The change of intimate relationship between people with Alzheimer's disease and their adult child caregivers: An interpretative phenomenological analysis.

This study aims to explore the change of intimate relationship between people with Alzheimer's disease and their adult child caregivers as the disease progresses. Twelve adult child caregivers were recruited through purposive sampling. Explanatory phenomenological analysis was conducted to analyse data collected by semi-structured in-depth interviews. This study found a dynamically changing relationship between adult child caregivers and their parents with Alzheimer's disease during care giving that evolved with the progress of the disease. The relationship was the most intimate in the middle stage of the disease for most caregivers and a new reciprocal relationship developed due to caregiving. Caregivers experienced different degrees of self-growth when providing care, though caregiver burdens were common. The positive experience and perception of caregivers were important for improving the quality of life for adult child caregivers of people with Alzheimer's disease.

Treatment of Syringomyelia Characterized by Focal Dilatation of the Central Canal Using Mesenchymal Stem Cells and Neural Stem Cells.

BACKGROUND: Syringomyelia is a progressive chronic disease that leads to nerve pain, sensory dissociation, and dyskinesia. Symptoms often do not improve after surgery. Stem cells have been widely explored for the treatment of nervous system diseases due to their immunoregulatory and neural replacement abilities. METHODS: In this study, we used a rat model of syringomyelia characterized by focal dilatation of the central canal to explore an effective transplantation scheme and evaluate the effect of mesenchymal stem cells and induced neural stem cells for the treatment of syringomyelia. RESULTS: The results showed that cell transplantation could not only promote syrinx shrinkage but also stimulate the proliferation of ependymal cells, and the effect of this result was related to the transplantation location. These reactions appeared only when the cells were transplanted into the cavity. Additionally, we discovered that cell transplantation transformed activated microglia into the M2 phenotype. IGF1-expressing M2 microglia may play a significant role in the repair of nerve pain. CONCLUSION: Cell transplantation can promote cavity shrinkage and regulate the local inflammatory environment. Moreover, the proliferation of ependymal cells may indicate the activation of endogenous stem cells, which is important for the regeneration and repair of spinal cord injury.

Causes and global, regional, and national burdens of traumatic brain injury from 1990 to 2019.

PURPOSE: Traumatic brain injury (TBI), currently a major global public health problem, imposes a significant economic burden on society and families. We aimed to quantify and predict the incidence and severity of TBI by analyzing its incidence, prevalence, and years lived with disability (YLDs). The epidemiological changes in TBI from 1990 to 2019 were described and updated to provide a reference for developing prevention, treatment, and incidence-reducing measures for TBI. METHODS: A secondary analysis was performed on the incidence, prevalence, and YLDs of TBI by sex, age group, and region (n = 21,204 countries and territories) between 1990 and 2019 using the Global Burden of Diseases, Injuries, and Risk Factors Study 2019. Proportions in the age-standardized incidence rate due to underlying causes of TBI and proportions of minor and moderate or severe TBI were also reported. RESULTS: In 2019, there were 27.16 million (95% uncertainty intervals (UI): 23.36 - 31.42) new cases of TBI worldwide, with age-standardized incidence and prevalence rates of 346 per 100,000 population (95% UI: 298-401) and 599 per 100,000 population (95% UI: 573-627), respectively. From 1990 to 2019, there were no significant trends in global age-standardized incidence (estimated annual percentage changes: -0.11%, 95% UI: -0.18% - -0.04%) or prevalence (estimated annual percentage changes: 0.01%, 95% UI: -0.04% - 0.06%). TBI caused 7.08 million (95% UI: 5.00 - 9.59) YLDs in 2019, with age-standardized rates of 86.5 per 100,000 population (95% UI: 61.1 - 117.2). In 2019, the countries with higher incidence rates were mainly distributed in Central Europe, Eastern Europe, and Australia. The 2019 global age-standardized incidence rate was higher in males than in females. The 2019 global incidence of moderate and severe TBI was 182.7 per 100,000 population, accounting for 52.8% of all TBI, with falls and road traffic injuries being the main causes in most regions. CONCLUSIONS: The incidence of moderate and severe TBI was slightly higher in 2019, and TBI still accounts for a significant portion of the global injury burden. The likelihood of moderate to severe TBI and the trend of major injury under each injury cause from 1990 to 2019 and the characteristics of injury mechanisms in each age group are presented, providing a basis for further research on injury causes in each age group and the future establishment of corresponding policies and protective measures.

PARP inhibitors suppress tumours via centrosome error-induced senescence independent of DNA damage response.

BACKGROUND: Poly(ADP-ribose) polymerase (PARP) inhibitors have emerged as promising chemotherapeutic drugs primarily against BRCA1/2-associated tumours, known as synthetic lethality. However, recent clinical trials reported patients' survival benefits from PARP inhibitor treatments, irrelevant to homologous recombination deficiency. Therefore, revealing the therapeutic mechanism of PARP inhibitors beyond DNA damage repair is urgently needed, which can facilitate precision medicine. METHODS: A CRISPR-based knock-in technology was used to establish stable BRCA1 mutant cancer cells. The effects of PARP inhibitors on BRCA1 mutant cancer cells were evaluated by biochemical and cell biological experiments. Finally, we validated its in vivo effects in xenograft and patient-derived xenograft (PDX) tumour mice. FINDINGS: In this study, we uncovered that the majority of clinical BRCA1 mutations in breast cancers were in and near the middle of the gene, rather than in essential regions for DNA damage repair. Representative mutations such as R1085I and E1222Q caused transient extra spindle poles during mitosis in cancer cells. PAR, which is synthesized by PARP2 but not PARP1 at mitotic centrosomes, clustered these transient extra poles, independent of DNA damage response. Common PARP inhibitors could effectively suppress PARP2-synthesized PAR and induce cell senescence by abrogating the correction of mitotic extra-pole error. INTERPRETATION: Our findings uncover an alternative mechanism by which PARP inhibitors efficiently suppress tumours, thereby pointing to a potential new therapeutic strategy for centrosome error-related tumours. FUNDING: Funded by National Natural Science Foundation of China (NSFC) (T2225006, 82272948, 82103106), Beijing Municipal Natural Science Foundation (Key program Z220011), and the National Clinical Key Specialty Construction Program, P. R. China (2023).

Ordered mesoporous hairbrush-like nanocarbon assembled microfibers for solid-phase microextraction of benzene series in oilfield sewage.

The development of advanced functional nanomaterials for solid-phase microextraction (SPME) remains an imperative aspect of sample pretreatment. Herein, we introduce a novel SPME fiber consisting of graphene fibers modified with ordered mesoporous carbon nanotubes arrays (CNTAs) tailored for the determination of benzene series in oilfield wastewater, which is synthesized by an ionic liquid-assisted wet spinning process of graphene nanosheets, followed by a precisely controlled growth of metal-organic framework and subsequent pyrolysis treatment. The resulting robust microfiber structure resembles a "hairbrush" configuration, with a crumpled graphene fiber "stem" and high-order mesoporous CNTAs "hairs". This unique architecture significantly enhances the SPME capacity, as validated by gas chromatography-mass spectrometry. The hairbrush-like nanocarbon assembled microfibers possess structural characteristics, a high specific surface area, and numerous binding sites, offering efficient enrichment of benzene series compounds in oilfield wastewater, including benzene, ethylbenzene, m-xylene, p-xylene, and toluene. Our analysis demonstrates that these microfibers exhibit broad linear ranges (0.2-600 µg L-1), low detection limits (0.005-0.03 mg L-1), and excellent repeatability (3.2-5.5% for one fiber, 2.1-6.7% for fiber-to-fiber) for detection. When compared to commercial alternatives, these hairbrush-like nanocarbon-assembled microfibers exhibit significantly enhanced extraction efficiency for benzene series compounds.

IPEV: identification of prokaryotic and eukaryotic virus-derived sequences in virome using deep learning.

BACKGROUND: The virome obtained through virus-like particle enrichment contains a mixture of prokaryotic and eukaryotic virus-derived fragments. Accurate identification and classification of these elements are crucial to understanding their roles and functions in microbial communities. However, the rapid mutation rates of viral genomes pose challenges in developing high-performance tools for classification, potentially limiting downstream analyses. FINDINGS: We present IPEV, a novel method to distinguish prokaryotic and eukaryotic viruses in viromes, with a 2-dimensional convolutional neural network combining trinucleotide pair relative distance and frequency. Cross-validation assessments of IPEV demonstrate its state-of-the-art precision, significantly improving the F1-score by approximately 22% on an independent test set compared to existing methods when query viruses share less than 30% sequence similarity with known viruses. Furthermore, IPEV outperforms other methods in accuracy on marine and gut virome samples based on annotations by sequence alignments. IPEV reduces runtime by at most 1,225 times compared to existing methods under the same computing configuration. We also utilized IPEV to analyze longitudinal samples and found that the gut virome exhibits a higher degree of temporal stability than previously observed in persistent personal viromes, providing novel insights into the resilience of the gut virome in individuals. CONCLUSIONS: IPEV is a high-performance, user-friendly tool that assists biologists in identifying and classifying prokaryotic and eukaryotic viruses within viromes. The tool is available at https://github.com/basehc/IPEV.

Protocol for identifying metabolite biomarkers in patient uterine fluid for early ovarian cancer detection.

High mortality of ovarian cancer (OC) is primarily attributed to the lack of effective early detection methods. Uterine fluid, pooling molecules from neighboring ovaries, presents an organ-specific advantage over conventional blood samples. Here, we present a protocol for identifying metabolite biomarkers in uterine fluid for early OC detection. We describe steps for uterine fluid collection from patients, metabolite extraction, metabolomics experiments, and candidate metabolite biomarker screening. This standardized workflow holds the potential to achieve early OC diagnosis in clinical practice. For complete details on the use and execution of this protocol, please refer to Wang et al.1.

Effects of Platelet-Rich Plasma-Derived Exosomes on Proliferation and Migration of Tendon Stem/Progenitor Cell.

Objective To investigate the effects of platelet-rich plasma-derived exosomes (PRP-Exos) on the proliferation and migration of tendon stem/progenitor cell (TSPC). Methods PRP-Exos were extracted through the combination of polymer-based precipitation and ultracentrifugation.The morphology,concentration,and particle size of PRP-Exos were identified by transmission electron microscopy and nanoparticle tracking analysis.The expression levels of surface marker proteins on PRP-Exos and platelet membrane glycoproteins were determined by Western blot analysis.Rat TSPC was extracted and cultured,and the expression of surface marker molecules on TSPC was detected using flow cytometry and immunofluorescence staining.The proliferation of TSPC influenced by PRP-Exos was evaluated using CCK-8 assay and EdU assay.The effect of PRP-Exos on the migration of TSPC was evaluated by cell scratch assay and Transwell assay. Results The extracted PRP-Exos exhibit typical saucer-like structures,with a concentration of 4.9×1011 particles/mL,an average particle size of (132.2±56.8) nm,and surface expression of CD9,CD63 and CD41.The extracted TSPC expressed the CD44 protein.PRP-Exos can be taken up by TSPC,and after co-cultured for 48 h,concentrations of 50 and 100 µg/mL of PRP-Exos significantly promoted the proliferation of TSPC (both P<0.001),with no statistical difference between the two concentrations (P=0.283).Additionally,after co-cultured for 24 h,50 µg/mL of PRP-Exos significantly promoted the migration of TSPC (P<0.001). Conclusion Under in vitro culture conditions,PRP-Exos significantly promote the proliferation and migration of rat TSPC.

A preparation of debranched waxy maize starch derivatives: Effect of drying temperatures on crystallization and digestibility.

The impact of recrystallization conditions and drying temperatures on the crystallization and digestibility of native waxy maize (Zea mays L.) starch (NWMS) was explored. This study involved subjecting NWMS to concurrent debranching and crystallization at 50 °C for up to 7 days. Samples were collected by oven-drying at 40, 60, and 80 °C for 24 h. This simultaneous debranching and crystallization process increased the resistant starch (RS) content by approximately 48 % compared to the native starch. The drying temperatures significantly influenced the RS content, with samples dried at 60 °C exhibiting the lowest digestibility. X-ray diffraction (XRD) analysis revealed that most crystals demonstrated a characteristic A-type arrangement. Debranching and crystallization processes enhanced the crystallinity of the samples. The specific crystal arrangement (A- or B-type) depended on the crystallization conditions. A 15 min heating of NWMS in a boiling water bath increased the digestible fraction to over 90 %, while the samples subjected to debranching and crystallization showed an increase to only about 45 %. A linear correlation between starch fractions and enthalpy was also observed.

Elucidating immune cell dynamics in chronic lung allograft dysfunction: A comprehensive single-cell transcriptomic study.

Chronic Lung Allograft Dysfunction (CLAD) is a critical post-transplant complication that predominantly determines the long-term survival rates and quality of life of patients undergoing lung transplantation. The limited efficacy of current immunosuppressive strategies underscores our incomplete understanding of the immunological aspects of CLAD. Hence, there is an urgent need for more comprehensive and targeted research to unravel the complex interplay of immune cells in the development and progression of CLAD. This study conducts an in-depth analysis of the immune environment in CLAD. By examining the gene expression profiles of T cells, natural killer cells, B cells, macrophages, and monocytes, we have elucidated a unique immunological landscape in CLAD compared to healthy controls. We highlight the heterogeneity within the immune populations and provide a comprehensive understanding of the immune mechanisms driving CLAD. Enrichment analysis identified specific pathways that are either overactive or suppressed in CLAD, revealing potential molecular targets for therapeutic intervention. Our findings emphasize the crucial role of T cells in the pathophysiology of CLAD, coordinating the immune response and revealing an amplified immune cell network, potentially leading to maladaptive tissue responses. By integrating a comprehensive cellular and molecular portrait of the immune environment, our research not only deepens our understanding of the pathogenesis of CLAD but also lays a foundational approach for the development of targeted therapies.

A phase 2 pilot study of water irrigation after transurethral resection of bladder tumor (WATIP) demonstrating safety, feasibility and activity.

PURPOSE: Non-muscle-invasive bladder cancer (NMIBC) can recur, partly due to seeding of free tumour cells after transurethral resection of bladder tumour (TURBT). Intravesical chemotherapy post-TURBT can reduce the risk but is used infrequently and inconsistently due to cost, complexity and side effects. The objective of this study was to prospectively assess continuous bladder irrigation using water, which may be a safer and easier alternative with comparable effectiveness. METHODS: WATIP was a prospective, single-arm phase 2 study of water irrigation during and for at least 3 h after TURBT for bladder tumours noted on imaging or flexible cystoscopy. Participants were assessed clinically for adverse effects and with blood tests within 24 h for sodium, haemoglobin and lactate dehydrogenase. The primary endpoints were safety (defined as < 10% adverse events of CTCAE grade ≥ 3), and feasibility (defined as the intervention being delivered as planned in > 90% of cases) and secondary endpoint was recurrence-free rates (RFR). RESULTS: Water irrigation was delivered as planned in 29 (97%) of 30 participants (median age 67 years, 25 (83%) males). The only adverse event (grade 2) was clot retention in one (3.3%) participant. Water irrigation significantly reduced urothelial cell counts in catheter effluent over time, unlike saline irrigation which did not. RFR was 56.2% (9/16 participants with low-risk NMIBC) at first cystoscopy (median interval 108 days) and 62.5% (5/8 evaluable low-risk NMIBC) at 12 months. CONCLUSION: Water irrigation during and after TURBT is feasible and safe. Prospective assessment of its effect on NMIBC recurrence compared to post-TURBT intravesical chemotherapy is needed before recommending its use in routine clinical practice. Trial registration ANZCTR registration ID ACTRN12619000517178 on 1 April 2019.

Deep Eutectic Solvents as New Extraction Media for Flavonoids in Mung Bean.

Mung beans contain abundant flavonoids like vitexin and isovitexin, which contribute to their strong bioactivities, such as antioxidant effects, so efforts should focus on extracting bioactive flavonoids as well as aligning with the goal of green extraction for specific applications. Deep eutectic solvent coupled with ultrasound-assisted extraction (DES-UAE) was applied to extract flavonoids from mung beans, and eight different DESs were compared on the extraction yield. In addition, the traditional extraction method with 30% ethanol was performed as the reference. The results showed that ethylene glycol-glycolic acid achieved the highest yield among all the DESs, 1.6 times that of the reference values. Furthermore, the DES-UAE parameters were optimized as a 60 mL/g liquid-solid ratio, 30% water content in DES, 200 W ultrasonic power, 67 °C ultrasonic temperature, and 10 min extraction time, leading to the DES extract with the maximum extraction yield of 2339.45 ± 42.98 µg/g, and the significantly stronger DPPH and ABTS radical scavenging ability than the traditional extract. Therefore, employing DES and ultrasonic extraction together offers a green method for extracting flavonoids from mung beans, advancing the development and utilization of plant-derived effective components in a sustainable manner.

Expanding Multiple-Resonance Structure of a Double-Borylated Skeleton by Fusing with Indolocarbazole a Multiple-Resonance Donor for Narrowband Green Emission.

Double-borylated multiple-resonance (MR) skeletons are promising templates for high performance, while the chemical design space is relatively limited. Peripheral segments are often used to decorate/fuse MR skeletons and modulate the photophysics but they can also cause unwanted spectral broadening. Herein, a narrowband MR emitter ICzDBA by fusing an MR-featured donor segment indolocarbazole into a double-borylated MR skeleton is developed. In ICzDBA, the nitrogen atom located away from the core benzene ring can also contribute to the generation of the overall MR-featured distribution through the long-range conjugation effect, along with the other boron/nitrogen atoms on the phenyl center. Thus, ICzDBA in toluene displays a narrowband emission peaking at 507 nm with a full width at half maximum of merely 20 nm (0.09 eV). Moreover, organic light-emitting diode devices using ICzDBA emitter exhibit ultrapure green emission with Commission Internationale de l'Eclairage (CIE) coordinates of (0.27, 0.70) and a high external quantum efficiency of 32.5%. These results manifest the importance of MR characters of peripheral decorations/fusions in preserving the narrowband features of MR skeletons, which provides a solution for further expanding MR structures with well-maintained narrowband characters.

Recycling of straw-biochar-biogas-electricity for sustainable food production pathways: Toward an integrated modeling approach.

As global greenhouse gas emissions increase and fossil energy sources decline dramatically, the energy transition is at the heart of many countries' development initiatives. As a biomass resource, straw plays a positive role in energy transformation and environmental improvement. However, there is still a challenge to explore the best options and models for straw production and utilization of green and efficient biomass energy in agricultural systems. This study establishes an economic-environmental-resource synergistic Straw Green recycling optimization model based on straw-electricity-biochar-biogas core (Straw Green recycling optimization model, SGROM). Firstly, we explore the effects of biochar return to the field on crop yield and greenhouse gas emission by Meta-analysis method, and on this basis, we construct SGROM to weigh the three objectives of economic-greenhouse gas emission-resource utilization, and explore the best allocation ratio between four utilization methods of straw: power generation, biochar preparation, biogas and derivatives preparation and sale, so as to obtain a straw recycling and efficient low-carbon utilization model. Exploring the response of straw green utilization patterns to crop market prices with the help of deep learning methods, SGROM has been applied to the main grain producing areas in the Sanjiang Plain of China, and the results of comparison with the traditional straw utilization (TSU) model show that the greenhouse gas emissions per unit of production value of SGROM are 19.66 % lower than that of TSU model, the electricity consumption is saved by 2.00 %, and the optimal ratios of straw for power generation, biogas and biochar production, and sale are 1.00 %, 10.75 %, 62.11 % and 26.14 %. The economic benefits and total greenhouse gas emissions of the integrated straw utilization mode are better than those of the single straw utilization mode, proving the superiority of SGROM in optimizing the straw utilization mode.

KAT8-catalyzed lactylation promotes eEF1A2-mediated protein synthesis and colorectal carcinogenesis.

Aberrant lysine lactylation (Kla) is associated with various diseases which are caused by excessive glycolysis metabolism. However, the regulatory molecules and downstream protein targets of Kla remain largely unclear. Here, we observed a global Kla abundance profile in colorectal cancer (CRC) that negatively correlates with prognosis. Among lactylated proteins detected in CRC, lactylation of eEF1A2K408 resulted in boosted translation elongation and enhanced protein synthesis which contributed to tumorigenesis. By screening eEF1A2 interacting proteins, we identified that KAT8, a lysine acetyltransferase that acted as a pan-Kla writer, was responsible for installing Kla on many protein substrates involving in diverse biological processes. Deletion of KAT8 inhibited CRC tumor growth, especially in a high-lactic tumor microenvironment. Therefore, the KAT8-eEF1A2 Kla axis is utilized to meet increased translational requirements for oncogenic adaptation. As a lactyltransferase, KAT8 may represent a potential therapeutic target for CRC.

Microneedle-assisted percutaneous delivery of methotrexate-loaded nanoparticles enabling sustained anti-inflammatory effects in psoriasis therapy.

Methotrexate (MTX) is one of the first-line drugs used for the treatment of moderate to severe psoriasis. However, low bioavailability and systemic side effects of traditional oral and injectable MTX greatly limit its clinical application. Delivering MTX using dissolving microneedles (MNs) into psoriasis-like skin lesion could improve the in situ therapeutic effects with higher bioavailability and less side effects. Here, we propose a novel therapeutic approach for psoriasis involving MN-assisted percutaneous delivery of chitosan-coated hollow mesoporous silica nanoparticles containing MTX (MTX@HMSN/CS). The MTX@HMSN/CS-loaded MNs were strong enough to successfully penetrate the psoriasiform thickened epidermis, allowing MTX@HMSN/CS to be accurately delivered to the site of skin lesion following the rapid dissolution of MNs. MTX was then released continuously from HMSN/CS for at least one week to maintain effective therapeutic drug concentration for skin lesion with long-term anti-proliferative and anti-inflammatory effects. Incubation with MTX@HMSN/CS not only inhibited the proliferation of human immortalized keratinocytes (HaCaT cells), but also significantly reduced the expression of proinflammatory cytokines and chemokines. In addition, MTX@HMSN/CS-loaded MNs showed better efficacy in alleviating psoriasis-like skin inflammation than MTX-loaded MNs at the same dose. Compared to psoriasiform mice treated with 15.8 µg MTX-loaded MNs every day, 47.4 µg MTX@HMSN/CS-loaded MNs reduce the frequency of treatment to once every 3 days and achieve comparable amelioration. Therefore, MTX@HMSN/CS loaded MNs are a promising treatment strategy for psoriasis due to their durability, efficacy, convenience, and safety in relieving psoriasis-like skin inflammation.

Extra (embryonic) dialogues: Keys to improved stem cell-based embryo models.

Despite advances in stem cell cultures, modeling early human development with stem cells in a dish remains challenging. Research by Hislop et al.,1 Okubo et al.,2 and Wei et al.3 paves the way for improved in vitro embryo models and culture conditions, offering valuable insights for regenerative medicine.

Grafted human-induced pluripotent stem cells-derived oligodendrocyte progenitor cells combined with human umbilical vein endothelial cells contribute to functional recovery following spinal cord injury.

BACKGROUND: Spinal cord injury (SCI) is a devastating disease that causes extensive damage to oligodendrocytes and neurons leading to demyelination and axonal degeneration. In this study, we co-transplanted cell grafts containing oligodendrocyte progenitor cells (OPCs) derived from human-induced pluripotent stem cells (iPSCs) combined with human umbilical vein endothelial cells (HUVECs), which were reported to promote OPCs survival and migration, into rat contusion models to promote functional recovery after SCI. METHODS: OPCs were derived from iPSCs and identified by immunofluorescence at different time points. Functional assays in vitro were performed to evaluate the effect of HUVECs on the proliferation, migration, and survival of OPCs by co-culture and migration assay, as well as on the neuronal axonal growth. A combination of OPCs and HUVECs was transplanted into the rat contusive model. Upon 8 weeks, immunofluorescence staining was performed to test the safety of transplanted cells and to observe the neuronal repairment, myelination, and neural circuit reconstruction at the injured area; also, the functional recovery was assessed by Basso, Beattie, and Bresnahan open-field scale, Ladder climb, SEP, and MEP. Furthermore, the effect of HUVECs on grafts was also determined in vivo. RESULTS: Data showed that HUVECs promote the proliferation, migration, and survival of OPCs both in vitro and in vivo. Furthermore, 8 weeks upon engraftment, the rats with OPCs and HUVECs co-transplantation noticeably facilitated remyelination, enhanced functional connection between the grafts and the host and promoted functional recovery. In addition, compared with the OPCs-alone transplantation, the co-transplantation generated more sensory neurons at the lesion border and significantly improved the sensory functional recovery. CONCLUSIONS: Our study demonstrates that transplantation of OPCs combined with HUVECs significantly enhances both motor and sensory functional recovery after SCI. No significance was observed between OPCs combined with HUVECs group and OPCs-alone group in motor function recovery, while the sensory function recovery was significantly promoted in OPCs combined with HUVECs groups compared with the other two groups. These findings provide novel insights into the field of SCI research.

HucMSCs delay muscle atrophy after peripheral nerve injury through exosomes by repressing muscle-specific ubiquitin ligases.

Cell therapy based on mesenchymal stem cells (MSCs) alleviates muscle atrophy caused by diabetes and aging，however, the impact of human umbilical cord mesenchymal stem cells on muscle atrophy following nerve injury and the underlying mechanisms remain unclear. In this study, we evaluated the therapeutic efficacy of human umbilical cord MSCs (hucMSCs) and hucMSC-derived exosomes (hucMSC-EXOs) for muscle atrophy following nerve injury and identified the underlying molecular mechanisms. Sciatic nerve crush injury in rats and the induction of myotubes in L6 cells were used to determine the ameliorating effect of hucMSCs and hucMSC-EXOs on muscle atrophy. Q-PCR and western blot analyses were used to measure the expression of muscle-specific ubiquitin ligases Fbxo32 (Atrogin1, MAFbx) and Trim63 (MuRF-1). Dual-luciferase reporter gene experiments were conducted to validate the direct binding of miRNAs to their target genes. Local injection of hucMSCs and hucMSC-EXOs mitigated atrophy in the rat gastrocnemius muscle following sciatic nerve crush injury. In vitro, hucMSC-EXOs alleviated atrophy in L6 myotubes. Mechanistic analysis indicated the upregulation of miR-23b-3p levels in L6 myotubes following hucMSC-EXOs treatment. MiR-23b-3p significantly inhibited the expression of its target genes, Fbxo32 and Trim63, and suppressed myotube atrophy. Notably, a miR-23b-3p inhibitor reversed the inhibitory effect of miR-23b-3p on myotube atrophy in vitro. These results suggest that hucMSCs and their exosomes alleviate muscle atrophy following nerve injury. MiR-23b-3p in exosomes secreted by hucMSCs contributes to this mechanism by inhibiting the muscle specific ubiquitination ligases Fbxo32 and Trim63.

E3 ubiquitin ligase FBXW11 as a novel inflammatory biomarker is associated with immune infiltration and NF-κB pathway activation in pancreatitis and pancreatic cancer.

BACKGROUND: Pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) is an aggressive disease with an overall poor prognosis. Pancreatitis is a major risk factor for the development of PDAC. Due to the lack of reliable and accurate biomarkers, the diagnosis, treatment, and prognosis of PDAC face great challenges. It is of great significance to elucidate the pathogenesis of PDAC and explore novel inflammatory biomarkers. METHODS: We identified E3 ubiquitin ligases associated with pancreatic inflammation by combining multiple GEO datasets and UbiNet 2.0, and integrating the WGCNA algorithm and Limma R package. A risk score model for PDAC patients was established by using LASSO regression. We investigated the correlation between FBXW11 and immune cell infiltration using CIBERSORT, mMCP-counter, ImmuCellAI-mouse, QUANTISEQ, and TIMER algorithms, based on GEO, ArrayExpress, and TCGA datasets. We used Ubibrowser 2.0 to predict potential substrates for FBXW11. WikiPathway, MSigDB Hallmark, and Elsevier pathway analysis of FBXW11 key substrates were also performed using the EnrichR database. We detected protein expression through IHC, immunofluorescence, and western blot in the cerulein-induced acute pancreatitis mouse model. RESULTS: We first identified that FBXW11 exhibited a clear tendency to gradually increase in normal, pancreatitis, and PDAC patients. The validation analysis revealed that the FBXW11 protein exhibited significantly high expression in cerulein-induced acute pancreatitis mice, with its distribution primarily observed in the cytoplasm. Simultaneously, we developed a risk model utilizing the genes associated with FBXW11 to forecast the outcome of patients with PDAC and the likelihood of pancreatitis advancing to pancreatic cancer. Functional analysis showed that FBXW11, as a novel inflammatory biomarker, had a significant positive correlation with macrophage infiltration and the NF-κB signaling pathway. Finally, the western blot assay of the NF-κB signaling pathway in pancreatic tissues demonstrated that high activation of NF-κB was correlated with high expression of FBXW11. CONCLUSIONS: Our research not only provides evidence for FBXW11 as a novel inflammatory biomarker but also provides new insights into the research and clinical treatment of pancreatic cancer.