Differential impact of quiescent non-coding loci on chromatin entropy.

Non-coding regions of the human genome are important for functional regulations, but their mechanisms remain elusive. We used machine learning to guide a CRISPR screening on hubs (i.e. non-coding loci forming many 3D contacts) and significantly increased the discovery rate of hubs essential for cell growth. We found no clear genetic or epigenetic differences between essential and nonessential hubs, but we observed that some neighboring hubs in the linear genome have distinct spatial contacts and opposite effects on cell growth. One such pair in an epigenetically quiescent region showed different impacts on gene expression, chromatin accessibility and chromatin organization. We also found that deleting the essential hub altered the genetic network activity and increased the entropy of chromatin accessibility, more severe than that caused by deletion of the nonessential hub, suggesting that they are critical for maintaining an ordered chromatin structure. Our study reveals new insights into the system-level roles of non-coding regions in the human genome.

Periodontal pathogen Fusobacterium nucleatum infection accelerates hepatic steatosis in high-fat diet-fed ApoE knockout mice by inhibiting Nrf2/Keap1 signaling.

AIMS: This study sought to explore the impact of Fusobacterium nucleatum on hepatic steatosis in apolipoprotein E (ApoE) knockout (KO) mice induced by a high-fat diet (HFD) and elucidate the underlying mechanism. METHODS: ApoE KO mice, on a HFD, received F. nucleatum oral inoculation every other day. After 24 weeks, body weight, liver weight, and liver index were assessed. Serum biochemistry and pro-inflammatory factors in serum and liver were analyzed. The histopathology of right maxilla and live were performed. Oil red O, immunohistochemistry, and immunofluorescence staining for the liver were conducted. Myeloperoxidase (MPO) activity, apoptosis, lipid reactive oxygen species (ROS), ROS, lipid peroxides, and hepatic lipids were also evaluated. Liver inflammation, fibrosis, de novo lipogenesis (DNL)-related molecule, and Nrf2/Keap1-related signaling molecule gene/protein expression were determined by real-time PCR (RT-PCR) and/or Western blot (WB) analysis. RESULTS: HFD-fed ApoE KO mice infected by F. nucleatum demonstrated significant changes, including increased body and liver weight, elevated proinflammatory factors and lipids in serum and liver, as well as neutrophil infiltration, fibrosis, apoptosis, oxidative stress, and lipid peroxidation in the liver. Additionally, F. nucleatum stimulates hepatic lipid accumulation and activates de novo lipogenesis (DNL), while simultaneously suppressing the Nrf2/Keap1 antioxidant pathway. CONCLUSION: In conclusion, our study reveals that oral inoculation of F. nucleatum might promote hepatic steatosis by inhibiting Nrf2/Keap1 pathway.

Regulatory elements can be essential for maintaining broad chromatin organization and cell viability.

Increasing evidence shows that promoters and enhancers could be related to 3D chromatin structure, thus affecting cellular functions. Except for their roles in forming canonical chromatin loops, promoters and enhancers have not been well studied regarding the maintenance of broad chromatin organization. Here, we focused on the active promoters/enhancers predicted to form many 3D contacts with other active promoters/enhancers (referred to as hotspots) and identified dozens of loci essential for cell growth and survival through CRISPR screening. We found that the deletion of an essential hotspot could lead to changes in broad chromatin organization and the expression of distal genes. We showed that the essentiality of hotspots does not result from their association with individual genes that are essential for cell viability but rather from their association with multiple dysregulated non-essential genes to synergistically impact cell fitness.

Periodontal health status in cirrhotic patients: a systematic review and meta-analysis.

OBJECTIVES: Liver cirrhosis is a disease with widespread prevalence and high mortality. Oral manifestations, particularly periodontal-related manifestations such as bleeding gums, red and swollen gums, are common in cirrhotic patients but may often be overshadowed by other systemic complications, making them easy to ignore. So this article conducts a systematic review and meta-analysis of periodontal health status in patients with cirrhosis. MATERIAL AND METHODS: We performed electronic searches on the following databases: PubMed, EMBASE, Scopus, Web of Science, and Cochrane Library. Risk of bias evaluation was carried out according to the Fowkes and Fulton guidelines. Meta-analyses were performed with tests for sensitivity and statistical heterogeneity. RESULTS: Of the 368 potentially eligible articles, 12 studies were included for qualitative analysis, and 9 contributed to the meta-analysis. In terms of periodontal-related parameters, cirrhotic patients presented a greater mean of clinical attachment loss (CAL) (weighted mean differences [WMD] = 1.078, 95% confidence interval [95% CI]: 0.546-1.609, p < 0.001), probing depth (PD) (WMD = 0.796, 95% CI: 0.158 to 1.434, p = 0.015) and alveolar bone loss (ABL) (WMD = 3.465, 95% CI: 2.946-3.984, p < 0.001) than those without, while no statistical difference was found in the papillary bleeding index (PBI) (WMD = 0.166, 95% CI: -0546 to 0.878, p = 0.647) and bleeding on probing (BOP) (WMD = 4.913, 95% CI: -3.099 to 12.926, p = 0.229). The prevalence of periodontitis was higher in cirrhotic patients than in the control group (odds ratio [OR] = 2.630, 95% CI: 1.531-4.520, p < 0.001). CONCLUSIONS: The results indicate that cirrhotic patients have poor periodontal conditions and a higher prevalence of periodontitis. We advocate that they should receive regular oral hygiene and basic periodontal treatment.

Identification and characterization of non-coding RNA networks in infected macrophages revealing the pathogenesis of F. nucleatum-associated diseases.

BACKGROUND: F. nucleatum, as an important periodontal pathogen, is not only closely associated with the development of periodontitis, but also implicated in systemic diseases. Macrophages may act as an important mediator in the pathogenic process of F. nucleatum infection. As non-coding RNAs (ncRNAs) have attracted extensive attention as important epigenetic regulatory mechanisms recently, we focus on the competing endogenous RNA (ceRNA) regulatory networks to elucidate the pathogenesis of F. nucleatum-associated diseases. RESULTS: We screen abnormally expressed mRNAs, miRNAs, lncRNAs and circRNAs in macrophages after F. nucleatum infection via the whole transcriptome sequencing technology, including 375 mRNAs, 5 miRNAs, 64 lncRNAs, and 180 circRNAs. The accuracy of RNA-seq and microRNA-seq result was further verified by qRT-PCR analysis. GO and KEGG analysis show that the differentially expressed genes were mainly involved in MAPK pathway, Toll-like receptor pathway, NF-κB pathway and apoptosis. KEGG disease analysis reveals that they were closely involved in immune system diseases, cardiovascular disease, cancers, inflammatory bowel disease (IBD) et al. We constructed the underlying lncRNA/circRNA-miRNA-mRNA networks to understand their interaction based on the correlation analysis between the differentially expressed RNAs, and then screen the core non-coding RNAs. In which, AKT2 is controlled by hsa_circ_0078617, hsa_circ_0069227, hsa_circ_0084089, lncRNA NUP210, lncRNA ABCB9, lncRNA DIXDC1, lncRNA ATXN1 and lncRNA XLOC_237387 through miR-150-5p; hsa_circ_0001165, hsa_circ_0008460, hsa_circ_0001118, lncRNA XLOC_237387 and lncRNA ATXN1 were identified as the ceRNAs of hsa-miR-146a-3p and thereby indirectly modulating the expression of MITF. CONCLUSIONS: Our data identified promising candidate ncRNAs responsible for regulating immune response in the F. nucleatum-associated diseases, offering new insights regarding the pathogenic mechanism of this pathogen.

Development of a novel oral complex lipid emulsion containing triptolide for targeting pancreatic cancer.

Triptolide (TP), a diterpenoid triepoxide, exhibits strong anti-cancer activities, especially against pancreatic cancer, but its clinical application is limited by organ toxicity. TP was combined with diammonium glycyrrhizinate (DG), as a cytoprotective agent, in a novel oral complex lipid emulsion (TP/DG-CLE) to increase the therapeutic index of TP against pancreatic cancer. The emulsion was produced by subjecting phospholipid and active components to high shear conditions using high-pressure homogenisation resulting in droplets of essentially neutral or small positive charge and consistent size below 200 nm. Pharmacokinetic studies in Sprague Dawley rats revealed an AUC(0-8 h) of TP following oral dosing of TP/DG-CLE that was fourfold higher than that achieved for TP/DG suspension, demonstrating significantly higher TP bioavailability and longer residence time in the bloodstream. Tissue distribution data obtained in mice demonstrated that TP/DG-CLE having a TP/DG weight ratio of 1:22.5 preferentially accumulated in the pancreas. Moreover, toxicology assays in rats provided indications of minor liver damage following daily administration of the emulsion for two weeks. Together these studies establish complex lipid emulsions containing TP and DG as a promising oral formulation for treatment of pancreatic cancer and establish a platform for developing new chemotherapeutic treatments.

Thiolated Nanoparticles Overcome the Mucus Barrier and Epithelial Barrier for Oral Delivery of Insulin.

Oral administration is an ideal alternative for drug delivery due to its convenience and safety. However, oral protein delivery is limited by biological barriers such as the mucus barrier and epithelial barrier, which hamper drugs from entering the blood successfully. Here we presented PC6/CS NPs, a thiolated-polymer-based nanodrug delivery system in the form of poly(acrylic acid)-cysteine-6-mercaptonicotinic acid (PAA-Cys-6MNA, PC6), which is a kind of preactivated thiolated polymer, coated on chitosan (CS) nanoparticles (NPs). Its ability to overcome the mucus barrier and epithelial barrier was investigated. The existence of PC6 made the NPs prone to penetrate the mucus layer as well as strengthened the transcellular transport of insulin on epithelial cells. PC6/CS NPs efficiently enhanced the oral bioavailability of insulin to 16.2%. The improvement resulted from the function of PC6: (1) "diluting" mucus to promote nanoparticle penetration, (2) opening a tight junction to help insulin transport via the paracellular pathway, (3) making the nanoparticle more electrically neutral during the penetration process, and (4) uncoating from PC6/CS NPs so that positive CS NPs were adhered and uptaken by epithelial cells. Our study proves that PC6/CS NPs, which can achieve mucus penetration and epithelial permeation efficiently, are a potential nanocarrier for oral protein delivery.

Possible Mechanisms Involved in the Cooccurrence of Oral Lichen Planus and Hashimoto's Thyroiditis.

Oral lichen planus (OLP) is a chronic inflammatory oral mucosal disorder mediated by T cells, with a multifactorial etiology. Hashimoto's thyroiditis (HT) is a common autoimmune disease characterized by hypothyroidism. Although many clinical studies conducted over the past several decades have reported the cooccurrence of OLP and HT, the underlying mechanism remains unclear. This review summarizes potential mechanisms that might be involved in the cooccurrence of OLP and HT. We find that OLP and HT share a common or overlapping pathogenesis in terms of immune, heredity, environmental, and hormonal factors, which might cause cooccurrence. Furthermore, considering the latency of HT, a routine screen for thyroid diseases, particularly HT, is suggested for confirmed OLP patients.

SP/NK-1R promotes gallbladder cancer cell proliferation and migration.

Aberrant substance P/neurokinin-1 receptor (SP/NK-1R) system activation plays a critical role in various disorders, however, little is known about the expression and the detailed molecular mechanism of the SP and NK-1R in gallbladder cancer (GBC). In this study, we firstly analyzed the expression and clinical significance of them in patients with GBC. Then, cellular assays were performed to clarify their biological role in GBC cells. Moreover, we investigated the molecular mechanisms regulated by SP/NK-1R. Meanwhile, mice xenografted with human GBC cells were analyzed regarding the effects of SP/NK1R complex in vivo. Finally, patient samples were utilized to investigate the effect of SP/NK-1R. The results showed that SP and NK-1R were highly expressed in GBC. We found that SP strongly induced GBC cell proliferation, clone formation, migration and invasion, whereas antagonizing NK-1R resulted in the opposite effects. Moreover, SP significantly enhanced the expression of NF-κB p65 and the tumor-associated cytokines, while, Akt inhibitor could reverse these effects. Further studies indicated that decreasing activation of NF-κB or Akt diminished GBC cell proliferation and migration. In consistent with results, immunohistochemical staining showed high levels of Akt, NF-κB and cytokines in tumor tissues. Most importantly, the similar conclusion was obtained in xenograft mouse model. Our findings demonstrate that NK-1R, after binding with the endogenous agonist SP, could induce GBC cell migration and spreading via modulation of Akt/NF-κB pathway.

Long noncoding RNAs as potential biomarkers and therapeutic targets in gallbladder cancer: a systematic review and meta-analysis.

BACKGROUND: Mounting evidence has shown that long noncoding RNAs (lncRNAs) can play a substantial role in gallbladder cancer (GBC) development as tumor promotors or suppressors, and their abnormal expression is relevant to GBC patient outcomes. We completed this systematic review and meta-analysis to explore the clinical significance and mechanisms of lncRNAs in GBC. METHODS: We conducted a comprehensive literature search and selected eligible records according to the inclusion and exclusion criteria. Hazard ratios (HRs) and odds ratios (ORs) were extracted or calculated to estimate the relationships of high lncRNA expression with GBC patient survival and clinical outcomes. RESULTS: Eighteen studies were identified as eligible for this systematic review and meta-analysis. Heterogeneity among HRs of overall survival (OS) was notably high (I2 = 86.2%, p < 0.001). Subgroup analysis suggested that overexpression of lncRNAs in a group that is upregulated in GBC showed a significant association with poor OS (HR = 2.454, 95% CI 2.004-3.004, I2 = 0%). Conversely, overexpression of lncRNAs in a downregulated group was markedly related to good OS (HR = 0.371, 95% CI 0.267-0.517, I2 = 0%). High expression levels of lncRNA AFAP1-AS1, MALAT1 and ROR were positively correlated with tumor size. Expression of lncRNA LET, LINC00152 and HEGBC exhibited a positive correlation with high T status. LncRNA LINC00152, HEGBC, MALAT1 and ROR showed a marked correlation with positive lymph node metastasis (LNM), while lncRNA GCASPC, MEG3, LET and UCA1 had the opposite effect. High expression levels of lncRNA HEGBC, PAGBC, PVT1 and UCA1 predicted high tumor node metastasis (TNM) stages, while lncRNA LET, GCASPC and MEG3 indicated low TNM stages. We also summarized the mechanisms of lncRNAs in GBC. CONCLUSION: Aberrant expression of several lncRNAs was indicative of the prognosis of GBC patients, and lncRNAs showed promise as biomarkers and therapeutic targets for GBC.

Ordering of colloidal hard spheres under gravity: from monolayer to multilayer.

The phase behaviour of hard spheres confined by a gravitational potential to a thin layer (up to several monolayers) near a hard, flat surface is investigated using grand canonical Monte Carlo simulation. Depending on the strength of the gravitational field, the bottom monolayer of spheres may adopt uniform hexagonal order before, during, or after the growth of the second layer of particles. The crossover from ordering with a sparsely populated overlayer to ordering with almost one-third of the system's particles forming a second layer is observed upon decreasing the dimensionless Péclet number Pe = mgσ/kBT from 18 to 16. The particular sensitivity of the nature of the transition to particle size in this range is interpreted in terms of competing influences on the base layer structure by particles in the overlayer: promotion of order through increased pressure, versus stabilization of defects through occupation of low-lying sites on top of them. Simulations of grain boundaries between 2-D ordered domains of different orientation are used to correlate the degree of overlayer coverage to its effects on grain boundary stiffness as an indicator of defect free energy. Finally, we examine the structure of the ordered phases at coexistence over a range of gravitational strengths and find that orientational ordering of the second monolayer occurs along with first-order transition of the base layer at Pe = 8 but not at Pe = 10.

Small Molecule and Peptide Recognition of Protein Transmembrane Domains.

Membrane proteins play vital roles in cell signaling, molecular transportation, and cell adhesion. The interactions of transmembrane domains are much less well understood than those of their water-soluble counterparts, and they have been deemed "undruggable" despite their important biological functions such as protein anchoring, signal transduction, and ligand recognition. Nevertheless, continual developments in this area have revealed useful probes for investigating and regulating these membrane proteins. This review summarizes and evaluates the strategies available for discovering small molecules and peptides that recognize the protein transmembrane domains of membrane proteins, with a particular focus on rational design and library screening.

Comprehensive multimodal and multiomic profiling reveals epigenetic and transcriptional reprogramming in lung tumors.

Epigenomic mechanisms are critically involved in mediation of genetic and environmental factors that underlie cancer development. Histone modifications represent highly informative epigenomic marks that reveal activation and repression of gene activities and dysregulation of transcriptional control due to tumorigenesis. Here, we present a comprehensive epigenomic and transcriptomic mapping of 18 tumor and 20 non-neoplastic tissues from non-small cell lung adenocarcinoma patients. Our profiling covers 5 histone marks including activating (H3K4me3, H3K4me1, and H3K27ac) and repressive (H3K27me3 and H3K9me3) marks and the transcriptome using only 20 mg of tissue per sample, enabled by low-input omic technologies. Using advanced integrative bioinformatic analysis, we uncovered cancer-driving signaling cascade networks, changes in 3D genome modularity, and differential expression and functionalities of transcription factors and noncoding RNAs. Many of these identified genes and regulatory molecules showed no significant change in their expression or a single epigenomic modality, emphasizing the power of integrative multimodal and multiomic analysis using patient samples.

Distinct 3D contacts and phenotypic consequences of adjacent non-coding loci in the epigenetically quiescent regions.

Non-coding regions of the human genome are important for functional regulations, but their mechanisms remain elusive. We used machine learning to guide a CRISPR screening on hubs (i.e. non-coding loci forming many 3D contacts) and significantly increased the discovery rate of hubs essential for cell growth. We found no clear genetic or epigenetic differences between essential and nonessential hubs, but we observed that some neighboring hubs in the linear genome have distinct spatial contacts and opposite effects on cell growth. One such pair in an epigenetically quiescent region showed different impacts on gene expression, chromatin accessibility and chromatin organization. We also found that deleting the essential hub altered the genetic network activity and increased the entropy of chromatin accessibility, more severe than that caused by deletion of the nonessential hub, suggesting that they are critical for maintaining an ordered chromatin structure. Our study reveals new insights into the system-level roles of non-coding regions in the human genome.

Organelle-Specific Mechanisms in Crosstalk between Apoptosis and Ferroptosis.

Apoptosis has been extensively studied, whereas ferroptosis is a newly discovered form of regulated cell death that involves iron-dependent accumulations of lipid hydroperoxides. While these two cell death mechanisms were initially believed to be mutually exclusive, recent studies have revealed cellular contexts requiring a balanced interaction between them. Numerous subcellular sites and signaling molecules within these sites are involved in both processes, either as modules or switches that allow cells to choose on how to proceed. The close relationships between apoptosis and ferroptosis, as well as the possibility of switching from one to the other, are described in this review. To understand the crosstalk between apoptosis and ferroptosis, various organelle-specific mechanisms must be analyzed and compared. The ability to switch apoptosis to ferroptosis by targeting cellular organelles has a great potential in cancer therapy.

Oral administration of nanoformulated indoximod ameliorates ulcerative colitis by promoting mitochondrial function and mucosal healing.

Ulcerative colitis (UC) is a chronic relapsing inflammatory bowel disease with serious mucosal inflammation mainly in the colon and rectum. Currently, there is no effective therapeutics for UC. Indoximod (IND) is a water-insoluble inhibitor for indolamine 2, 3-dioxygenase (IDO) and has been mainly reported in cancer therapy. Here, we prepared orally administrated IND nanoparticles (IND-NPs) for UC treatment and investigated their functions and mechanisms in cellular and animal inflammatory models. Confocal imaging demonstrated that IND-NPs maintained the expression level of ZO-1, Occludin and E-cadherin, thereby stabilizing of intercellular junction in Caco-2 cells. It was found that IND-NPs could lower the ROS level and increase mitochondrial membrane potential as well as ATP level, indicating that IND-NPs could restore DSS-induced mitochondrial dysfunction. In the mice model with DSS-induced colitis, IND-NPs were found to alleviate UC-associated symptoms, inhibit inflammatory response, and improve the integrity of epithelial barrier. The untargeted metabolomics analysis validated that IND-NPs also contributed to regulate the metabolite levels to normal. As an agonist of aryl hydrocarbon receptor (AhR), IND-NPs might repair mucosa via the AhR pathway. These findings demonstrated that IND-NPs prominently ameliorated DSS-induced colonic injury and inflammation and preserved intestinal barrier integrity, showing a promising potential in UC treatment.

Fusobacterium nucleatum Accelerates Atherosclerosis via Macrophage-Driven Aberrant Proinflammatory Response and Lipid Metabolism.

Periodontitis, an oral chronic inflammatory disease, is reported to show an association with atherosclerotic vascular disease. Fusobacterium nucleatum is an oral commensal bacterium that is abundantly implicated in various forms of periodontal diseases; however, its role in the pathogenesis of atherosclerosis is unclear. This study aimed to elucidate the underlying pathogenic mechanisms of atherosclerosis induced by F. nucleatum to provide new insight on the prevention and treatment of atherosclerosis. We used an animal model, that is, ApoE-/- mice were infected with F. nucleatum by oral gavage, and in vitro co-culture models to assess the pathogenicity of F. nucleatum. The results indicate that F. nucleatum ATCC 25586 invaded aortic tissues and substantially increased the progression of atherosclerotic lesions. In addition, F. nucleatum changed plaque composition into a less-stable phenotype, characterized with increased subcutaneous macrophage infiltration, M1 polarization, lipid deposition, cell apoptosis, and reduced extracellular matrix and collagen content. The serum levels of pro-atherosclerotic factors, such as interleukin (IL)-6, IL-1ß, tumor necrosis factor (TNF)-α, monocyte chemoattractant protein-1 (MCP-1), c-reactive protein, and oxidized low-density lipoprotein (ox-LDL) and microRNAs (miR-146a, miR-155, and miR-23b) were considerably increased after F. nucleatum stimulation, whereas HDL-c level was reduced. F. nucleatum induced in vitro macrophage apoptosis in a time- and dose-dependent manner. F. nucleatum facilitated ox-LDL-induced cholesterol phagocytosis and accumulation by regulating the expression of lipid metabolism-related genes (AR-A1, ACAT1, ABCA1, and ABCG1). F. nucleatum further worsened the atherosclerotic plaque microenvironment by considerably increasing the levels of IL-6; IL-1ß; TNF-α; MCP-1; and MMP-2, 8, and 9 and by suppressing fibronectin (FN) 1 levels during foam cell formation. This study shows that F. nucleatum ATCC 25586 is implicated in atherosclerosis by causing aberrant activation and lipid metabolism in macrophage.

Lactate promotes the growth of patient-derived organoids from hepatopancreatobiliary cancers via ENO1/HIF1α pathway and does not affect their drug sensitivities.

The long culture duration of patient-derived organoids (PDOs) have severely limited their clinical applications. The aim of this study was to determine the effect of lactate supplementation on the growth, genetic profiles and drug sensitivities of PDOs from hepatopancreatobiliary tumors. LM3, Huh7, Panc02, and RBE cell lines were cultured as organoids in the presence or absence of lactate, and total protein was extracted to measure the expression of α-enolase (ENO1), hypoxia-inducible factor-1α (HIF1α), AKT, and PI3 kinase (PI3K). Thirteen hepatopancreatobiliary tumor specimens were collected during surgical resection and cultured as PDOs with or without L-lactate. Hematoxylin and eosin (H&E) staining and immunohistochemical staining were performed on the original tissues and PDOs to compare their pathological structures, and their genetic profiles were analyzed by whole-exome sequencing (WES). The sensitivity of the PDOs to gemcitabine, 5-fluorouracil, cisplatin, paclitaxel, ivosidenib, infigratinib, and lenvatinib were evaluated in terms of cell viability. Peripheral blood mononuclear cells (PBMCs) were isolated and co-cultured with PDOs to test the sensitivity of PDOs to tislelizumab. The addition of 20 mM lactate significantly promoted the growth of LM3 and Huh 7 organoids by 217% and 36%, respectively, compared to the control group, and the inhibition of lactate transporter decreased their growth. The HIF1α/ENO1/AKT/PI3K pathway was also activated by lactate. The inhibition of enolase also partly decreased the growth of organoids treated with lactate. Furthermore, 20 mM lactate increased the viability of 9 PDOs from 135% to 317% without affecting their pathological features. The genetic similarity, in terms of single nucleotide variations, insertions, and deletions, between original tissues and lactate-treated PDOs ranged from 83.2% to 94.1%, and that between the untreated and lactate-treated PDOs was at least 93.2%. Furthermore, the addition of lactate did not significantly change the dose-response curves of the PDOs to chemotherapeutic drugs, targeted drugs, and immune checkpoint inhibitor, especially for the drugs to which the cells were sensitive. Thus, lactate can be added to the culture medium of PDOs to promote their growth without altering their genetic profiles and drug sensitivities.

Nanoparticulates reduce tumor cell migration through affinity interactions with extracellular migrasomes and retraction fibers.

Nano-tumor interactions are fundamental for cancer nanotherapy, and the cross-talk of nanomedicines with the extracellular matrix (ECM) is increasingly considered essential. Here, we specifically investigate the nano-ECM interactivity using drug-free nanoparticulates (NPs) and highly metastatic cancer cells as models. We discover with surprise that NPs closely bind to specific types of ECM components, namely, retraction fibers (RFs) and migrasomes, which are located at the rear of tumor cells during their migration. This interaction is observed to alter cell morphology, limit cell motion range and change cell adhesion. Importantly, NPs are demonstrated to inhibit tumor cell removal in vitro, and their anti-metastasis potential is preliminarily confirmed in vivo. Mechanically, the NPs are found to coat and form a rigid shell on the surface of migrasomes and retraction fibers via interaction with lipid raft/caveolae substructures. In this way, NPs block the recognition, endocytosis and elimination of migrasomes by their surrounding tumor cells. Thereby, NPs interfere with the cell-ECM interaction and reduce the promotion effect of migrasomes on cell movement. Additionally, NPs trigger alteration of the expression of proteins related to cell-cell adhesion and cytoskeleton organization, which also restricts cell migration. In summary, all the findings here provide a potential target for anti-tumor metastasis nanomedicines.

The emerging role of Interleukin 37 in bone homeostasis and inflammatory bone diseases.

Interleukin 37 (IL-37) is a newly identified cytokine that belongs to the IL-1 family. Unlike other members of the IL-1 family, it has been demonstrated that IL-37 possesses anti-inflammatory characteristics in both innate and acquired immune responses. Recently, significant progress has been made in understanding the role of IL-37 in inflammatory signaling pathways. Meanwhile, IL-37 has also attracted more and more attention in bone homeostasis and inflammatory bone diseases. The latest studies have revealed that IL-37 palys an essential role in the regulation of osteoclastogenesis and osteoblastogenesis. The levels of IL-37 are abnormal in patients with inflammatory bone diseases such as rheumatoid arthritis (RA), osteoarthritis (OA), ankylosing spondylitis (AS), and periodontitis. In addition, in vivo studies have further confirmed that recombinant IL-37 treatment displayed therapeutic potential in these diseases. The present review article aims to provide an overview describing the biological functions of IL-37 in bone homeostasis and inflammatory bone diseases, thus shedding new light on a novel therapeutic strategy in the future.