A genomic and epigenomic atlas of prostate cancer in Asian populations.

Prostate cancer is the second most common cancer in men worldwide1. Over the past decade, large-scale integrative genomics efforts have enhanced our understanding of this disease by characterizing its genetic and epigenetic landscape in thousands of patients2,3. However, most tumours profiled in these studies were obtained from patients from Western populations. Here we produced and analysed whole-genome, whole-transcriptome and DNA methylation data for 208 pairs of tumour tissue samples and matched healthy control tissue from Chinese patients with primary prostate cancer. Systematic comparison with published data from 2,554 prostate tumours revealed that the genomic alteration signatures in Chinese patients were markedly distinct from those of Western cohorts: specifically, 41% of tumours contained mutations in FOXA1 and 18% each had deletions in ZNF292 and CHD1. Alterations of the genome and epigenome were correlated and were predictive of disease phenotype and progression. Coding and noncoding mutations, as well as epimutations, converged on pathways that are important for prostate cancer, providing insights into this devastating disease. These discoveries underscore the importance of including population context in constructing comprehensive genomic maps for disease.

Ganglioside GM3 Protects Against Abdominal Aortic Aneurysm by Suppressing Ferroptosis.

BACKGROUND: Abdominal aortic aneurysm (AAA) is a potentially life-threatening vascular condition, but approved medical therapies to prevent AAA progression and rupture are currently lacking. Sphingolipid metabolism disorders are associated with the occurrence and development of AAA. It has been discovered that ganglioside GM3, a sialic acid-containing type of glycosphingolipid, plays a protective role in atherosclerosis, which is an important risk factor for AAA; however, the potential contribution of GM3 to AAA development has not been investigated. METHODS: We performed a metabolomics study to evaluated GM3 level in plasma of human patients with AAA. We profiled GM3 synthase (ST3GAL5) expression in the mouse model of aneurysm and human AAA tissues through Western blotting and immunofluorescence staining. RNA sequencing, affinity purification and mass spectrometry, proteomic analysis, surface plasmon resonance analysis, and functional studies were used to dissect the molecular mechanism of GM3-regulating ferroptosis. We conditionally deleted and overexpressed St3gal5 in smooth muscle cells (SMCs) in vivo to investigate its role in AAA. RESULTS: We found significantly reduced plasma levels of GM3 in human patients with AAA. GM3 content and ST3GAL5 expression were decreased in abdominal aortic vascular SMCs in patients with AAA and an AAA mouse model. RNA sequencing analysis showed that ST3GAL5 silencing in human aortic SMCs induced ferroptosis. We showed that GM3 interacted directly with the extracellular domain of TFR1 (transferrin receptor 1), a cell membrane protein critical for cellular iron uptake, and disrupted its interaction with holo-transferrin. SMC-specific St3gal5 knockout exacerbated iron accumulation at lesion sites and significantly promoted AAA development in mice, whereas GM3 supplementation suppressed lipid peroxidation, reduced iron deposition in aortic vascular SMCs, and markedly decreased AAA incidence. CONCLUSIONS: Together, these results suggest that GM3 dysregulation promotes ferroptosis of vascular SMCs in AAA. Furthermore, GM3 may constitute a new therapeutic target for AAA.

Influenza A virus infection activates caspase-8 to enhance innate antiviral immunity by cleaving CYLD and blocking TAK1 and RIG-I deubiquitination.

Caspase-8, an aspartate-specific cysteine protease that primarily functions as an initiator caspase to induce apoptosis, can downregulate innate immunity in part by cleaving RIPK1 and IRF3. However, patients with caspase-8 mutations or deficiency develop immunodeficiency and are prone to viral infections. The molecular mechanism underlying this controversy remains unknown. Whether caspase-8 enhances or suppresses antiviral responses against influenza A virus (IAV) infection remains to be determined. Here, we report that caspase-8 is readily activated in A549 and NL20 cells infected with the H5N1, H5N6, and H1N1 subtypes of IAV. Surprisingly, caspase-8 deficiency and two caspase-8 inhibitors, Z-VAD and Z-IETD, do not enhance but rather downregulate antiviral innate immunity, as evidenced by decreased TBK1, IRF3, IκBα, and p65 phosphorylation, decreased IL-6, IFN-ß, MX1, and ISG15 gene expression; and decreased IFN-ß production but increased virus replication. Mechanistically, caspase-8 cleaves and inactivates CYLD, a tumor suppressor that functions as a deubiquitinase. Caspase-8 inhibition suppresses CYLD cleavage, RIG-I and TAK1 ubiquitination, and innate immune signaling. In contrast, CYLD deficiency enhances IAV-induced RIG-I and TAK1 ubiquitination and innate antiviral immunity. Neither caspase-3 deficiency nor treatment with its inhibitor Z-DEVD affects CYLD cleavage or antiviral innate immunity. Our study provides evidence that caspase-8 activation in two human airway epithelial cell lines does not silence but rather enhances innate immunity by inactivating CYLD.

Transcriptome analysis of long non-coding RNA and mRNA Profiles in VSV-infected BHK-21 Cells.

BACKGROUND: Vesicular stomatitis virus (VSV) is a typical non-segmented negative-sense RNA virus of the genus Vesiculovirus in the family Rhabdoviridae. VSV can infect a wide range of animals, including humans, with oral blister epithelial lesions. VSV is an excellent model virus with a wide range of applications as a molecular tool, a vaccine vector, and an oncolytic vector. To further understand the interaction between VSV and host cells and to provide a theoretical basis for the application prospects of VSV, we analyzed the expression of host differentially expressed genes (DEGs) during VSV infection using RNA-Seq. RESULTS: Our analyses found a total of 1015 differentially expressed mRNAs and 161 differentially expressed LncRNAs in BHK-21 cells infected with VSV for 24 h compared with controls. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment showed that the differentially expressed lncRNAs and their target genes were mainly concentrated in pathways related to apoptosis, cancer, disease, and immune system activation, including the TNF, P53, MAPK, and NF-kappaB signaling pathways. The differentially expressed lncRNA can modulate immune processes by regulating genes involved in these signaling transmissions. Ten randomly selected DEGs, namely, Il12rb2, F2, Masp2, Mcl1, FGF18, Ripk1, Fas, BMF, POLK, and JAG1, were validated using RT-qPCR. As predicted through RNA-Seq analysis, these DEGs underwent either up- or downregulation, suggesting that they may play key regulatory roles in the pathways mentioned previously. CONCLUSIONS: Our study showed that VSV infection alters the host metabolic network and activates immune-related pathways, such as MAPK and TNF. The above findings provide unique insights for further study of the mechanism of VSV-host interactions and, more importantly, provide a theoretical basis for VSV as an excellent vaccine carrier.

Multilocus Distance-Regulated Sensor Array for Recognition of Polyphenols via Machine Learning and Indicator Displacement Assay.

Developing new strategies to construct sensor arrays that can effectively distinguish multiple natural components with similar structures in mixtures is an exceptionally challenging task. Here, we propose a new multilocus distance-modulated indicator displacement assay (IDA) strategy for constructing a sensor array, incorporating machine learning optimization to identify polyphenols. An 8-element array, comprising two fluorophores and their six dynamic covalent complexes (C1-C6) formed by pairing two fluorophores with three distinct distance-regulated quenchers, has been constructed. Polyphenols with diverse spatial arrangements and combinatorial forms compete with the fluorophores by forming pseudocycles with quenchers within the complexes, leading to varying degrees of fluorescence recovery. The array accurately and effectively distinguished four tea polyphenols and 16 tea varieties, thereby demonstrating the broad applicability of the multilocus distance-modulated IDA array in detecting polyhydroxy foods and natural medicines.

Bacteroid cerium oxide particles promote macrophage polarization to achieve early vascularization and subsequent osseointegration around implants.

The establishment of an osseointegration is crucial for the long-term stability and functionality of implant materials, and early angiogenesis is the key to successful osseointegration. However, the bioinertness of titanium implants affects osseointegration, limiting their clinical application. In this study, inspired by the rapid polarization of macrophages following the phagocytosis of bacteria, we developed bacteroid cerium oxide particles; these particles were composed of CeO2 and had a size similar to that of Bacillus (0.5 µ m). These particles were constructed on the implant surfaces using a hydrothermal method. In vitro experiments demonstrated that the particles effectively decreased the reactive oxygen species (ROS) levels in macrophages (RAW264.7). Furthermore, these particles exerted effects on M1 macrophage polarization, enhanced nitric oxide (NO) secretion to promote vascular regeneration, and facilitated rapid macrophage transition to the M2 phenotype. Subsequently, the particles facilitated human umbilical vein endothelial cell (HUVEC) migration. In vivo studies showed that these particles rapidly stimulated innate immune responses in animal models, leading to enhanced angiogenesis around the implant and improved osseointegration. In summary, the presence of bacteroid cerium oxide particles on the implant surface regulated and accelerated macrophage polarization, thereby enhancing angiogenesis during the immune response and improving peri-implant osseointegration.

Fine mapping and identification of two NtTOM2A homeologs responsible for tobacco mosaic virus replication in tobacco (Nicotiana tabacum L.).

BACKGROUND: Tobacco mosaic virus (TMV) is a widely distributed viral disease that threatens many vegetables and horticultural species. Using the resistance gene N which induces a hypersensitivity reaction, is a common strategy for controlling this disease in tobacco (Nicotiana tabacum L.). However, N gene-mediated resistance has its limitations, consequently, identifying resistance genes from resistant germplasms and developing resistant cultivars is an ideal strategy for controlling the damage caused by TMV. RESULTS: Here, we identified highly TMV-resistant tobacco germplasm, JT88, with markedly reduced viral accumulation following TMV infection. We mapped and cloned two tobamovirus multiplication protein 2A (TOM2A) homeologs responsible for TMV replication using an F2 population derived from a cross between the TMV-susceptible cultivar K326 and the TMV-resistant cultivar JT88. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (CRISPR/Cas9)-mediated loss-of-function mutations of two NtTOM2A homeologs almost completely suppressed TMV replication; however, the single gene mutants showed symptoms similar to those of the wild type. Moreover, NtTOM2A natural mutations were rarely detected in 577 tobacco germplasms, and CRISPR/Cas9-mediated variation of NtTOM2A led to shortened plant height, these results indicating that the natural variations in NtTOM2A were rarely applied in tobacco breeding and the NtTOM2A maybe has an impact on growth and development. CONCLUSIONS: The two NtTOM2A homeologs are functionally redundant and negatively regulate TMV resistance. These results deepen our understanding of the molecular mechanisms underlying TMV resistance in tobacco and provide important information for the potential application of NtTOM2A in TMV resistance breeding.

Fabrication of Nanocatalytic Medicine from Self-Assembling Peptides Containing an ATCUN-Like Copper-Binding Motif for Anticancer Therapy.

Development of nanomaterials with multiple enzymatic activities via a facile approach receives growing interests in recent years. Although peptide self-assembling provides an effective approach for the construction of biomimetic materials in recent years, fabrication of artificial enzymes from self-assembling peptides with multiple catalytic activities for anticancer therapy is still a challenge. Here, we report a simple method to prepare nanocatalysts with multienzyme-like activities from self-assembling peptides containing ATCUN copper-binding motifs. With the aid of the coordination interactions between the ATCUN motif and Cu(II) ions, these peptides could perform supramolecular self-assembly to form nanomaterials with biomimetic peroxidase, ascorbate oxidase and glutathione peroxidase activities. Moreover, these trienzyme-like effects can elevate oxidative stress levels and suppress the antioxidative capability of cancer cells, which synergistically induce the apoptosis of cancer cells. Because of the high biocompatibility, catalytic activities and drug encapsulation properties, this self-assembled peptide provides a biomimetic platform for the development of new nanocatalytic medicines for multimodal synergistic cancer therapies.

Type 2 diabetic mellitus related osteoporosis: focusing on ferroptosis.

With the aging global population, type 2 diabetes mellitus (T2DM) and osteoporosis(OP) are becoming increasingly prevalent. Diabetic osteoporosis (DOP) is a metabolic bone disorder characterized by abnormal bone tissue structure and reduced bone strength in patients with diabetes. Studies have revealed a close association among diabetes, increased fracture risk, and disturbances in iron metabolism. This review explores the concept of ferroptosis, a non-apoptotic cell death process dependent on intracellular iron, focusing on its role in DOP. Iron-dependent lipid peroxidation, particularly impacting pancreatic ß-cells, osteoblasts (OBs) and osteoclasts (OCs), contributes to DOP. The intricate interplay between iron dysregulation, which comprises deficiency and overload, and DOP has been discussed, emphasizing how excessive iron accumulation triggers ferroptosis in DOP. This concise overview highlights the need to understand the complex relationship between T2DM and OP, particularly ferroptosis. This review aimed to elucidate the pathogenesis of ferroptosis in DOP and provide a prospective for future research targeting interventions in the field of ferroptosis.

X-ray focusing below 3 nm with aberration-corrected multilayer Laue lenses.

Multilayer Laue lenses are volume diffractive optical elements for hard X-rays with the potential to focus beams to sizes as small as 1 nm. This ability is limited by the precision of the manufacturing process, whereby systematic errors that arise during fabrication contribute to wavefront aberrations even after calibration of the deposition process based on wavefront metrology. Such aberrations can be compensated by using a phase plate. However, current high numerical aperture lenses for nanometer resolution exhibit errors that exceed those that can be corrected by a single phase plate. To address this, we accumulate a large wavefront correction by propagation through a linear array of 3D-printed phase correcting elements. With such a compound refractive corrector, we report on a point spread function with a full-width at half maximum area of 2.9 × 2.8 nm2 at a photon energy of 17.5 keV.

A BODIPY-Ferrocene Conjugate for the Combined Photodynamic Therapy and Chemodynamic Therapy with Improved Antitumor Efficiency.

Photodynamic therapy (PDT) can destroy tumor cells by generating singlet oxygen (1O2) under light irradiation, which is limited by the hypoxia of the neoplastic tissue. Chemodynamic therapy (CDT) can produce toxic hydroxyl radical (⋅OH) to eradicate tumor cells by catalytic decomposition of endogenous hydrogen peroxide (H2O2), the therapeutic effect of which is highly dependent on the concentration of H2O2. Herein, we propose a BODIPY-ferrocene conjugate with a balanced 1O2 and ⋅OH generation capacity, which can serve as a high-efficiency antitumor agent by combining PDT and CDT. The ferrocene moieties endow the as-prepared conjugates with the ability of chemodynamic killing of tumor cells. Moreover, combined PDT/CDT therapy with improved antitumor efficiency can be realized after exposure to light irradiation. Compared with the monotherapy by PDT or CDT, the BODIPY-ferrocene conjugates can significantly increase the intracellular ROS levels of the tumor cells after light irradiation, thereby inducing the tumor cell apoptosis at low drug doses. In this way, a synergistic antitumor treatment is achieved by the combination of PDT and CDT.

High expression of SRSF1 facilitates osteosarcoma progression and unveils its potential mechanisms.

BACKGROUND: SRSF1, a member of Serine/Arginine-Rich Splicing Factors (SRSFs), has been observed to significantly influence cancer progression. However, the precise role of SRSF1 in osteosarcoma (OS) remains unclear. This study aims to investigate the functions of SRSF1 and its underlying mechanism in OS. METHODS: SRSF1 expression level in OS was evaluated on the TCGA dataset, TAGET-OS database. qRT-PCR and Western blotting were employed to assess SRSF1 expression in human OS cell lines as well as the interfered ectopic expression states. The effect of SRSF1 on cell migration, invasion, proliferation, and apoptosis of OS cells were measured by transwell assay and flow cytometry. RNA sequence and bioinformatic analyses were conducted to elucidate the targeted genes, relevant biological pathways, and alternative splicing (AS) events regulated by SRSF1. RESULTS: SRSF1 expression was consistently upregulated in both OS samples and OS cell lines. Diminishing SRSF1 resulted in reduced proliferation, migration, and invasion and increased apoptosis in OS cells while overexpressing SRSF1 led to enhanced growth, migration, invasion, and decreased apoptosis. Mechanistically, Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and Gene Set Enrichment Analysis (GSEA) revealed that the biological functions of SRSF1 were closely associated with the dysregulation of the protein targeting processes, location of the cytosolic ribosome, extracellular matrix (ECM), and proteinaceous extracellular matrix, along with the PI3K-AKT pathway, Wnt pathway, and HIPPO pathway. Transcriptome analysis identified AS events modulated by SRSF1, especially (Skipped Exon) SE events and (Mutually exclusive Exons) MXE events, revealing potential roles of targeted molecules in mRNA surveillance, RNA degradation, and RNA transport during OS development. qRT-PCR confirmed that SRSF1 knockdown resulted in the occurrence of alternative splicing of SRRM2, DMKN, and SCAT1 in OS. CONCLUSIONS: Our results highlight the oncogenic role of high SRSF1 expression in promoting OS progression, and further explore the potential mechanisms of action. The significant involvement of SRSF1 in OS development suggests its potential utility as a therapeutic target in OS.

Preclinical Evaluation of a Radiolabeled Pan-RAF Inhibitor for RAF-Specific PET/CT Imaging.

Abnormalities in the RAS-RAF signaling pathway occur in many solid tumors, leading to aberrant tumor proliferation, invasion, and metastasis. Due to the elusive pharmacology of RAS, RAF inhibitors have become the main targeted therapeutic drugs. Naporafenib (LXH-254) is a high-affinity pan-RAF inhibitor with FDA Fast Track Qualification. We sought to develop an 18F-labeled molecular probe from LXH-254 for PET imaging of tumors overexpressing RAF to noninvasively screen patients for susceptibility to targeted RAF therapy. To reduce the lipid solubility, LXH-254 was designed with triethylene glycol di(p-toluenesulfonate) (TsO-PEG3-OTs) to obtain the precursor (LXH-254-OTs) and a nucleophilic substitution reaction with 18F to obtain the tracer ([18F]F-LXH-254). [18F]F-LXH-254 exhibited good molar activity (7.16 ± 0.81 GBq/µmol), radiochemical purity (>95%), and stability. Micro-PET imaging revealed distinct radioactivity accumulation of [18F]F-LXH-254 in tumors in the imaging groups, whereas in the blocked group, the tumor radioactivity level was consistent with the background tissue, illustrating the affinity and specificity of [18F]F-LXH-254 in targeting RAF. Overall, [18F]F-LXH-254 is a promising radiotracer for screening and diagnosing patients with RAF-related disease and monitoring their treatment. This is the first attempt at using an 18F-labeled RAF-specific radiotracer.

Deepened Photodynamic Therapy through Skin Optical Clearing Technology in the Visible Light Window.

The trade-off that shorter wavelength light facilitates the efficient generation of reactive oxygen species (ROS) from photosensitizer (PS) while facing the drawback of limited penetration depth through skin tissue restricts the further development of photodynamic therapy (PDT). Here, we address this contradiction and achieve visible-light-tailored deep PDT combined with the skin optical clearing technology. With the help of the prepared skin optical clearing gel, the refractive index inhomogeneity between skin tissue components is greatly attenuated, and the light scattering effect within the skin tissue is remarkably reduced. As a consequence, the transmittance of visible light at 600 nm through in vitro porcine skin and in vivo mouse skin after treatment increases from approximately 10 and 40 to 70 and 70%, respectively. Furthermore, in the tumor cell eradication experiment, the local ROS generation efficiency in the experimental group is several times higher than that in the control group owing to improved visible transmittance, which is thus responsible for the complete eradication of tumor cells, even when shaded by skin tissue. The results suggest that this strategy may serve as a valuable supplement to the current deep PDT strategies.

A transmembrane scaffold from CD20 helps recombinant expression of a chimeric claudin 18.2 in an in vitro coupled transcription and translation system.

Cluster of differentiation 20 (CD20) is a nonglycosylated, multispanning transmembrane protein specifically integrated by B lymphocytes. Similar to CD20, another four-pass transmembrane protein, claudin 18.2, has attracted attention as an emerging therapeutic target for cancer. However, their poor solubility and toxic nature often hinder downstream applications, such as antibody drug development. Therefore, developing a cost-effective method for producing drug targets with multiple membrane-spanning domains is crucial. In this study, a high yield of recombinant CD20 was achieved through an E. coli-based in vitro coupled transcription-translation system. Surface plasmon resonance results showed that rituximab (an antileukemia drug) has nanomolar affinity with the CD20 protein, which aligns with published results. Notably, a previously hard-to-express claudin 18.2 recombinant protein was successfully expressed in the same reaction system by replacing its membrane-spanning domains with the transmembrane domains of CD20. The folding of the extracellular domain of the chimeric protein was verified using a commercial anti-claudin 18 antibody. This study provides a novel concept for promoting the expression of four-pass transmembrane proteins and lays the foundation for the large-scale industrial production of membrane-associated drug targets, similar to claudin 18.2.

Photoinduced Radical Annulations of Tetrahydroisoquinoline Derivatives with 2-Benzothiazolimines: Highly Diastereoselective Synthesis of Fused Hexahydroimidazo[2,1-a]isoquinolines.

We report herein a photoinduced radical 1,3-dipolar cycloaddition between the 2-benzothiazolimines and tetrahydroisoquinoline derivatives with an organo-photocatalyst. A variety of benzothiazole-based hexahydroimidazo[2,1-a]isoquinoline architectures with great synthetic value were conveniently and efficiently constructed in moderate to good yields and excellent diastereoselectivities with highly tolerant functional groups. Moreover, the practicality and utility of this protocol were demonstrated by scale-up synthesis and facile elaboration. Preliminary mechanistic investigations indicated that the reaction proceeded via a visible-light-induced radical 1,3-dipolar cycloaddition pathway. This finding is expected to stimulate a more extensive exploration of the green and concise synthesis of structurally diverse heterocyclic molecules in the synthetic community.

Association between autoimmune liver diseases and chronic hepatitis B: A multivariable Mendelian randomization study in European population.

BACKGROUND: Observational studies have indicated a link between autoimmune liver diseases (AILD) and chronic hepatitis B (CHB) through observational studies. The association between AILD and CHB remains indeterminate. METHODS: A two-sample Mendelian randomization (MR) analysis was conducted to scrutinize the causal nexus between AILD and CHB utilizing summary statistics derived from extensive genome-wide association studies (GWASs) in European populations. The primary statistical methodology employed was the inverse variance-weighted (IVW) method to deduce the causal connection of AILD on CHB. This study incorporated primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH) as subtypes of AILD. Additionally, we conducted a multivariable MR (MVMR) analysis to account for the potential confounding effects of smoking, alcohol consumption, body mass index (BMI), and some autoimmune diseases. RESULTS: Our MR investigation encompassed a cohort of 725,816 individuals. The MR analysis revealed that genetically predicted PSC significantly correlated with a reduced risk of CHB (IVW OR = 0.857; 95%CI: 0.770-0.953, P = 0.005). Conversely, the reverse MR analysis suggested that genetic susceptibility to PSC might not modify the risk of CHB (IVW OR = 1.004; 95% CI: 0.958-1.053, P = 0.866). Genetically proxied PBC and AIH exhibited no discernible causal association with CHB in the MR analysis using the IVW method (P = 0.583; P = 0.425). The MVMR analysis still indicated a decreased risk of CHB associated with PSC (OR = 0.853, P = 0.003). CONCLUSION: Our study elucidates a causal relationship between PSC and a diminished risk of CHB.

Separation of Palladium by an Imine-Linked Cu(I)-Organic Framework.

Selective capture of palladium (Pd) is one of the important works in science due to its high application and low content in the Earth's crust. To this end, we present herein a new Cu(I)-organic framework (ECUT-MOF-1) by introducing pyridine N active sites to chelate Pd(II). ECUT-MOF-1 demonstrated that the maximal adsorption capacity of Pd(II) was 350 mg/g in pH = 3 solution. In addition, kinetic analysis, cycle performance, selectivity, and adsorption mechanisms were also investigated. All of the results suggested its superior application in the recovery of Pd(II).

Capture of Iodine in Vapor and Solution Phases by a Th-Based Metal-Organic Framework.

The efficient capture of radioactive iodine is of paramount importance due to its harmfulness. In this work, a new Th-based metal-organic framework (ECUT-Th-11) for iodine capture was reported. ECUT-Th-11 exhibited a relatively high capacity of capturing vapor iodine (2.03 g/g). Besides, the maximal adsorption capacity of iodine in a cyclohexane solution reaches 258.03 mg/g. All of the results demonstrated that ECUT-Th-11 could be a candidate material for the effective removal of waste iodine.

Exosomal long non-coding RNA TRAFD1-4:1 derived from fibroblast-like synoviocytes suppresses chondrocyte proliferation and migration by degrading cartilage extracellular matrix in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic, autoimmune and systemic inflammatory disease affecting 1% of the population worldwide. Immune suppression of the activity and progress of RA is vital to reduce the disability and mortality rate as well as improve the quality of life of RA patients. However, the immune molecular mechanism of RA has not been clarified yet. Our results indicated that exosomes derived from TNFα-stimulated RA fibroblast-like synoviocytes (RA-FLSs) suppressed chondrocyte proliferation and migration through modulating cartilage extracellular matrix (CECM) determining by MTS assay, cell cycle analysis, Transwell assay and Western blot (WB). Besides, RNA sequencing and verification by qRT-PCR revealed that exosomal long non-coding RNA (lncRNA) tumor necrosis factor-associated factor 1 (TRAF1)-4:1 derived from RA-FLSs treated with TNFα was a candidate lncRNA, which also inhibited chondrocyte proliferation and migration through degrading CECM. Moreover, RNA sequencing and bioinformatics analysis identified that C-X-C motif chemokine ligand 1 (CXCL1) was a target mRNA of miR-27a-3p while miR-27a-3p was a target miRNA of lnc-TRAF1-4:1 in chondrocytes. Mechanistically, lnc-TRAF1-4:1 upregulated CXCL1 expression through sponging miR-27a-3p as a competing endogenous RNA (ceRNA) in chondrocytes identifying by Dual-luciferase reporter gene assay. Summarily, exosomal lncRNA TRAFD1-4:1 derived from RA-FLSs suppressed chondrocyte proliferation and migration through degrading CECM by upregulating CXCL1 as a sponge of miR-27a-3p. This study uncovered a novel RA-related lncRNA and investigated the roles of RA-FLS-derived exosomes and exosomal lnc-TRAF1-4:1 in articular cartilage impairment, which might provide novel therapeutic targets for RA.