Multiarmed DNA jumper and metal-organic frameworks-functionalized paper-based bioplatform for small extracellular vesicle-derived miRNAs assay.

Small extracellular vesicle-derived microRNAs (sEV-miRNAs) have emerged as promising noninvasive biomarkers for early cancer diagnosis. Herein, we developed a molecular probe based on three-dimensional (3D) multiarmed DNA tetrahedral jumpers (mDNA-Js)-assisted DNAzyme activated by Na+, combined with a disposable paper-based electrode modified with a Zr-MOF-rGO-Au NP nanocomplex (ZrGA) to fabricate a novel biosensor for sEV-miRNAs Assay. Zr-MOF tightly wrapped by rGO was prepared via a one-step method, and it effectively aids electron transfer and maximizes the effective reaction area. In addition, the mechanically rigid, and nanoscale-addressable mDNA-Js assembled from the bottom up ensure the distance and orientation between fixed biological probes as well as avoid probe entanglement, considerably improving the efficiency of molecular hybridization. The fabricated bioplatform achieved the sensitive detection of sEV-miR-21 with a detection limit of 34.6 aM and a dynamic range from100 aM to 0.2 µM. In clinical blood sample tests, the proposed bioplatform showed results highly consistent with those of qRT-PCRs and the signal increased proportionally with the NSCLC staging. The proposed biosensor with a portable wireless USB-type analyzer is promising for the fast, easy, low-cost, and highly sensitive detection of various nucleic acids and their mutation derivatives, making it ideal for POC biosensing.

Anti-Spoofing Method for Improving GNSS Security by Jointly Monitoring Pseudo-Range Difference and Pseudo-Range Sum Sequence Linearity.

Spoofing interference is one of the most emerging threats to the Global Navigation Satellite System (GNSS); therefore, the research on anti-spoofing technology is of great significance to improving the security of GNSS. For single spoofing source interference, all the spoofing signals are broadcast from the same antenna. When the receiver is in motion, the pseudo-range of spoofing signals changes nonlinearly, while the difference between any two pseudo-ranges changes linearly. Authentic signals do not have this characteristic. On this basis, an anti-spoofing method is proposed by jointly monitoring the linearity of the pseudo-range difference (PRD) sequence and pseudo-range sum (PRS) sequence, which transforms the spoofing detection problem into the sequence linearity detection problem. In this paper, the model of PRD and PRS is derived, the hypothesis based on the linearity of PRD sequence and PRS sequence is given, and the detection performance of the method is evaluated. This method uses the sum of squares of errors (SSE) of linear fitting of the PRD sequence and PRS sequence to construct detection statistics, and has low computational complexity. Simulation results show that this method can effectively detect spoofing interference and distinguish spoofing signals from authentic signals.

PPARG: A Novel Target for Yellow Tea in Kidney Stone Prevention.

Kidney stones are a common urological disorder with increasing prevalence worldwide. The treatment of kidney stones mainly relies on surgical procedures or extracorporeal shock wave lithotripsy, which can effectively remove the stones but also result in some complications and recurrence. Therefore, finding a drug or natural compound that can prevent and treat kidney stones is an important research topic. In this study, we aimed to investigate the effects of yellow tea on kidney stone formation and its mechanisms of action. We induced kidney stones in rats by feeding them an ethylene glycol diet and found that yellow tea infusion reduced crystal deposits, inflammation, oxidative stress, and fibrosis in a dose-dependent manner. Through network pharmacology and quantitative structure-activity relationship modeling, we analyzed the interaction network between the compounds in yellow tea and kidney stone-related targets and verified it through in vitro and in vivo experiments. Our results showed that flavonoids in yellow tea could bind directly or indirectly to peroxisome proliferator-activated receptor gamma (PPARG) protein and affect kidney stone formation by regulating PPARG transcription factor activity. In conclusion, yellow tea may act as a potential PPARG agonist for the prevention and treatment of renal oxidative damage and fibrosis caused by kidney stones.

Highly Reactive Thermite Energetic Materials: Preparation, Characterization, and Applications: A Review.

As a promising kind of functional material, highly reactive thermite energetic materials (tEMs) with outstanding reactive activation can release heat quickly at a high reaction rate after low-energy stimulation, which is widely used in sensors, triggers, mining, propellants, demolition, ordnance or weapons, and space technology. Thus, this review aims to provide a holistic view of the recent progress in the development of multifunctional highly reactive tEMs with controllable micro/nano-structures for various engineering applications via different fabricated techniques, including the mechanical mixing method, vapor deposition method, assembly method, sol-gel method, electrospinning method, and so on. The systematic classification of novel structured tEMs in terms of nano-structural superiority and exothermic performance are clarified, based on which, suggestions regarding possible future research directions are proposed. Their potential applications within these rapidly expanding areas are further highlighted. Notably, the prospects or challenges of current works, as well as possible innovative research ideas, are discussed in detail, providing further valuable guidelines for future study.

Protein 4.1R negatively regulates P815 cells proliferation by inhibiting C-Kit-mediated signal transduction.

The proliferation of mast cells (MCs) plays a crucial role in either physiological or pathological progression of human physical. C-Kit-mediated signaling pathway has been confirmed to play a key role in MCs proliferation, and the regulatory mechanisms of C-Kit-mediated MCs proliferation need to be further explored. Our previous study found that protein 4.1R could negatively regulate T cell receptor (TCR) mediated signal pathways in CD4+ T cells. Little is known about the function of 4.1R in C-Kit-mediated proliferation of MCs. In this study, P815-4.1R-/- cells were constructed by using CRISPR/Cas9 technique. Lack of 4.1R significantly enhanced P815 cells proliferation by accelerating the progression of cell cycle. 4.1R could also significantly alleviate the clinical symptoms of systemic mastocytosis (SM) and improve the overall survival of SM mice. Further study showed that 4.1R could interact directly with C-Kit to inhibit the activation of C-Kit-mediated Ras-Raf-MAPKs and PI3K-AKT signal pathways. Taken together, our findings demonstrate that protein 4.1R, a novel negative regulator, negatively regulates MCs proliferation by inhibiting C-Kit-mediated signal transduction, which maybe provide a potential target to the prevention and treatment of abnormal MCs proliferation-related diseases.

Cytoskeleton protein 4.1R regulates B-cell fate by modulating the canonical NF-κB pathway.

During the immune response, B cells can enter the memory pathway, which is characterized by class switch recombination (CSR), or they may undergo plasma cell differentiation (PCD) to secrete immunoglobulin. Both of these processes occur in activated B cells, which are reported to relate to membrane-association proteins and adaptors. Protein 4.1R acts as an adaptor, linking membrane proteins to the cytoskeleton, and is involved in many cell events such as cell activation and differentiation, and cytokine secretion. However, the effect of 4.1R on regulating B-cell fate is unclear. Here, we show an important association between B-cell fate and 4.1R. In vitro, primary B cells were stimulated with lipopolysaccharide combined with interleukin-4; results showed that 4.1R-deficient (4.1R-/- ) cells compared with wild-type (4.1R+/+ ) B cells augmented expression of activation-induced cytidine deaminase and germline, resulting in increased IgG1+ B cells, whereas the secretion of IgG1 and IgM was reduced, and CD138+ B cells were also decreased. Throughout the process, 4.1R regulated canonical nuclear factor (NF-κB) rather than non-canonical NF-κB to promote the expression of CSR complex components, leading to up-regulation of B-cell CSR. In contrast, 4.1R-deficient B cells showed reduced expression of Blimp-1, which caused B cells to down-regulate PCD. Furthermore, over-activation of canonical NF-κB may induce apoptosis signaling to cause PCD apoptosis to reduce PCD number. In summary, our results suggest that 4.1R acts as a B-cell fate regulator by inhibiting the canonical NF-κB signaling pathway.

Abnormal expression and prognostic significance of EPB41L1 in kidney renal clear cell carcinoma based on data mining.

BACKGROUND: EPB41L1 gene (erythrocyte membrane protein band 4.1 like 1) encodes the protein 4.1N, a member of 4.1 family, playing a vital role in cell adhesion and migration, which is associated with the malignant progression of various human cancers. However, the expression and prognostic significance of EPB41L1 in kidney renal clear cell carcinoma (KIRC) remain to be investigated. METHODS: In this study, we collected the mRNA expression of EPB41L1 in KIRC through the Oncomine platform, and used the HPA database to perform the pathological tissue immunohistochemistry in patients. Then, the sub-groups and prognosis of KIRC were performed by UALCAN and GEPIA web-tool, respectively. Further, the mutation of EPB41L1 in KIRC was analyzed by c-Bioportal. The co-expression genes of EPB41L1 in KIRC were displayed from the LinkedOmics database, and function enrichment analysis was used by LinkFinder module in LinkedOmics. The function of EPB41L1 in cell adhesion and migration was confirmed by wound healing assay using 786-O cells in vitro. Co-expression gene network was constructed through the STRING database, and the MCODE plug-in of which was used to build the gene modules, both of them was visualized by Cytoscape software. Finally, the top modular genes in the same patient cohort were constructed through data mining in TCGA by using the UCSC Xena browser. RESULTS: The results indicated that EPB41L1 was down-expressed in KIRC, leading to a poor prognosis. Moreover, there is a mutation in the FERM domain of EPB41L1, but it has no significant effect on the prognosis of KIRC. The co-expressed genes of EPB41L1 were associated with cell adhesion and confirmed in vitro. Further analysis suggested that EPB41L1 and amyloid beta precursor protein (APP) were coordinated to regulated cancer cell adhesion, thereby increasing the incidence of cancer cell metastasis and tumor invasion. CONCLUSIONS: In summary, EPB41L1 is constantly down-expressed in KIRC tissues, resulting a poor prognosis. Therefore, we suggest that it can be an effective biomarker for the diagnosis of KIRC.

Controllably facile design of electrophoretic-induced film-forming of nano tungsten oxide (VI) and their anti-wetting functionalization.

There is keen interest for designing promising tungsten oxide (VI, WO3) films or coatings due to their wide applications in fields of energy, engineering, etc. Thus, this paper firstly introduce a novel convenient method of electrophoretic assembly technique (EAT) in an optimal stable suspension of isopropyl alcohol, PEG-1000 and polyethyleneimine for designing the promising anti-wetting functional WO3 (VI) films with relative rough structures and uniform distribution in mild conditions. The product possess a high crystallinity and pureness by x-ray powder diffraction analysis. The EAT dynamic behaviours of WO3 (VI) nanoparticles are investigated in detail. Moreover, obtained films shows excellent anti-wetting properties after suface modification, and the hydrophobic studies results demonstrate that product have a high static water CA of approximate 169° and keep nearly stable even after ultralong exposure time (360 d), and show outstanding properties of anti-soaking, impacting-proof, and moisture resistance even in high relative humidity (90%). These breakthroughs will substantially push forward the convenient processing of other anti-wetting functional coatings with wide potential applications.

Cytoskeleton protein 4.1R suppresses murine keratinocyte cell hyperproliferation via activating the Akt/ERK pathway in an EGFR-dependent manner.

The correct functioning of epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, is required for normal skin development and homeostasis. Cellular hyperproliferation induced by dysregulation of EGFR is tightly associated with structural and functional defects of hair follicles, skin lesions, and tumorigenesis. However, a number of questions still remain regarding the mechanism of EGFR activation and signaling. Here, we report that 4.1R, a member of the membrane-cytoskeleton linker FERM family proteins, plays critical roles in EGFR activation and signaling in keratinocytes. We demonstrated that knockout of 4.1R augments the excessive proliferation potential of keratinocytes by immunohistochemical analysis using murine skin samples. 4.1R-/- keratinocytes display enhanced EGFR-mediated Akt/ERK signaling by upregulating EGFR expression and phosphorylation, which can be reversed by either EGFR or MEK phosphorylation inhibitors. Mechanistically, coimmunoprecipitation and immunofluorescent staining results confirmed that 4.1R can impair the activation of EGFR through direct binding to EGFR and reduce the downstream signaling. Taken together, a deficiency of 4.1R would therefore serve to sustain aberrant EGFR-mediated cellular signaling, leading to hyperproliferation. Our findings highlight the role of 4.1R in the regulation of EGFR signaling in keratinocytes and suggest that 4.1R acts as a novel regulator for EGFR activation.

HP-NAP ameliorates OXA-induced atopic dermatitis symptoms in mice.

BACKGROUND: Atopic dermatitis (AD) is a chronic skin inflammatory disease characterized by disequilibrium between Th1/Th2 lymphocytes. Helicobacter pylori neutrophil-activating protein (HP-NAP) has been reported that it has the potential immunomodulatory effect able to regulate the Th1/Th2 balance. OBJECTIVE: This study aimed to investigate the therapeutic effect of HP-NAP in AD mice model. METHODS: The model of AD was built with oxazolone (OXA) in BALB/c mice, then HP-NAP was used to treat AD by intraperitoneal injection. Ear thickness was measured by a digital thickness gauge. The ears tissues were collected and subjected to hematoxylin-eosin (H&E) and toluidine blue (TB) staining. The mRNA expression levels of inflammatory cytokines (IL-1ß, IL-5, IL-6, and TNF-α) in ear tissue were measured using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The secretion of IgE, IL-4, and IFN-γ was measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Treatment with HP-NAP successfully alleviated the symptoms of AD, such as erythema, horny substance, and swelling. The infiltration of lymphocytes and mast cells were significantly reduced following HP-NAP therapy. The secretion of IgE and IL-4 was significantly attenuated following treatment with HP-NAP. Additionally, HP-NAP observably downregulated inflammatory cytokine expression (e.g. IL-1ß, IL-5, IL-6, and TNF-α) in ear tissues. CONCLUSIONS AND CLINICAL RELEVANCE: Taken together, our results showed that HP-NAP possessed the potential to be a novel immunomodulatory candidate drug against AD.

Engineering the Structure of Mesoporous Bioactive Glass Microspheres by the Surface Effect of Inverse Opal Templates and Temperature.

The interactions of ions and molecules with material surface are highly dependent on the surface properties of the material. Therefore, the distribution of ions or molecules near the material surface may be affected by the surface properties. This phenomenon can be significant enough for controlling the structure of a material synthesized in the sub-micrometer scale confinement space of a template. This work confirms that inverse opals are perfect templates for offering confinement space, while their different surface properties can strongly affect ion and block copolymer distribution in the confinement space. This surface effect principle can be used for the controlled synthesis of colloids with complex composition. As an example, four kinds of mesoporous magnetic bioactive glass colloids with ordered mesopores, core-shell structure, open surface pores, or disordered mesopores are prepared by using polystyrene and carbon inverse opal templates. This work reveals that inverse opal templates possess great advantage in controlled synthesizing colloidal structures due to their surface effect on ions and molecules and confinement space.

Protein 4.1B Suppresses Tumor Metastasis by Regulating Epithelial-mesenchymal Transition Progression in Melanoma Cells.

Epithelial-mesenchymal transition (EMT), which involves the dramatic reorganization of the cytoskeleton, is a crucial initiating step in tumor invasion and metastasis. Protein 4.1B is a membrane-cytoskeleton cross-linker that plays an important role in tumor progression and metastasis; however, the functional roles of 4.1B in melanoma remain unclear. In this study, we aimed to investigate the effect and underlying mechanism of 4.1B on melanoma cells. Our results demonstrated that 4.1B expression was downregulated in murine B16 and B16-F10 melanoma cell lines. Ectopic 4.1B expression significantly inhibited the migration of melanoma cells and pulmonary metastasis. We further investigated the possible mechanism underlying the effect of 4.1B on EMT. The results showed that ectopic 4.1B expression altered the expression of representative EMT markers (E-cadherin, vimentin and N-cadherin), and inhibited the expression of three important transcription factors (Slug, Snail, and Twist) related to EMT in melanoma cells. Moreover, the expression of integrin α5, ß3 and matrix metalloproteinase 9 (MMP-9), which is known to regulate cell adhesion, migration and invasion, were suppressed. In conclusion, our data indicate that 4.1B is an important regulator during EMT progression in melanoma cells, which may present a potential target for the prevention and treatment of melanoma.

Recombinant protein rMBP-NAP restricts tumor progression by triggering antitumor immunity in mouse metastatic lung cancer.

Recombinant Helicobacter pylori neutrophil-activating protein fused with maltose-binding protein (rMBP-NAP), a potential TLR2 ligand, was reported to possess immunomodulatory effects on in situ tumors in our previous study. In the present work, we attempt to elucidate the effect of rMBP-NAP at the local immune modulation in B16-F10-induced metastatic lung cancer. Our results demonstrated that growth of B16-F10 melanoma metastases in the lung was significantly arrested after rMBP-NAP treatment, along with marked reduction in metastatic lung nodules and significant increase in survival. The treatment induced both local and systemic immune responses, which were associated with higher influx of CD4+/CD8+ T cells and drove toward Th1-like and cytotoxic immune environment. Moreover, rMBP-NAP also showed significant anti-angiogenic activity by reducing vascularization in lung tumor sections. rMBP-NAP could induce antitumor immunity through activating Th1 cells and producing pro-inflammatory cytokines, which are responsible for the effective cytotoxic immune response against cancer progression. Our findings indicate that rMBP-NAP might be a novel antitumor therapeutic strategy.

Protein 4.1R regulates M1 macrophages polarization via glycolysis, alleviating sepsis-induced liver injury in mice.

Acute liver injury (ALI) is a common clinical disease caused by sepsis, metabolic syndrome, hepatitis virus. Macrophage plays an important role in the development of ALI, which is characterized by polarization and inflammatory regulation. The polarization process of macrophages is related to membrane binding proteins and adaptors. Protein 4.1R acts as an adaptor, linking membrane proteins to the cytoskeleton, and is involved in cell activation and cytokine secretion. However, whether protein 4.1R is involved in regulating macrophage polarization and inflammation-induced liver injury remains unknown. In this study, protein 4.1R is identified with the special effect on macrophage M1 polarization. And it is further demonstrated that protein 4.1R deficiency significantly enhance glycolytic metabolism. Mechanistically, the regulation of protein 4.1R on pyruvate kinase M2 (PKM2) plays a key role in glycolysis metabolism. In addition, we found that protein 4.1R directly interacts with toll-like receptor 4 (TLR4), inhibits the activation of the AKT/HIF-1α signaling pathway. In conclusion, protein 4.1R targets HIF-1α mediated glycolysis regulates M1 macrophage polarization, indicating that protein 4.1R is a candidate for regulating macrophage mediated inflammatory response. In conclusion, we have revealed a novel function of protein 4.1R in macrophage polarization and ALI, providing important insights into the metabolic reprogramming, which is important for ALI therapy. We have revealed a novel function of protein 4.1R in macrophage polarization and ALI, providing important insights into the metabolic reprogramming, which is important for ALI therapy.

Regulatory effects of IRF4 on immune cells in the tumor microenvironment.

The tumor microenvironment (TME) is implicated in tumorigenesis, chemoresistance, immunotherapy failure and tumor recurrence. Multiple immunosuppressive cells and soluble secreted cytokines together drive and accelerate TME disorders, T cell immunodeficiency and tumor growth. Thus, it is essential to comprehensively understand the TME status, immune cells involved and key transcriptional factors, and extend this knowledge to therapies that target dysfunctional T cells in the TME. Interferon regulatory factor 4 (IRF4) is a unique IRF family member that is not regulated by interferons, instead, is mainly induced upon T-cell receptor signaling, Toll-like receptors and tumor necrosis factor receptors. IRF4 is largely restricted to immune cells and plays critical roles in the differentiation and function of effector cells and immunosuppressive cells, particularly during clonal expansion and the effector function of T cells. However, in a specific biological context, it is also involved in the transcriptional process of T cell exhaustion with its binding partners. Given the multiple effects of IRF4 on immune cells, especially T cells, manipulating IRF4 may be an important therapeutic target for reversing T cell exhaustion and TME disorders, thus promoting anti-tumor immunity. This study reviews the regulatory effects of IRF4 on various immune cells in the TME, and reveals its potential mechanisms, providing a novel direction for clinical immune intervention.

Efficacy and safety of lenalidomide in diffuse large B-cell lymphoma: a meta-analysis of randomized controlled trials.

As an immunomodulatory agent with antitumor activity, lenalidomide has been evaluated for its value in diffuse large B-cell lymphoma (DLBCL). We performed a meta-analysis to gain a better understanding of the efficacy and safety of lenalidomide in DLBCL. PubMed, Cochrane Library, and Embase were searched up to March 2022 for potential studies. The pooled hazard ratio (HR) and relative risk (RR) with 95% confidence interval (CI) were estimated by the fixed/random effects model. Overall, 6 randomized controlled trials including 1938 patients were included. The complete response rate (CRR) of the group containing lenalidomide was 47.7% (95%CI 28.5-67.2%), which was higher than the 37.8% (95%CI 16.7-61.5%) of the control group without lenalidomide (RR = 1.11, 95%CI 1.03-1.20, P = 0.008). The overall estimation of survival showed a benefit for progression-free survival (PFS) (HR = 0.77, 95%CI 0.66-0.90, P = 0.001) but not overall survival (OS) or event-free survival (EFS). The lenalidomide group had a significant incidence of grade ≥ 3 hematological adverse events (AEs) involving neutropenia (RR = 1.56, 95%CI 1.15-2.11, P = 0.004) and febrile neutropenia (RR = 1.81, 95%CI 1.31-2.49, P < 0.001), with the incidence of neutropenia (48.3%, 95%CI 37.5-59.1%) being highest. In conclusion, addition of lenalidomide results in a higher CRR and better PFS but a higher incidence of grade ≥ 3 hematological AEs involving neutropenia and febrile neutropenia.

Integrative single-cell RNA and ATAC sequencing reveals that the FOXO1-PRDX2-TNF axis regulates tendinopathy.

Introduction: Tendinopathy, the most common form of chronic tendon disorder, leads to persistent tendon pain and loss of function. Profiling the heterogeneous cellular composition in the tendon microenvironment helps to elucidate rational molecular mechanisms of tendinopathy. Methods and results: In this study, through a multi-modal analysis, a single-cell RNA- and ATAC-seq integrated tendinopathy landscape was generated for the first time. We found that a specific cell subpopulation with low PRDX2 expression exhibited a higher level of inflammation, lower proliferation and migration ability, which not only promoted tendon injury but also led to microenvironment deterioration. Mechanistically, a motif enrichment analysis of chromatin accessibility showed that FOXO1 was an upstream regulator of PRDX2 transcription, and we confirmed that functional blockade of FOXO1 activity induced PRDX2 silencing. The TNF signaling pathway was significantly activated in the PRDX2-low group, and TNF inhibition effectively restored diseased cell degradation. Discussion: We revealed an essential role of diseased cells in tendinopathy and proposed the FOXO1-PRDX2-TNF axis is a potential regulatory mechanism for the treatment of tendinopathy.

Potential role of tea drinking in preventing hyperuricaemia in rats: biochemical and molecular evidence.

BACKGROUND: Lifestyle and diet play a significant role in hyperuricaemia. Accumulating evidence indicates that tea consumption is associated with hyperuricaemia and gout. However, diverse compounds in different types of tea make it quite difficult to determine the relevant molecular mechanism. Here, we compared the effects of six types of tea on hyperuricaemia induced by potassium oxonate (PO) and hypoxanthine in rats and investigated the possible underlying mechanisms. METHODS: Rats were randomly assigned to ten groups: the control, hyperuricaemia model, benzbromarone positive control, traditional Chinese medicine Simiao San positive control, green tea, yellow tea, black tea, white tea, red tea, and cyan tea treatment groups. After 21 days, uric acid (UA), xanthine oxidase (XOD), alanine aminotransferase (ALT),blood urea nitrogen (BUN), and creatinine (CRE) were assessed. Serum levels of interleukin-1ß (IL-1ß) were measured with an enzyme-linked immunosorbent assay. Haematoxylin-eosin staining and immunohistochemistry were used to assess liver and kidney injury. RESULTS: The levels of UA, CRE, and BUN in the treatment group were decreased to varying degrees. There was a significant reduction in UA, CRE, and BUN levels for yellow tea compared to the positive control drugs. Yellow tea suppressed XOD activity and alleviated hepatic and kidney injury. Network pharmacology and untargeted metabolomics indicated that ten yellow tea bioactive ingredients and 35 targets were responsible for preventing hyperuricaemia, which was mediated by 94 signalling pathways, including IL-1ß and TNF. CONCLUSION: These findings indicate that green tea cannot reduce the serum uric acid level of hyperuricaemic rats. Yellow tea can significantly improve hyperuricaemia by regulating the inflammatory response, autophagy, and apoptosis. This study provides a potential candidate for the treatment of hyperuricaemia and a basis for selecting therapeutic tea for patients with hyperuricaemia.

Single-Cell Profiling of Tumor Microenvironment Heterogeneity in Osteosarcoma Identifies a Highly Invasive Subcluster for Predicting Prognosis.

Osteosarcoma is the most common malignant bone tumor in adolescents, and metastasis is the key reason for treatment failure and poor prognosis. Once metastasis occurs, the 5-year survival rate is only approximately 20%, and assessing and predicting the risk of osteosarcoma metastasis are still difficult tasks. In this study, cellular communication between tumor cells and nontumor cells was identified through comprehensive analysis of osteosarcoma single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data, illustrating the complex regulatory network in the osteosarcoma microenvironment. In line with the heterogeneity of osteosarcoma, we found subpopulations of osteosarcoma cells that highly expressed COL6A1, COL6A3 and MIF and were closely associated with lung metastasis. Then, BCDEG, a reliable risk regression model that could accurately assess the metastasis risk and prognosis of patients, was established, providing a new strategy for the diagnosis and treatment of osteosarcoma.

Single-cell analysis reveals that Jinwu Gutong capsule attenuates the inflammatory activity of synovial cells in osteoarthritis by inhibiting AKR1C3.

Jinwu Gutong capsule (JGC) is a traditional Chinese medicine formula for the treatment of osteoarthritis (OA). Synovitis is a typical pathological change in OA and promotes disease progression. Elucidating the therapeutic mechanism of JGC is crucial for the precise treatment of OA synovitis. In this study, we demonstrate that JGC effectively inhibits hyperproliferation, attenuates inflammation, and promotes apoptosis of synovial cells. Through scRNA-seq data analysis of OA synovitis, we dissected two distinct cell fates that influence disease progression (one fate led to recovery while the other fate resulted in deterioration), which illustrates the principles of fate determination. By intersecting JGC targets with synovitis hub genes and then mimicking picomolar affinity interactions between bioactive compounds and binding pockets, we found that the quercetin-AKR1C3 pair exhibited the best affinity, indicating that this pair constitutes the most promising molecular mechanism. In vitro experiments confirmed that the expression of AKR1C3 in synovial cells was reduced after JGC addition. Further overexpression of AKR1C3 significantly attenuated the therapeutic efficacy of JGC. Thus, we revealed that JGC effectively treats OA synovitis by inhibiting AKR1C3 expression.