An injectable and antifouling hydrogel prevents the development of abdominal adhesions by inhibiting the CCL2/CCR2 interaction.

Abdominal adhesion, a serious complication of abdominal surgery, often resists mitigation by current drug administration and physical barriers. To address this issue, we developed an injectable, antifouling hydrogel through the free-radical polymerization of methacrylate chondroitin sulfate (CS-GMA) and 2-methacryloyloxyethyl phosphorylcholine (MPC) monomers, dubbed the CGM hydrogel. We systematically analyzed its physicochemical properties, including rheological strength, biocompatibility, and antifouling capabilities. A rat abdominal cecum adhesion model was constructed to assess the effectiveness of CGM hydrogel in preventing postoperative adhesion and recurrent adhesion. In addition, multi-omics analyses identified the relationship between adhesion development and CCL2/CCR2 interaction. Notably, CGM hydrogel can thwart the recruitment and aggregation of fibroblasts and macrophages by inhibiting the CCL2/CCR2 interaction. Moreover, CGM hydrogel significantly dampens the activity of fibrosis-linked cytokines (TGF-ßR1) and recalibrates extracellular matrix deposition-related cytokines (t-PA and PAI-1, Col Ⅰ and MMP-9). Cumulatively, the dual action of CGM hydrogel-as a physical barrier and cytokine regulator-highlights its promising potential in clinical application for abdominal adhesion prevention.

Astragalus polysaccharides driven stretchable nanofibrous membrane wound dressing for joint wound healing.

Joint wound dressings are currently significantly limited in their clinical applications due to their inferior mechanical properties and single therapeutic effect. Therefore, it is imperative to develop a versatile joint wound dressing that integrates adequate stretchability, desirable biocompatibility, and multiple biological effects into one system. We implemented the electrospinning technique in this study to fabricate a novel nanofibrous membrane (NFM) composed of gelatin (GEL) and astragalus polysaccharides (APS), termed GEL/APS NFM. The selection of GEL and APS confers excellent biocompatibility to GEL/APS NFM. Furthermore, the optimally proportioned GEL/APS NFM exhibits satisfactory stretchability and desirable wound healing efficiency. Furthermore, released APS can exert anti-inflammatory, procollagen deposition, and proangiogenic effects to accelerate epithelial tissue, enhancing joint wound healing. In summary, GEL/APS NFM offers a convenient and effective approach to promoting rapid joint wound healing, providing a novel approach to joint wound care.

A wound-friendly antibacterial hyaluronic acid dressing with on-demand removability for infected wound healing.

BACKGROUND: Antibacterial activity and on-demand removability are key characteristics governing the effectiveness of clinic wound dressing. However, the excellent tissue adhesion of new dressings is often overemphasized without a detailed discussion of dressing replacement. Besides, the inherent antibacterial ability of dressings is beneficial for promoting the healing of infected wound. Therefore, we rationally design an injectable antibacterial wound dressing with on-demand removability to accelerate infected wound healing. METHOD: We design this wound dressing with a simple and feasible method based on the electrostatic self-assembly of hyaluronic acid and ε-polylysine. We investigated the efficacy of this dressing in terms of its microtopography, rheology, self-healing performance, adhesive ability, antimicrobial, hemostatic, on-demand removal properties, and wound healing promotion through various tests. RESULTS: The prepared dressing possesses injectability, self-healing ability and antibacterial activity, showing NaCl-triggered on-demand dissolution due to the disruption of electrostatic interactions. When used as dressings for healing full-thickness wounds, it could effectively accelerate wound healing by killing bacteria, downregulating inflammation, promoting collagen deposition, enhancing keratinocyte migration and angiogenesis due to its excellent adhesion ability, favorable hemostatic property, and potent antibacterial performance. CONCLUSION: All results indicate that this is a simple and practical dressing for clinical application. This strategy provides a novel idea for developing on-demand removal dressings with antibacterial and injectable properties.

Hyaluronic acid-modified curcumin-copper complex nano delivery system for rapid healing of bacterial prostatitis.

Bacterial prostatitis is a bacterial infection of the prostate gland presenting with lower quadrant abdominal pain, urination disorders and poor fertility. In recent years, reports have emerged on the significantly reduced efficacy of fluoroquinolone drugs attributed to multiple drug-resistant bacteria, emphasizing the need for new drugs. In this study, we designed a targeting drug delivery system via curcumin copper complex grafted with hyaluronic acid. Subsequently, the prepared system was characterized using FT-IR, XRD, SEM, XPS and 1H NMR methods. In addition to the substantial improvement in the solubility of the carrier, its antibacterial performance and targeting ability were improved. Interestingly, the grafting of hyaluronic acid endowed the carrier with excellent CD44 receptor targeting function and good water solubility, and the complexation of copper ions greatly enhanced its antibacterial capability, especially the inhibitory effect on E. coli. The anti-prostatitis effect of the drug was evaluated comprehensively by establishing a bacterial prostatitis model infected by E. coli. Assessment of the anti-prostatitis effects in vivo indicated that the Cur-Cu@HA delivery system could effectively promote recovery from bacterial prostatitis by downregulating inflammation. In conclusion, our Cur-Cu@HA delivery system has great potential for treating bacterial prostatitis.

Identifying tumour microenvironment-related signature that correlates with prognosis and immunotherapy response in breast cancer.

Tumor microenvironment (TME) plays important roles in prognosis and immune evasion. However, the relationship between TME-related genes and clinical prognosis, immune cell infiltration, and immunotherapy response in breast cancer (BRCA) remains unclear. This study described the TME pattern to construct a TME-related prognosis signature, including risk factors PXDNL, LINC02038 and protective factors SLC27A2, KLRB1, IGHV1-12 and IGKV1OR2-108, as an independent prognostic factor for BRCA. We found that the prognosis signature was negatively correlated with the survival time of BRCA patients, infiltration of immune cells and the expression of immune checkpoints, while positively correlated with tumor mutation burden and adverse treatment effects of immunotherapy. Upregulation of PXDNL and LINC02038 and downregulation of SLC27A2, KLRB1, IGHV1-12 and IGKV1OR2-108 in high-risk score group synergistically contribute to immunosuppressive microenvironment which characterized by immunosuppressive neutrophils, impaired cytotoxic T lymphocytes migration and natural killer cell cytotoxicity. In summary, we identified a TME-related prognostic signature in BRCA, which was connected with immune cell infiltration, immune checkpoints, immunotherapy response and could be developed for immunotherapy targets.

Hyaluronic acid/serotonin-decorated cerium dioxide nanomedicine for targeted treatment of ulcerative colitis.

Ulcerative colitis (UC) is a chronic nonspecific inflammatory bowel disease often characterized by rapid progression and frequent comorbidities that make its treatment challenging. In colonic ulcers of UC patients, myeloperoxidase (MPO) is highly expressed, which results in an abundance of macrophages and reactive oxygen species. This study developed an active MPO-targeting hyaluronic acid/serotonin ceria nanoenzyme (HA-5-HT@CeO2) using the electrostatic interaction between CeO2 nanoparticles, 5-hydroxyserotonin-cerium oxide and hyaluronic acid. Based on the dual targeting effects of MPO and the macrophage CD44+ receptor in locating the inflammatory site in conjunction with the inflammatory area of the colon through electrostatic action, CeO2 nanoparticles along with multiple similar enzymes were used to eliminate O2, H2O2 and ˙OH and other reactive oxygen species, achieving targeted repair of the intestinal epithelial barrier through the elimination of inflammatory factors. In studies involving pharmacodynamics in vitro and DSS-induced animal models of acute colitis in vivo, HA-5-HT@CeO2 has been shown to reduce inflammation further and treat ulcerative colitis compared to traditional drugs. Additionally, active targeting of MPO inflammation can lead to accurate drug delivery to the site and can minimize the side effects associated with the drug. HA-5-HT@CeO2 is a promising novel drug for the treatment of ulcerative colitis. In addition to illustrating the benefits of this novel nanodrug delivery in treating ulcerative colitis compared to traditional medications, this study provides theoretical and experimental support for its application to any targeted therapy for ulcerative colitis.

LncTarD 2.0: an updated comprehensive database for experimentally-supported functional lncRNA-target regulations in human diseases.

An updated LncTarD 2.0 database provides a comprehensive resource on key lncRNA-target regulations, their influenced functions and lncRNA-mediated regulatory mechanisms in human diseases. LncTarD 2.0 is freely available at (http://bio-bigdata.hrbmu.edu.cn/LncTarD or https://lnctard.bio-database.com/). LncTarD 2.0 was updated with several new features, including (i) an increased number of disease-associated lncRNA entries, where the current release provides 8360 key lncRNA-target regulations, with 419 disease subtypes and 1355 lncRNAs; (ii) predicted 3312 out of 8360 lncRNA-target regulations as potential diagnostic or therapeutic biomarkers in circulating tumor cells (CTCs); (iii) addition of 536 new, experimentally supported lncRNA-target regulations that modulate properties of cancer stem cells; (iv) addition of an experimentally supported clinical application section of 2894 lncRNA-target regulations for potential clinical application. Importantly, LncTarD 2.0 provides RNA-seq/microarray and single-cell web tools for customizable analysis and visualization of lncRNA-target regulations in diseases. RNA-seq/microarray web tool was used to mining lncRNA-target regulations in both disease tissue samples and CTCs blood samples. The single-cell web tools provide single-cell lncRNA-target annotation from the perspectives of pan-cancer analysis and cancer-specific analysis at the single-cell level. LncTarD 2.0 will be a useful resource and mining tool for the investigation of the functions and mechanisms of lncRNA deregulation in human disease.

The dynamic dysregulated network identifies stage-specific markers during lung adenocarcinoma malignant progression and metastasis.

Brain metastasis occurs in approximately 30% of patients with lung adenocarcinoma (LUAD) and is closely associated with poor prognosis, recurrence, and death. However, dynamic gene regulation and molecular mechanism driving LUAD progression remain poorly understood. In this study, we performed a comprehensive single-cell transcriptome analysis using data from normal, early stage, advanced stage, and brain metastasis LUAD. Our single-cell-level analysis reveals the cellular composition heterogeneity at different stages during LUAD progression. We identified stage-specific risk genes that could contribute to LUAD progression and metastasis by reprogramming immune-related and metabolic-related functions. We constructed an early advanced metastatic dysregulated network and revealed the dynamic changes in gene regulations during LUAD progression. We identified 6 early advanced (HLA-DRB1, HLA-DQB1, SFTPB, SFTPC, PLA2G1B, and FOLR1), 8 advanced metastasis (RPS15, RPS11, RPL13A, RPS24, HLA-DRB5, LYPLA1, KCNJ15, and PSMA3), and 2 common risk genes in different stages (SFTPD and HLA-DRA) as prognostic markers in LUAD. Particularly, decreased expression of HLA-DRA, HLA-DRB1, HLA-DQB1, and HLA-DRB5 refer poor prognosis in LUAD by controlling antigen processing and presentation and T cell activation. Increased expression of PSMA3 and LYPLA1 refer poor prognosis by reprogramming fatty acid metabolism and RNA catabolic process. Our findings will help further understanding the pathobiology of brain metastases in LUAD.

Identifying enhancer-driven subtype-specific prognostic markers in breast cancer based on multi-omics data.

Breast cancer is a cancer of high complexity and heterogeneity, with differences in prognosis and survival among patients of different subtypes. Copy number variations (CNVs) within enhancers are crucial drivers of tumorigenesis by influencing expression of their targets. In this study, we performed an integrative approach to identify CNA-driven enhancers and their effect on expression of target genes in four breast cancer subtypes by integrating expression data, copy number data and H3K27ac data. We identified 672, 555, 531, 361 CNA-driven enhancer-gene pairs and 280, 189, 113 and 98 CNA-driven enhancer-lncRNA pairs in the Basal-like, Her2, LumA and LumB subtypes, respectively. We then reconstructed a CNV-driven enhancer-lncRNA-mRNA regulatory network in each subtype. Functional analysis showed CNA-driven enhancers play an important role in the progression of breast cancer subtypes by influencing P53 signaling pathway, PPAR signaling pathway, systemic lupus erythematosus and MAPK signaling pathway in the Basal-like, Her2, LumA and LumB subtypes, respectively. We characterized the potentially prognostic value of target genes of CNV-driven enhancer and lncRNA-mRNA pairs in the subtype-specific network. We identified MUM1 and AC016876.1 as prognostic biomarkers in LumA and Basal-like subtypes, respectively. Higher expression of MUM1 with an amplified enhancer exhibited poorer prognosis in LumA patients. Lower expression of AC016876.1 with a deleted enhancer exhibited poorer survival outcomes of Basal-like patients. We also identified enhancer-related lncRNA-mRNA pairs as prognostic biomarkers, including AC012313.2-MUM1 in the LumA, AC026471.4-PLK5 in the LumB, AC027307.2-OAZ1 in the Basal-like and AC022431.1-HCN2 in the Her2 subtypes. Finally, our results highlighted target genes of CNA-driven enhancers and enhancer-related lncRNA-mRNA pairs could act as prognostic markers and potential therapeutic targets in breast cancer subtypes.

Apigenin-Mn(II) loaded hyaluronic acid nanoparticles for ulcerative colitis therapy in mice.

Ulcerative colitis (UC) is a chronic idiopathic inflammatory bowel disease characterized by rapid progression and frequent comorbidities that make its treatment challenging. Nanomaterial-based strategies have been extensively studied to target the GI mucosal immune system in recent years. Herein, we propose a novel apigenin-Mn(II) loaded sodium hyaluronate nanoparticles where apigenin (API) was incorporated in the Mn2+ ramework, coated with hyaluronic acid. The apigenin-Mn(II) loaded sodium hyaluronate nanoparticles (API-Mn(II)@HA NPs) exhibited a diameter of 200 nm and were effective against UC. The preparation of the API-Mn(II) complex was relatively simple, and the mechanism underlying its therapeutic effect on UC induced by sodium dextran sulfate (DSS) was studied in detail. We found that API-Mn(II)@HA nanoparticles could effectively repair the intestinal barrier and significantly improve the damaged colon tissue by mediating inflammatory factors. This study provides novel insights on a new kind of active targeted nanoparticle for improving the efficacy of drugs for UC treatment.

Glucose trajectory prediction by deep learning for personal home care of type 2 diabetes mellitus: modelling and applying.

Glucose management for people with type 2 diabetes mellitus is essential but challenging due to the multi-factored and chronic disease nature of diabetes. To control glucose levels in a safe range and lessen abnormal glucose variability efficiently and economically, an intelligent prediction of glucose is demanding. A glucose trajectory prediction system based on subcutaneous interstitial continuous glucose monitoring data and deep learning models for ensuing glucose trajectory was constructed, followed by the application of personalised prediction models on one participant with type 2 diabetes in a community. The predictive accuracy was then assessed by RMSE (root mean square error) using blood glucose data. Changes in glycaemic parameters of the participant before and after model intervention were also compared to examine the efficacy of this intelligence-aided health care. Individual Recurrent Neural Network model was developed on glucose data, with an average daily RMSE of 1.59 mmol/L in the application segment. In terms of the glucose variation, the mean glucose decreased by 0.66 mmol/L, and HBGI dropped from 12.99 × 102 to 9.17 × 102. However, the participant also had increased stress, especially in eating and social support. Our research presented a personalised care system for people with diabetes based on deep learning. The intelligence-aided health management system is promising to enhance the outcome of diabetic patients, but further research is also necessary to decrease stress in the intelligence-aided health management and investigate the stress impacts on diabetic patients.

Comprehensive characterization of clonality of driver genes revealing their clinical relevance in colorectal cancer.

BACKGROUND: Genomic studies of colorectal cancer have revealed the complex genomic heterogeneity of the tumor. The acquisition and selection of genomic alterations may be critical to understanding the initiation and progression of this disease. METHODS: In this study, we have systematically characterized the clonal architecture of 97 driver genes in 536 colorectal cancer patients from TCGA. RESULTS: A high proportion of clonal mutations in 93 driver genes were observed. 40 genes showed significant associations between their clonality and multiple clinicopathologic factors. Kaplan-Meier analysis suggested that the mutation clonality of ANK1, CASP8, SMAD2, and ARID1A had a significant impact on the CRC patients' outcomes. Multivariable analysis revealed that subclonal ANK1 mutations, clonal CASP8 mutations, and clonal SMAD2 mutations independently predicted for shorter overall survival after adjusting for clinicopathological factors. The poor outcome of the subclonal ANK1 mutation may be caused by upregulation of IL4I1, IDO1, IFNG and MAPK12 which showed potential roles in tumor immune evasion through accumulation of immunosuppressive cells such as regulatory T cells and myeloid derived suppressor cells. CONCLUSION: These results suggested that the clonality of driver genes could act as prognostic markers and potential therapeutic targets in human colorectal cancer.

Bottlebrush inspired injectable hydrogel for rapid prevention of postoperative and recurrent adhesion.

Postsurgical adhesion is a common clinic disease induced by surgical trauma, accompanying serious subsequent complications. Current non-surgical approaches of drugs treatment and biomaterial barrier administration only show limited prevention effects and couldn't effectively promote peritoneum repair. Herein, inspired by bottlebrush, a novel self-fused, antifouling, and injectable hydrogel is fabricated by the free-radical polymerization in aqueous solution between the methacrylate hyaluronic acid (HA-GMA) and N-(2-hydroxypropyl) methacrylamide (HPMA) monomer without any chemical crosslinkers, termed as H-HPMA hydrogel. The H-HPMA hydrogel can be tuned to perform excellent self-fused properties and suitable abdominal metabolism time. Intriguingly, the introduction of the ultra-hydrophilic HPMA chains to the H-HPMA hydrogel affords an unprecedented antifouling capability. The HPMA chains establish a dense hydrated layer that rapidly prevents the postsurgical adhesions and recurrent adhesions after adhesiolysis in vivo. The H-HPMA hydrogel can repair the peritoneal wound of the rat model within 5 days. Furthermore, an underlying mechanism study reveals that the H-HPMA hydrogel significantly regulated the mesothelial-to-mesenchymal transition (MMT) process dominated by the TGF-ß-Smad2/3 signal pathway. Thus, we developed a simple, effective, and available approach to rapidly promote peritoneum regeneration and prevent peritoneal adhesion and adhesion recurrence after adhesiolysis, offering novel design ideas for developing biomaterials to prevent peritoneal adhesion.