, however, in a distinct manner. While class I HDAC family members (HDAC1/2/3/8) were positively associated with cancer stemness across most of the tested tumor types, class IIA HDAC members (HDAC4/5/7/9) exhibited an inverse correlation. In support of these observations, we found that the most robust and stringent positive associations with cancer stemness were evidenced for HDAC2 expression, whereas a negative association was demonstrated for HDAC7 expression. Importantly, our data clearly highlighted the enrichment of stemness-associated “Hallmarks” terms in HDAC2-related transcriptome profiles and significant depletion of those terms in HDAC7-high expressing tumors. Furthermore, our analyses demonstrated that high HDAC2 levels are linked to the immune cell infiltration status resembling the immunosuppressive environment. In contrast, HDAC7 expression level positively correlates with increased immune cells’ abundance, suggesting an augmented cancer immunogenicity. In line with these data, we noted a very strong and versatile positive association between HDAC7 level and the expression of chemokines or chemokine receptors. Finally, our analyses suggest that HDAC2 expression may have a potential value as a biomarker of immunotherapy.
|
[
"Kacper Maciejewski",
"Marek Giers",
"Urszula Oleksiewicz",
"Patrycja Czerwinska"
] |
https://doi.org/10.3390/ijms25147841
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277355_p27
|
PMC11277355
|
sec[2]/p[1]
|
3. Discussion
| 4.132813 |
biomedical
|
Review
|
[
0.99853515625,
0.0007214546203613281,
0.0007910728454589844
] |
[
0.255859375,
0.00147247314453125,
0.7421875,
0.0004825592041015625
] |
The involvement of HDAC family members in cancerogenesis has been studied for several decades, identifying specific HDACs’ roles in distinct cellular and molecular events, including cell cycle and cellular proliferation, apoptosis, DNA damage response, autophagy, EMT, or angiogenesis —all crucial players in cancer development and progression. Also, the total pan-HDAC activity, including all family members, was determined as essential for proper cell differentiation and regulation of pluripotency of normal stem cells . However, the role of specific HDAC members in facilitating the acquisition or maintenance of cancer stem cell-like phenotype has not been fully explored. Also, the involvement of most HDAC members in regulating anti-tumor immune response remains elusive.
|
[
"Kacper Maciejewski",
"Marek Giers",
"Urszula Oleksiewicz",
"Patrycja Czerwinska"
] |
https://doi.org/10.3390/ijms25147841
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
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