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Glycosylation plays critical roles in various biological processes and is closely related to diseases. Deciphering the glycocode in diverse cells and tissues offers opportunities to develop new disease biomarkers and more effective recombinant therapeutics. In the past few decades, with the development of glycobiology, glycomics, and glycoproteomics technologies, a large amount of glycoscience data has been generated. Subsequently, a number of glycobiology databases covering glycan structure, the glycosylation sites, the protein scaffolds, and related glycogenes have been developed to store, analyze, and integrate these data. However, these databases and tools are not well known or widely used by the public, including clinicians and other researchers who are not in the field of glycobiology, but are interested in glycoproteins. In this study, the representative databases of glycan structure, glycoprotein, glycan–protein interactions, glycogenes, and the newly developed bioinformatic tools and integrated portal for glycoproteomics are reviewed. We hope this overview could assist readers in searching for information on glycoproteins of interest, and promote further clinical application of glycobiology.

Background Preclinical studies have suggested that adipose-derived mesenchymal stem cells (ADSCs) transplantation can suppress abdominal aortic inflammation and aneurysm expansion through paracrine factors. Yet, the mechanism of action is not fully understood. In the present study, we further examined the function and mechanism of ADSC-derived exosomes (ADSC-exos) and their microRNA-17-5p (miR-17-5p) on the abdominal aortic aneurysm (AAA) progression. Methods ADSC-exos were isolated and identified. DiR and PKH67 staining were used to trace ADSC-exo in vivo and in vitro. Raw264.7 cells were applied to perform in vitro experiments, while a murine AAA model induced using angiotensin II (Ang II) was used for in vivo testing. The expression level of miR-17-5p in macrophages and Ang II-treated macrophages after ADSC-exos treatment was determined using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The target relation between miR-17-5p and thioredoxin-interacting protein (TXNIP) was identified by a dual-luciferase reporter gene assay. Artificial activation and block of experiments of miR-17-5p and TXNIP were conducted to clarify their functions in inflammation during AAA progression. The severity of AAA between groups was assessed by maximal aorta diameter, AAA incidence, survival rate, and histological stainings. Besides, inflammasome-related proteins and macrophage pyroptosis were further evaluated using western blot, RT-qPCR, and enzyme-linked immunosorbent assay (ELISA). Results The ADSC-exos were isolated and identified. In vivo testing showed that ADSC-exos were mainly distributed in the liver. Meanwhile, in vitro experiments suggested that ADSC-derived exosomes were taken up by macrophages, while inside, ADSC-exos miR-17-5p decreased a TXNIP induced by Ang II by directly binding to its 3′-untranslated region (3’UTR). Furthermore, overexpression of miR-17-5p enhanced the therapeutic function of ADSC-exos on inflammation during AAA expansion in vivo, while its inhibition reversed this process. Finally, overexpressed TXNIP triggered macrophage pyroptosis and was alleviated by ADSC-derived exosomes in vitro. Conclusion ADSC-exos miR-17-5p regulated AAA progression and inflammation via the TXNIP-NLRP3 signaling pathway, thus providing a novel insight in AAA treatment.

Background Diabetic limb ischemia is a clinical syndrome and refractory to therapy. Our previous study demonstrated that adipose-derived stem cells (ADSCs) overexpressing glyoxalase-1 (GLO-1) promoted the regeneration of ischemic lower limbs in diabetic mice, but low survival rate, difficulty in differentiation, and tumorigenicity of the transplanted cells restricted its application. Recent studies have found that exosomes secreted by the ADSCs have the advantages of containing parental beneficial factors and exhibiting non-immunogenic, non-tumorigenic, and strong stable characteristics. Methods ADSCs overexpressing GLO-1 (G-ADSCs) were established using lentivirus transfection, and exosomes secreted from ADSCs (G-ADSC-Exos) were isolated and characterized to coculture with human umbilical vein endothelial cells (HUVECs). Proliferation, apoptosis, migration, and tube formation of the HUVECs were detected under high-glucose conditions. The G-ADSC-Exos were injected into ischemic hindlimb muscles of type 2 diabetes mellitus (T2DM) mice, and the laser Doppler perfusion index, Masson’s staining, immunofluorescence, and immunohistochemistry assays were adopted to assess the treatment efficiency. Moreover, the underlying regulatory mechanisms of the G-ADSC-Exos on the proliferation, migration, angiogenesis, and apoptosis of the HUVECs were explored. Results The G-ADSC-Exos enhanced the proliferation, migration, tube formation, and anti-apoptosis of the HUVECs in vitro under high-glucose conditions. After in vivo transplantation, the G-ADSC-Exo group showed significantly higher laser Doppler perfusion index, better muscle structural integrity, and higher microvessel’s density than the ADSC-Exo and control groups by Masson’s staining and immunofluorescence assays. The underlying mechanisms by which the G-ADSC-Exos protected endothelial cells both in vitro and in vivo might be via the activation of eNOS/AKT/ERK/P-38 signaling pathways, inhibition of AP-1/ROS/NLRP3/ASC/Caspase-1/IL-1β, as well as the increased secretion of VEGF, IGF-1, and FGF. Conclusion Exosomes derived from adipose-derived stem cells overexpressing GLO-1 protected the endothelial cells and promoted the angiogenesis in type 2 diabetic mice with limb ischemia, which will be a promising clinical treatment in diabetic lower limb ischemia.

Aims There remains clinical uncertainty concerning the relationship between systemic inflammation and subsequent abdominal aortic aneurysm (AAA) risk. To investigate the association between chronic systematic inflammation markers (C-reactive protein (CRP), peripheral immune cell counts, and their derived ratios) and risk of AAA incidence, and identify potential effect modifiers. Methods We included 271,068 individuals from the UK Biobank, who were free of aortic aneurysm and other conditions impacting their inflammatory states at baseline. Cox proportional-hazards model was used to analyze associations between inflammatory biomarkers and AAA, adjusting for AAA polygenetic risk score (PRS) and major risk factors. Restricted cubic splines were plotted to visualize non-linear relationship. Subgroup analyses by age, sex, hypertension, smoking and PRS were performed to identify any interaction. Results Over a median follow-up of 13·9 years, 629 incident AAAs were recorded. For each 1-SD increase in baseline CRP, lymphocyte, monocyte, and neutrophil counts, the risk of AAA increased by 46%, 17%, 27% and 27%, respectively (all p  < 0·001). The cubic splines showed the CRP-AAA association to be monotonic. The highest tertile of PRS was associated with an 80% increased AAA risk compared with the lowest tertile. The association between CRP and AAA was significant and comparable across PRS tertile groups. Sex and smoking status modified the CRP-AAA association, with the strongest association observed in males and current smokers. Conclusions Our study found a significant association between chronic systemic inflammation and risk of AAA incidence. CRP compliments PRS and other AAA risk factors in better identifying high-risk populations. Lay summary Current indexes for identifying patients to screen for AAA are family history, age, sex and smoking. This study revealed that a healthy public with a high level of CRP and one of the above traditional high-risk factors of AAA (high genetic risk, ≥ 65 years old, male, or current smoker) had a high risk of incident AAA and is recommended to screen for AAA.

Peripheral nerve injury (PNI) affects over 20 million individuals globally each year, with incomplete nerve regeneration presenting a significant socioeconomic burden, particularly in diabetic patients. M2 macrophages play a crucial role in nerve regeneration by promoting tissue remodeling and repair. However, the post-injury microenvironment impedes the stabilization of the M2 phenotype, limiting their therapeutic potential. In vitro experiments demonstrate that macrophages modified with Netrin-1 can be polarized toward the M2 phenotype. Exosomes secreted by these Netrin-1-modified macrophages (N-Exos) significantly enhance endothelial cell proliferation, migration, tube formation, and survival under hyperglycemic conditions. The underlying mechanism is likely mediated by the activation of the PI3K/AKT/mTOR pathway through Unc5b. To further enhance the therapeutic effects of N-Exos, we incorporated these exosomes into a berberine-modified chitosan-based hydrogel (NE@CSB), thereby developing an innovative synergistic therapeutic approach. The NE@CSB hydrogel demonstrates favorable injectability, thermoresponsive sol-gel transition, strong tissue adhesion, and sustained release of exosomes. In the sciatic nerve injury model of diabetic mice, blood flow perfusion and histological analysis of injured nerves demonstrated that NE@CSB hydrogel could effectively enhanced angiogenesis and sciatic nerve regeneration. Overall, NE@CSB presents a promising and safe therapeutic strategy for the clinical treatment of diabetic PNI. Injectable Hydrogel with Engineered Exosomes Repairs Diabetic Peripheral Nerve Injury Peripheral nerve injury (PNI) affects millions annually, with diabetic patients facing additional challenges due to impaired healing. Traditional treatments like nerve autografts have limitations, prompting the need for innovative solutions. This study introduces an injectable, thermoresponsive chitosan-based hydrogel (NE@CSB) for sustained delivery of Netrin-1-enriched exosomes (N-Exos) to enhance nerve regeneration in diabetic PNI. Researchers transfected macrophages with Netrin-1, promoted M2 polarization, and isolated N-Exos, which were encapsulated in the hydrogel. The NE@CSB hydrogel demonstrated excellent injectability, tissue adhesion, and sustained release of N-Exos, significantly improving angiogenesis and nerve regeneration in diabetic mice with sciatic nerve injury. Mechanistically, N-Exos activated the PI3K/AKT/mTOR pathway via the Unc5b receptor to inhibit pyroptosis, reducing inflammation and promoting angiogenesis. This composite hydrogel offers a promising therapeutic strategy for diabetic PNI, with potential for future clinical applications. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author. We developed an injectable thermosensitive chitosan hydrogel (NE@CSB) for sustained release of Netrin-1-overexpressing macrophage-derived exosomes (N-Exos) to promote peripheral nerve regeneration and angiogenesis synchronously. In vitro experiments demonstrated that N-Exos significantly enhanced endothelial cell functions and inhibited pyroptosis via the Unc5b/PI3K/AKT/mTOR pathway. In a diabetic mouse model of peripheral nerve injury, NE@CSB effectively promoted angiogenesis, axonal regeneration, and functional recovery. These findings suggest a promising synergistic strategy for diabetic peripheral nerve repair.

ObjectivesTo conduct a comprehensive analysis of demographic information, medical history, and blood pressure (BP) and heart rate (HR) variability during hospitalisation so as to establish a predictive model for preoperative in-hospital mortality of patients with acute aortic dissection (AD) by using machine learning techniques.DesignRetrospective cohort study.SettingData were collected from the electronic records and the databases of Shanghai Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine and the First Affiliated Hospital of Anhui Medical University between 2004 and 2018.Participants380 inpatients diagnosed with acute AD were included in the study.Primary outcomePreoperative in-hospital mortality rate.ResultsA total of 55 patients (14.47%) died in the hospital before surgery. The results of the areas under the receiver operating characteristic curves, decision curve analysis and calibration curves indicated that the eXtreme Gradient Boosting (XGBoost) model had the highest accuracy and robustness. According to the SHapley Additive exPlanations analysis of the XGBoost model, Stanford type A, maximum aortic diameter >5.5 cm, high variability in HR, high variability in diastolic BP and involvement of the aortic arch had the greatest impact on the occurrence of in-hospital deaths before surgery. Moreover, the predictive model can accurately predict the preoperative in-hospital mortality rate at the individual level.ConclusionIn the current study, we successfully constructed machine learning models to predict the preoperative in-hospital mortality of patients with acute AD, which can help identify high-risk patients and optimise the clinical decision-making. Further applications in clinical practice require the validation of these models using a large-sample, prospective database.Trial registration numberChiCTR1900025818.

Hydrogel nanofibers provide a regeneration-permissive environment conducive to the regrowth of numerous nerve fibers, thereby enhancing regenerative capacity in cases of peripheral nerve injury and spinal cord injury. However, developing hydrogel nanofiber-based nerve guidance conduits (NGCs) with tailored drug release profiles to synergistically promote angiogenesis and axonal regeneration remains a significant challenge. In this study, novel polydopamine (PDA)-modified gelatin methacryloyl (GelMA) hydrogel nanofibers are developed as an efficient drug delivery platform for sustained release of Secreted Frizzled-Related Protein-2 (SFRP2). This platform aims to promote neurite outgrowth, facilitate nerve function recovery, and enhance angiogenesis through Wnt signaling pathways. Results indicate that PDA coating significantly improves the hydrophilicity and mechanical properties of GelMA hydrogel nanofibers, which were fabricated using a combination of electrospinning and photo-crosslinking technology. This modification enables SFRP2 loading for sustained release through π-π stacking interactions and hydrogen bonding. In vitro experiments demonstrate that SFRP2-loaded hydrogel nanofibers effectively enhance the adhesion, proliferation, viability, and migration of Mouse Schwann Cells (MSCs), while also promoting tube formation and ameliorating the inflammatory microenvironment of Human Umbilical Vein Endothelial Cells (HUVECs). Furthermore, the SFRP2-loaded hydrogel nanofibers are confirmed to exert their functions for angiogenesis and peripheral nerve regeneration via the calcium-dependent calcineurin/NFATc3 signaling pathway. Finally, the hydrogel nanofiber-based NGCs are applied in a mouse model of peripheral nerve injury, and results demonstrate that the SFRP2 ~ PDA@GelMA conduit significantly enhances angiogenesis, promotes peripheral nerve repair, and facilitates target muscle restoration and functional recovery, thus presents a promising therapeutic strategy for patients with peripheral nerve injuries. We developed novel polydopamine (PDA)-modified gelatin methacryloyl (GelMA) hydrogel nanofibers for sustained Secreted Frizzled-Related Protein 2 (SFRP2) release to promote peripheral nerve regeneration and angiogenesis synchronously. In vitro experiments demonstrated that these nanofibers significantly enhanced Schwann cell migration and endothelial cell tube formation. In a mouse model of peripheral nerve injury, the SFRP2-loaded nanofibers effectively promoted angiogenesis, nerve repair, and target muscle restoration via the calcineurin/NFATc3 signaling pathway. These findings suggest a promising therapeutic strategy for peripheral nerve injuries.

Abdominal aortic aneurysm (AAA) is a common and potentially life‐threatening condition. Chronic aortic inflammation is closely associated with the pathogenesis of AAA. Nerve injury‐induced protein 1 (NINJ1) is increasingly acknowledged as a significant regulator of the inflammatory process. However, the precise involvement of NINJ1 in AAA formation remains largely unexplored. The present study finds that the expression level of NINJ1 is elevated, along with the specific expression level in macrophages within human and angiotensin II (Ang II)‐induced murine AAA lesions. Furthermore, Ninj1flox/flox and Ninj1flox/floxLyz2‐Cre mice on an ApoE−/− background are generated, and macrophage NINJ1 deficiency inhibits AAA formation and reduces macrophage infiltration in mice infused with Ang II. Consistently, in vitro suppressing the expression level of NINJ1 in macrophages significantly restricts macrophage adhesion and migration, while attenuating macrophage pro‐inflammatory responses. Bulk RNA‐sequencing and pathway analysis uncover that NINJ1 can modulate macrophage infiltration through the TLR4/NF‐κB/CCR2 signaling pathway. Protein‐protein interaction analysis indicates that NINJ1 can activate TLR4 by competitively binding with ANXA2, an inhibitory interacting protein of TLR4. These findings reveal that NINJ1 can modulate AAA formation by promoting macrophage infiltration and pro‐inflammatory responses, highlighting the potential of NINJ1 as a therapeutic target for AAA. NINJ1 is highly expressed in macrophages within human and murine abdominal aortic aneurysm (AAA) lesions, which enhances macrophage infiltration through the TLR4/NF‐κB/CCR2 signaling pathway, thus facilitating AAA formation. NINJ1 activates TLR4 by competitively binding with ANXA2, an inhibitory interacting protein of TLR4. This study highlights the potential of NINJ1 as a therapeutic target for AAA.

Preoperative assessment of tumor invasiveness is essential to avoid overtreatment for patients with small-sized ground-glass nodules (GGNs) of 10 mm or less in diameter. However, it is difficult to determine the pathological state by computed tomography (CT) examination alone. Aberrant glycans has emerged as a tool to identify novel potential disease biomarkers. In this study, we used a lectin microarray-based strategy to investigate whether glycosylation changes in plasma immunoglobulin G (IgG) provide additional information about the invasiveness of small GGNs before surgery. Two independent cohorts (discovery set, n = 92; test set, n = 210) of GGN patients were used. Five of 45 lectins (Sambucus nigra agglutinin, SNA; Datura stramonium agglutinin, DSA; Galanthus nivalis agglutinin, GNA; Euonymus europaeus lectin, EEL; and Vicia villosa agglutinin, VVA) were identified as independent factors associated with pathological invasiveness of small GGNs (p < 0.01). Receiver-operating characteristic (ROC) curve analysis indicated the combination of these five lectins could significantly improve the accuracy of CT in diagnosing invasive GGNs, with an area under the curve (AUC) of 0.792 (p < 0.001), a sensitivity of 74.6%, and specificity of 74.4%, which was superior to current clinical biomarkers. These results suggest that the multilectin assay based on plasma IgG glycosylation may be a useful in vitro complementary test to enhance preoperative determination of the invasiveness of GGNs and guide surgeons to select proper clinical management to avoid overtreatment.

The occurrence of abdominal aortic aneurysms (AAAs) is related to the disorder of immune microenvironment. Cuprotosis was reported to influence the immune microenvironment. The objective of this study is to identify cuprotosis-related genes involved in the pathogenesis and progression of AAA. Differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) in mouse were identified following AAA through high-throughput RNA sequencing. The enrichment analyses of pathway were selected through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG). The validation of cuprotosis-related genes was conducted through immunofluorescence and western blot analyses. Totally, 27616 lncRNAs and 2189 mRNAs were observed to be differentially expressed (|Fold Change| ≥ 2 and q< 0.05) after AAA, including 10424 up-regulated and 17192 down-regulated lncRNAs, 1904 up-regulated and 285 down-regulated mRNAs. Gene ontology and KEGG pathway analysis showed that the DElncRNAs and DEmRNAs were implicated in many different biological processes and pathways. Furthermore, Cuprotosis-related genes (NLRP3, FDX1) were upregulated in the AAA samples compared with the normal one. Cuprotosis-related genes (NLRP3,FDX1) involved in AAA immune environment might be critical for providing new insight into identification of potential targets for AAA therapy.