-
Research Square Jun 2024The Cystine-xCT transporter-Glutathione (GSH)-GPX4 axis is the canonical pathway to protect against ferroptosis. While not required for ferroptosis-inducing compounds...
The Cystine-xCT transporter-Glutathione (GSH)-GPX4 axis is the canonical pathway to protect against ferroptosis. While not required for ferroptosis-inducing compounds (FINs) targeting GPX4, FINs targeting the xCT transporter require mitochondria and its lipid peroxidation to trigger ferroptosis. However, the mechanism underlying the difference between these FINs is still unknown. Given that cysteine is also required for coenzyme A (CoA) biosynthesis, here we show that CoA supplementation specifically prevents ferroptosis induced by xCT inhibitors but not GPX4 inhibitors. We find that, auranofin, a thioredoxin reductase inhibitor, abolishes the protective effect of CoA. We also find that CoA availability determines the enzymatic activity of thioredoxin reductase, but not thioredoxin. Importantly, the mitochondrial thioredoxin system, but not the cytosolic thioredoxin system, determines CoA-mediated ferroptosis inhibition. Our data show that the CoA regulates the enzymatic activity of mitochondrial thioredoxin reductase (TXNRD2) by covalently modifying the thiol group of cysteine (CoAlation) on Cys-483. Replacing Cys-483 with alanine on TXNRD2 abolishes its enzymatic activity and ability to protect cells from ferroptosis. Targeting xCT to limit cysteine import and, therefore, CoA biosynthesis reduced CoAlation on TXNRD2, an effect that was rescued by CoA supplementation. Furthermore, the fibroblasts from patients with disrupted CoA metabolism demonstrate increased mitochondrial lipid peroxidation. In organotypic brain slice cultures, inhibition of CoA biosynthesis leads to an oxidized thioredoxin system, mitochondrial lipid peroxidation, and loss in cell viability, which were all rescued by ferrostatin-1. These findings identify CoA-mediated post-translation modification to regulate the thioredoxin system as an alternative ferroptosis protection pathway with potential clinical relevance for patients with disrupted CoA metabolism.
PubMed: 38947036
DOI: 10.21203/rs.3.rs-4522617/v1 -
Research Square Jun 2024Purpose Spontaneously occurring glioma in pet dogs is increasingly recognized as a valuable translational model for human glioblastoma. Canine high grade glioma and...
Purpose Spontaneously occurring glioma in pet dogs is increasingly recognized as a valuable translational model for human glioblastoma. Canine high grade glioma and human glioblastomas share many molecular similarities, including accumulation of immunosuppressive regulatory T cells (Tregs) that inhibit anti-tumor immune responses. Identifying in dog mechanisms responsible for Treg recruitment may afford targeting the cellular population driving immunosuppression, the results providing a rationale for translational clinical studies in human patients. Our group has previously identified C-C motif chemokine 2 (CCL2) as a glioma-derived T-reg chemoattractant acting on chemokine receptor 4 (CCR4) in a murine orthotopic model of glioma. Recently, we demonstrated a robust increase of CCL2 in the brain tissue of canine patients bearing high-grade glioma. Methods We performed a series of in vitro experiments using canine Tregs and patient-derived canine glioma cell lines (GSC 1110, GSC 0514, J3T-Bg, G06A) to interrogate the CCL2-CCR4 signaling axis in the canine. Results We established a flow cytometry gating strategy for identification and isolation of FOXP3 Tregs in dogs. The canine CD4 + CD25 T-cell population was highly enriched in FOXP3 and CCR4 expression, indicating they are bona fide Tregs. Canine Treg migration was enhanced by CCL2 or by glioma cell line-derived supernatant. Blockade of the CCL2-CCR4 axis significantly reduced migration of canine Tregs. CCL2 mRNA was expressed in all glioma cell lines and expression increased when exposed to Tregs but not to CD4 + helper T-cells. Conclusion Our study validates CCL2-CCR4 as a bi-directional Treg-glioma immunosuppressive and tumor-promoting axis in canine high-grade glioma.
PubMed: 38947002
DOI: 10.21203/rs.3.rs-4474288/v1 -
World Journal of Gastroenterology Jun 2024Metabolic dysfunction-associated fatty liver disease (MAFLD) is a hepatic manifestation of the metabolic syndrome. It is one of the most common liver diseases worldwide... (Review)
Review
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a hepatic manifestation of the metabolic syndrome. It is one of the most common liver diseases worldwide and shows increasing prevalence rates in most countries. MAFLD is a progressive disease with the most severe cases presenting as advanced fibrosis or cirrhosis with an increased risk of hepatocellular carcinoma. Gut microbiota play a significant role in the pathogenesis and progression of MAFLD by disrupting the gut-liver axis. The mechanisms involved in maintaining gut-liver axis homeostasis are complex. One critical aspect involves preserving an appropriate intestinal barrier permeability and levels of intestinal lumen metabolites to ensure gut-liver axis functionality. An increase in intestinal barrier permeability induces metabolic endotoxemia that leads to steatohepatitis. Moreover, alterations in the absorption of various metabolites can affect liver metabolism and induce liver steatosis and fibrosis. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a class of drugs developed for the treatment of type 2 diabetes mellitus. They are also commonly used to combat obesity and have been proven to be effective in reversing hepatic steatosis. The mechanisms reported to be involved in this effect include an improved regulation of glycemia, reduced lipid synthesis, β-oxidation of free fatty acids, and induction of autophagy in hepatic cells. Recently, multiple peptide receptor agonists have been introduced and are expected to increase the effectiveness of the treatment. A modulation of gut microbiota has also been observed with the use of these drugs that may contribute to the amelioration of MAFLD. This review presents the current understanding of the role of the gut-liver axis in the development of MAFLD and use of members of the GLP-1 RA family as pleiotropic agents in the treatment of MAFLD.
Topics: Humans; Glucagon-Like Peptide-1 Receptor; Gastrointestinal Microbiome; Liver; Non-alcoholic Fatty Liver Disease; Animals; Metabolic Syndrome; Hypoglycemic Agents; Diabetes Mellitus, Type 2; Incretins; Intestinal Mucosa; Glucagon-Like Peptide-1 Receptor Agonists
PubMed: 38946874
DOI: 10.3748/wjg.v30.i23.2964 -
Frontiers in Cell and Developmental... 2024Embryo implantation involves a series of events that bring the embryo and maternal tissues into contact to support post-implantation development in mammals. During...
Embryo implantation involves a series of events that bring the embryo and maternal tissues into contact to support post-implantation development in mammals. During implantation, alignment of the embryonic-abembryonic (E-Ab) axis of the blastocyst with the mesometrial-antimesometrial (M-AM) axis of the uterus precedes post-implantation embryonic development and placentation. In the present study, we observed the morphological changes in blastocysts and the endometrial luminal epithelium (LE) that occur during the alignment of the embryonic and the uterine axes. We found that at the time that the blastocysts attached to the LE at the mural trophectoderm, the embryonic axis was not aligned with the uterine axis. Alignment of the embryonic E-Ab axis with the uterine M-AM axis occurred after E4.0, and the embryo was significantly elongated during the process. The depth of the implantation chamber (IC) correlated with the degree of alignment, suggesting that elongated embryos are oriented along the M-AM axis during IC formation. Transplantation of the Concanavalin A (Con A)-coated beads induced IC formation, and the alignment of two Con A-coated beads present in the same IC in the M-AM direction suggested that elongated materials can align along the M-AM axis. These data suggest that an elongated shape of the embryo and IC formation coordinate the alignment of the embryonic and uterine axes.
PubMed: 38946796
DOI: 10.3389/fcell.2024.1421222 -
Frontiers in Cell and Developmental... 2024[This retracts the article DOI: 10.3389/fcell.2021.628573.].
[This retracts the article DOI: 10.3389/fcell.2021.628573.].
PubMed: 38946795
DOI: 10.3389/fcell.2024.1445363 -
Journal of Cell Communication and... Jun 2024Liver fibrosis is a persistent damage repair response triggered by various injury factors, which leads to an abnormal accumulation of extracellular matrix within liver...
Liver fibrosis is a persistent damage repair response triggered by various injury factors, which leads to an abnormal accumulation of extracellular matrix within liver tissue samples. The current clinical treatment of liver fibrosis is currently ineffective; therefore, elucidating the mechanism of liver fibrogenesis is of significant importance. Herein, the function and related mechanisms of lncRNA within hepatic fibrosis were investigated. expression was shown to be increased in mouse hepatic fibrotic tissue samples, and knockdown suppressed hepatic pathological injury and down-regulated the expression levels of fibrosis-associated proteins. Mechanistically, played a role in the early activation of mouse hepatic stellate cells (mHSCs) based on bioinformatics analysis, and was positively correlated with Igfbp3 expression. Further experimental results demonstrated that knockdown impeded mHSCs proliferation and activation and also downregulated the protein expression of Igfbp3. could interact with IGFBP3 and boost its protein stability, and overexpression of partially reversed the inhibition of mHSCsproliferation and activation by the knockdown of . In conclusion, LncRNA mediates liver fibrosis by targeting IGFBP3 and promoting its protein stability, thereby promoting mHSC proliferation and activation. has been identified as an underlying target for treating liver fibrosis.
PubMed: 38946724
DOI: 10.1002/ccs3.12033 -
Journal of Cell Communication and... Jun 2024Resistance to chemotherapy leads to poor prognosis for osteosarcoma (OS) patients. However, due to the high metastasis of tumor and the decrease in sensitivity of tumor...
Resistance to chemotherapy leads to poor prognosis for osteosarcoma (OS) patients. However, due to the high metastasis of tumor and the decrease in sensitivity of tumor cells to cisplatin (DDP), the 5-year survival rate of OS patients is still unsatisfactory. This study explored a mechanism for improving the sensitivity of OS cells to DDP. A DDP-resistant OS cell model was established, and we have found that circORC2 and TRIM2 were upregulated in DDP-resistant OS cells, but miR-485-3p was downregulated. The cell viability and proliferation of the OS cells decreased gradually with the increase of DDP dose, but a gradual increase in apoptosis was noted. CircORC2 promoted OS cell proliferation and DDP resistance and upregulated TRIM2 expression by targeting miR-485-3p. Functionally, circORC2 downregulated miR-485-3p to promote OS cell proliferation and inhibit DDP sensitivity. Additionally, it promoted cell proliferation and inhibited the sensitivity of DDP by regulating the miR-485-3p/TRIM2 axis. In conclusion, circORC2 promoted cell proliferation and inhibited the DDP sensitivity in OS cells via the miR-485-3p/TRIM2 axis. These findings indicated the role of circORC2 in regulating the sensitivity of OS cells to DDP.
PubMed: 38946721
DOI: 10.1002/ccs3.12029 -
Journal of Cell Communication and... Jun 2024lncRNA ZFAS1 was identified to facilitate thyroid cancer, but its role in medullary thyroid carcinoma (MTC) remains unknown. This study aimed to unravel the potential...
lncRNA ZFAS1 was identified to facilitate thyroid cancer, but its role in medullary thyroid carcinoma (MTC) remains unknown. This study aimed to unravel the potential function of this lncRNA in MTC by investigating the involvement of the lncRNA ZFAS1 in a ceRNA network that regulates MTC invasion. Proliferation, invasion, and migration of cells were evaluated using EdU staining and Transwell assays. Immunoprecipitation (IP) assays, dual-fluorescence reporter, and RNA IP assays were employed to examine the binding interaction among genes. Nude mice were used to explore the role of lncRNA ZFAS1 in MTC in vivo. ZFAS1 and EPAS1 were upregulated in MTC. Silencing ZFAS1 inhibited MTC cell proliferation and invasion under hypoxic conditions, which reduced EPAS1 protein levels. UCHL1 knockdown increased EPAS1 ubiquitination. ZFAS1 positively regulated UCHL1 expression by binding to miR-214-3p. Finally, silencing ZFAS1 significantly repressed tumor formation and metastasis in MTC. LncRNA ZFAS1 promotes invasion of MTC by upregulating EPAS1 expression via the miR-214-3p/UCHL1 axis.
PubMed: 38946718
DOI: 10.1002/ccs3.12021 -
Dalton Transactions (Cambridge, England... Jul 2024In this work, PbSbO-type oxides LaMTeO (M = Ga and Mn) were synthesized and structurally characterized by Rietveld refinements against high-resolution X-ray powder...
In this work, PbSbO-type oxides LaMTeO (M = Ga and Mn) were synthesized and structurally characterized by Rietveld refinements against high-resolution X-ray powder diffraction data. The Ga/Te partial ordering within the honeycomb-like two-dimensional [GaTeO] anionic layer leads to the loss of the inversion center between Ga and Te; however the inversion center on the 3̄-roto-inversion axis is preserved, thereby resulting in a 2-fold PbSbO-type superstructure by doubling the -axis associated with a structural symmetry descending from the original 3̄1 to 3̄1 symmetry. In contrast, LaMnTeO (2/) adopts a monoclinically distorted 4-fold superstructure with lattice dimensions of ≈ , ≈ √3, ≈ 2, where and represent the lattice parameters of trigonal PbSbO. The formation of this 2/-superstructure is attributed to the combination of complete Mn/Te ordering and the first-order Jahn-Teller distortion of Mn with the electronic configuration of . Such a monoclinic distortion can effectively lift the Mn spin moments arranged on the triangular sublattice, resulting in a sharp peak for antiferromagnetic transition, which is in stark contrast to subtle magnetic transitions for PbSbO-type tellurates AMn(VI)TeO (A = alkaline earth and Pb) and LnCrTeO (Ln = rare earth) with higher structural symmetry. Our findings highlight that the electronic configuration effects of M-cations play a critical role in controlling the structure symmetry of LaMTeO, providing a strategy to fine-tune the crystal structures and physical properties.
PubMed: 38946522
DOI: 10.1039/d4dt01486c -
Journal of Indian Prosthodontic Society Jul 2024This study investigates the interaction of zirconia and polyetheretherketone (PEEK) with indirect composite in fixed dental prostheses. This investigation aimed to... (Comparative Study)
Comparative Study
Comparative evaluation of bond strength and color stability of polyetheretherketone and zirconia layered with indirect composite before and after thermocycling: An in vitro study.
AIM
This study investigates the interaction of zirconia and polyetheretherketone (PEEK) with indirect composite in fixed dental prostheses. This investigation aimed to assess the shear bond strength (SBS) and color stability of zirconia and PEEK before and after aging, addressing critical concerns in dental restorative applications.
SETTINGS AND DESIGN
The current in vitro study used 96 samples, 48 of which were divided into two groups, zirconia and PEEK, before and after thermocycling. A dual-axis chewing simulator was used for thermocycling. SBS was measured using a universal testing machine, and color stability was checked using a reflective spectrophotometer.
MATERIALS AND METHODS
Ninety-six samples were categorized into zirconia and PEEK groups, each with subgroups undergoing thermocycling. Samples were prepared using computer-aided design/computer-aided manufacturing milling and veneered with composite resin. Thermocycling involved 10,000 cycles, simulating stress levels equivalent to approximately 1 year of clinical use. SBS was assessed using standardized tests. Stereomicroscopic analysis was performed to evaluate the type of failure. Color stability of the core materials with indirect composite was done using a spectrophotometer before and after aging.
STATISTICAL ANALYSIS USED
Statistical analysis included paired t-tests and independent t-tests in SPSS software.
RESULTS
The results revealed that SBS values for composite on PEEK decreased from 13.86 ± 0.164 MPa before thermocycling to 13.46 ± 0.185 MPa after thermocycling, with a significant difference (P < 0.005). However, both pre- and postthermocycling values for PEEK were higher than zirconia. The t-test confirmed the lower bond strength of composite to zirconia, with a noteworthy improvement after aging. Stereomicroscopic images revealed adhesive failure for the zirconia group and mixed (adhesive and cohesive) failure for the PEEK group. ΔE values were 3.21 ± 0.127 and 2.93 ± 0.142 for zirconia and PEEK groups, respectively (P < 0.005).
CONCLUSION
Within the limitations of this study, it can be deduced that PEEK is a feasible substitute for zirconia when used in conjunction with indirect composite for the fabrication of dental prostheses.
Topics: Benzophenones; Zirconium; Ketones; Polyethylene Glycols; Polymers; Composite Resins; In Vitro Techniques; Dental Bonding; Color; Materials Testing; Shear Strength; Dental Materials; Dental Stress Analysis; Humans
PubMed: 38946508
DOI: 10.4103/jips.jips_36_24