Forkhead box O6 (FoxO6) promotes cardiac pathological remodeling and dysfunction by activating Kif15–TGF‐β1 under aggravated afterload
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ABSTRACT:
SUBMITTER: Zhang B
PROVIDER: S-EPMC10547936 | biostudies-literature | 2023 Oct
REPOSITORIES: biostudies-literature
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Project description:The Forkhead box, subclass O (FOXO) proteins are critical transcription factors, ubiquitously expressed in the human body. These proteins are characterized by a remarkable functional diversity, being involved in cell cycle arrest, apoptosis, oxidative detoxification, DNA damage repair, stem cell maintenance, cell differentiation, cell metabolism, angiogenesis, cardiac development, aging and others. In addition, FOXO have critical implications in both normal and cancer stem cell biology. New strategies to modulate FOXO expression and activity may now be developed since the discovery of novel FOXO regulators and non-coding RNAs (such as microRNAs) targeting FOXO transcription factors. This review focuses on physiological and pathological functions of FOXO proteins and on their action as fine regulators of cell fate and context-dependent cell decisions. A better understanding of the structure and critical functions of FOXO transcription factors and tumor suppressors may contribute to the development of novel therapies for cancer and other diseases.
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Project description:Dysregulation in the cutaneous wound-healing process is a consequence of alterations in the efficiency and activity of the various components involved in the healing process. This dysregulation may result in various clinical appearances of a lesion, such as skin ulcers, keloids, hypertrophic and atrophic scars. The collagen type V alpha 2 (COL5A2) gene provides a template for a component of type V collagen, found primarily within the skin basement membrane. Transforming growth factor (TGF)-β is involved in inflammation, angiogenesis, proliferation of fibroblasts, collagen synthesis and extracellular matrix remodeling. Hypertrophic scar fibroblasts possess a disrupted expression pattern of the TGF-β signaling compared to normal healing, while an increased TGF-β signaling reduces the epidermal proliferation rate, triggering atrophic scarring. In the present study, 71 female patients who had undergone planned Caesarean section, without postoperative complications, were examined. These patients were clinically and molecularly evaluated after developing scars in order to determine the role of TGF-β1 (rs201700967 and rs200230083) and COL5A2 (rs369072636) in pathological scarring. Clinical scar evaluation was carried out using SCAR and POSAS scales and genotyping was performed by RT-PCR. No statistical differences were found between the subgroups regarding the genotype and the pathological scarring, since all the patients included were wild-type allele carriers. Further investigations and a more representative study group may highlight the involvement of COL5A2 and TGF-β1 single nucleotide variants in pathological scarring.
| S-EPMC8355659 | biostudies-literature
Project description:Esophageal cancer (EC) is one of the most lethal cancers currently known. Members of the forkhead-box A (FOXA) family, including FOXA1 and FOXA2, have been reported to regulate EC progression. However, the role of FOXA3, which is another FOXA member, has not yet been investigated. In the present study, public dataset analyses and immunohistochemistry of 96 samples from patients with EC were performed to determine the potential roles of FOXA3 in EC. The results revealed that FOXA3 was significantly upregulated in EC tumor tissues and Barrett's esophagus tissues. In addition, FOXA3 upregulation was positively associated with tumor invasion, distant metastasis, tumor-node-metastasis stage and shorter overall survival in patients with EC, and multivariate analysis identified FOXA3 as an independent prognostic marker. In vitro experiments demonstrated that the migratory and invasive abilities of EC109 and EC9706 cell lines were inhibited following FOXA3 knockdown. Notably, FOXA3 expression levels were positively correlated with FOXA1 and FOXA2 expression levels according to The Cancer Genome Atlas dataset analysis. Furthermore, FOXA3 knockdown decreased the expression levels of FOXA1 and FOXA2 in EC109 and EC9706 cell lines. Conversely, FOXA1 or FOXA2 overexpression compensated for the effects of FOXA3 knockdown on the migratory and invasive capacities of EC cells. In conclusion, the present study demonstrated that FOXA3 upregulation in EC cells promoted metastasis through regulation of other FOXA members.
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Project description:Background and aimsThe pathogenesis of liver fibrosis involves liver damage, inflammation, oxidative stress, and intestinal dysfunction. Indole-3-propionic acid (IPA) has been demonstrated to have antioxidant, anti-inflammatory and anticancer activities, and a role in maintaining gut homeostasis. The current study aimed to investigate the role of IPA in carbon tetrachloride (CCl4)-induced liver fibrosis and explore the underlying mechanisms.MethodsThe liver fibrosis model was established in male C57BL/6 mice by intraperitoneal injection of CCl4 twice weekly. IPA intervention was made orally (20 mg/kg daily). The degree of liver injury and fibrosis were assessed by serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and histopathology. Enzyme-linked immunosorbent assay and quantitative real-time polymerase chain reaction (qPCR) were used to detect the inflammatory cytokines. The malondialdehyde (MDA), glutathione, glutathione peroxidase, superoxide dismutase, and catalase were determined via commercial kits. Hepatocyte apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay. The expression of mRNA and protein was assayed by qPCR, Western blotting, or immunohistochemical staining.ResultsAfter IPA treatment, the ALT and AST, apoptotic cells, and pro-inflammatory factor levels were enhanced significantly. Moreover, IPA intervention up-regulated the expression of collagen I, α-smooth muscle actin, tissue inhibitor of matrix metalloproteinase-1, matrix metalloproteinase-2, transforming growth factor-β1 (TGF-β1), Smad3, and phosphorylated-Smad2/3. Additionally, IPA intervention did not affect the MDA level. Attractively, the administration of IPA remodeled the gut flora structure.ConclusionsIPA aggravated CCl4-induced liver damage and fibrosis by activating HSCs via the TGF-β1/Smads signaling pathway.
| S-EPMC8666369 | biostudies-literature
Project description:High myopia is a leading cause of blindness worldwide. Myopia progression may lead to pathological changes of lens and affect the outcome of lens surgery, but the underlying mechanism remains unclear. Here, we find an increased lens size in highly myopic eyes associated with up-regulation of β/γ-crystallin expressions. Similar findings are replicated in two independent mouse models of high myopia. Mechanistic studies show that the transcription factor MAF plays an essential role in up-regulating β/γ-crystallins in high myopia, by direct activation of the crystallin gene promoters and by activation of TGF-β1-Smad signaling. Our results establish lens morphological and molecular changes as a characteristic feature of high myopia, and point to the dysregulation of the MAF-TGF-β1-crystallin axis as an underlying mechanism, providing an insight for therapeutic interventions.
| S-EPMC8032689 | biostudies-literature
Project description:Prolonged and elevated transforming growth factor-β1 (TGF-β1) signaling can lead to undesired scar formation during tissue repair and fibrosis that is often a result of chronic inflammation in the lung, kidney, liver, heart, skin, and joints. We report new TGF-β1 binding peptides that interfere with TGF-β1 binding to its cognate receptors and thus attenuate its biological activity. We identified TGF-β1 binding peptides from the TGF-β1 binding domains of TGF-β receptors and engineered their sequences to facilitate chemical conjugation to biomaterials using molecular docking simulations. The in vitro binding studies and cell-based assays showed that RIPΔ, which was derived from TGF-β type I receptor, bound TGF-β1 in a sequence-specific manner and reduced the biological activity of TGF-β1 when the peptide was presented either in soluble form or conjugated to a commonly used synthetic biomaterial. This approach may have implications for clinical applications such as treatment of various fibrotic diseases and soft tissue repair and offer a design strategy for peptide antibodies based on the biomimicry of ligand-receptor interactions.
| S-EPMC9254699 | biostudies-literature
Project description:PurposePathological fibrosis of the myodural bridge (MDB) affects cerebrospinal fluid circulation. However, no optimal drug treatments are available. We aimed to explore the antifibrotic effect of resveratrol on bleomycin-induced pathological fibrosis of the MDB and its underlying mechanisms.MethodsGenes common to the potential targets of resveratrol were determined using network pharmacology, genes related to muscle and tendon fibrosis were acquired from the GeneCards database, and genes related to MDB development were determined using Venny. These genes were considered potential resveratrol treatment targets in bleomycin-induced pathological fibrosis of the MDB and were annotated using bioinformatics methods. We validated the intersected genes using quantitative real-time polymerase chain reaction (qRT-PCR) and performed molecular docking analysis to calculate the binding activity between the target gene and resveratrol. Hematoxylin and eosin and Masson staining were used to detect the morphological changes in bleomycin-induced fibrosis of the MDB following resveratrol treatment. We used qRT-PCR and immunohistochemistry to evaluate the expression of the sirtuin 3 (SIRT3)/transforming growth factor-β1 (TGF-β1)/Smad pathway and the profibrotic markers α-smooth muscle actin (α-SMA) and Collagen Ⅰ.ResultsThrough network pharmacology and bioinformatics analyses, we identified four core intersected genes, and SIRT3 expression was validated using qRT-PCR. Molecular docking analysis revealed that resveratrol had good binding affinity for SIRT3. Resveratrol ameliorated morphological abnormalities in bleomycin-induced pathological fibrosis of the MDB by inhibiting fibroblast activation and excessive collagen fiber deposition. Resveratrol exerted its antifibrotic effect by regulating the SIRT3/TGF-β1/Smad pathway.ConclusionResveratrol has an antifibrotic effect in bleomycin-induced pathological fibrosis of the MDB in vivo and may be considered a novel therapeutic strategy.
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Project description:Increased afterload results in 'pathological' cardiac hypertrophy, the most important risk factor for the development of heart failure. Current in vitro models fall short in deciphering the mechanisms of hypertrophy induced by afterload enhancement. The aim of this study was to develop an experimental model that allows investigating the impact of afterload enhancement (AE) on work-performing heart muscles in vitro. Fibrin-based engineered heart tissue (EHT) was cast between two hollow elastic silicone posts in a 24-well cell culture format. After 2 weeks, the posts were reinforced with metal braces, which markedly increased afterload of the spontaneously beating EHTs. Serum-free, triiodothyronine-, and hydrocortisone-supplemented medium conditions were established to prevent undefined serum effects. Control EHTs were handled identically without reinforcement. Endothelin-1 (ET-1)- or phenylephrine (PE)-stimulated EHTs served as positive control for hypertrophy. Cardiomyocytes in EHTs enlarged by 28.4 % under AE and to a similar extent by ET-1- or PE-stimulation (40.6 or 23.6 %), as determined by dystrophin staining. Cardiomyocyte hypertrophy was accompanied by activation of the fetal gene program, increased glucose consumption, and increased mRNA levels and extracellular deposition of collagen-1. Importantly, afterload-enhanced EHTs exhibited reduced contractile force and impaired diastolic relaxation directly after release of the metal braces. These deleterious effects of afterload enhancement were preventable by endothelin-A, but not endothelin-B receptor blockade. Sustained afterload enhancement of EHTs alone is sufficient to induce pathological cardiac remodeling with reduced contractile function and increased glucose consumption. The model will be useful to investigate novel therapeutic approaches in a simple and fast manner.
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Project description:Forkhead box N1 (FOXN1) is a member of the forkhead box family of transcription factors and plays an important role in thymic epithelial cell differentiation and development. FOXN1 mutations in humans and mice give rise to the "nude" phenotype, which is marked by athymia. FOXN1 belongs to a subset of the FOX family that recognizes an alternative forkhead-like (FHL) consensus sequence (GACGC) that is different from the more widely recognized forkhead (FKH) sequence RYAAAYA (where R is purine, and Y is pyrimidine). Here, we present the FOXN1 structure in complex with DNA containing an FHL motif at 1.6 Å resolution, in which the DNA sequence is recognized by a mixture of direct and water-mediated contacts provided by residues in an α-helix inserted in the DNA major groove (the recognition helix). Comparisons with the structure of other FOX family members revealed that the FKH and FHL DNA sequences are bound in two distinct modes, with partially different registers for the protein DNA contacts. We identified a single alternative rotamer within the recognition helix itself as an important determinant of DNA specificity and found protein sequence features in the recognition helix that could be used to predict the specificity of other FOX family members. Finally, we demonstrate that the C-terminal region of FOXN1 is required for high-affinity DNA binding and that FOXN1 has a significantly reduced affinity for DNA that contains 5'-methylcytosine, which may have implications for the role of FOXN1 in thymic involution.
| S-EPMC7062188 | biostudies-literature
Project description:Glycosaminoglycans are known to bind biological mediators thereby modulating their biological activity. Sulfated hyaluronans (sHA) were reported to strongly interact with transforming growth factor (TGF)-β1 leading to impaired bioactivity in fibroblasts. The underlying mechanism is not fully elucidated yet. Examining the interaction of all components of the TGF-β1:receptor complex with sHA by surface plasmon resonance, we could show that highly sulfated HA (sHA3) blocks binding of TGF-β1 to its TGF-β receptor-I (TβR-I) and -II (TβR-II). However, sequential addition of sHA3 to the TβR-II/TGF-β1 complex led to a significantly stronger recruitment of TβR-I compared to a complex lacking sHA3, indicating that the order of binding events is very important. Molecular modeling suggested a possible molecular mechanism in which sHA3 could potentially favor the association of TβR-I when added sequentially. For the first time bioactivity of TGF-β1 in conjunction with sHA was investigated at the receptor level. TβR-I and, furthermore, Smad2 phosphorylation were decreased in the presence of sHA3 indicating the formation of an inactive signaling complex. The results contribute to an improved understanding of the interference of sHA3 with TGF-β1:receptor complex formation and will help to further improve the design of functional biomaterials that interfere with TGF-β1-driven skin fibrosis.
| S-EPMC5430790 | biostudies-literature