Impacts of Nutlin-3a and exercise on murine double minute 2-enriched glioma treatment.

JOURNAL/nrgr/04.03/01300535-202504000-00029/figure1/v/2024-07-06T104127Z/r/image-tiff Recent research has demonstrated the impact of physical activity on the prognosis of glioma patients, with evidence suggesting exercise may reduce mortality risks and aid neural regeneration. The role of the small ubiquitin-like modifier (SUMO) protein, especially post-exercise, in cancer progression, is gaining attention, as are the potential anti-cancer effects of SUMOylation. We used machine learning to create the exercise and SUMO-related gene signature (ESLRS). This signature shows how physical activity might help improve the outlook for low-grade glioma and other cancers. We demonstrated the prognostic and immunotherapeutic significance of ESLRS markers, specifically highlighting how murine double minute 2 (MDM2), a component of the ESLRS, can be targeted by nutlin-3. This underscores the intricate relationship between natural compounds such as nutlin-3 and immune regulation. Using comprehensive CRISPR screening, we validated the effects of specific ESLRS genes on low-grade glioma progression. We also revealed insights into the effectiveness of Nutlin-3a as a potent MDM2 inhibitor through molecular docking and dynamic simulation. Nutlin-3a inhibited glioma cell proliferation and activated the p53 pathway. Its efficacy decreased with MDM2 overexpression, and this was reversed by Nutlin-3a or exercise. Experiments using a low-grade glioma mouse model highlighted the effect of physical activity on oxidative stress and molecular pathway regulation. Notably, both physical exercise and Nutlin-3a administration improved physical function in mice bearing tumors derived from MDM2-overexpressing cells. These results suggest the potential for Nutlin-3a, an MDM2 inhibitor, with physical exercise as a therapeutic approach for glioma management. Our research also supports the use of natural products for therapy and sheds light on the interaction of exercise, natural products, and immune regulation in cancer treatment.

Voluntary exercise sensitizes cancer immunotherapy via the collagen inhibition-orchestrated inflammatory tumor immune microenvironment.

Physical activity reduces cancer-associated mortality through multiple mechanisms, including tumor immune microenvironment (TIME) reprogramming. However, whether and how physiological interventions promote anti-tumor immunity remain elusive. Here, we report that clinically relevant voluntary exercise promotes muscle-derived extracellular vesicle (EV)-associated miR-29a-3p for tumor extracellular matrix (ECM) inhibition in patients and mouse models, thereby permitting immune cell infiltration and immunotherapy. Mechanistically, an unbiased screening identifies EV-associated miR-29a-3p in response to leisure-time physical activity or voluntary exercise. MiR-29a-3p-containing EVs accumulate in tumors and downregulate collagen composition by targeting COL1A1. Gain- and loss-of-function experiments and cytometry by time of flight (CyTOF) demonstrate that myocyte-secreted miR-29a-3p promotes anti-tumor immunity. Combining immunotherapy with voluntary exercise or miR-29a-3p further enhances anti-tumor efficacy. Clinically, miR-29a-3p correlates with reduced ECM, increased T cell infiltration, and response to immunotherapy. Our work reveals the predictive value of miR-29a-3p for immunotherapy, provides mechanistic insights into exercise-induced anti-cancer immunity, and highlights the potential of voluntary exercise in sensitizing immunotherapy.

Exosomes derived from tendon stem/progenitor cells enhance tendon-bone interface healing after rotator cuff repair in a rat model.

The rate of retear after surgical repair remains high. Mesenchymal stem cells (MSCs) have been extensively employed in regenerative medicine for several decades. However, safety and ethical concerns constrain their clinical application. Tendon Stem/Progenitor Cells (TSPCs)-derived exosomes have emerged as promising cell-free therapeutic agents. Therefore, urgent studies are needed to investigate whether TSPC-Exos could enhance tendon-bone healing and elucidate the underlying mechanisms. In this study, TSPC-Exos were found to promote the proliferation, migration, and expression of fibrogenesis markers in BMSCs. Furthermore, TSPC-Exos demonstrated an ability to suppress the polarization of M1 macrophages while promoting M2 macrophage polarization. In a rat model of rotator cuff repair, TSPC-Exos modulated inflammation and improved the histological structure of the tendon-bone interface, the biomechanical properties of the repaired tendon, and the function of the joint. Mechanistically, TSPC-Exos exhibited high expression of miR-21a-5p, which regulated the expression of PDCD4. The PDCD4/AKT/mTOR axis was implicated in the therapeutic effects of TSPC-Exos on proliferation, migration, and fibrogenesis in BMSCs. This study introduces a novel approach utilizing TSPC-Exos therapy as a promising strategy for cell-free therapies, potentially benefiting patients with rotator cuff tear in the future.

Outcome comparison of meniscal allograft transplantation (MAT) and meniscal scaffold implantation (MSI): a systematic review.

BACKGROUND: Although numerous studies have reported successful clinical outcomes of meniscal allograft transplantation (MAT) or meniscal scaffold implantation (MSI), the difference between the outcome of MAT and MSI remains unclear. PURPOSE: To compare the overall outcomes and survival rates of MAT and MSI, aiming to provide comprehensive evidence for determining the optimal treatment strategy for meniscal defects. METHODS: A systematic review was performed via a comprehensive search of PubMed, Embase, and the Cochrane Library. Studies of MAT or MSI were included according to the inclusion and exclusion criteria. The Lysholm score was chosen as the primary outcome measure, while secondary outcomes encompassed patient-reported outcome measures (PROMs), return to sports (RTS) rates, survival rates, and complication rates. The outcomes were stratified into two groups: MAT group and MSI group, followed by statistical comparison ( P <0.05). The quality of the included studies was assessed by the Cochrane Risk of Bias 2 (RoB2) assessment tool for randomized controlled trials (RCTs) and the Coleman Methodology Score (CMS) for non-randomized controlled trials. RESULTS: A total of 3932 patients (2859 MAT, 1073 MSI) in 83 studies (51 MAT, 32 MSI) had the overall significant improvement in all clinical scores. The group MSI had a higher Lysholm score of both preoperative ( P =0.002) and postoperative ( P <0.001) than group MAT; however, the mean improvements were similar between the two groups ( P =0.105). Additionally, MSI had higher improvements of IKDC ( P <0.001), KOOS symptom ( P =0.010), KOOS pain ( P =0.036), and KOOS ADL ( P =0.004) than MAT. Interestingly, MAT had higher preoperative ( P =0.018) and less postoperative VAS pain ( P =0.006), which was more improved in MAT ( P <0.001). Compared with MAT, MSI had a higher 10-year survival rate ( P =0.034), a similar mid-term survival rate MAT ( P =0.964), and a lower complication rate ( P <0.001). CONCLUSION: Both MAT and MSI could have good clinical outcomes after surgery with a similar improvement in Lysholm score. MSI had a higher 10-year survival rate and fewer complications than MAT. LEVEL OF EVIDENCE: Level IV, systematic review.

Ambient air pollution exposure and the risk of probable sarcopenia: A prospective cohort study.

BACKGROUND: Sarcopenia is characterized by decreased muscle mass and strength, posing threat to quality of life. Air pollutants are increasingly recognized as risk factors for diseases, while the relationship between the two remains to be elucidated. This study investigated whether exposure to ambient air pollution contributes to the development of sarcopenia. METHODS: We employed the data from the UK Biobank with 303,031 eligible participants. Concentrations of PM2·5, NO2, and NOx were estimated. Cox proportional hazard regression models were applied to investigate the associations between pollutants and sarcopenia. RESULTS: 30,766 probable sarcopenia cases was identified during the follow-up. We observed that exposure to PM2.5 (HR, 1.232; 95% CI, 1.053-1.440), NO2 (HR, 1.055; 95% CI, 1.032-1.078) and NOx (HR, 1.016; 95% CI, 1.007-1.026) were all significantly associated with increased risk for probable sarcopenia for each 10 µg/m3 increase in pollutant concentration. In comparison with individuals in the lowest quartiles of exposure, those in the upper quartiles had significantly increased risk of probable sarcopenia. Sarcopenia-related factors, e.g., reduced lean muscle mass, diminished walking pace, and elevated muscle fat infiltration ratio, also exhibited positive associations with exposure to ambient air pollution. On the contrary, high level physical activity significantly mitigated the influence of air pollutants on the development of probable sarcopenia. CONCLUSIONS: Air pollution exposure elevated the risk of developing sarcopenia and related manifestations in a dose-dependent manner, while physical activity maintained protective under this circumstance. Efforts should be made to control air pollution and emphasize the importance of physical activity for skeletal muscle health under this circumstance.

Agomir-122-loaded nanoparticles coated with cell membrane of activated fibroblasts to treat frozen shoulder based on homologous targeting.

As a common musculoskeletal disorder, frozen shoulder is characterized by thickened joint capsule and limited range of motion, affecting 2-5% of the general population and more than 20% of patients with diabetes mellitus. Pathologically, joint capsule fibrosis resulting from fibroblast activation is the key event. The activated fibroblasts are proliferative and contractive, producing excessive collagen. Albeit high prevalence, effective anti-fibrosis modalities, especially fibroblast-targeting therapies, are still lacking. In this study, microRNA-122 was first identified from sequencing data as a potential therapeutic agent to antagonize fibroblast activation. Then, Agomir-122, an analog of microRNA-122, was loaded into poly(lactic-co-glycolic acid) (PLGA) nanoparticles (Agomir-122@NP), a carrier with excellent biocompatibility for the agent delivery. Moreover, relying on the homologous targeting effect, we coated Agomir-122@NP with the cell membrane derived from activated fibroblasts (Agomir-122@MNP), with an attempt to inhibit the proliferation, contraction, and collagen production of abnormally activated fibroblasts. After confirming the targeting effect of Agomir-122@MNP on activated fibroblasts in vitro, we proved that Agomir-122@MNP effectively curtailed fibroblasts activation, ameliorated joint capsule fibrosis, and restored range of motion in mouse models both prophylactically and therapeutically. Overall, an effective targeted delivery method was developed with promising translational value against frozen shoulder.

Conserved immuno-collagenic subtypes predict response to immune checkpoint blockade.

BACKGROUND: Immune checkpoint blockade (ICB) has revolutionized the treatment of various cancer types. Despite significant preclinical advancements in understanding mechanisms, identifying the molecular basis and predictive biomarkers for clinical ICB responses remains challenging. Recent evidence, both preclinical and clinical, underscores the pivotal role of the extracellular matrix (ECM) in modulating immune cell infiltration and behaviors. This study aimed to create an innovative classifier that leverages ECM characteristics to enhance the effectiveness of ICB therapy. METHODS: We analyzed transcriptomic collagen activity and immune signatures in 649 patients with cancer undergoing ICB therapy. This analysis led to the identification of three distinct immuno-collagenic subtypes predictive of ICB responses. We validated these subtypes using the transcriptome data from 9,363 cancer patients from The Cancer Genome Atlas (TCGA) dataset and 1,084 in-house samples. Additionally, novel therapeutic targets were identified based on these established immuno-collagenic subtypes. RESULTS: Our categorization divided tumors into three subtypes: "soft & hot" (low collagen activity and high immune infiltration), "armored & cold" (high collagen activity and low immune infiltration), and "quiescent" (low collagen activity and immune infiltration). Notably, "soft & hot" tumors exhibited the most robust response to ICB therapy across various cancer types. Mechanistically, inhibiting collagen augmented the response to ICB in preclinical models. Furthermore, these subtypes demonstrated associations with immune activity and prognostic predictive potential across multiple cancer types. Additionally, an unbiased approach identified B7 homolog 3 (B7-H3), an available drug target, as strongly expressed in "armored & cold" tumors, relating with poor prognosis. CONCLUSION: This study introduces histopathology-based universal immuno-collagenic subtypes capable of predicting ICB responses across diverse cancer types. These findings offer insights that could contribute to tailoring personalized immunotherapeutic strategies for patients with cancer.

Macrophage-Myofibroblast Transition as a Potential Origin for Skeletal Muscle Fibrosis After Injury via Complement System Activation.

Background: Acute skeletal muscle injury is common in sports. The injured muscle cannot fully recover due to fibrosis resulting from myofibroblasts. Understanding the origin of fibroblasts is, therefore, important for the development of anti-fibrotic therapies. Accumulating evidence shows that a mechanism called macrophage-myofibroblast transition (MMT) can lead to tissue or organ fibrosis, yet it is still unclear whether MMT exists in skeletal muscle and the exact mechanisms. Methods: Single-cell transcriptome of mice skeletal muscle after acute injury was analyzed with a specific attention on the process of MMT. Cell-cell interaction network, pseudotime trajectory analysis, Gene Ontology (GO), and Kyoto Genome Encyclopedia (KEGG) were conducted. A series of experiments in vivo and in vitro were launched for verification. Results: Single cell transcriptomic analysis indicated that, following acute injury, there were much interactions between macrophages and myofibroblasts. A detailed analysis on macrophages indicated that, CD68+α-SMA+ cells, which represented the status of MMT, mainly appeared at five days post-injury. KEGG/GO analysis underlined the involvement of complement system, within which C3ar1, C1qa, C1qb, and C1qc were up-regulated. Trajectory analysis also confirmed a potential shift from macrophages to myofibroblasts. These findings were verified by histological study in mice skeletal muscle, that there were much MMT cells at five days, declined gradually, and vanished 14 days after trauma, when there was remarkable fibrosis formation within the injured muscle. Moreover, C3a stimulation could directly induce MMT in BMDMs. Conclusion: Fibrosis following acute injury is disastrous to skeletal muscle, but the origin of myofibroblasts remains unclear. We proved that, following acute injury, macrophage-myofibroblast transition happened in skeletal muscle, which may contribute to fibrosis formation. This phenomenon mainly occurred at five days post-injury. The complement system can activate MMT. More evidence is needed to directly support the pro-fibrotic role of MMT in skeletal muscle fibrosis after acute injury.

Ageing of skeletal muscle extracellular matrix and mitochondria: finding a potential link.

Aim: To discuss the progress of extracellular matrix (ECM) characteristics, mitochondrial homeostasis, and their potential crosstalk in the pathogenesis of sarcopenia, a geriatric syndrome characterized by a generalized and progressive reduction in muscle mass, strength, and physical performance.Methods: This review focuses on the anatomy and physiology of skeletal muscle, alterations of ECM and mitochondria during ageing, and the role of the interplay between ECM and mitochondria in the pathogenesis of sarcopenia.Results: Emerging evidence points to a clear interplay between mitochondria and ECM in various tissues and organs. Under the ageing process, the ECM undergoes changes in composition and physical properties that may mediate mitochondrial changes via the systematic metabolism, ROS, SPARC pathway, and AMPK/PGC-1α signalling, which in turn exacerbate muscle degeneration. However, the precise effects of such crosstalk on the pathobiology of ageing, particularly in skeletal muscle, have not yet been fully understood.Conclusion: The changes in skeletal muscle ECM and mitochondria are partially responsible for the worsened muscle function during the ageing process. A deeper understanding of their alterations and interactions in sarcopenic patients can help prevent sarcopenia and improve its prognoses.

Sarcopenia is a senile syndrome featured by a progressive and generalized decline of muscle mass, strength, and physical performance. Given the complexity and importance of the extracellular matrix (ECM) and mitochondria of skeletal muscle, we, in this review, summarized current progress in the alterations of ECM properties and mitochondrial homeostasis in aged skeletal muscle, and have found several potential links between them. And we believe that this work could provide new insight into the prevention and treatment of age-related sarcopenia.

Advancements in Sports Medicine.

Sports medicine has developed rapidly in recent years [...].

Bone marrow mesenchymal stem cell-derived exosomal microRNAs target PI3K/Akt signaling pathway to promote the activation of fibroblasts.

BACKGROUND: Fibroblast plays a major role in tendon-bone healing. Exosomes derived from bone marrow mesenchymal stem cells (BMSCs) can activate fibroblasts and promote tendon-bone healing via the contained microRNAs (miRNAs). However, the underlying mechanism is not comprehensively understood. Herein, this study aimed to identify overlapped BMSC-derived exosomal miRNAs in three GSE datasets, and to verify their effects as well as mechanisms on fibroblasts. AIM: To identify overlapped BMSC-derived exosomal miRNAs in three GSE datasets and verify their effects as well as mechanisms on fibroblasts. METHODS: BMSC-derived exosomal miRNAs data (GSE71241, GSE153752, and GSE85341) were downloaded from the Gene Expression Omnibus (GEO) database. The candidate miRNAs were obtained by the intersection of three data sets. TargetScan was used to predict potential target genes for the candidate miRNAs. Functional and pathway analyses were conducted using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases, respectively, by processing data with the Metascape. Highly interconnected genes in the protein-protein interaction (PPI) network were analyzed using Cytoscape software. Bromodeoxyuridine, wound healing assay, collagen contraction assay and the expression of COL I and α-smooth muscle actin positive were applied to investigate the cell proliferation, migration and collagen synthesis. Quantitative real-time reverse transcription polymerase chain reaction was applied to determine the cell fibroblastic, tenogenic, and chondrogenic potential. RESULTS: Bioinformatics analyses found two BMSC-derived exosomal miRNAs, has-miR-144-3p and has-miR-23b-3p, were overlapped in three GSE datasets. PPI network analysis and functional enrichment analyses in the GO and KEGG databases indicated that both miRNAs regulated the PI3K/Akt signaling pathway by targeting phosphatase and tensin homolog (PTEN). In vitro experiments confirmed that miR-144-3p and miR-23b-3p stimulated proliferation, migration and collagen synthesis of NIH3T3 fibroblasts. Interfering with PTEN affected the phosphorylation of Akt and thus activated fibroblasts. Inhibition of PTEN also promoted the fibroblastic, tenogenic, and chondrogenic potential of NIH3T3 fibroblasts. CONCLUSION: BMSC-derived exosomes promote fibroblast activation possibly through the PTEN and PI3K/Akt signaling pathways, which may serve as potential targets to further promote tendon-bone healing.

Low-intensity pulsed ultrasound promotes skeletal muscle regeneration via modulating the inflammatory immune microenvironment.

Background: Low-intensity pulsed ultrasound (LIPUS, a form of mechanical stimulation) can promote skeletal muscle functional repair, but a lack of mechanistic understanding of its relationship and tissue regeneration limits progress in this field. We investigated the hypothesis that specific energy levels of LIPUS mediates skeletal muscle regeneration by modulating the inflammatory microenvironment. Methods: To address these gaps, LIPUS irritation was applied in vivo for 5 min at two different intensities (30mW/cm2 and 60mW/cm2) in next 7 consecutive days, and the treatment begun at 24h after air drop-induced contusion injury. In vitro experiments, LIPUS irritation was applied at three different intensities (30mW/cm2, 45mW/cm2, and 60mW/cm2) for 2 times 24h after introduction of LPS in RAW264.7. Then, we comprehensively assessed the functional and histological parameters of skeletal muscle injury in mice and the phenotype shifting in macrophages through molecular biological methods and immunofluorescence analysis both in vivo and in vitro. Results: We reported that LIPUS therapy at intensity of 60mW/cm2 exhibited the most significant differences in functional recovery of contusion-injured muscle in mice. The comprehensive functional tests and histological analysis in vivo indirectly and directly proved the effectiveness of LIPUS for muscle recovery. Through biological methods and immunofluorescence analysis both in vivo and in vitro, we found that this improvement was attributable in part to the clearance of M1 macrophages populations and the increase in M2 subtypes with the change of macrophage-mediated factors. Depletion of macrophages in vivo eliminated the therapeutic effects of LIPUS, indicating that improvement in muscle function was the result of M2-shifted macrophage polarization. Moreover, the M2-inducing effects of LIPUS were proved partially through the WNT pathway by upregulating FZD5 expression and enhancing ß-catenin nuclear translocation in macrophages both in vitro and in vivo. The inhibition and augment of WNT pathway in vitro further verified our results. Conclusion: LIPUS at intensity of 60mW/cm2 could significantly promoted skeletal muscle regeneration through shifting macrophage phenotype from M1 to M2. The ability of LIPUS to direct macrophage polarization may be a beneficial target in the clinical treatment of many injuries and inflammatory diseases.

Exercise-induced IL-15 acted as a positive prognostic implication and tumor-suppressed role in pan-cancer.

Objective: Exercise can produce a large number of cytokines that may benefit cancer patients, including Interleukin 15 (IL-15). IL-15 is a cytokine that has multiple functions in regulating the adaptive and innate immune systems and tumorigenesis of lung and breast cancers. However, the roles of IL-15 in other types of cancer remain unknown. In this article, we try to systematically analyze if IL-15 is a potential molecular biomarker for predicting patient prognosis in pan-cancer and its connection with anti-cancer effects of exercise. Methods: The expression of IL-15 was detected by The Cancer Genome Atlas (TCGA) database, Human protein Atlas (HPA), and Genotype Tissue-Expression (GTEX) database. Analysis of IL-15 genomic alterations and protein expression in human organic tissues was analyzed by the cBioPortal database and HPA. The correlations between IL-15 expression and survival outcomes, clinical features, immune-associated cell infiltration, and ferroptosis/cuproptosis were analyzed using the TCGA, ESTIMATE algorithm, and TIMER databases. Gene Set Enrichment Analysis (GSEA) was performed to evaluate the biological functions of IL-15 in pan-cancer. Results: The differential analysis suggested that the level of IL-15 mRNA expression was significantly downregulated in 12 tumor types compared with normal tissues, which is similar to the protein expression in most cancer types. The high expression of IL-15 could predict the positive survival outcome of patients with LUAD (lung adenocarcinoma), COAD (colon adenocarcinoma), COADREAD (colon and rectum adenocarcinoma), ESCA (esophageal carcinoma), SKCM (skin cutaneous melanoma), UCS (uterine carcinosarcoma), and READ (rectum adenocarcinoma). Moreover, amplification was found to be the most frequent mutation type of IL-15 genomic. Furthermore, the expression of IL-15 was correlated to the infiltration levels of various immune-associated cells in pan-cancer assessed by the ESTIMATE algorithm and TIMER database. In addition, IL-15 is positively correlated with ferroptosis/cuproptosis-related genes (ACSL4 and LIPT1) in pan-cancer. Levels of IL-15 were reported to be elevated in humans for 10-120 min following an acute exercise. Therefore, we hypothesized that the better prognosis of pan-cancer patients with regular exercise may be achieved by regulating level of IL-15. Conclusion: Our results demonstrated that IL-15 is a potential molecular biomarker for predicting patient prognosis, immunoreaction, and ferroptosis/cuproptosis in pan-cancer and partly explained the anti-cancer effects of exercise.

Catalytic anti-oxidative stress for osteoarthritis treatment by few-layered phosphorene.

As one of the most common representations of articular cartilage damage, osteoarthritis (OA) is characterized by the apoptosis and dysfunction of chondrocytes as well as the progressive degradation of extracellular matrix, of which the main components are glycosaminoglycan and type Ⅱ collagen. Few-layered phosphorene (FLP) has been attracting great attentions in biomedical fields owing to the excellent capability of in-situ catalysis for scavenging oxidate-associated molecules, especially the reactive oxygen species (ROS) and reactive nitrogen species (RNS). Herein, FLP has been fabricated and employed for articular cartilage protection by means of deleting oxidate-associated molecules. The in vitro results show that as low as 200 â€‹µg/mL FLP is capable of diminishing oxidative damages on the osteoarthritic chondrocytes through the efficient elimination of ROS, H2O2 and NO. Meanwhile, the cartilage matrix protection has also been achieved at 200 â€‹µg/mL FLP by the uniform restoration of glycosaminoglycan and type Ⅱ collagen. FLP enables the nanocatalytic treatment for the overloaded oxidative stress in the injured articular cartilage and represents a promising alternative for osteoarthritis therapy.

Exercise improves choroid plexus epithelial cells metabolism to prevent glial cell-associated neurodegeneration.

Recent studies have shown that physical activities can prevent aging-related neurodegeneration. Exercise improves the metabolic landscape of the body. However, the role of these differential metabolites in preventing neurovascular unit degeneration (NVU) is still unclear. Here, we performed single-cell analysis of brain tissue from young and old mice. Normalized mutual information (NMI) was used to measure heterogeneity between each pair of cells using the non-negative Matrix Factorization (NMF) method. Astrocytes and choroid plexus epithelial cells (CPC), two types of CNS glial cells, differed significantly in heterogeneity depending on their aging status and intercellular interactions. The MetaboAnalyst 5.0 database and the scMetabolism package were used to analyze and calculate the differential metabolic pathways associated with aging in the CPC. These mRNAs and corresponding proteins were involved in the metabolites (R)-3-Hydroxybutyric acid, 2-Hydroxyglutarate, 2-Ketobutyric acid, 3-Hydroxyanthranilic acid, Fumaric acid, L-Leucine, and Oxidized glutathione pathways in CPC. Our results showed that CPC age heterogeneity-associated proteins (ECHS1, GSTT1, HSD17B10, LDHA, and LDHB) might be directly targeted by the metabolite of oxidized glutathione (GSSG). Further molecular dynamics and free-energy simulations confirmed the insight into GSSG's targeting function and free-energy barrier on these CPC age heterogeneity-associated proteins. By inhibiting these proteins in CPC, GSSG inhibits brain energy metabolism, whereas exercise improves the metabolic pathway activity of CPC in NVU by regulating GSSG homeostasis. In order to develop drugs targeting neurodegenerative diseases, further studies are needed to understand how physical exercise enhances NVU function and metabolism by modulating CPC-glial cell interactions.

Knee Cartilage Change within 5 Years after Aclr Using Hamstring Tendons with Preserved Tibial-Insertion: A Prospective Randomized Controlled Study Based on Magnetic Resonance Imaging.

Background: Comparing to anterior cruciate ligament reconstructions (ACLR) with free hamstring tendon (FHT), ACLR with preserved tibial-insertion hamstring tendon (HT-PTI) could ensure the blood supply of the graft and avoid graft necrosis. Yet, whether HT-PTI could protect the cartilage and clinical outcomes in mid-long period after ACLR was still unclear. Purpose: To compare the cartilage change and clinical results between the HT-PTI and FHT in 5 years after ACLR. Study design: Randomized controlled trial; Level of evidence, 2. Methods: A total of 45 patients who underwent isolated ACLR with the autograft of hamstring tendons were enrolled and randomized into 2 groups. The study group undertook ACLR with HT-PTI, whereas the control group had FHT. At pre-operation, and 6, 12, 24, and 60 months post-operation, all cases underwent evaluation with Knee Injury and Osteoarthritis Outcome Score (KOOS), and MR examination. The knee cartilage was divided into 8 sub-regions of which the T2 value and cartilage volume on MRI were measured and documented. The data of two groups were compared and their correlations were analyzed. Results: A total of 18 patients in the HT-PTI group and 19 patients in the FHT group completed the follow-up. The KOOS scores were improved at each follow-up time point (p < 0.001), reached the most superior at 12 months and maintained until 60 months but had no significant difference between the two groups. At 60 months, the cartilage in most subregions in FHT group had higher T2 values than those of pre-operation (p < 0.05) and also higher than HT-PTI group; The cartilage volume changes (CV%) are positive at 6 months and negative from 12 to 60 months in the FHT group, while being negative at all time points in the HT-PTI group. The values of absolute CV% in most subregions in FHT group were significantly higher than those in the HT-PTI group at 6 and 60 months (p < 0.05). Conclusion: The improvement of KOOS score peaked at 12 months in all cases and had no difference between the two groups. The cartilage in the FHT group had more volume loss, earlier and wider damage than that in the HT-PTI group within 5 years. No significant correlation was found among KOOS score, CV%, and T2 value.

The effect of denture-wearing on physical activity is associated with cognitive impairment in the elderly: A cross-sectional study based on the CHARLS database.

Background: Currently, only a few studies have examined the link between dental health, cognitive impairment, and physical activity. The current study examined the relationship between denture use and physical activity in elderly patients with different cognitive abilities. Methods: The study data was sourced from the 2018 China Health and Retirement Longitudinal Study (CHARLS) database, which included information on denture use and amount of daily physical activity undertaken by older persons. Physical activity was categorized into three levels using the International Physical Activity General Questionnaire and the International Physical Activity Scale (IPAQ) rubric. The relationship between denture use and physical activity in middle-aged and older persons with varying degrees of cognitive functioning was studied using logistic regression models. Results: A total of 5,892 older people with varying cognitive abilities were included. Denture use was linked to physical activity in the cognitively healthy 60 + age group (p = 0.004). Denture use was positively related with moderate physical activity in the population (odds ratio, OR: 1.336, 95% confidence interval: 1.173-1.520, p < 0.001), according to a multivariate logistic regression analysis, a finding that was supported by the calibration curve. Furthermore, the moderate physical activity group was more likely to wear dentures than the mild physical activity group among age-adjusted cognitively unimpaired middle-aged and older persons (OR: 1.213, 95% CI: 1.053-1.397, p < 0.01). In a fully adjusted logistic regression model, moderate physical activity population had increased ORs of 1.163 (95% CI: 1.008-1.341, p < 0.05) of dentures and vigorous physical activity population had not increased ORs of 1.016 (95% CI: 0.853-1.210, p > 0.05), compared with mild physical activity population. Conclusion: This findings revealed that wearing dentures affects physical activity differently in older persons with different cognitive conditions. In cognitively unimpaired older adults, wearing dentures was associated with an active and appropriate physical activity status.

si-Tgfbr1-loading liposomes inhibit shoulder capsule fibrosis via mimicking the protective function of exosomes from patients with adhesive capsulitis.

BACKGROUND: Adhesive capsulitis is a common shoulder disorder inducing joint capsule fibrosis and pain. When combined with rotator cuff tear (RCT), treatments can be more complex. Currently, targeted therapy is lacking. Since adhesive capsulitis is reported to be related to circulating materials, we analyzed the contents and biology of circulating exosomes from RCT patients with and without adhesive capsulitis, in an attempt to developing a targeting treatment. METHODS: Samples from a consecutive cohort of patients with RCT for surgery were collected. Circulating exosomal miRNAs sequencing were used to detect differentially expressed miRNAs in patients with and without adhesive capsulitis. For experiments in vitro, Brdu staining, CCK-8 assay, wound healing test, collagen contraction test, real-time quantitative polymerase chain reaction, and western blot were conducted. Histological and immunofluorescent staining, and biomechanical analysis were applied in a mouse model of shoulder stiffness. The characteristics of liposomes loaded with siRNA were measured via dynamic light scattering or electron microscopy. RESULTS: Circulating exosomal miRNAs sequencing showed that, compared to exosomes from patients without adhesive capsulitis, miR-142 was significantly up-regulated in exosomes from adhesive capsulitis (Exo-S). Both Exo-S and miR-142 could inhibit fibrogenesis, and the anti-fibrotic effect of Exo-S relied on miR-142. The target of miR-142 was proven to be transforming growth factor ß receptor 1 (Tgfbr1). Then, liposomes were developed and loaded with si-Tgfbr1. The si-Tgfbr1-loading liposomes exhibited promising therapeutic effect against shoulder stiffness in mouse model with no evidence toxicity. CONCLUSION: This study showed that, in RCT patients with adhesive capsulitis, circulating exosomes are protective and have anti-fibrotic potential. This effect is related to the contained miR-142, which targets Tgfbr1. By mimicking this biological function, liposomes loaded with si-Tgfbr1 can mitigate shoulder stiffness pre-clinically.

Nanoparticle functionalization with genetically-engineered mesenchymal stem cell membrane for targeted drug delivery and enhanced cartilage protection.

Articular cartilage encounters structural damage and tissue degeneration during osteoarthritis. It is of great significance to effectively deliver the therapeutic drug to the location of the cartilage lesion. Nanoparticle-based biomimetic systems provide an important solution for drug delivery, but they still lack the active targeting capability. Although some physical and chemical modifications could decrease non-specific interactions to some extent, a specific bio-interaction for active targeting is still required for many biomedical purposes. In this study, we proposed genetically-engineered mesenchymal stem cell membrane-derived nanoparticles with the active targeting capability. BMSCs were engineered for the high expression of CXCR4 to actively migrate to the injured locations, and cell membrane of the engineered BMSCs was isolated and camouflaged to fluorescent nanoparticles. The modified nanoparticles that loaded with the therapeutic drug were incubated with IL-1ß-induced injured articular chondrocytes and cartilage. The results invisibly demonstrated that these engineered nanoparticles could increase both cellular uptake and penetration depth in the target cells and tissues under inflammatory microenvironments to protect the injured cartilage. Therefore, this genetically-modified nanoparticle functionalization strategy is expected to provide evidence for active targeting in the tissue injury treatment.