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Autoluminescent plants have been genetically modified to express the fungal bioluminescence pathway (FBP). However, a bottleneck in precursor production has limited the brightness of these luminescent plants. Here, we demonstrate the effectiveness of utilizing a computational model to guide a multiplex five-gene-silencing strategy by an artificial microRNA array to enhance caffeic acid and hispidin levels in plants. By combining loss-of-function-directed metabolic flux with a tyrosine-derived caffeic acid pathway, we achieved substantially enhanced bioluminescence levels. We successfully generated eFBP2 plants that emit considerably brighter bioluminescence for naked-eye reading by integrating all validated DNA modules. Our analysis revealed that the luminous energy conversion efficiency of the eFBP2 plants is currently very low, suggesting that luminescence intensity can be improved in future iterations. These findings highlight the potential to enhance plant luminescence through the integration of biological and information technologies.
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Background Pyoderma gangrenosum (PG) is a rare extraintestinal manifestation of inflammatory bowel disease. In recent years, the use of biologics in PG has been on the rise and has shown promising results. The surgical treatment of PG remains a topic of debate, with limited reports on the use of postoperative biologic therapy. Case reprt: This case report describes a 52-year-old woman who presented with multiple skin ulcers, pus discharge, and bloody diarrhea. The patient was diagnosed with PG with ulcerative colitis based on medical history, ulcer appearance, histopathology, treatment response, and the presence of ulcerative colitis. Surgical intervention was performed to repair the ulcers and amputate the fourth finger and fourth toe of both feet. Additionally, infliximab induction therapy was initiated two weeks after the surgery. The patient's intestinal symptoms demonstrated improvement, and after 10 months of treatment, the lesions were completely healed with no recurrence of skin ulcers. Conclusions This case report highlights a rare instance of successful treatment for PG with ulcerative colitis through a combination of surgery and postoperative infliximab.
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PURPOSE: There is not enough information to position medications for the treatment of Crohn's disease (CD). Therefore, using a network meta-analysis and systematic review, we evaluated the efficacy and safety of combination therapy and infliximab (IFX) monotherapy in CD patients. METHODS: We identified randomized controlled trials (RCTs) in CD patients who were given IFX-containing combination therapy versus IFX monotherapy. Induction and maintenance of clinical remission were the efficacy outcomes, while adverse events were the safety outcomes. The surface under cumulative ranking (SUCRA) probabilities was used to assess ranking in the network meta-analysis. RESULTS: In total, 15 RCTs with 1586 CD patients were included in this study. There was no statistical difference between different combination therapies in induction and maintenance of remission. In terms of inducing clinical remission, IFX + EN (SUCRA: 0.91) ranked highest; in terms of maintaining clinical remission, IFX + AZA (SUCRA: 0.85) ranked highest. There was no treatment that was significantly safer than the others. In terms of any adverse events, serious adverse events, serious infections, and infusion/injection-site reactions, IFX + AZA (SUCRA: 0.36, 0.12, 0.19, and 0.24) was ranked lowest for all risks; while IFX + MTX (SUCRA: 0.34, 0.06, 0.13, 0.08, 0.34, and 0.08) was rated lowest for risk of abdominal pain, arthralgia, headache, nausea, pyrexia, and upper respiratory tract infection. CONCLUSION: Indirect comparisons suggested that efficacy and safety of different combination treatments are comparable in CD patients. For maintenance therapies, IFX + AZA was ranked highest for clinical remission and lowest for adverse events. Further head-to-head trials are required.
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Doença de Crohn , Humanos , Infliximab/efeitos adversos , Doença de Crohn/tratamento farmacológico , Imunossupressores/uso terapêutico , Metanálise em Rede , Indução de RemissãoRESUMO
Cell-specific aptamers offer a powerful tool to study membrane receptors at the single-molecule level. Most target receptors of aptamers are highly expressed on the cell surface, but difficult to analyze in situ because of dense distribution and fast velocity. Therefore, we herein propose a random sampling-based analysis strategy termed ligand dilution analysis (LDA) for easily implemented aptamer-based receptor study. Receptor density on the cell surface can be calculated based on a regression model. By using a synergistic ligand dilution design, colocalization and differentiation of aptamer and monoclonal antibody (mAb) binding on a single receptor can be realized. Once this is accomplished, precise binding site and detailed aptamer-receptor binding mode can be further determined using molecular docking and molecular dynamics simulation. The ligand dilution strategy also sets the stage for an aptamer-based dynamics analysis of two- and three-dimensional motion and fluctuation of highly expressed receptors on the live cell membrane.
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Aptâmeros de Nucleotídeos , Ligantes , Simulação de Acoplamento Molecular , Aptâmeros de Nucleotídeos/química , Sítios de Ligação , Ligação Proteica , Técnica de Seleção de AptâmerosRESUMO
BACKGROUND: Immunotherapy has been recently established as a new direction for the treatment of colorectal cancer (CRC), a gastrointestinal cancer. In this investigation, we aimed to expound how the posttranscriptional regulation modulated by microRNA-222 (miR-222) from mesenchymal stem cells-derived extracellular vesicles (MSC-EVs) affected the AKT pathway and the immune escape in CRC. METHODS: CRC cell malignant phenotype, including proliferation, migration, invasion, and apoptosis, was firstly detected after co-culture with MSC-EVs. miRNAs with differential changes in CRC cells before and after EVs treatment were filtered by microarray analysis. miR-222 was then downregulated to examine its role in CRC cells in response to EVs. Cells were implanted in mice to induce xenograft tumors, and infiltrating T cells was assessed by immunohistochemistry. The mRNA microarray was used to screen target genes, followed by rescue experiments. ChIP and western blot were conducted to validate the downstream biomolecule of ATF3. RESULTS: After treatment of CRC cells with MSC-EVs, the expression of miR-222 was upregulated, and cell activity was increased. Inhibition of miR-222 decreased CRC malignant aggressiveness in vitro and reduced tumorigenesis and immune escape in vivo. miR-222 targeted and bound to ATF3. Downregulation of ATF3 enhanced CRC cell malignant aggressiveness, tumorigenic capacity and immune escape. Mechanistically, ATF3 inhibited AKT1 transcription and mediated the AKT pathway. CONCLUSION: MSC-EVs carry miR-222 to promote CRC cell malignant aggressiveness and immune escape. miR-222 targets and binds to ATF3, which inhibits AKT1 transcriptional activity and thereby mediates the AKT pathway.
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Fator 3 Ativador da Transcrição/metabolismo , Neoplasias Colorretais/genética , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Fator 3 Ativador da Transcrição/genética , Animais , Apoptose/fisiologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Feminino , Humanos , Imunoterapia , Camundongos , Camundongos Nus , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
NEDD4 is an E3 ubiquitin ligase that recognizes substrates through protein-protein interactions and is involved in cancer development. This study aimed to elucidate the function of NEDD4 in colon cancer (CC) progression and its mechanism of action. NEDD4 was abundantly expressed in CC tissues and cells, and the overexpression of NEDD4 promoted the growth and metastasis of xenograft tumours as well as the tumorigenesis rate of primary CC in mouse models. In in vitro experiments, the silencing (or upregulation) of NEDD4 inhibited (or increased) the viability, invasion, and epithelial-to-mesenchymal transition of CC cells. The binding relationships between NEDD4 and FOXA1, FOXA1 and microRNA (miRNA)-340-5p, and miR-340-5p and ATF1 were validated by Co-immunoprecipitation, chromatin immunoprecipitation and luciferase assays, and NEDD4 was demonstrated to trigger FOXA1 ubiquitination and degradation. FOXA1 transcriptionally activated miR-340-5p, which subsequently bound to ATF1 mRNA. The upregulation of FOXA1 or miR-340-5p or the downregulation of ATF1 blocked certain functions of NEDD4 in CC cells. Altogether, NEDD4 was demonstrated to trigger FOXA1 ubiquitination and promote CC progression under the involvement of microRNA-340-5p suppression and ATF1 upregulation.
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Fator 1 Ativador da Transcrição/metabolismo , Neoplasias do Colo/tratamento farmacológico , Proteínas de Ligação ao GTP/metabolismo , Regulação Neoplásica da Expressão Gênica , Fator 3-alfa Nuclear de Hepatócito/metabolismo , MicroRNAs/antagonistas & inibidores , Ubiquitinação , Fator 1 Ativador da Transcrição/genética , Animais , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Transição Epitelial-Mesenquimal , Feminino , Proteínas de Ligação ao GTP/genética , Fator 3-alfa Nuclear de Hepatócito/genética , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , MicroRNAs/genética , Prognóstico , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
This study aimed to investigate the role of circ0106714-miR-942-5p-discs large homolog 2 (DLG2), a novel interactome, in colorectal cancer (CRC). Circ0106714 was found to be the most significantly downregulated circular RNA in CRC using a bioinformatics method, and we researched whether the ability of circ0106714 to sponge miR-942-5p and release DLG2 could affect CRC development via Hippo-YES-associated protein (YAP) signaling. We first employed qRT-PCR and immunoblotting to detect messenger RNA (mRNA) and protein expression, respectively. Live imaging of mice tumor xenografts was then conducted to study the effect of circ0106714 on tumor progression in vivo. Reporter gene assays were subsequently conducted to verify the predicted targeting relationship between circ0106714, miR-942-5p, and DLG2 mRNA in SW480 and HCT116 cell lines. As well as using flow cytometry for both apoptosis and cell cycle profile analyses, CCK-8 and clone foci formation assays were performed to assess cell survival. Wound healing assay and transwell invasion assay were later carried out to evaluate the migration and invasion of the cell lines. Findings revealed that circ0106714 and DLG2 were significantly downregulated, while miR-942-5p was significantly upregulated in human CRC tissues and cell lines. However, circ0106714 upregulation significantly suppressed tumor progression in vivo and inhibited the malignancy phenotypes of tumor cells in vitro by targeting miR-942-5p. Also discovered in this research was that miR-942-5p could directly target DLG2 mRNA, thus enhancing the malignancy phenotypes of CRC cells. We even found that DLG2 overexpression resulted in enhanced phosphorylation of YAP, a critical downstream effector of DLG2. This downstream effector was demonstrated to have a tumor-suppressive capacity in CRC cell lines. In sum, circ0106714 could suppress CRC by sponging miR-942-5p and releasing DLG2, thus promoting YAP phosphorylation.
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Neoplasias Colorretais/patologia , Guanilato Quinases/genética , MicroRNAs/genética , RNA Circular/genética , Proteínas Supressoras de Tumor/genética , Idoso , Animais , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Guanilato Quinases/metabolismo , Células HCT116 , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Transplante de Neoplasias , Fosforilação , Transdução de Sinais , Análise de Sobrevida , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismoRESUMO
Transmembrane protein 158 (TMEM158) plays pivotal roles in many cancers, including colorectal cancer (CRC). It has been reported that it is a recently identified upregulated gene during Ras-induced senescence. However, the clinical significance and biological functions of TMEM158 in CRC remain largely unknown. In this study, we found that TMEM158 was highly expressed in CRC tissues and cell lines compared with the corresponding noncancerous samples and normal colon epithelial cells. In vitro studies showed that TMEM158 silencing inhibited proliferation, and migration and increased apoptosis of CRC cells, whereas overexpression of TMEM158 increased proliferation, migration, and apoptosis escape of CRC cells. Mechanically, the levels of drug resistance-associated molecules, including multidrug resistance 1 and multidrug resistance protein 1, as well as the expression of antiapoptotic Bcl-2 were significantly upregulated. In addition, TMEM158 knockdown significantly inhibited tumor growth in vivo. Collectively, these results demonstrated that TMEM158 is a significant regulator of tumorigenesis and drug resistance in CRC and provided evidence that TMEM158 may be a promising target for CRC therapy.
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Neoplasias Colorretais/etiologia , Proteínas de Membrana/fisiologia , Proteínas Supressoras de Tumor/fisiologia , Animais , Apoptose , Carcinogênese , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/prevenção & controle , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Células HCT116 , Humanos , Masculino , Proteínas de Membrana/antagonistas & inibidores , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Supressoras de Tumor/antagonistas & inibidores , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVE: This study aimed to investigate the potential molecular mechanism of SPDEF in immune evasion of colorectal cancer (CRC) and examine its impact on macrophage M2 polarization using the TCGA and GEO databases. METHODS: By combining TCGA and GEO databases, differential gene expression between CRC samples and standard tissue samples was analyzed to screen for immune-related genes (IRGs) associated with the prognosis of CRC patients. A predictive risk model was constructed based on 18 key IRGs, which were then validated using the GEO dataset. The relationship between transcription factors and IRGs was further explored to investigate their regulatory network in CRC. In vivo and in vitro experiments were carried out to validate these regulatory relationships and explore the function of SPDEF and CCL28 in CRC. RESULTS: Twelve key IRGs associated with clinical and pathological characteristics of CRC patients were identified. Among them, CCL28 significantly impacted macrophage infiltration in CRC cells and may be a critical factor in immune evasion. In both in vitro and in vivo experiments, overexpression of SPDEF upregulated CCL28 expression, thereby suppressing M2 polarization of macrophages and inhibiting CRC cell proliferation and tumor growth. Notably, interference with CCL28 could reverse the effect of SPDEF overexpression. CONCLUSION: SPDEF can suppress immune evasion of CRC cells by activating CCL28, which is achieved through the modulation of M2 polarization of macrophages. This provides a new research direction and potential therapeutic target for immunotherapy in CRC.
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The rise of DNA nanotechnology has driven the development of DNA-based molecular machines, which are capable of performing specific operations and tasks at the nanoscale. Benefitting from the programmability of DNA molecules and the predictability of DNA hybridization and strand displacement, DNA-based molecular machines can be designed with various structures and dynamic behaviors and have been implemented for wide applications in the field of biosensing due to their unique advantages. This review summarizes the reported controlling mechanisms of DNA-based molecular machines and introduces biosensing applications of DNA-based molecular machines in amplified detection, multiplex detection, real-time monitoring, spatial recognition detection, and single-molecule detection of biomarkers. The challenges and future directions of DNA-based molecular machines in biosensing are also discussed.
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Técnicas Biossensoriais , DNA , Nanotecnologia , Hibridização de Ácido Nucleico , HumanosRESUMO
Sodium-selenium (Na-Se) batteries have gained attention due to their high energy density and power density, resulting from the liquid-liquid reaction at the interface in the dimethoxyethane electrolyte. Nevertheless, the pronounced shuttle effect of polyselenides causes low coulomb efficiency and inadequate cycling stability for Na-Se batteries. Herein, the iron nanoparticles surface modified accordion-like Ti3C2Tx MXene (MXene/Fe) synthesized via the molten salt etching is utilized as the host of Se species for high-performance Na-Se battery cathode. Benefiting from the layered structure and chemical adsorption of accordion-like MXene, the shuttle effect of the cathode is effectively inhibited. Simultaneously, electrochemical kinetics is boosted due to the catalytic effect of Fe nanoparticles, which facilitate the transformation of polyselenide from long-chain to short-chain, contributing to pseudocapacitive capacity. Consequently, the Se-based cathode delivers a steady capacity of 575.0 mA h g-1 at 0.2 A/g, and even a high capacity of 500 mAh/g at 50 A/g based on the mass of Se@MXene/Fe electrode, indicating the ultrafast Na+ ion storage. Most notably, this structure demonstrated remarkable long-term cycling stability for 5000 cycles with a high capacity retention of 97.4 %. The electrochemical energy storage mechanism is further revealed by in situ Raman. Herein, the confinement-catalysis structure shines light on inhibiting shuttling and facilitating ultrafast ion storage.
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Sodium-selenium (Na-Se) batteries are promising energy storage systems with high energy density, high safety, and low cost. However, the huge volume change of selenium, the dissolution shuttle of polyselenides, and low selenium loading need to be solved. Herein, Cu nanoparticles decorated MXene nanosheets composite (MXene/Cu) are synthesized by etching Ti3AlC2 using a molten salt etching strategy. The Se-loaded MXene/Cu (Se@MXene/Cu) electrode delivers superior electrochemical performance even with a high Se loading of â¼74.3 wt%, owing to the synergistic effect of the two-dimensional (2D) confined structure and catalytic role of the unique MXene/Cu host. Specifically, the obtained electrode provides a reversible capacity of 587.3 mAh/g at 0.2 A/g, a discharge capacity as high as 511.3 mAh/g at a high rate of 50 A/g, and still maintains a capacity of 471.9 mAh/g even after 5000 cycles based on the mass of Se@MXene/Cu. With such excellent electrochemical kinetic properties, this study highlights the importance of designing various MXene-based composites with synergistic effects of 2D confined structure and Cu catalytic center for the development of high-performance alkali metal-chalcogen battery systems.
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Degradation and interference of the nucleic acid probes in complex biological environments like cytoplasm or body fluid can cause obvious false-positive signals and inefficient bioregulation in biosensing and biomedicine. To solve this problem, here, we proposed a universal strategy, termed L-DNA assembly mirror-image box-based environment resistance (L-AMBER), to protect nucleic acid probes from degradation and maintain their responsive activity in complex biological environments. Strand displacement reaction (SDR), aptamer, or DNAzyme-based D-DNA probes were encapsulated into an L-DNA box by using an L-D-L block DNA carrier strand to construct different kinds of L-AMBER probes. We proved that the L-DNA box could effectively protect the encapsulated D-DNA probes by shielding the interference of complex biological environments and only allowing small target molecules to enter for recognition. Compared with the D-AMBER probes, the L-AMBER probes can realize DNase I-assisted amplification detection of biological samples, low false-positive bioimaging, and highly efficient miRNA silence in living cells. Therefore, L-AMBER provided a universal and effective strategy for enhancing the resistance to environmental interference of nucleic acid probes in biosensing and biomedicine applications.
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DNA , Humanos , DNA/química , DNA/genética , Técnicas Biossensoriais , MicroRNAs/genética , MicroRNAs/análise , Desoxirribonuclease I/metabolismo , DNA Catalítico/química , DNA Catalítico/metabolismo , Sondas de Ácido Nucleico/química , Células HeLa , Sondas de DNA/químicaRESUMO
Gut microbiota and related metabolites are both crucial factors that significantly influence how individuals with Crohn's disease respond to immunotherapy. However, little is known about the interplay among gut microbiota, metabolites, Crohn's disease, and the response to anti-α4ß7-integrin in current studies. Our research utilized 2,4,6-trinitrobenzene sulfonic acid to induce colitis based on the humanized immune system mouse model and employed a combination of whole-genome shotgun metagenomics and non-targeted metabolomics to investigate immunotherapy responses. Additionally, clinical cases with Crohn's disease initiating anti-α4ß7-integrin therapy were evaluated comprehensively. Particularly, 16S-rDNA gene high-throughput sequencing and targeted bile acid metabolomics were conducted at weeks 0, 14, and 54. We found that anti-α4ß7-integrin therapy has shown significant potential for mitigating disease phenotypes in remission-achieving colitis mice. Microbial profiles demonstrated that not only microbial composition but also microbially encoded metabolic pathways could predict immunotherapy responses. Metabonomic signatures revealed that bile acid metabolism alteration, especially elevated secondary bile acids, was a determinant of immunotherapy responses. Especially, the remission mice significantly enriched the proportion of the beneficial Lactobacillus and Clostridium genera, which were correlated with increased gastrointestinal levels of BAs involving lithocholic acid and deoxycholic acid. Moreover, most of the omics features observed in colitis mice were replicated in clinical cases. Notably, anti-α4ß7 integrin provided sustained therapeutic benefits in clinical remitters during follow-up, and long-lasting remission was linked to persistent changes in the microbial-related bile acids. In conclusion, gut microbiota-mediated bile acid metabolism alteration could play a crucial role in regulating immunotherapy responses to anti-α4ß7-integrin in Crohn's disease. Therefore, the identification of prognostic microbial signals facilitates the advancement of targeted probiotics that activate anti-inflammatory bile acid metabolic pathways, thereby improving immunotherapy responses. The integrated multi-omics established in our research provide valuable insights into potential mechanisms that impact treatment responses in complex diseases.
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Colite , Doença de Crohn , Microbioma Gastrointestinal , Animais , Camundongos , Doença de Crohn/tratamento farmacológico , Multiômica , Integrinas/genética , Integrinas/uso terapêutico , Colite/induzido quimicamente , Colite/terapia , Ácidos e Sais Biliares/uso terapêutico , ImunoterapiaRESUMO
Photoelectrocatalysis (PEC) is regarded as a promising and sustainable process for removal of organic contaminants from wastewater. Meanwhile, enzymatic catalysis also provides an effective way to carry out polluted environment remediation under mild conditions. In this study, a biophotoelectrocatalytic (BPEC) system is designed to remove 4-nitrophenol (4-NP) based on a combination of PEC and enzymatic catalysis. The developed BPEC system is constructed with a Ag3 PO4 /BiVO4 photoanode and a horseradish peroxidase (HRP)-loaded carbon cloth (CC) cathode. On the photoanode, the construction of a direct Z-scheme Ag3 PO4 /BiVO4 heterojunction enhanced the separation efficiency of photogenerated carriers, which promoted the PEC degradation of 4-NP under visible light irradiation. After HRP was immobilized on the cathode, the degradation efficiency of 4-NP reached 97.1 % after 60â min PEC treatment. The result could be ascribed to the HRP-catalyzed oxidation reaction via inâ situ-generated H2 O2 from the CC cathode during the PEC process. Moreover, the possible degradation pathways of 4-NP in such a BPEC system are also discussed.
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Extracellular vesicles (EVs) exhibit pivotal functions in cancer via intercellular communication through shuttling microRNA (miRNA) and protein. Therefore, we aim to elucidate the function of EVs containing miR-143-3p derived from M2 macrophages in colorectal cancer (CRC). EVs derived from M2 macrophages were isolated and characterized. Expression changes in miR-143-3p were calculated in the EVs. The effects of M2 macrophage-derived EV carrying miR-143-3p on cell biological processes and in vivo tumorigenic ability concerning ZC3H12A were examined. EVs derived from M2 macrophages could stimulate the aggressive tumor biology of CRC cells. Meanwhile, in vivo results showed that M2 macrophage-derived EVs facilitated tumor growth and epithelial-mesenchymal transition. M2 macrophage-secreted EVs could transfer miR-143-3p to CRC cells, in which miR-143-3p bound to the 3'UTR of ZC3H12A and inhibited its expression, leading to elevation of the expression of transcription factor C/EBPß. Overall, M2 macrophage-derived EV miR-143-3p inhibits ZC3H12A gene and increases C/EBPß expression to facilitate the development of CRC, which provides novel targets for the molecular treatment of CRC.
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Neoplasias Colorretais , Vesículas Extracelulares , MicroRNAs , Humanos , Macrófagos/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Vesículas Extracelulares/metabolismo , Transição Epitelial-Mesenquimal , Neoplasias Colorretais/patologia , Ribonucleases , Fatores de Transcrição/metabolismoRESUMO
[This retracts the article DOI: 10.1016/j.omtn.2021.04.007.].
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The gut microbiota and bile acid metabolism are key determinants of the response of inflammatory bowel disease to biologic therapy. However, the molecular mechanisms underlying the interactions between the response to anti-α4ß7-integrin therapy and the gut microbiota and bile acid metabolism remain unknown. In this research, we investigated the role of gut microbiota-related bile acid metabolism on the response to anti-α4ß7-integrin therapy in a humanized immune system mouse model with colitis induced by 2,4,6-trinitrobenzene sulfonic acid. We found that anti-α4ß7-integrin significantly mitigated intestinal inflammation, pathological symptoms, and gut barrier disruption in remission-achieving colitis mice. Whole-genome shotgun metagenomic sequencing demonstrated that employing baseline microbiome profiles to predict remission and the treatment response was a promising strategy. Antibiotic-mediated gut microbiota depletion and fecal microbiome transplantation revealed that the baseline gut microbiota contained common microbes with anti-inflammatory effects and reduced mucosal barrier damage, improving the treatment response. Targeted metabolomics analysis illustrated that bile acids associated with microbial diversity were involved in colitis remission. Furthermore, the activation effects of the microbiome and bile acids on FXR and TGR5 were evaluated in colitis mice and Caco-2 cells. The findings revealed that the production of gastrointestinal bile acids, particularly CDCA and LCA, further directly promoted the stimulation of FXR and TGR5, significantly improving gut barrier function and suppressing the inflammatory process. Taken together, gut microbiota-related bile acid metabolism-FXR/TGR5 axis may be a potential mechanism for impacting the response to anti-α4ß7-integrin in experimental colitis. Thus, our research provides novel insights into the treatment response in inflammatory bowel disease.
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Colite , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Animais , Camundongos , Humanos , Células CACO-2 , Colite/induzido quimicamente , Colite/tratamento farmacológico , Ácidos e Sais Biliares , IntegrinasRESUMO
BACKGROUND: Hepatic fibrosis is a common pathological process of chronic liver diseases with various causes, which can progress to cirrhosis. AIM: To evaluate the effect and mechanism of action annexin (Anx)A1 in liver fibrosis and how this could be targeted therapeutically. METHODS: CCl4 (20%) and active N-terminal peptide of AnxA1 (Ac2-26) and N-formylpeptide receptor antagonist N-Boc-Phe-Leu-Phe-Leu-Phe (Boc2) were injected intraperitoneally to induce liver fibrosis in eight wild-type mice/Anxa1 knockout mice, and to detect expression of inflammatory factors, collagen deposition, and the role of the Wnt/ß-catenin pathway in hepatic fibrosis. RESULTS: Compared with the control group, AnxA1, transforming growth factor (TGF)-ß1, interleukin (IL)-1ß and IL-6 expression in the liver of mice with hepatic fibrosis induced by CCl4 was significantly increased, which promoted collagen deposition and expression of α-smooth muscle actin (α-SMA), collagen type I and connective tissue growth factor (CTGF), and increased progressively with time. CCl4 induced an increase in TGF-ß1, IL-1ß and IL-6 in liver tissue of AnxA1 knockout mice, and the degree of liver inflammation and fibrosis and expression of α-SMA, collagen I and CTGF were significantly increased compared with in wild-type mice. After treatment with Ac2-26, expression of liver inflammatory factors, degree of collagen deposition and expression of a-SMA, collagen I and CTGF were decreased compared with before treatment. Boc2 inhibited the anti-inflammatory and antifibrotic effects of Ac2-26. AnxA1 downregulated expression of the Wnt/ß-catenin pathway in CCl4-induced hepatic fibrosis. In vitro, lipopolysaccharide (LPS) induced hepatocyte and hepatic stellate cell (HSC) expression of AnxA1. Ac2-26 inhibited LPS-induced RAW264.7 cell activation and HSC proliferation, decreased expression of α-SMA, collagen I and CTGF in HSCs, and inhibited expression of the Wnt/ß-catenin pathway after HSC activation. These therapeutic effects were inhibited by Boc2. CONCLUSION: AnxA1 inhibited liver fibrosis in mice, and its mechanism may be related to inhibition of HSC Wnt/ß-catenin pathway activation by targeting formylpeptide receptors to regulate macrophage function.
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Anexina A1 , beta Catenina , Animais , Camundongos , Anexina A1/genética , Células Estreladas do Fígado , Interleucina-6 , Lipopolissacarídeos , Macrófagos , Cirrose Hepática/induzido quimicamente , Colágeno Tipo IRESUMO
Statement of RetractionWe, the Editors and Publisher of the journal Expert Review of Molecular Diagnostics, have retracted the following article:Sen Hong, Zhenkun Yan, YuMei Song, MiaoMiao Bi & Shiquan Li. Down-regulation of lncRNA FEZF1-AS1 mediates regulatory T cell differentiation and further blocks immune escape in colon cancer. Expert Review of Molecular Diagnostics. 2021. DOI: 10.1080/14737159.2022.2012157Since publication, significant concerns have been raised about the integrity of the data and reported results in the article. When approached for an explanation, the authors did not provide their original data or any necessary supporting information. As verifying the validity of published work is core to the integrity of the scholarly record, we are therefore retracting the article. The corresponding author listed in this publication has been informed.We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines on retractions.The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as 'Retracted'.