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1.
J Immunol Res ; 2022: 9166370, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35340587

RESUMO

Tumor necrosis factor-α (TNF-α) lies at the apex of signal transduction cascades that results in induced destruction of joints in rheumatoid arthritis. It is therefore of great medicinal interest to modulate the cellular responses to TNF-α. Ebosin, a novel exopolysaccharide derived from Streptomyces sp, has been demonstrated to have remarkable therapeutic actions on collagen-induced arthritis in rats, while it also suppressed the production of IL-1ß, TNF-α, and IL-6 at both mRNA and protein levels in cultured fibroblast-like synoviocytes. In order to further understand the potential mechanisms involved in the anti-inflammatory effects of ebosin at molecular level, we investigated the impact of it on the activation of MAPK and NF-κB pathways following TNF-α induced in fibroblast-like synoviocytes (FLS). The results showed that the phosphorylation levels of TNF-α-induced p38, JNK1, JNK2, IKKα, IKKß, and IκB, as well as NF-κB nuclear translocation, were reduced significantly in FLS cells in response to ebosin. Furthermore, we proved that ebosin decreased the level of NF-κB in the nucleus and blocked the DNA-binding ability of NF-κB using electrophoresis mobility gel shift assay. Besides, low levels of matrix metalloproteinases (MMP-1 and MMP-3) and chemokines (interleukin-8 and RANTES) were found in TNF-α-stimulated fibroblast-like synoviocytes treated with ebosin. These results indicate that ebosin can suppress a range of activities in both MAPK and NF-κB pathways induced by TNF-α in rat fibroblast-like synoviocytes, which provides a rationale for examining the use of ebosin as a potential therapeutic candidate for rheumatic arthritis.


Assuntos
NF-kappa B , Sinoviócitos , Animais , Fibroblastos , NF-kappa B/metabolismo , Polissacarídeos Bacterianos , Ratos , Sinoviócitos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
2.
Foods ; 11(9)2022 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-35564010

RESUMO

In order to achieve rapid and precise quantification detection of carbendazim residues, surface-enhanced Raman spectroscopy (SERS) combined with variable selected regression methods were developed. A higher sensitivity and greater density of "hot spots" in three-dimensional (3D) SERS substrates based on silver nanoparticles compound polyacrylonitrile (Ag-NPs @PAN) nanohump arrays were fabricated to capture and amplify the SERS signal of carbendazim. Four Raman spectral variable selection regression models were established and comparatively assessed. The results showed that the bootstrapping soft shrinkage-partial least squares (BOSS-PLS) method achieved the best predictive capacity after variable selection, and the final BOSS-PLS model has the correlation coefficient (RP) of 0.992. Then, this method used to detect the carbendazim residue in apple samples; the recoveries were 86~116%, and relative standard deviation (RSD) is less than 10%. The 3D SERS substrates combined with the BOSS-PLS algorithm can deliver a simple and accurate method for trace detection of carbendazim residues in apples.

3.
Nanomaterials (Basel) ; 12(9)2022 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-35564199

RESUMO

The phosphosilicate fiber-based Raman fiber laser (RFL) has great potential in achieving low-quantum defect (QD) high-power laser output. However, the laser's performance could be seriously degraded by the Raman-assisted four-wave mixing (FWM) effect and spontaneous Raman generation at 14.7 THz. To find possible ways to suppress the Raman-assisted FWM effect and spontaneous Raman generation, here, we propose a revised power-balanced model to simulate the nonlinear process in the low-QD RFL. The power evolution characteristics in this low-QD RFL with different pump directions are calculated. The simulation results show that, compared to the forward-pumped low-QD RFL, the threshold powers of spontaneous Raman generation in the backward-pumped RFL are increased by 40% and the Raman-assisted FWM effect is well suppressed. Based on the simulation work, we change the pump direction of a forward-pumped low-QD RFL into backward pumping. As a result, the maximum signal power is increased by 20% and the corresponding spectral purity is increased to 99.8%. This work offers a way for nonlinear effects controlling in low-QD RFL, which is essential in its further performance scaling.

4.
Front Pharmacol ; 13: 879204, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35559240

RESUMO

Pulmonary diseases are main causes of morbidity and mortality worldwide. Current studies show that though specific pulmonary diseases and correlative lung-metabolic deviance own unique pathophysiology and clinical manifestations, they always tend to exhibit common characteristics including reactive oxygen species (ROS) signaling and disruptions of proteostasis bringing about accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER). ER is generated by the unfolded protein response. When the adaptive unfolded protein response (UPR) fails to preserve ER homeostasis, a maladaptive or terminal UPR is engaged, leading to the disruption of ER integrity and to apoptosis, which is called ER stress. The ER stress mainly includes the accumulation of misfolded and unfolded proteins in lumen and the disorder of Ca2+ balance. ROS mediates several critical aspects of the ER stress response. We summarize the latest advances in of the UPR and ER stress in the pathogenesis of pulmonary disease and discuss potential therapeutic strategies aimed at restoring ER proteostasis in pulmonary disease.

5.
Front Immunol ; 13: 868480, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35572523

RESUMO

Background: Although checkpoint blockade is a promising approach for the treatment of hepatocellular carcinoma (HCC), subsets of patients expected to show a response have not been established. As T cell-mediated tumor killing (TTK) is the fundamental principle of immune checkpoint inhibitor therapy, we established subtypes based on genes related to the sensitivity to TKK and evaluated their prognostic value for HCC immunotherapies. Methods: Genes regulating the sensitivity of tumor cells to T cell-mediated killing (referred to as GSTTKs) showing differential expression in HCC and correlations with prognosis were identified by high-throughput screening assays. Unsupervised clustering was applied to classify patients with HCC into subtypes based on the GSTTKs. The tumor microenvironment, metabolic properties, and genetic variation were compared among the subgroups. A scoring algorithm based on the prognostic GSTTKs, referred to as the TCscore, was developed, and its clinical and predictive value for the response to immunotherapy were evaluated. Results: In total, 18 out of 641 GSTTKs simultaneously showed differential expression in HCC and were correlated with prognosis. Based on the 18 GSTTKs, patients were clustered into two subgroups, which reflected distinct TTK patterns in HCC. Tumor-infiltrating immune cells, immune-related gene expression, glycolipid metabolism, somatic mutations, and signaling pathways differed between the two subgroups. The TCscore effectively distinguished between populations with different responses to chemotherapeutics or immunotherapy and overall survival. Conclusions: TTK patterns played a nonnegligible role in formation of TME diversity and metabolic complexity. Evaluating the TTK patterns of individual tumor will contribute to enhancing our cognition of TME characterization, reflects differences in the functionality of T cells in HCC and guiding more effective therapy strategies.

6.
Front Immunol ; 13: 851096, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35572557

RESUMO

The characteristic feature of immune-related pancytopenia (IRP) is autoantibody-mediated bone marrow (BM) damage and peripheral blood cytopenia. We found that the potential antigen of IRP was Ferritin light chain (FTL) by SEREX (serological analysis of recombinant cDNA expression libraries) in the previous study. In this study, we tried to explore the antigenic epitopes of FTL and verify its antigenicity in IRP. We found the possible FTL epitope: VNLYLQASYTYLSLG by phage random peptide library. Through ELISPOT, it was found that peptide VNLYLQASYTYLSLG can significantly stimulate the production of interleukin-4 and cannot stimulate the production of interferon-γ, which suggested that the peptide can obviously activate Th2 cells. Peptide-major histocompatibility complex tetramer elicited antigen-specific T cell responses. The expression levels of FTL were significantly increased in the patients with untreated IRP (P < 0.05). In conclusion, we found that FTL is the target antigen for some patients with IRP. The peptide of VNLYLQASYTYLSLG is an epitope of the target antigen. The target antigen is abnormally overexpressed on the membrane of BM cells, especially on the surface of CD34+ BM cells of patients with IRP. In addition, it is related to the severity of disease. These results provide a possible new target for the treatment of IRP in the future.

7.
Front Immunol ; 13: 871200, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35572588

RESUMO

Objective: Residual scarring after cleft lip repair surgery remains a challenge for both surgeons and patients and novel therapeutics are critically needed. The objective of this preclinical experimental study was to evaluate the impact of the methyl-ester of pro-resolving lipid mediator lipoxin A4 (LXA4-ME) on scarring in a novel rabbit model of cleft lip repair. Methods: A defect of the lip was surgically created and repaired in eight six-week old New Zealand white rabbits to simulate human cleft lip scars. Rabbits were randomly assigned to topical application of PBS (control) or 1 ug of LXA4-ME (treatment). 42 days post surgery all animals were euthanized. Photographs of the cleft lip area defect and histologic specimens were evaluated. Multiple scar assessment scales were used to compare scarring. Results: Animals treated with LXA4-ME exhibited lower Visual Scar Assessment scores compared to animals treated with PBS. Treatment with LXA4-ME resulted in a significant reduction of inflammatory cell infiltrate and density of collagen fibers. Control animals showed reduced 2D directional variance (orientation) of collagen fibers compared to animals treated with LXA4-ME demonstrating thicker and more parallel collagen fibers, consistent with scar tissue. Conclusions: These data suggest that LXA4-ME limits scarring after cleft lip repair and improves wound healing outcomes in rabbits favoring the resolution of inflammation. Further studies are needed to explore the mechanisms that underlie the positive therapeutic impact of LXA4-ME on scarring to set the stage for future human clinical trials of LXA4-ME for scar prevention or treatment after cleft lip repair.

8.
Front Bioeng Biotechnol ; 10: 890668, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35547157

RESUMO

Hepatocellular carcinoma (HCC), the fifth most common cancer worldwide, poses a severe threat to public health. Intraoperative fluorescence imaging provides a golden opportunity for surgeons to visualize tumor-involved margins, thereby implementing precise HCC resection with minimal damage to normal tissues. Here, a novel-acting contrast agent, which facilely bridges indocyanine green (ICG) and lipiodol using self-emulsifying nanotechnology, was developed for optical surgical navigation. Compared to clinically available ICG probe, our prepared nanoemulsion showed obviously red-shifted optical absorption and enhanced fluorescence intensity. Further benefiting from the shielding effect of lipiodol, the fluorescence stability and anti-photobleaching ability of nanoemulsion were highly improved, indicating a great capacity for long-lasting in vivo intraoperative imaging. Under the fluorescence guidance of nanoemulsion, the tumor tissues were clearly delineated with a signal-to-noise ratio above 5-fold, and then underwent a complete surgical resection from orthotopic HCC-bearing mice. Such superior fluorescence performances, ultrahigh tumor-to-liver contrast, as well as great bio-safety, warrants the great translational potential of nanoemulsion in precise HCC imaging and intraoperative navigation.

9.
Ying Yong Sheng Tai Xue Bao ; 33(3): 648-654, 2022 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-35524515

RESUMO

Global changes have profound impacts on the structure and function of terrestrial ecosystems. It is a prerequisite to realize the sustainable use of ecosystem to clarify the response and adaptation mechanism of ecosystems to global changes. Network of control experiment is an important way to understand the response and adaptation of the structure and function of ecosystems to global change factors at regional and global scales. The scientific top-level design is conducive to the integration, comparison and analysis of integrative network-data, and then supports the development of universal ecological theory. We comprehensively expounded the theoretical basis, methodological principles and brand-new concepts of experimental network design for future global change control experiment networks design from several aspects, such as research progress, development needs, innovative design and research prospects. Taking Chinese grassland ecosystems as an example, based on the concept of space reference points (mean point of water and heat), the innovative design technology system of China's grassland ecosystem networking experiment was proposed, in order to promote the development of networking research of control experiments at both regional and global scales in the future.


Assuntos
Ecossistema , Pradaria , China , Temperatura Alta , Água
10.
Artigo em Inglês | MEDLINE | ID: mdl-35533658

RESUMO

The detection of drugs containing hydrochloric salt with conventional methods is time consuming and expensive. In this work, upon exposure to ciprofloxacin hydrochloride at different concentrations, the emission from CsPbBr3 NCs shifts to the blue from 513 nm to 442 nm. CsPbBr(3-x)Clx NCs are formed by the ion exchange and substitution of Br- and Cl- ions from surface to core of NCs. The first-principles calculations suggest that the substitution of Br- by Cl- ions plays a critical role in the tuning of the energy bandgap. The color of paper test strips changes immediately after exposure to different Ciproxan solutions. We propose that this rapid and portable method has a high potential application in other chloride salts for food safety.

11.
J Voice ; 2022 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-35534328

RESUMO

OBJECTIVES: An improved data-driven glottal flow model for fluid-structure interaction (FSI) simulation of the vocal fold vibration is proposed in this paper. This model aims to improve the prediction performance of the previously developed deep neural network (DNN) based empirical flow model (EFM)1 on accuracy and efficiency. METHODS: A Seq2Seq long short-term memory (LSTM) network is employed in the present model to infer the flow rate and pressure distribution from the subglottal pressure and cross-section area distribution of the glottis. The training data is collected from the generalized glottal shape library generated in Zhang et al.1 RESULTS AND CONCLUSIONS: Compared to the EFM, the present model not only discards the time-consuming optimization process, but also drastically reduces the errors, therefore the prediction performance can be greatly improved. The present model is evaluated by coupling with a solid dynamics solver for FSI simulation, and the results demonstrate a great improvement on accuracy and efficiency.

12.
Nucleic Acids Res ; 2022 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-35536281

RESUMO

Most proteins in nature contain multiple folding units (or domains). The revolutionary success of AlphaFold2 in single-domain structure prediction showed potential to extend deep-learning techniques for multi-domain structure modeling. This work presents a significantly improved method, DEMO2, which integrates analogous template structural alignments with deep-learning techniques for high-accuracy domain structure assembly. Starting from individual domain models, inter-domain spatial restraints are first predicted with deep residual convolutional networks, where full-length structure models are assembled using L-BFGS simulations under the guidance of a hybrid energy function combining deep-learning restraints and analogous multi-domain template alignments searched from the PDB. The output of DEMO2 contains deep-learning inter-domain restraints, top-ranked multi-domain structure templates, and up to five full-length structure models. DEMO2 was tested on a large-scale benchmark and the blind CASP14 experiment, where DEMO2 was shown to significantly outperform its predecessor and the state-of-the-art protein structure prediction methods. By integrating with new deep-learning techniques, DEMO2 should help fill the rapidly increasing gap between the improved ability of tertiary structure determination and the high demand for the high-quality multi-domain protein structures. The DEMO2 server is available at https://zhanggroup.org/DEMO/.

13.
Mol Med Rep ; 25(6)2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35506449

RESUMO

Liver fibrosis is a common pathological process of chronic liver diseases, including viral hepatitis and alcoholic liver disease, and ultimately progresses to irreversible cirrhosis and cancer. Hepatic stellate cells (HSCs) are activated to produce amounts of collagens in response to liver injury, thus triggering the initiation and progression of fibrogenesis. Natural killer (NK) cells serve as the essential component of hepatic innate immunity and are considered to alleviate fibrosis by killing activated HSCs. Current antifibrotic interventions have improved fibrosis, but fail to halt its progression in the advanced stage. Clarifying the interaction between NK cells and HSCs will provide clues to the pathogenesis and potential therapies for advanced liver fibrosis.


Assuntos
Células Estreladas do Fígado , Cirrose Hepática , Fibrose , Células Estreladas do Fígado/patologia , Humanos , Células Matadoras Naturais , Cirrose Hepática/patologia
14.
Front Pharmacol ; 13: 676831, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35517782

RESUMO

Introduction: Extensive use of antiretroviral therapy has remarkably improved the survival rates of people living with HIV. Doravirine (DOR) is a newly-approved antiretroviral belonging to the class of non-nucleoside reverse transcriptase inhibitors. Here, we compared the efficacy and safety of DOR + tenofovir dipivoxil fumarate (TDF)+Lamivudine (3TC)/Emtritabine (FTC) with traditional triple therapies in treatment-naïve HIV-1-positive adults. Methods: Randomized controlled trials involving treatment-naïve HIV-1-positive adults that met inclusion criteria were systematically retrieved and data on the following outcomes extracted: virological suppression, adverse events, severe adverse events, and drug-related adverse events. A Bayesian network meta-analysis was then performed on the data. Results: This study included a total of 39 randomized controlled trials involving 26 antiretroviral therapies and 21,110 HIV1-positive patients. At week 48, relative to the other 25 regimens included in the network of virological suppression, DOR + TDF+3TC/FTC exhibited superiority to some efavirenz, nevirapine, atazanavir, or lopinavir-based regimens, including efavirenz + abacavir+3TC [Odd Ratio (OR) = 0.52, 95% confidence interval (CrI) = 0.35-0.77]. At week 48, the performance of DOR + TDF+3TC/FTC was relatively similar to all other analyzed regimens in terms of adverse events. The DOR + TDF+3TC/FTC regimen performed better in terms of severe adverse events and drug-related adverse events. Conclusion: The network meta-analysis showed that DOR + TDF+3TC/FTC has good efficacy and safety at 48 weeks. Systematic Review Registration: Open Science Framework, https://osf.io/6ybp7.

15.
JAMA Oncol ; 2022 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-35511148

RESUMO

Importance: The antibody drug conjugate drug MRG003 comprises an anti-epidermal growth factor receptor (EGFR) humanized immunoglobulin G1 monoclonal antibody that is conjugated with monomethyl auristatin E via a valine-citrulline linker. There is currently insufficient evidence of this drug's safety and efficacy. Objective: To evaluate the safety and maximum tolerated dose of MRG003 in a phase 1a study and investigate the preliminary antitumor activity in EGFR-expressing patients in a phase 1b study. Design, Setting, and Participants: This nonrandomized open-label, single-arm, phase 1, multicenter study of solid tumors was divided into 2 parts, phase 1a dose escalation and phase 1b dose expansion. Patients with advanced or metastatic solid tumors who had failed outcomes from or were not able to receive standard treatment were enrolled in phase 1a without EGFR prescreening. Phase 1b recruited EGFR-positive patients with refractory advanced squamous cell carcinomas of the head and neck (SCCHN), nasopharyngeal carcinoma (NPC), and colorectal cancer (CRC). This study was conducted at 7 Chinese centers between April 11, 2018, and March 29, 2021 (data cutoff date). Data analysis took place between April 2021 and June 2021. Interventions: An intravenous dose of 0.1 to 2.5 mg/kg of MRG003 was administered every 3 weeks during phase 1a. During phase 1b, patients were administered the recommended dose identified in phase 1a. Main Outcomes and Measures: The primary end points were dose-limiting toxic effects in phase 1a and objective response rate in phase 1b. The safety, tolerability, immunogenicity, and pharmacokinetics of MRG003 were assessed. Tumor assessment was evaluated by RECIST 1.1. Results: Twenty-two patients (mean [range] age, 54.5 [32.0-67.0] years; 9 women [41%]) were enrolled in phase 1a and 39 patients (mean [range] age, 50.4 [27.0-75.0] years; 8 women [21%]) in phase 1b. The recommended dose was identified as 2.5 mg/kg. Eighty-nine percent of adverse events (AEs) were associated with MRG003 treatment, and most AEs were grade 1 to 2. Nineteen patients (31%) reported grade 3 or greater treatment-related AEs, including hyponatremia, leukocytopenia, neutropenia, increased aspartate aminotransferase levels, and febrile neutropenia. In phase 1a, 1 patient (5%) achieved a partial response, and 5 (23%) achieved stable disease. In phase 1b, 8 patients (21%) achieved a confirmed partial response, and 12 (31%) achieved stable disease. The objective response rates for SCCHN, NPC, and CRC were 40%, 44%, and 0%, and the disease control rates were 100%, 89%, and 25%, respectively. Conclusions and Relevance: The findings of this nonrandomized clinical trial suggest that MRG003 showed a manageable safety profile and promising antitumor activity in patients with EGFR-positive NPC and SCCHN. Trial Registration: Clinicaltrials.gov Identifier: NCT04868344.

16.
Artigo em Inglês | MEDLINE | ID: mdl-35511833

RESUMO

Drug-drug interactions are one of the main concerns in drug discovery. Accurate prediction of drug-drug interactions plays a key role in increasing the efficiency of drug research and safety when multiple drugs are co-prescribed. With various data sources that describe the relationships and properties between drugs, the comprehensive approach that integrates multiple data sources would be considerably effective in making high-accuracy prediction. In this paper, we propose a Deep Attention Neural Network based Drug-Drug Interaction prediction framework, abbreviated as DANN-DDI, to predict unobserved drug-drug interactions. First, we construct multiple drug feature networks and learn drug representations from these networks using the graph embedding method; then, we concatenate the learned drug embeddings and adopt an attention neural network to learn representations of drug-drug pairs; finally, we design a deep neural network to accurately predict drug-drug interactions. The experimental results demonstrate that our model DANN-DDI has improved prediction performance compared with state-of-the-art methods. Moreover, the proposed model can predict novel drug-drug interactions and drug-drug interaction-associated events.

18.
World J Surg Oncol ; 20(1): 152, 2022 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-35545785

RESUMO

BACKGROUND: To evaluate the diagnostic accuracy of single gastroscopy, multi-slice spiral CT, HER-2 or tumor markers, and their combination in the diagnosis of gastric cancer. METHODS: A total of 98 patients with gastric cancer were selected as the research subjects. All patients underwent preoperative gastroscopy, MSCT, and the expression levels of HER-2, CEA, CA199, CA724, and CA242 were detected. A control group of 98 normal adults was selected to compare the risk factors for gastric cancer and to analyze the data. RESULTS: There was statistical significance in the expression of the 5 markers in tumor size (P < 0.05), but no statistical significance in other clinical data (P > 0.05). The tumor marker CEA in gastric mucosal tissue of patients with gastric cancer had the highest positive detection rate for gastric cancer, and the difference was statistically significant (P < 0.05) compared with gastroscopy, MSCT and other markers. The combined diagnosis had higher sensitivity, specificity and accuracy compared with the single diagnosis of gastric cancer staging, and the difference was statistically significant (P < 0.05). Compared with normal adults, patients with gastric cancer had statistically significant differences in diet, body mass index, and family genetic history (P < 0.05), while there was no statistically significant difference in whether they had type A blood (P > 0.05). CONCLUSION: The combined diagnosis of gastroscopy, MSCT, immunohistochemical marker Her-2, and tumor markers CEA, CA199, CA724, and CA242 can more accurately determine the clinical staging and lesion invasion depth of patients with gastric cancer and can significantly improve the sensitivity of diagnosis.


Assuntos
Neoplasias Gástricas , Adulto , Biomarcadores Tumorais , Antígeno Carcinoembrionário , Gastroscopia , Humanos , Estadiamento de Neoplasias , Neoplasias Gástricas/diagnóstico por imagem , Neoplasias Gástricas/patologia , Tomografia Computadorizada Espiral
19.
Crit Rev Anal Chem ; : 1-18, 2022 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-35549959

RESUMO

Artificial enzymes based on inorganic solids with both enzyme-mimetic activities and the special material features has been a promising candidate to overcome many deleterious effects of native enzymes in analytical applications. Polyoxometalates (POMs) are an importance class of molecular metal-oxygen anionic clusters. Their outstanding physicochemical properties, versatility and potential applications in energy conversion, magnetism, catalysis, molecular electronics and biomedicine have long been studied. However, the analytical applications of them is limited. Recently, the intrinsic enzymatic activities of POMs have also been found and become an area of growing interest. In this review, along with other reports, we aimed to classify the enzymatic activity of POMs, summarize the construction of POMs-based enzymes, and survey their recent advances in analytical fields. Finally, the current challenges and trends of the polyoxometalates with enzymatic activity in future chemo-/bio-sensing applications are briefly discussed.

20.
FASEB J ; 36 Suppl 12022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35553942

RESUMO

BACKGROUND: Colorectal cancer (CRC) is the third leading cause of cancer-related death worldwide. There is an urgent need for new therapeutic targets and methods of early detection to improve patient outcomes. Extracellular Vesicles (EVs) and EV cargo are promising new biomarkers and therapeutic targets. EVs are secreted nanoparticles that carry DNA, RNA, and proteins. EVs can target specific cell types and once taken up by a destination cell, EV cargo can shape cell gene expression and physiology. EVs can shape the tumor microenvironment (TME) (i.e., stromal, immune, and endothelial cells), which plays critical roles in patient survival and disease outcomes. Our current understanding of how EV cargo is determined and how it influences the CRC cell TME is limited. One promising but understudied molecular aspect of EVs is RNA binding proteins (RNAbps). RNAbps are post-transcriptional regulators of gene expression and could provide a link between host cell gene expression and EV cargo. Insulin-like growth factor 2 RNA binding protein 1 (IMP1, IGF2BP1) is an RNAbp with a critical role in CRC development and progression. IMP1 is expressed highly in CRC tumors, expression correlates with worse prognosis, and IMP1 binds/potently regulates tumor-associated transcripts. How EV cargo is influenced by IMP1 and effects on EV targeting to destination cells and on target cell gene expression and function is not known. Understanding how IMP1 shapes EV cargo and which TME cells are targeted, will identify new mechanisms of cancer development/progression through IMP1-EV-mediated alteration of the TME and novel EV cargo as candidates for early detection biomarkers. HYPOTHESIS: We hypothesize that IMP1 facilitates the packaging of tumor-promoting EV cargo that interact and communicate with the TME to enhance tumor progression. METHODS: EVs were isolated from IMP1 null and IMP1-overexpressing (IMP1OE ) CRC cell lines, HT-29, SW480, as well as wildtype Caco2 cells (express high levels of IMP1) by size-exclusion chromatography. EVs were assessed by nanoparticle tracking analysis, western blot, electron microscopy, and qPCR. RESULTS: We found that IMP1 enters EVs from Caco2 and SW480 IMP1OE cell lines, but not HT-29 IMP1OE or corresponding null controls. IMP1 did not alter EV secretion in CRC cell lines. We found that IMP1 target mRNAs, such as KRAS, cMYC are present within EVs, but not the IMP1 target PTGS2. CONCLUSIONS: Our novel findings suggest that IMP1 enters the EV to directly influence EV cargo in specific CRC cell lines. Our findings have implications for the development of novel early detection biomarkers and therapeutic approaches in CRC.

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