ABSTRACT
Systemic sclerosis (SSc) is an autoimmune disease affecting multiple tissues. The underlying causes and mechanisms of subcutaneous adipose tissue (SAT) loss in SSc remain unclear. Recent studies have highlighted the role of microRNAs in adipogenesis. Our study found that miR-4769-3p was upregulated in SSc patients and its silencing promoted SAT recovery in bleomycin-induced SSc mice, suggesting that miR-4769-3p might affect adipogenesis in SSc. Manipulating miR-4769-3p expression in 3T3-L1 cells revealed that its inhibition enhanced adipogenesis, while its overexpression weakened it. Further investigations showed that miR-4769-3p bound to 3'UTR of ubiquitin-specific protease-18 (USP18), inhibiting its expression, while USP18 interacted with voltage-dependent anion channel-2 (VDAC2), both of which were reduced in SSc. Silencing either USP18 or VDAC2 attenuated adipogenesis. Notably, USP18 inhibited VDAC2 ubiquitination and degradation, whereas miR-4769-3p reversed the VDAC2-induced elevation of adipogenesis, suggesting that miR-4769-3p inhibited adipogenesis by negatively regulating the USP18/VDAC2 pathway, providing a potential therapeutic target for SSc.
ABSTRACT
A substantive body of evidence has demonstrated the significant roles of circular RNA (circRNA) in cancer. However, the contribution of dysregulated circRNAs to ovarian cancer (OC) remains elusive. We aim to elucidate the critical roles and mechanisms of hsa_circ_0020093, which was demonstrated to be downregulated in OC tissues in our previous study. In this study, we confirmed the decreased expression of hsa_circ_0020093 in OC tissues and cell lines and demonstrated the negative correlation between its expression and FIGO stage, abdominal implantation and CA125 level of OC patients. Through gain and loss of function studies, we confirmed the inhibitory role of hsa_circ_0020093 in ovarian tumor growth in vitro and in vivo. Mechanistically, based on the peri-nuclear accumulation of hsa_circ_0020093, we discovered the interaction between hsa_circ_0020093 and the mitochondrial protein LRPPRC by RNA pull-down, mass spectrometry, RNA Binding Protein Immunoprecipitation. As a result, qRT-PCR and transmission electron microscopy results showed that the mitochondria mRNA expression and mitochondria abundance were decreased upon hsa_circ_0020093-overexpression. Meanwhile, we also unearthed the hsa_circ_0020093/miR-107/LATS2 axis in OC according to RNA-sequencing, RIP and luciferase reporter assay data. Furthermore, LRPPRC and LATS2 are both reported as the upstream regulators of YAP, our study also studied the crosstalk between hsa_circ_0020093, LRPPRC and miR-107/LATS2, and unearthed the up-regulation of phosphorylated YAP in hsa_circ_0020093-overexpressing OC cells and xenograft tumors. Collectively, our study indicated the novel mechanism of hsa_circ_0020093 in suppressing OC progression through both hsa_circ_0020093/LRPPRC and hsa_circ_0020093/miR-107/LATS2 axes, providing a potential therapeutic target for OC patients.
Subject(s)
MicroRNAs , Ovarian Neoplasms , Protein Serine-Threonine Kinases , RNA, Circular , Signal Transduction , Tumor Suppressor Proteins , Humans , Female , Ovarian Neoplasms/genetics , Ovarian Neoplasms/metabolism , RNA, Circular/genetics , RNA, Circular/metabolism , MicroRNAs/genetics , MicroRNAs/metabolism , Cell Line, Tumor , Mice , Animals , Protein Serine-Threonine Kinases/metabolism , Protein Serine-Threonine Kinases/genetics , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolism , Disease Progression , Gene Expression Regulation, Neoplastic , Mice, NudeABSTRACT
A novel and efficient method for functionalizing organosulfones has been established, utilizing a visible-light-driven intermolecular radical cascade cyclization of α-allyl-ß-ketosulfones. This process employs fac-Ir(ppy)3 as the photoredox catalyst and α-carbonyl alkyl bromide as the oxidizing agent. Via this approach, the substrates experience intermolecular addition of α-carbonyl alkyl radicals to the alkene bonds, initiating a sequence of C-C bond formations that culminate in the production of organosulfone derivatives. Notably, this technique features gentle reaction conditions and an exceptional compatibility with a wide array of functional groups, making it a versatile and valuable addition to the field of organic synthesis.
ABSTRACT
The disruption of mitochondria homeostasis can impair the contractile function of cardiomyocytes, leading to cardiac dysfunction and an increased risk of heart failure. This study introduces a pioneering therapeutic strategy employing mitochondria derived from human umbilical cord mesenchymal stem cells (hu-MSC) (MSC-Mito) for heart failure treatment. Initially, we isolated MSC-Mito, confirming their functionality. Subsequently, we monitored the process of single mitochondria transplantation into recipient cells and observed a time-dependent uptake of mitochondria in vivo. Evidence of human-specific mitochondrial DNA (mtDNA) in murine cardiomyocytes was observed after MSC-Mito transplantation. Employing a doxorubicin (DOX)-induced heart failure model, we demonstrated that MSC-Mito transplantation could safeguard cardiac function and avert cardiomyocyte apoptosis, indicating metabolic compatibility between hu-MSC-derived mitochondria and recipient mitochondria. Finally, through RNA sequencing and validation experiments, we discovered that MSC-Mito transplantation potentially exerted cardioprotection by reinstating ATP production and curtailing AMPKα-mTOR-mediated excessive autophagy.
Subject(s)
AMP-Activated Protein Kinases , Apoptosis , Autophagy , Mesenchymal Stem Cells , Mitochondria , Myocytes, Cardiac , TOR Serine-Threonine Kinases , Animals , Humans , Male , Mice , AMP-Activated Protein Kinases/metabolism , Doxorubicin/pharmacology , Heart Failure/metabolism , Mesenchymal Stem Cells/metabolism , Mice, Inbred C57BL , Mitochondria/metabolism , Mitochondria/transplantation , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , TOR Serine-Threonine Kinases/metabolismABSTRACT
Nowadays, silica products are widely used in daily life, especially in skin applications, which inevitably increases the risk of silica exposure in general population. However, inadequate awareness of silica's potential hazards and lack of self-protection are of concern. Systemic sclerosis (SSc) is characterized by progressive tissue fibrosis under environmental and genetic interactions. Silica exposure is considered an important causative factor for SSc, but its pathogenesis remains unclear. Within this study, we showed that lower doses of silica significantly promoted the proliferation, migration, and activation of human skin fibroblasts (HSFs) within 24 h. Silica injected subcutaneously into mice induced and exacerbated skin fibrosis. Notably, silica increased histone deacetylase-4 (HDAC4) expression by inducing its DNA hypomethylation in normal HSFs. The elevated HDAC4 expression was also confirmed in SSc HSFs. Furthermore, HDAC4 was positively correlated with Smad2/3 phosphorylation and COL1, α-SMA, and CTGF expression. The HDAC4 inhibitor LMK235 mitigated silica-induced upregulation of these factors and alleviated skin fibrosis in SSc mice. Taken together, silica induces and exacerbates skin fibrosis in SSc patients by targeting the HDAC4/Smad2/3 pathway. Our findings provide new insights for evaluating the health hazards of silica exposure and identify HDAC4 as a potential interventional target for silica-induced SSc skin fibrosis.
Subject(s)
Fibrosis , Histone Deacetylases , Scleroderma, Systemic , Silicon Dioxide , Skin , Smad2 Protein , Smad3 Protein , Scleroderma, Systemic/metabolism , Scleroderma, Systemic/chemically induced , Histone Deacetylases/metabolism , Histone Deacetylases/genetics , Animals , Mice , Humans , Smad3 Protein/metabolism , Skin/metabolism , Smad2 Protein/metabolism , Fibroblasts/metabolism , Fibroblasts/drug effects , Repressor Proteins/metabolism , Repressor Proteins/genetics , Signal Transduction/drug effectsABSTRACT
Herein we have pioneered an innovative synthetic strategy for the efficient assembly of various heteroarene-condensed benzofuran derivatives, utilizing benzofuran-derived azadienes (BDAs) and quinolines as the starting materials. This method functions with transition-metal catalysis and uses cost-effective formic acid as the reducing agent. Mechanistic investigations indicate that this transformation would involve a [4 + 2] annulation cascade process. This approach demonstrates a high tolerance to various functional groups and yields excellent results.
ABSTRACT
JAK2/STAT3/MYC axis is dysregulated in nearly 70 % of human cancers, but targeting this pathway therapeutically remains a big challenge in cancer therapy. In this study, genes associated with JAK2, STAT3, and MYC were analyzed, and potential target genes were selected. Leucine-rich PPR motif-containing protein (LRPPRC) whose function and regulation are not fully understood, emerged as one of top 3 genes in terms of RNA epigenetic modification. Here, we demonstrate LRPPRC may be an independent prognostic indicator besides JAK2, STAT3, and MYC. Mechanistically, LRPPRC impairs N6-methyladenosine (m6A) modification of JAK2, STAT3, and MYC to facilitate nuclear mRNA export and expression. Meanwhile, excess LRPPRC act as a scaffold protein binding to JAK2 and STAT3 to enhance stability of JAK2-STAT3 complex, thereby facilitating JAK2/STAT3/MYC axis activation to promote esophageal squamous cell carcinoma (ESCC) progression. Furthermore, 5,7,4'-trimethoxyflavone was verified to bind to LRPPRC, STAT3, and CDK1, dissociating LRPPRC-JAK2-STAT3 and JAK2-STAT3-CDK1 interaction, leading to impaired tumorigenesis in 4-Nitroquinoline N-oxide induced ESCC mouse models and suppressed tumor growth in ESCC patient derived xenograft mouse models. In summary, this study suggests regulation of m6A modification by LRPPRC, and identifies a novel triplex target compound, suggesting that targeting LRPPRC-mediated JAK2/STAT3/MYC axis may overcome JAK2/STAT3/MYC dependent tumor therapeutic dilemma.
Subject(s)
Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Janus Kinase 2 , STAT3 Transcription Factor , Humans , Esophageal Squamous Cell Carcinoma/drug therapy , Esophageal Squamous Cell Carcinoma/metabolism , Esophageal Squamous Cell Carcinoma/pathology , Esophageal Squamous Cell Carcinoma/genetics , STAT3 Transcription Factor/metabolism , Animals , Janus Kinase 2/metabolism , Mice , Esophageal Neoplasms/metabolism , Esophageal Neoplasms/drug therapy , Esophageal Neoplasms/pathology , Esophageal Neoplasms/genetics , Cell Line, Tumor , Gene Expression Regulation, Neoplastic/drug effects , Cell Proliferation/drug effects , Disease Progression , Adenosine/analogs & derivatives , Adenosine/pharmacology , Adenosine/metabolism , Adenosine/chemistry , Flavones/pharmacology , Flavones/chemistry , CDC2 Protein Kinase/metabolism , CDC2 Protein Kinase/genetics , Signal Transduction/drug effects , Proto-Oncogene Proteins c-myc/metabolism , Proto-Oncogene Proteins c-myc/genetics , Female , Male , Flavonoids/pharmacology , Flavonoids/chemistry , Xenograft Model Antitumor Assays , Neoplasm Proteins/metabolism , Neoplasm Proteins/geneticsABSTRACT
INTRODUCTION: The safety and effectiveness of prophylactic hyperthermic intraperitoneal chemotherapy (HIPEC) in pathological T3-4 locally advanced (pT3N + M0 and pT4NxM0) colon cancer (CC) patients with radical resection need further study. METHODS: Clinical and pathological information of pT3-4 locally advanced CC patients who received radical surgery in our hospital from January 2018 to December 2020 were analyzed. The prognosis of patients was estimated using Cox proportional hazards regression analysis and Kaplan-Meier method. RESULTS: Among 927 patients, 10.4% (96/927) received prophylactic HIPEC based on 5-FU, 4.6% (43/927) received prophylactic HIPEC based on lobaplatin, 85.0% (788/927) received conventional therapy. The incidence of metachronous peritoneal carcinomatosis (mPC) was 9.4%. Complications occurred in 32 patients (4.1%) in the conventional therapy group, 6 patients (6.3%) in the prophylactic HIPEC group based on 5-FU and 3 patients (7.0%) in the prophylactic HIPEC group based on lobaplatin within 30 days after surgery (5-FU vs. conventional therapy group, p = 0.464; Lobaplatin vs. conventional therapy group, p = 0.591). Multivariate Cox regression analysis revealed that prophylactic HIPEC based on either 5-FU or lobaplatin regimen could not effectively improve mPC-free survival (5-FU: p = 0.020, HR = 1.927, 95% CI, 1.111-3.343; Lobaplatin: p = 0.167, HR = 0.247, 95% CI, 0.034-1.796), overall survival (5-FU: p = 0.361, HR = 1.360, 95% CI, 0.703-2.634; Lobaplatin: p = 0.780, HR = 0.816, 95% CI, 0.195-3.416) and disease-free survival (5-FU: p = 0.525, HR = 1.149, 95% CI, 0.749-1.760; Lobaplatin: p = 0.117, HR = 0.488, 95% CI, 0.199-1.198). CONCLUSION: Early prophylactic HIPEC based on 5-FU or lobaplatin subsequent to radical resection for patients with pT3-4 locally advanced CC is safe, but not effective in reducing the risk for mPC.
ABSTRACT
Non-tuberculous mycobacteria (NTM) infection of the skin and soft tissues is a complication of cosmetic procedures. The incidence of cutaneous NTM infections has increased significantly as aesthetic operations have become more commonplace. With the rise of cosmetic tourism, the geographic expansion of NTM infections is a major concern. Due to the unique pathogenesis of NTM infections, diagnosis and treatment remain significant challenges for clinicians. Clinical management relies on a combination of antibiotic therapy with drug susceptibility testing and appropriate surgical debridement. Some new drugs, photodynamic therapy, and bacteriophage therapy have been developed in recent years, and may improve the aesthetic outcomes. This review summarizes the cosmetic procedures prone to NTM infections in recent years and their clinical features. We propose a 2-stage treatment procedure, including a hospitalization phase and a follow-up phase. We aim to increase the alertness of clinicians to NTM infections for timely detection and treatment.
Subject(s)
Anti-Bacterial Agents , Cosmetic Techniques , Mycobacterium Infections, Nontuberculous , Humans , Mycobacterium Infections, Nontuberculous/diagnosis , Mycobacterium Infections, Nontuberculous/etiology , Mycobacterium Infections, Nontuberculous/therapy , Mycobacterium Infections, Nontuberculous/drug therapy , Cosmetic Techniques/adverse effects , Anti-Bacterial Agents/therapeutic use , Anti-Bacterial Agents/administration & dosage , Nontuberculous Mycobacteria/isolation & purificationABSTRACT
BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the leading causes of digestive system tumor related death in the world. Unfortunately, effective chemopreventive agent is lack for patients with ESCC in clinical practice, which leads to the extremely high mortality rate. METHODS: A library of prescribed drugs was screened for finding critical anti-tumor properties in ESCC cells. The phosphoproteomics, kinase array, pulldown assay and drug affinity responsive target stabilization assay (DARTS) were applied to explore mechanisms and searched for synergistic targets. Established models of PDX in mice were used to determine the therapeutic effect of domperidone. RESULTS: After screening a library of prescribed drugs, we discovered that domperidone has anti-tumor properties. Domperidone, acting as a gastroprokinetic agent, has been widely used in clinic for gastrointestinal motility disorders. Despite limited research, there are indications that domperidone may have anti-tumor properties. In this study, we determined that domperidone significantly inhibited ESCC proliferation in vitro and in vivo. We employed phosphoproteomics to reveal p-ERK, and p-SMAD3 down-regulation upon domperidone treatment. Then, the results of kinase assay and pulldown assay further validated that domperidone directly combined with MEK1/2 and CDK4, leading to the inhibition of their kinase activity. Furthermore, our results revealed that MEK/ERK and CDK4/SMAD3 signal pathway were major pathways in domperidone against ESCC. CONCLUSION: Collectively, these findings suggest that domperidone serves as an effective "multi-target" inhibitor of MEK1/2 and CDK4, offering potential benefits for the chemoprevention of ESCC.
ABSTRACT
The E3 ubiquitin ligase Tripartite-motif 3 (TRIM3) is known to play a crucial role in tumor suppression in various tumors through different mechanisms. However, its function and mechanism in ovarian cancer have yet to be elucidated. Our study aims to investigate the expression of TRIM3 in ovarian cancer and evaluate its role in the development of the disease. Our findings revealed a significant decrease in TRIM3 mRNA and protein levels in ovarian cancer tissues and cells when compared to normal ovarian epithelial tissues and cells. Furthermore, we observed a negative correlation between the protein level of TRIM3 and the FIGO stage, as well as a positive correlation with the survival of ovarian cancer patients. Using gain and loss of function experiments, we demonstrated that TRIM3 can inhibit cell proliferation, migration and invasion of the ovarian cancer cells in vitro, as well as suppress tumor growth in vivo. Mechanistic studies showed that TRIM3 interacts with lactate dehydrogenase A, a key enzyme in the glycolytic pathway, through its B-box and coiled-coil domains and induces its ubiquitination and proteasomal degradation, leading to the inhibition of glycolytic ability in ovarian cancer cells. RNA-sequencing analysis revealed significant alterations in the phosphatidylinositol signaling pathways upon TRIM3 overexpression. Additionally, overexpression of TRIM3 inhibited the phosphorylation of AKT. In conclusion, our study demonstrated that TRIM3 exerts a tumor-suppressive effect in ovarian cancer, at least partially, by downregulating LDHA and inhibiting the AKT signaling pathway, and thus leading to the inhibition of glycolysis and limiting the growth of ovarian cancer cells.
ABSTRACT
Acute liver failure (ALF) is a significant global issue with elevated morbidity and mortality rates. There is an urgent and pressing need for secure and effective treatments. Ferroptosis, a novel iron-dependent regulation of cell death, plays a significant role in multiple pathological processes associated with liver diseases, including ALF. Several studies have demonstrated that mesenchymal stem cells (MSCs) have promising therapeutic potential in the treatment of ALF. This study aims to investigate the positive effects of MSCs against ferroptosis in an ALF model and explore the underlying molecular mechanisms of their therapeutic function. Our results show that intravenously injected MSCs protect against ferroptosis in ALF mouse models. MSCs decrease iron deposition in the liver of ALF mice by downregulating hepcidin level and upregulating FPN1 level. MSCs labelled with Dil are mainly observed in the hepatic sinusoid and exhibit colocalization with the macrophage marker CD11b fluorescence. ELISA demonstrates a high level of IGF1 in the CCL 4+MSC group. Suppressing the IGF1 effect by the PPP blocks the therapeutic effect of MSCs against ferroptosis in ALF mice. Furthermore, disruption of IGF1 function results in iron deposition in the liver tissue due to impaired inhibitory effects of MSCs on hepcidin level. Our findings suggest that MSCs alleviate ferroptosis induced by disorders of iron metabolism in ALF mice by elevating IGF1 level. Moreover, MSCs are identified as a promising cell source for ferroptosis treatment in ALF mice.
Subject(s)
Ferroptosis , Liver Failure, Acute , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells , Humans , Mice , Animals , Hepcidins/adverse effects , Hepcidins/metabolism , Liver Failure, Acute/therapy , Liver Failure, Acute/chemically induced , Liver Failure, Acute/pathology , Mesenchymal Stem Cells/metabolism , Umbilical Cord , Mesenchymal Stem Cell Transplantation/methods , Insulin-Like Growth Factor I/metabolismABSTRACT
Ovarian cancer (OC) is the second leading cause of gynecological cancer-related death in women worldwide. N6-methyladenosine (m6 A) is the most abundant internal modification in eukaryotic RNA. Human insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), an m6 A reader, can enhance mRNA stability and promote translation by recognizing m6 A modifications. Its tumor-promoting effects have been demonstrated in several cancers. However, the roles of m6 A modification and IGF2BP2 in OC remain unclear. Here, by using methylated RNA immunoprecipitation sequencing, we demonstrated that there is widespread dysregulation of m6 A modification in OC tissues. The m6 A modification and the mRNA and protein levels of IGF2BP2 were significantly elevated in OC. Overexpression of IGF2BP2 facilitated OC cell proliferation, migration, and invasion in vitro and accelerated tumor growth and metastasis in vivo. While IGF2BP2-knockdown showed the opposite effect. Mechanistically, we identified cytoskeleton-associated protein 2-like (CKAP2L) as a target of IGF2BP2. IGF2BP2 promoted CKAP2L translation dependent on m6 A modification, rather than affecting mRNA and protein stability. Overexpression of CKAP2L rescued the tumor-suppressive effect of IGF2BP2 knockdown in OC cells. In conclusion, this study revealed the potential role of IGF2BP2 in tumor progression, at least partially via promoting the translation of CKAP2L in an m6 A-dependent manner.
Subject(s)
Cytoskeletal Proteins , Ovarian Neoplasms , RNA-Binding Proteins , Female , Humans , Adenosine , Cell Proliferation , Cytoskeletal Proteins/genetics , Immunoprecipitation , Ovarian Neoplasms/genetics , RNA-Binding Proteins/geneticsABSTRACT
Systemic sclerosis (SSc) is an autoimmune disease characterized by immune dysfunction, vascular system dysfunction, and tissue fibrosis. Vascular injury, vascular remodeling, and endothelial dysfunction are the hallmark pathological changes of the disease. In the early stages of SSc development, endothelial cell injury and apoptosis can lead to vascular and perivascular inflammation, oxidative stress, and tissue hypoxia, which can cause clinical manifestations in various organs from the skin to the parenchymal organs. Early diagnosis and rational treatment can improve patient survival and quality of life. Ancillary examinations such as nailfold capillaroscopy as well as optical coherence tomography can help early detect vascular injury in SSc patients. Studies targeting the mechanisms of vascular lesions will provide new perspectives for treatment of SSc.
Subject(s)
Scleroderma, Systemic , Vascular Diseases , Vascular System Injuries , Humans , Quality of Life , FibrosisABSTRACT
Pyroptosis, a form of programmed cell death with a high pro-inflammatory effect, causes cell lysis and leads to the secretion of countless interleukin-1ß (IL-1ß) and IL-18 cytokines, resulting in a subsequent extreme inflammatory response through the caspase-1-dependent pathway or caspase-1-independent pathway. Adult-onset Still's disease (AOSD) is a systemic inflammatory disease with extensive disease manifestations and severe complications such as macrophage activation syndrome, which is characterized by high-grade inflammation and cytokine storms regulated by IL-1ß and IL-18. To date, the pathogenesis of AOSD is unclear, and the available therapy is unsatisfactory. As such, AOSD is still a challenging disease. In addition, the high inflammatory states and the increased expression of multiple pyroptosis markers in AOSD indicate that pyroptosis plays an important role in the pathogenesis of AOSD. Accordingly, this review summarizes the molecular mechanisms of pyroptosis and describes the potential role of pyroptosis in AOSD, the therapeutic practicalities of pyroptosis target drugs in AOSD, and the therapeutic blueprint of other pyroptosis target drugs.
Subject(s)
Still's Disease, Adult-Onset , Adult , Humans , Still's Disease, Adult-Onset/drug therapy , Still's Disease, Adult-Onset/etiology , Still's Disease, Adult-Onset/pathology , Interleukin-18 , Pyroptosis , Cytokines , Biomarkers , Caspase 1ABSTRACT
By conducting density functional theory (DFT) calculations, the detailed reaction mechanisms of aldimines with tributyltin cyanide under the catalytic influence of chiral oxazaborolidinium ion (COBI) have been uncovered. Three potential reaction pathways were examined, and two stereoselective routes were determined for the most energetically favorable mechanism. In the primary route, a proton is transferred from the COBI catalyst to the aldimine substrate, which is then followed by the C-C bond formation to produce the final product. Subsequently, NBO analyses of the stereoselectivity-determining transition states were conducted to identify the crucial role of hydrogen bond interactions in controlling stereoselectivity. These computed findings should prove invaluable in comprehending the detailed mechanisms and underlying origins of stereoselectivity for COBI-mediated reactions of this type.
ABSTRACT
Systemic sclerosis (SSc) is an autoimmune connective tissue disease that leads to irreversible fibrosis of the skin and the internal organs. The etiology of SSc is complex, its pathophysiology is poorly understood, and clinical therapeutic options are restricted. Thus, research into medications and targets for treating fibrosis is essential and urgent. Fos-related antigen 2 (Fra2) is a transcription factor that is a member of the activator protein-1 family. Fra2 transgenic mice were shown to have spontaneous fibrosis. All-trans retinoic acid (ATRA) is a vitamin A intermediate metabolite and ligand for the retinoic acid receptor (RAR), which possesses anti-inflammatory and anti-proliferative properties. Recent research has demonstrated that ATRA also has an anti-fibrotic effect. However, the exact mechanism is not fully understood. Interestingly, we identified potential binding sites for the transcription factor RARα to the promoter region of the FRA2 gene through JASPAR and PROMO databases. In this study, the pro-fibrotic effect of Fra2 in SSc is confirmed. SSc dermal fibroblasts and bleomycin-induced fibrotic tissues of SSc animals exhibit increased levels of Fra2. Inhibition of Fra2 expression in SSc dermal fibroblasts with Fra2 siRNA markedly decreased collagen I expression. ATRA reduced the expressions of Fra2, collagen I, and α-smooth muscle actin(α-SMA) in SSc dermal fibroblasts and bleomycin-induced fibrotic tissues of SSc mice. In addition, chromatin immunoprecipitation and dual-luciferase assays demonstrated that retinoic acid receptor RARα binds to the FRA2 promoter and modulates its transcriptional activity. ATRA decreases collagen I expression both in vivo and in vitro via the reduction of Fra2 expression. This work establishes the rationale for expanding the use of ATRA in the treatment of SSc and indicates that Fra2 can be used as an anti-fibrotic target.
Subject(s)
Scleroderma, Systemic , Transcription Factor AP-1 , Mice , Animals , Transcription Factor AP-1/metabolism , Fibrosis , Scleroderma, Systemic/metabolism , Mice, Transgenic , Collagen Type I/metabolism , Tretinoin/pharmacology , Receptors, Retinoic Acid/metabolism , Bleomycin/metabolism , Fibroblasts , Skin/pathology , Disease Models, AnimalABSTRACT
Ovarian cancer is the second leading cause of death in women with gynecological malignancy in China. Circular RNAs are a class of noncoding regulatory RNAs reported to be involved in cancer development and progression. Previous studies, including our own, have indicated that hsa_circ_0007444 is downregulated in ovarian cancer tissues. This study aims to elucidate the function and mechanism of hsa_circ_0007444 in ovarian cancer progression. The expression of hsa_circ_0007444 is determined by quantitative real-time PCR (qRT-PCR). Cell proliferation, invasion, migration and apoptosis are examined by cell counting-kit 8 (CCK-8), transwell and flow cytometry assays. Tumor growth and metastasis are assessed in vivo using Balb/c nude mouse xenograft model and tail vein injection model. And the mechanism of action of hsa_circ_0007444 is analysed by RNA-binding protein immunoprecipitation (RIP), luciferase reporter and rescue assays. hsa_circ_0007444 is downregulated in ovarian cancer tissues and cell lines compared with that in normal ovarian tissues and normal epithelial cell line. Gain- and loss-of-function results indicate that hsa_circ_0007444 inhibits cell proliferation, invasion, migration and increases cell apoptosis of ovarian cancer cells in vitro, and inhibits tumor growth and lung metastasis in vivo. Mechanistically, hsa_circ_0007444 can interact with AGO2 and sponge miR-23a-3p, thereby upregulating DICER1 expression, which is an important tumor suppressor in ovarian cancer. And miR-23a-3p mimics can rescue the inhibitory effect of hsa_circ_0007444 on ovarian cancer cell proliferation, invasion and migration. Therefore, hsa_circ_0007444 can inhibit ovarian cancer progression through the hsa_circ_0007444/miR-23a-3p/DICER1 axis.
Subject(s)
Lung Neoplasms , MicroRNAs , Ovarian Neoplasms , Animals , Female , Humans , Mice , Cell Line, Tumor , Cell Movement/genetics , Cell Proliferation/genetics , DEAD-box RNA Helicases/genetics , Gene Expression Regulation, Neoplastic , MicroRNAs/genetics , Ovarian Neoplasms/genetics , Ribonuclease III , RNA, Circular/geneticsABSTRACT
The fibrosis of tissues and organs occurs via an aberrant tissue remodeling process characterized by an excessive deposition of extracellular matrix, which can lead to organ dysfunction, organ failure, and death. Because the pathogenesis of fibrosis remains unclear and elusive, there is currently no medication to reverse it; hence, this process deserves further study. Activating protein-1 (AP-1)-comprising Jun (c-Jun, JunB, JunD), Fos (c-fos, FosB, Fra1, and Fra2), and activating transcription factor-is a versatile dimeric transcription factor. Numerous studies have demonstrated that AP-1 plays a crucial role in advancing tissue and organ fibrosis via induction of the expression of fibrotic molecules and activating fibroblasts. This review focuses on the role of AP-1 in a range of fibrotic disorders as well as on the antifibrotic effects of AP-1 inhibitors. It also discusses the potential of AP-1 as a new therapeutic target in conditions involving tissue and organ fibrosis.
ABSTRACT
Scleroderma is an autoimmune disease mainly characterized by progressive fibrosis of the skin. There are two types of scleroderma, namely localized scleroderma (LS) and systemic sclerosis (SSc); skin lesions in both types of scleroderma are histologically identical. Progressive skin sclerosis induces psychological and ecological burden for scleroderma patients. However, there is no effective treatment for scleroderma due to its unclear etiology. Aryl hydrocarbon receptor (AhR) is recognized as an environmental chemical effector that can respond to ultraviolet radiation, which has been demonstrated to participate in the pathogenesis of SSc in our previous study. In this study, we verify whether the anti-fibrosis effect of ultraviolet A1 (UVA1) phototherapy could be partially induced through Ficz/AhR/MAPK signaling activation for fibrotic lesions in both SSc and LS patients. This is the first study to show the association between the AhR pathway and the anti-fibrotic mechanism of UVA1 phototherapy, which provides additional evidence of the role of AhR in the fibrotic mechanism of systemic scleroderma from different perspectives. Ficz and other AhR agonists may replace UVA1 phototherapy as anti-fibrotic agents in scleroderma.