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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.

Stem cells support homeostasis and injury repair of adult organs. It remains unclear when and how adult stem cells form during development. Here, we discover that incisor mesenchymal stem cells, marked by an extracellular matrix molecule Smoc2 , establish their identity and quiescence between E14.5 and E16.5, and persist into adulthood. They support both embryonic tooth development and postnatal organ turnover. Concurrently, the incisor mesenchyme evolves from a homogenous dental papilla into a heterogeneous dental pulp consisting of a complete lineage hierarchy, which persists into adulthood. Smoc2 and its homologous molecule Smoc1 are indispensable for maintaining the quiescence and hierarchy of mesenchymal stem cells. They function by disrupting the binding between canonical WNT ligands and glypican, a process critical for transporting hydrophobic WNT ligands within the aqueous niche. In conclusion, mesenchymal stem cells establish their quiescence during development through autocrine extracellular matrix molecules to keep canonical WNT ligands from accessing them. This study identifies Smoc2 as a marker of mesenchymal stem cells in mouse incisors and shows that Smoc1/2 establishes stem cell quiescence by inhibiting Wnt signaling during development.

Aiming to evaluate the predictive value of high-resolution computed tomography (HRCT) features for identifying acute/subacute progression in patients with polymyositis/dermatomyositis (PM/DM)-associated interstitial lung disease (ILD), and to develop a risk stratification algorithm based on clinico-radiologic parameters. This retrospective cohort study included 282 patients with PM/DM who underwent HRCT from January 2020 to December 2024. Baseline clinical data and HRCT imaging characteristics were systematically collected. Over time, 140 patients with PM/DM-ILD were followed. HRCT scores and imaging patterns were assessed, and cases of acute/subacute ILD progression were documented during the follow-up period. Penalized Cox regression (LASSO) was conducted to identify independent risk factors associated with disease progression and to develop a risk stratification method. The concordance index (C-index), net reclassification improvement (NRI), integrated discrimination improvement (IDI) and decision curve analysis (DCA) were used to evaluate the discriminative ability of this stratification. Algorithm performance was assessed using calibration plots to evaluate agreement between predicted and observed risks. During a median follow-up duration of 5.69 months (IQR, 1.77-5.91 months), 56 (40.0%) patients experienced acute/subacute ILD progression. The HRCT score was considered an independent predictor of acute/subacute progression in patients with PM/DM-ILD. A newly developed risk stratification scheme, according to thresholds of HRCT score, imaging classification (organizing pneumonia [OP] vs. non-OP patterns), and anti-MDA5 antibody status, demonstrated good predictive ability for identifying patients at risk of progression. In combination with clinical parameters, the integrated predictive algorithm significantly outperformed traditional clinical risk algorithm, with significant enhancements in C-index (to 0.764). The incremental predicted value was demonstrated by improved NRI (0.470), IDI (0.218), and DCA metrics. A high HRCT score is an independent predictor of acute/subacute progression in patients with PM/DM-ILD. Incorporating clinical parameters into the imaging-based algorithm significantly improves its predictive accuracy for progressive disease.

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.

IntroductionPrevention of recurrence after an episode of venous thromboembolism (VTE), and also the post-thrombotic syndrome (PTS), is still a recognised challenge. In this meta-analysis, we will summarise existing evidence to compare intelligent system follow-up and routine follow-up for patients with VTE.Methods and analysisRelevant randomised controlled trials (RCTs) and cohort studies will be included from the following databases: MEDLINE/PubMed, Web of Science and the Cochrane Library. The last search time will be 31 March 2024. Two reviewers will independently identify RCTs and cohort studies according to eligibility and exclusion criteria. The risk of bias of included cohort studies will be assessed with the Newcastle-Ottawa Scale, Methodological Index of Non-Randomised Studies, and the risk of bias of RCTs will be assessed with and Cochrane Collaboration’s tool. The primary outcomes include overall survival rate and PTS incidence rate. The Grades of Recommendations, Assessment, Development and Evaluation tool will be used to assess the level of evidence for outcome from RCTs. RevMan V.5.4 software will be used to pool outcomes.Ethics and disseminationEthical approval was obtained from Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine Science Research Ethics Committee (SH9H-2023-T466-1). The findings will be disseminated to the public through conference presentations and publication in peer-reviewed scientific journals.PROSPERO registration numberCRD42023410644.

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.

The functional recovery of peripheral nerve injury (PNI) is unsatisfactory, whereas diabetes mellitus (DM) and its related complications further attenuate the restoration of diabetic PNI (DPNI). Adipose-derived stem cells (ADSCs) are promising candidates for treatment of DPNI due to their abundant source, excellent differentiation and paracrine ability. Our results showed that ADSCs remarkably enhanced the proliferation and migration of Schwann cells and endothelial cells, and tube formation. Mechanistically, ADSCs could regulate Nrf2/HO-1, NF- κ B and PI3K/AKT/mTOR signaling pathways, showing multiple functions in reducing oxidative stress and inflammation, and regulating cell metabolism, growth, survival, proliferation, angiogenesis, differentiation of Schwann cell and myelin formation. In current study, novel graphene foam (GF)/hydrogel-based scaffold was developed to deliver ADSCs for treatment of DPNI. GF/hydrogel scaffold exhibited excellent mechanical strength, suitable porous network, superior electrical conductivity, and good biocompatibility. In vitro results revealed that GF/hydrogel scaffold could obviously accelerate proliferation of Schwann cells. Moreover, in vivo experiments demonstrated that ADSCs-loaded GF/hydrogel scaffold significantly promoted the recovery of DPNI and inhibited the atrophy of targeted muscles, thus providing a novel and attractive therapeutic approach for DPNI patients.

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.

ObjectivesAortic dissection (AD) is a life-threatening condition that requires intensive care and management. This paper explores the role of fluid management in the clinical care of AD patients, which has been unclear despite the substantial existing research that has been conducted on the treatment of AD.DesignA retrospective case-control study using data for AD patients from public databases.SettingTwo public intensive care unit (ICU) databases with hospital courses from the USA, Medical Information Mart for Intensive Care (MIMIC)-IV critical care dataset and the eICU Collaborative Research Database, with data from 2008 to 2019.ParticipantsA total of 751 adult AD patients with detailed fluid management records from two databases were included.InterventionsThe mean 24-hour intake and output were calculated by dividing the total amount of intake and output by the number of days in the ICU, respectively. The mean 24-hour fluid balance was generated by subtracting the output from the intake.Outcome measuresThe relationship between the mean 24-hour fluid management and all-cause in-hospital death was assessed through univariate and multivariable regression analyses.ResultsA positive correlation was found between mean 24-hour fluid intake and in-hospital mortality among AD patients (OR 1.029, 95% CI (1.018, 1.041), p<0.001), whereas a negative correlation was revealed between mean 24-hour fluid output and in-hospital mortality (OR 0.941, 95% CI (0.914, 0.968), p<0.001). A similar result was found for mean 24-hour fluid balance (OR 1.030, 95% CI (1.019, 1.042), p<0.001), and the cut-off was selected to be 5.12 dL (AUC=0.778, OR 3.066, 95% CI (1.634, 5.753), p<0.001).ConclusionsThis study stresses the importance of fluid balance in the clinical care of AD patients and provides new insights for optimising fluid management and monitoring strategies beyond the conventional focus on blood pressure and heart rate management.

Objectives Atherosclerosis of aortic wall has been suggested as a key pathological feature of abdominal aortic aneurysm (AAA). We conducted a first-ever prospective cohort study aiming at assessing the sex-specific association between atherogenic index of plasma (AIP) and risk of newly diagnosed AAA. Methods This study included 193,013 male and 226,785 female participants from the UK Biobank. AIP was calculated as a ratio of logarithmically transformed triglycerides to high-density lipoprotein-cholesterol. The outcome of interest was new AAA, identified by ICD-10 and OPCS-4 code, or by AAA-related death. All analyses were sex-stratified: Multivariable Cox proportional-hazard models were employed to assess the association between baseline AIP and AAA risk. Harrell’s c index was estimated to assess the value of AIP added to the discrimination of AAA prediction model. Results Over an average follow-up of 15.3 years, 1931 (1.00%) new AAA cases were recorded in males and 424 (0.19%) in females. In the fully adjusted models, compared with the bottom AIP quintile, HRs (95% CI) of newly diagnosed AAA was 1.67 (1.41, 1.96) in males and 1.75 (1.22, 2.52) in females within the top quintile. Subgroup analysis found smoking status significantly modified the association in females, with association existing only in female ever-smokers. Adding AIP into prediction model comprising age, smoking, and CVD history significantly improved the discrimination in males and male high-risk subgroups and in female ever-smokers ( p  < 0.05). Conclusions This study highlights the potential of AIP as a biomarker for AAA and its utility in identifying high-risk individuals qualified for AAA screening.