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JCI Insight Dec 2023Thyroid hormone (TH) levels are low during development, and the deiodinases control TH signaling through tissue-specific activation or inactivation of TH. Here, we...
Thyroid hormone (TH) levels are low during development, and the deiodinases control TH signaling through tissue-specific activation or inactivation of TH. Here, we studied human induced pluripotent stem cell-derived (iPSC-derived) hepatic organoids and identified a robust induction of DIO2 expression (the deiodinase that activates T4 to T3) that occurs in hepatoblasts. The surge in DIO2-T3 (the deiodinase that activates thyroxine [T4] to triiodothyronine [T3]) persists until the hepatoblasts differentiate into hepatocyte- or cholangiocyte-like cells, neither of which expresses DIO2. Preventing the induction of the DIO2-T3 signaling modified the expression of key transcription factors, decreased the number of hepatocyte-like cells by ~60%, and increased the number of cholangiocyte-like cells by ~55% without affecting the growth or the size of the mature liver organoid. Physiological levels of T3 could not fully restore the transition from hepatoblasts to mature cells. This indicates that the timed surge in DIO2-T3 signaling critically determines the fate of developing human hepatoblasts and the transcriptome of the maturing hepatocytes, with physiological and clinical implications for how the liver handles energy substrates.
Topics: Humans; Induced Pluripotent Stem Cells; Transcriptome; Liver; Hepatocytes; Thyroid Hormones; Iodide Peroxidase; Organoids
PubMed: 37856222
DOI: 10.1172/jci.insight.173780 -
Scientific Reports Sep 2023To maintain normal level of thyroid hormone, especially for free thyroxine (FT4), individuals with latent thyroid gland damage might have required higher thyroid...
To maintain normal level of thyroid hormone, especially for free thyroxine (FT4), individuals with latent thyroid gland damage might have required higher thyroid stimulating hormone (TSH) than those without latent thyroid gland damage. Anti-thyroid peroxidase antibody (TPO-Ab) is a main cause of auto-immune thyroiditis, and therefore euthyroid individuals positive for TPO-Ab might have latent damage to the thyroid gland. Therefore, the association between TSH values and TPO-Ab positivity may be useful to determine the influence of latent thyroid gland damage on requirement of TSH. Furthermore, because latent damage of thyroid might elevate TSH level but not FT4 level, those associations should be observed independent from FT4. This cross-sectional study analyzed 1431 Japanese with normal ranges of free triiodothyronine (FT3) and FT4. Since TPO-Ab is associated with atherosclerosis in euthyroid individuals, cardiovascular risk factors might underlie the association between TPO-Ab and TSH values. After adjusting for FT4 and known cardiovascular risk factors, the adjusted odds ratio (95% confidence interval) of TPO-Ab positivity for logarithmic value of TSH was 1.53 (1.20, 1.95). Essentially the same association was observed when the analysis was restricted to individuals without subclinical hypothyroidism (1.54 [1.15, 2.13]). Euthyroid individuals with latent thyroid gland damage might have increased the requirement of TSH.
Topics: Humans; Thyrotropin; Cross-Sectional Studies; Hypothyroidism; Peroxidases
PubMed: 37658108
DOI: 10.1038/s41598-023-40275-6 -
Journal of Endocrinological... Jun 2024Papillary thyroid carcinoma (PTC) is characterized by lymph-node metastasis (LNM), which affects recurrence and prognosis. This study analyzed PTC LNM by single-cell RNA...
PURPOSE
Papillary thyroid carcinoma (PTC) is characterized by lymph-node metastasis (LNM), which affects recurrence and prognosis. This study analyzed PTC LNM by single-cell RNA sequencing (scRNA-seq) data and bulk RNA sequencing (RNA-seq) to find diagnostic markers and therapeutic targets.
METHODS
ScRNA-seq data were clustered and malignant cells were identified. Differentially expressed genes (DEGs) were identified in malignant cells of scRNA-seq and bulk RNA-seq, respectively. PTC LNM diagnostic model was constructed based on intersecting DEGs using glmnet package. Next, PTC samples from 66 patients were used to validate the two most significant genes in the diagnostic model, S100A2 and type 2 deiodinase (DIO2) by quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and immunohistochemical (IHC). Further, the inhibitory effect of DIO2 on PTC cells was verified by cell biology behavior, western blot, cell cycle analysis, 5-ethynyl-2'-deoxyuridine (EdU) assay, and xenograft tumors.
RESULTS
Heterogeneity of PTC LNM was demonstrated by Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis. A total of 19 differential genes were used to construct the diagnostic model. S100A2 and DIO2 differ significantly at the RNA (p < 0.01) and protein level in LNM patient tissues (p < 0.001). And differed in PTC tissues with different pathologic typing (p < 0.001). Further, EdU (p < 0.001) and cell biology behavior revealed that PTC cells overexpressed DIO2 had reduced proliferative capacity. Cell cycle proteins were reduced and cells are more likely to be stuck in G2/M phase (p < 0.001).
CONCLUSIONS
This study explored the heterogeneity of PTC LNM using scRNA-seq. By combining with bulk RNA-seq data, diagnostic markers were explored and the model was established. Clinical diagnostic efficacy of S100A2 and DIO2 was validated and the treatment potential of DIO2 was discovered.
Topics: Humans; Thyroid Cancer, Papillary; Thyroid Neoplasms; Biomarkers, Tumor; Lymphatic Metastasis; Single-Cell Analysis; Animals; Mice; Sequence Analysis, RNA; Female; Male; S100 Proteins; Prognosis; Gene Expression Regulation, Neoplastic; Iodide Peroxidase; Iodothyronine Deiodinase Type II; Cell Proliferation; Middle Aged; Gene Expression Profiling; Chemotactic Factors
PubMed: 38146045
DOI: 10.1007/s40618-023-02262-6 -
Biomedicine & Pharmacotherapy =... Aug 2023Rheumatic diseases and disorders (RDDs) are a group of chronic autoimmune diseases that are collectively called "multicausal diseases". They have resulted from... (Review)
Review
Rheumatic diseases and disorders (RDDs) are a group of chronic autoimmune diseases that are collectively called "multicausal diseases". They have resulted from predisposing genetic profiles and exposure to a range of environmental, occupational and lifestyle risk factors. Other causative factors include bacterial and viral attacks, sexual habits, trauma, etc. In addition, numerous studies reported that redox imbalance is one of the most serious consequences of RDDs. For example, rheumatoid arthritis (RA) as a classic example of chronic RDDs is linked to oxidative stress. This paper summarizes the contributions of redox imbalance to RDDs. The findings suggest that establishing direct or indirect therapeutic strategies for RDDs requires a more in-depth understanding of the redox dysregulation in these diseases. For example, the recent awareness of the roles of peroxiredoxins (Prdxs, e.g. Prdx2, Prdx3) in RDDs provided one potential route of therapeutic intervention of these pathologies. Changes in stressful lifestyles and dietary habits may also provide additional benefits in the management of RDDs. Future studies should be directed to explore molecular interactions in redox regulations associated with RDDS and potential therapeutic interventions.
Topics: Humans; Oxidative Stress; Oxidation-Reduction; Arthritis, Rheumatoid; Peroxiredoxins; Autoimmune Diseases
PubMed: 37216707
DOI: 10.1016/j.biopha.2023.114900 -
Carbohydrate Research Nov 2023The development of human tissue models for regenerative medicine and animal-free drug screening requires glycosylated biomaterials such as collagen. An easy and fast...
The development of human tissue models for regenerative medicine and animal-free drug screening requires glycosylated biomaterials such as collagen. An easy and fast biomaterial glycosylation method exploiting Horseradish Peroxidase (HRP) phenol coupling reaction is proposed. The protocol is adaptable to any polymer functionalized with phenol residues or tyrosine containing proteins. As a model the tyrosine residues on collagen films were functionalized with salidroside, a natural β-glucoside with a phenol in the aglycone. Scanning Electron Microscope (SEM) and contact angle analysis revealed the influence of glycosylation on the sample's morphology and wettability. Preliminary biological evaluation showed the cytocompatibility of the glucosylated collagen films.
Topics: Humans; Tyrosine; Horseradish Peroxidase; Phenols; Phenol; Collagen
PubMed: 37713734
DOI: 10.1016/j.carres.2023.108938 -
Redox Biology Aug 2023As plants are sessile organisms, they are inevitably exposed to a variety of environmental stimuli that trigger rapid changes in the generation and disposal of reactive... (Review)
Review
As plants are sessile organisms, they are inevitably exposed to a variety of environmental stimuli that trigger rapid changes in the generation and disposal of reactive oxygen species such as hydrogen peroxide (HO). A major HO scavenging system in plant cells is the ascorbate-glutathione cycle, in which ascorbate peroxidase (APX) catalyzes the conversion of HO into water employing ascorbate as specific electron donor. In higher plants, distinct APX isoforms can occur in multiple subcellular compartments, including chloroplasts, mitochondria, and peroxisomes and the cytosol, to modulate organellar and cellular levels of HO. It is well established that APX plays crucial roles in protecting plant cells against diverse environmental stresses, as well as in plant growth and development. Apart from ascorbate, recently, APXs have been found to have a broader substrate specificity and possess chaperone activity, hence participating various biological processes. In this review, we describe the antioxidant properties of APXs and highlight their novel roles beyond 'ascorbate peroxidases'.
Topics: Antioxidants; Ascorbate Peroxidases; Hydrogen Peroxide; Plants; Ascorbic Acid; Peroxidases
PubMed: 37352686
DOI: 10.1016/j.redox.2023.102789 -
Biomolecules Jun 2024Reactive oxygen species (ROSs) are byproducts of normal cellular metabolism and play pivotal roles in various physiological processes. Disruptions in the balance between... (Review)
Review
Reactive oxygen species (ROSs) are byproducts of normal cellular metabolism and play pivotal roles in various physiological processes. Disruptions in the balance between ROS levels and the body's antioxidant defenses can lead to the development of numerous diseases. Glutathione peroxidase 3 (GPX3), a key component of the body's antioxidant system, is an oxidoreductase enzyme. GPX3 mitigates oxidative damage by catalyzing the conversion of hydrogen peroxide into water. Beyond its antioxidant function, GPX3 is vital in regulating metabolism, modulating cell growth, inducing apoptosis and facilitating signal transduction. It also serves as a significant tumor suppressor in various cancers. Recent studies have revealed aberrant expression of GPX3 in several non-neoplastic diseases, associating it with multiple pathological processes. This review synthesizes the current understanding of GPX3 expression and regulation, highlighting its extensive roles in noncancerous diseases. Additionally, this paper evaluates the potential of GPX3 as a diagnostic biomarker and explores emerging therapeutic strategies targeting this enzyme, offering potential avenues for future clinical treatment of non-neoplastic conditions.
Topics: Humans; Glutathione Peroxidase; Reactive Oxygen Species; Oxidative Stress; Animals; Antioxidants; Noncommunicable Diseases
PubMed: 38927092
DOI: 10.3390/biom14060689 -
BMC Plant Biology Oct 2023Industrial hemp is an important industrial crop and has strong resistance to saline-alkaline stress. However, research on the industrial hemp response to NaHCO stress is...
BACKGROUND
Industrial hemp is an important industrial crop and has strong resistance to saline-alkaline stress. However, research on the industrial hemp response to NaHCO stress is limited. Therefore, the response mechanisms of industrial hemp under NaHCO stress were analysed through miRNA-mRNA regulatory networks.
RESULTS
Seedlings of two salt-alkali tolerant and sensitive varieties were cultured in a solution containing 100 mM NaHCO and randomly sampled at 0, 6, 12, and 24 h. With prolonged NaHCO stress, the seedlings gradually withered, and the contents of jasmonic acid, lignin, trehalose, soluble protein, peroxidase, and superoxide dismutase in the roots increased significantly. The abscisic acid content decreased and then gradually increased. Overall, 18,215 mRNAs and 74 miRNAs were identified as differentially expressed under NaHCO stress. The network showed that 230 miRNA-mRNA interactions involved 16 miRNAs and 179 mRNAs, including some key hub novel mRNAs of these crucial pathways. Carbon metabolism, starch, sucrose metabolism, plant hormone signal transduction, and the spliceosome (SPL) were crucial pathways in industrial hemp's response to NaHCO stress.
CONCLUSIONS
It is speculated that industrial hemp can regulate SPL pathway by upregulating miRNAs such as novel_miR_179 and novel_miR_75, thus affecting starch and sucrose metabolism, plant hormone signal transduction and carbon metabolism and improving key physiological indices such as jasmonic acid content, trehalose content, and peroxidase and superoxide dismutase activities under NaHCO stress.
Topics: Cannabis; RNA, Messenger; MicroRNAs; Plant Growth Regulators; Trehalose; Superoxide Dismutase; Peroxidase; Carbon; Starch; Sucrose
PubMed: 37875794
DOI: 10.1186/s12870-023-04463-w -
Cell Reports Jun 2024Ferroptosis is an iron-dependent cell death mechanism characterized by the accumulation of toxic lipid peroxides and cell membrane rupture. GPX4 (glutathione peroxidase...
Ferroptosis is an iron-dependent cell death mechanism characterized by the accumulation of toxic lipid peroxides and cell membrane rupture. GPX4 (glutathione peroxidase 4) prevents ferroptosis by reducing these lipid peroxides into lipid alcohols. Ferroptosis induction by GPX4 inhibition has emerged as a vulnerability of cancer cells, highlighting the need to identify ferroptosis regulators that may be exploited therapeutically. Through genome-wide CRISPR activation screens, we identify the SWI/SNF (switch/sucrose non-fermentable) ATPases BRM (SMARCA2) and BRG1 (SMARCA4) as ferroptosis suppressors. Mechanistically, they bind to and increase chromatin accessibility at NRF2 target loci, thus boosting NRF2 transcriptional output to counter lipid peroxidation and confer resistance to GPX4 inhibition. We further demonstrate that the BRM/BRG1 ferroptosis connection can be leveraged to enhance the paralog dependency of BRG1 mutant cancer cells on BRM. Our data reveal ferroptosis induction as a potential avenue for broadening the efficacy of BRM degraders/inhibitors and define a specific genetic context for exploiting GPX4 dependency.
Topics: Ferroptosis; Humans; Transcription Factors; DNA Helicases; Nuclear Proteins; Phospholipid Hydroperoxide Glutathione Peroxidase; Clustered Regularly Interspaced Short Palindromic Repeats; NF-E2-Related Factor 2; Cell Line, Tumor; CRISPR-Cas Systems; Adenosine Triphosphatases
PubMed: 38870012
DOI: 10.1016/j.celrep.2024.114345 -
International Journal of Molecular... May 2024According to the World Health Organization (WHO), breast cancer (BC) is the deadliest and the most common type of cancer worldwide in women. Several factors associated... (Review)
Review
According to the World Health Organization (WHO), breast cancer (BC) is the deadliest and the most common type of cancer worldwide in women. Several factors associated with BC exert their effects by modulating the state of stress. They can induce genetic mutations or alterations in cell growth, encouraging neoplastic development and the production of reactive oxygen species (ROS). ROS are able to activate many signal transduction pathways, producing an inflammatory environment that leads to the suppression of programmed cell death and the promotion of tumor proliferation, angiogenesis, and metastasis; these effects promote the development and progression of malignant neoplasms. However, cells have both non-enzymatic and enzymatic antioxidant systems that protect them by neutralizing the harmful effects of ROS. In this sense, antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), thioredoxin reductase (TrxR), and peroxiredoxin (Prx) protect the body from diseases caused by oxidative damage. In this review, we will discuss mechanisms through which some enzymatic antioxidants inhibit or promote carcinogenesis, as well as the new therapeutic proposals developed to complement traditional treatments.
Topics: Humans; Antioxidants; Breast Neoplasms; Female; Reactive Oxygen Species; Oxidative Stress; Peroxiredoxins; Animals; Glutathione Peroxidase; Catalase; Superoxide Dismutase
PubMed: 38891864
DOI: 10.3390/ijms25115675