Microglial metabolic dysfunction is increasingly recognized as a key driver of neuroinflammation in Alzheimer’s disease (AD). However, the specific metabolic regulators linking lipid metabolism to pathological activation remain poorly defined. We performed integrative transcriptomic analysis on four human AD brain datasets to identify core metabolic hubs. Sprouty homolog 1 (SPRY1) expression was examined in human post-mortem tissues, and its functional role was validated in primary microglia, Drosophila, and APP/PS1-21 mice using genetic knockdown, behavioral assays, and histological analysis. Moreover, we employed co-immunoprecipitation, mass spectrometry, and metabolic flux assays to elucidate the underlying pathways. We identified SPRY1 as a key hub gene upregulated in the hippocampus of AD patients and mouse models. SPRY1 was predominantly expressed in plaque-associated microglia, and specifically correlated with advancing age, Aβ load and Braak stage. Functionally, microglial SPRY1 knockdown enhanced Aβ phagocytosis, reduced pro-inflammatory cytokines, and protected neurons from Aβ-induced damage in vitro. In vivo, glial-specific knockdown of the SPRY1 homolog sty rescued cognitive and motor deficits in AD flies, while microglia-specific knockdown in mice reduced amyloidosis and neuroinflammation. Mechanistically, SPRY1 acted as a metabolic switch by retaining fatty acid transport protein 3 (FATP3) on the endoplasmic reticulum (ER). This interaction blocked FATP3 translocation to mitochondria, thereby reducing fatty acid oxidation (FAO) and promoting lipid droplet (LD) accumulation, which drives a microglial pro-inflammatory phenotype. This study unveils a novel SPRY1-FATP3 retention mechanism that links impaired fatty acid metabolism to neuroinflammation. Targeting this axis represents a promising strategy to reprogram microglial metabolism and provide neuroprotection in AD.

Spinal cord injury (SCI) induces neuroinflammation predominantly mediated by microglia, thereby establishing a detrimental milieu that impedes neurological recovery. Extracellular vesicles (EVs) derived from umbilical cord mesenchymal stem cells (UCMSCs) possess considerable therapeutic potential; however, their clinical translation is constrained by insufficient bioactivity, poor targeting specificity, and uncontrolled release kinetics. Here, we present a multidimensional engineering strategy that overcomes these barriers synergistically. Tetramethylpyrazine (TMP)-pretreated extracellular vesicles (TEVs) are enriched with anti-inflammatory and pro-regenerative factors in their cargo, while Angiopep-2 (Ang2) peptide-modified TEVs (Ang-TEVs) confer significantly enhanced microglial targeting. A reactive oxygen species (ROS)-responsive hyaluronic acid (HA)-phenylboronic acid (PBA)/polyvinyl alcohol (PVA) hydrogel serves as an intelligent depot for sustained, on-demand Ang-TEVs release at the lesion site. This construct, Ang-TEVs@Gel, demonstrated robust lesion accumulation and selective microglial uptake. It delivered miR-664a-3p, which suppressed PIK3CA to attenuate PI3K-AKT-mTOR signaling and unleash autophagic flux, reprogramming microglia toward a reparative state that enhanced myelin debris clearance and quelled inflammation. Consequently, axonal regeneration and remyelination were markedly improved, driving significant motor recovery in SCI mice. By integrating preconditioning, active targeting, and stimuli-responsive biomaterials, this strategy provides an elegant blueprint for engineering EV-based therapies to repair the injured central nervous system.

Aberrant metabolic alterations underlie microglial dysfunction, which plays an important role during neurodegenerative progression. However, the role of aberrant glycogen metabolism remains elusive. Here, we identified glycogen accumulation and upregulated glycogenolytic enzymes in brain microglia from patients with Alzheimer’s disease (AD) and transgenic animal models. Particularly, the principal microglial glycogenolytic enzyme PYGL exhibited the most notable spatiotemporal upregulation during disease progression. Specific knockdown of microglial PYGL ameliorated neuropathological changes and cognitive deficits in AD mice. Bioinformatics analysis and experimental validation confirmed that enhancing microglial autophagic flux-dependent Aβ clearance was the underlying mechanism. Furthermore, among all possible glycogenolytic pathways, PYGL downregulation primarily reduced hexosamine biosynthesis pathway activity, diminished UDP-GlcNAc and O-GlcNAcylation of the autophagy key protein SNAP29, and thereby facilitated formation of the SNARE complex, which is essential for autophagosome–lysosome fusion. These findings reveal a glycogenolysis-driven post-translational pathway regulating microglial autophagy, establishing PYGL as a therapeutic target for AD.

BACKGROUND AND AIMS:Inflammageing represents both a critical pathophysiological hallmark and independent risk factor for myocardial infarction (MI), with age-related increases observed in MI incidence and severity of post-MI ventricular remodelling. Novel therapeutic strategies targeting inflammageing-driven mechanisms are urgently required to attenuate adverse ventricular remodelling following MI. This investigation was designed to elucidate the impact of fibroblast-specific p16INK4a on inflammageing-associated ventricular remodelling after MI and to develop a targeted nanotherapy to mitigate this process. METHODS AND RESULTS:We found that p16-mediated inflammageing positively correlated with the severity of post-infarction ventricular remodelling in patients. POSTN-driven p16INK4a knockout improved cardiac function, and reduced ventricular remodelling, myocardial inflammation and NLRP3 signalling activation following MI through downregulating STAT3-mediated NLRP3 inflammasome and upregulating glutathione metabolism pathway in fibroblasts. P16INK4a overexpression induced NLRP3 signalling activation through upregulating NLRP3 transcribed by STAT3 in fibroblasts. In terms of mechanisms, p16INK4a interacted with STAT3, which depended on the SH2 domain of STAT3; P16INK4a promoted the interaction of EZH2 and STAT3, increased the di-methylation on K49 and phosphorylation on Y705 of STAT3 by EZH2, and promoted NLRP3 transcription through regulating histone modification in the NLRP3 promoter by interfering the formation of Bmi-1-EZH2 or Bmi-1-BCL6 complex in fibroblasts. Injection of p16INK4a-accumulated ageing cardiac fibroblasts, or p16INK4a overexpression adenovirus aggravated profibrosis and proinflammation in MI area. However, a novel FH peptide 'FHKHKSPALSPV'-neutrophil membrane proteins (NMPs)-artificial lipid (Li) membranes-mesoporous silica nanoparticle (MSN) core (FNLM)-nanocaged p16INK4a-siRNA, as a newly constructed nanomaterial drug, could prevent post-infarction ventricular remodelling through inhibiting NLRP3 transcription in targeted cardiac fibroblasts and ameliorating proinflammation and profibrosis. CONCLUSIONS:P16INK4a drives inflammageing-mediated post-MI ventricular remodeling by activating STAT3/NLRP3 signaling in fibroblasts. Targeting p16INK4a via FNLM-siRNA nanotherapy represents a novel strategy to ameliorate adverse cardiac remodelling, offering translational potential for clinical intervention. KEY POINTS:Mechanistic Insight: P16INK4a activates NLRP3 transcription via STAT3-EZH2 crosstalk, disrupting epigenetic complexes (Bmi-1-EZH2/BCL6) to exacerbate post-MI remodelling. Therapeutic Innovation: A fibroblast-targeted FNLM nanoparticle delivering p16INK4a-siRNA effectively silences NLRP3, reducing post-MI inflammageing. Translational Impact: This study identifies p16INK4a-STAT3 as a druggable axis and proposes FNLM-p16INK4a-siRNA as a promising nanotherapy for clinical post-MI care.

New immunosenescence targets for preventing senescence-associated pathological cardiac hypertrophy (SA-PCH) need to be explored. In the present study, with physiologically aged human and mouse samples, the IL-17A level increased with physiological aging, heart failure (HF), and SA-PCH and was negatively correlated with thymic Bmi-1 expression. Bmi-1 f/f LckCre + mice and Bmi-1 f/f littermates were generated to determine whether Bmi-1 delayed T cell aging by maintaining thymic T cell development to prevent SA-PCH. As a result, Bmi-1 promoted thymic T cell development by upregulating Notch signaling and prevented DN1 T cells from differentiating into γδT17 cells by downregulating γδT17 cell differentiation signaling. Bmi-1 upregulated Notch signaling by inhibiting p53-mediated Ikzf1 transcription at the −1,863 to −1,849 Ikzf1 promoter region. Bmi-1–RING1B promoted RORγt ubiquitination and degradation by proteasome to inhibit the production of IL-17A in γδT17 cells. Bmi-1 also downregulated Rorc transcribed by c-Maf by trimethylating H3K27 at the −1,511 to −1,497 Rorc promoter region. Subsequently, the number of peripheral γδT17 cells infiltrating the heart tissues was reduced, while alleviating IL-17A-dependent cardiac aging, hypertrophy, dysfunction, senescence-associated secretory phenotype (SASP), and macrophage–myofibroblast transition, ultimately improving SA-PCH. The RORγt inhibitor SR1001 and IL-17A neutralizing antibody ixekizumab prevented thymic RORγt-IL-17A-dependent SA-PCH. Furthermore, RORγt bound to Bmi-1 through ARG237 and to RING1B through GLU235, which could be used as a therapeutic strategy for SA-PCH to construct binding peptides promoting Bmi-1–RING1B binding to RORγt and degrading RORγt for inhibiting γδT17 cell differentiation and IL-17A production. Thus, thymic Bmi-1 prevented IL-17A-dependent SA-PCH by decreasing γδT17 cell numbers.

Spinal cord injury (SCI) is a critical neurological disorder that frequently leads to permanent disability, profoundly affecting the quality of life of individuals with SCI. In this research, we examined the varied expression of genes associated with metabolic reprogramming–related genes in SCI. By employing the Gene Expression Omnibus datasets GSE5296 and GSE47681, 1001 differentially expressed genes (DEGs) were identified through the limma R package. Among these, 871 and 130 genes were upregulated and downregulated, respectively. A subset of 10 metabolic reprogramming–related differentially expressed genes (MRRDEGs) was recognized as key players in metabolic reprogramming. Analyses of enrichment performed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes indicated that the identified MRRDEGs predominantly participated in processes related to pyruvate metabolism and carbohydrate degradation. Nine hub genes were discerned using a protein–protein interaction network. Subsequently, an SCI mouse model was established using the LISA SCI modeling device, and preliminary validation was conducted through quantitative real-time PCR experiments at various time points after SCI, specifically on days 1, 3, and 7, suggesting their central role in SCI. Receiver operating characteristic curve analysis indicated that these MRRDEGs could be used to diagnose SCI. The CIBERSORT algorithm analysis of immune infiltration identified an inverse relationship between M0 and M2 macrophages. Furthermore, a positive relationship was observed between Ucp2 and M0 macrophages, underscoring their essential function in the immune response following SCI. These results highlight MRRDEGs’ importance in SCI and propose their potential roles as targets for therapeutic interventions. Using data from the public GEO database, we identified differentially expressed genes associated with metabolic reprogramming in spinal cord injury and successfully validated them through qPCR experiments.

Cardiovascular diseases with their related secondary complications are the main causes of morbidity and mortality worldwide. Abdominal aortic aneurysm (AAA) belongs to the cardiovascular diseases and causes approximately 1.3 % of all deaths among men between 65 and 85 years old in developed countries [1]. The pathogenesis of AAA mainly attributes to pathological dilation of the abdominal aorta, which will further lead to a high mortality rate up to 85 % due to excessive dilation and rupture [2]. A criterion was proposed in 1991 that AAA infrarenal aorta diameter should be 1.5 times the normal diameter [3], and McGregor additionally defined AAA as an aorta with a diameter greater than 30 mm in the infrarenal segment [4]. Although the diagnosis of AAA seems conclusive, there is no specific treatment to prevent AAA expansion. Elective aortic repair operation is conditional recommended when the aneurysm diameter reaches 55 mm in men, 50 mm in women or grows by 6 mm to 8 mm per year [5]. However, small aneurysms probably also grow rapidly or rupture at a high risk, and even some patients die from aneurysm rupture before they manifest surgical indications. Thus, controlling risk factors and exploring novel therapeutic approaches gradually substitute as key directions for aneurysm treatment. Smoking, hypertension, age and gender have been identified as the common risk factors during AAA progression in the past decades [6], but the mechanisms how these hazards contribute to pathological dilatation of abdominal aortas remain unclear. Interestingly, histone modifications have recently emerged as an important link between the intrinsic genetic landscape and extrinsic risk factors, and a plethora of studies have been dedicated to exploring the role of histone modifications in AAA pathogenesis. In this review, current progress on the contribution of histone modifications to the regulation of AAA will be summarized.

This study investigates the role of salidroside-pretreated small extracellular vesicles (SAL-sEVs) derived from human umbilical cord mesenchymal stem cells (Huc-MSCs) in spinal cord injury (SCI). Results demonstrate that these sEVs repair the damaged blood-spinal cord barrier (BSCB) and facilitate functional recovery. sEVs were collected from Huc-MSCs pretreated with salidroside via ultracentrifugation. sEVs were characterized using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot. The uptake of sEVs by endothelial cells was confirmed through immunofluorescence. The regulatory effects of SAL-sEVs on BSCB permeability and tight junction proteins were examined using immunofluorescence and Western blot. Microglial polarization was assessed via ELISA, qRT-PCR, and Western blot. Motor function was evaluated through behavioral tests. SAL-sEVs were endocytosed by endothelial cells, reduced BSCB permeability by regulating tight junction proteins, alleviated secondary inflammation, facilitated repair of spinal cord injury sites, and improved motor function in mice. Salidroside augments the therapeutic promise of Huc-MSC-derived small extracellular vesicles in repairing the BSCB, inflammation reduction, and functional recovery post-SCI, offering a novel therapeutic approach for the treatment of SCI.

Recent single-cell RNA sequencing study suggested that CRABP1 expressing neurons in the arcuate nucleus (ARCCRABP1 neurons) were a distinct group of neurons. However, the physiological role of ARCCRABP1 neurons remains unexplored. Here, we demonstrated that ARCCRABP1 neurons played a crucial role in regulation of energy homeostasis in male mice. Ablation of ARCCRABP1 neurons resulted in obesity and a diabetic phenotype in mice. By employing chemogenetic or optogenetic manipulation techniques, the inhibition and activation of ARCCRABP1 neurons resulted in an increase and decrease in food intake, respectively. The axon terminals from these ARCCRABP1 neurons project to several brain regions implicated in feeding regulation such as PVH, BNST, PBN, and NTS. Optogenetic manipulation of these axons within these brain regions resulted in significant alterations of food intake behavior in mice. Furthermore, the electrophysiological studies demonstrated that the activation of ARCCRABP1 neurons induces depolarization in POMC neurons in the hypothalamus. The hormone stimulation studies showed that most of the ARCCRABP1 neurons respond to insulin. Collectively, our findings demonstrate that ARCCRABP1 neurons represent a distinct neuronal subtype involved in energy homeostasis regulation. POMC and AgRP neurons in hypothalamus were widely known to regulate energy balance. Here, authors show that ARCCRABP1 neurons are identified as a new player influencing appetite and metabolism.

Parathyroid hormone-related peptide (PTHrP) is a factor that plays an important role in the growth and development of multiple organs. The role of PTHrP in lung development has not been characterized. In order to further investigate the in vivo functions of PTHrP nuclear localization sequence (NLS) and C-terminus, Professor Andrew Karaplis and Professor Dengshun Miao et al. used genetic engineering technology to knock in (KI) a stop codon (TGA) after the 84th amino acid sequence of PTHrP and constructed a mouse model expressing only PTHrP (1-84), but not NLS and C-terminus, namely PTHrP NLS and C-terminal knockout mice (also PTHrP KI mice). Using this genetically modified mouse model, we have characterized its effect on early postnatal lung development. Compared with those in littermate wild-type (WT) mice, the body size and lung volume were significantly reduced and the lung weight index was significantly increased in PTHrP KI mice. Histologically, deletion of the NLS and C-terminus of PTHrP could reduce lung cell proliferation, facilitate cell apoptosis, increase the expression of inflammatory factors, cause increased oxidative stress and DNA damage, and lead to lung dysplasia. Meanwhile, deletion of the NLS and C-terminus of PTHrP could also induce pulmonary fibrosis by activating the TGF-β/Smad signaling pathway. We conclude that PTHrP NLS and C-terminus play important roles in lung development.

Traumatic spinal cord injury (SCI) always leads to severe neurological deficits and permanent damage. Neuroinflammation is a vital process of SCI and have become a promising target for SCI treatment. However, the neuroinflammation-targeted therapy would hinder the functional recovery of spinal cord and lead to the treatment failure. Herein, a biomimic anti-neuroinflammatory nanoplatform (DHCNPs) was developed for active neutrophil extracellular traps (NETs) targeting and SCI treatment. The curcumin-loaded liposome with the anti-inflammatory property acted as the core of the DHCNPs. Platelet membrane and neutrophil membrane were fused to form the biomimic hybrid membrane of the DHCNPs for hijacking neutrophils and neutralizing the elevated neutrophil-related proinflammatory cytokines, respectively. DNAse I modification on the hybrid membrane could achieve NETs degradation, blood spinal cord barrier, and neuron repair. Further studies proved that the DHCNPs could reprogram the multifaceted neuroinflammation and reverse the SCI process via nuclear factor kappa-B (NF-κB) pathway. We believe that the current study provides a new perspective for neuroinflammation inhibition and may shed new light on the treatment of SCI.

In the domain of anatomy, some Chinese characters in anatomical terms possess distinctive morphological significance. Chinese characters evolved from pictographic characters, with some of these pictographs being created by ancient people based on their own body structure. This implies that the comprehension and depiction of the human body structure have been integral since the inception of Chinese characters, and this knowledge has been passed down and developed through the continued inheritance of Chinese characters. Even today, certain characters retain the appearance to reflect the shape of the human body structure. By examining the characters related to vertebrae, cranial fontanel and heart, we can find the unique and enduring link between Chinese characters and the fields of anatomy as well as Chinese traditional medicine.

In this study, we aimed to work through the key genes involved in the process of pyroptosis in Alzheimer's disease (AD) to identify potential biomarkers using bioinformatics technology and further explore the underlying molecular mechanisms. The transcriptome data of brain tissue in AD patients were screened from the GEO database, and pyroptosis-related genes were analyzed. The functions of differential genes were analyzed by enrichment analysis and protein-protein interaction. The diagnostic model was established using LASSO and logistic regression analysis, and the correlation of clinical data was analyzed. Based on single-cell analysis of brain tissues of patients with AD, immunofluorescence and western blotting were used to explore the key cells affected by the hub gene. After GSEA, qRT-PCR, western blotting, LDH, ROS, and JC-1 were used to investigate the potential mechanism of the hub gene on pyroptosis. A total of 15 pyroptosis differentially expressed genes were identified. A prediction model consisting of six genes was established by LASSO and logistic regression analysis, and the area under the curve was up to 0.81. As a hub gene, CHMP4B was negatively correlated with the severity of AD. CHMP4B expression was decreased in the hippocampal tissue of patients with AD and mice. Single-cell analysis showed that CHMP4B was downregulated in AD microglia. Overexpression of CHMP4B reduced the release of LDH and ROS and restored mitochondrial membrane potential, thereby alleviating the inflammatory response during microglial pyroptosis. In summary, CHMP4B as a hub gene provides a new strategy for the diagnosis and treatment of AD.

Background:Gigantocellular reticular nucleus (GRNs) executes a vital role in locomotor recovery after spinal cord injury. However, due to its unique anatomical location deep within the brainstem, intervening in GRNs for spinal cord injury research is challenging. To address this problem, this study adopted an extracorporeal magnetic stimulation system to observe the effects of selective magnetic stimulation of GRNs with iron oxide nanoparticles combined treadmill training on locomotor recovery after spinal cord injury, and explored the possible mechanisms. Methods:Superparamagnetic iron oxide (SPIO) nanoparticles were stereotactically injected into bilateral GRNs of mice with moderate T10 spinal cord contusion. Eight-week selective magnetic stimulation produced by extracorporeal magnetic stimulation system (MSS) combined with treadmill training was adopted for the animals from one week after surgery. Locomotor function of mice was evaluated by the Basso Mouse Scale, Grid-walking test and Treadscan analysis. Brain MRI, anterograde virus tracer and immunofluorescence staining were applied to observe the tissue compatibility of SPIO in GRNs, trace GRNs' projections and evaluate neurotransmitters' expression in spinal cord respectively. Motor-evoked potentials and H reflex were collected for assessing the integrity of cortical spinal tract and the excitation of motor neurons in anterior horn. Results:(1) SPIO persisted in GRNs for a minimum of 24 weeks without inducing apoptosis of GRN cells, and degraded slowly over time. (2) MSS-enabled treadmill training dramatically improved locomotor performances of injured mice, and promoted cortico-reticulo-spinal circuit reorganization. (3) MSS-enabled treadmill training took superimposed roles through both activating GRNs to drive more projections of GRNs across lesion site and rebalancing neurotransmitters' expression in anterior horn of lumbar spinal cord. Conclusion:These results indicate that selective MSS intervention of GRNs potentially serves as an innovative strategy to promote more spared fibers of GRNs across lesion site and rebalance neurotransmitters' expression after spinal cord injury, paving the way for the structural remodeling of neural systems collaborating with exercise training, thus ultimately contributing to the reconstruction of cortico-reticulo-spinal circuit.

AbstractWith the increase in the aging population, senile osteoporosis (SOP) has become a major global public health concern. Here, it is found that Prx1 and Bmi‐1 co‐localized in trabecular bone, bone marrow cavity, endosteum, and periosteum. Prx1‐driven Bmi‐1 knockout in bone‐marrow mesenchymal stem cells (BMSCs) reduced bone mass and increased bone marrow adiposity by inhibiting osteoblastic bone formation, promoting osteoclastic bone resorption, downregulating the proliferation and osteogenic differentiation of BMSCs, and upregulating the adipogenic differentiation of BMSCs. However, Prx1‐driven Bmi‐1 overexpression showed a contrasting phenotype to Prx1‐driven Bmi‐1 knockout in BMSCs. Regarding mechanism, Bmi‐1‐RING1B bound to DNMT3A and promoted its ubiquitination and inhibited DNA methylation of Runx2 at the region from 45047012 to 45047313 bp, thus promoting the osteogenic differentiation of BMSCs. Moreover, Bmi‐1‐EZH2 repressed the transcription of Cebpa by promoting H3K27 trimethylation at the promoter region −1605 to −1596 bp, thus inhibiting the adipogenic differentiation of BMSCs. It is also found that Prx1‐driven Bmi‐1 overexpression rescued the SOP induced by Prx1‐driven Bmi‐1 knockout in BMSCs. Thus, Bmi‐1 functioned as a hub protein in the epigenetic regulation of BMSCs differentiation to delay bone aging. The Prx1‐driven Bmi‐1 overexpression in BMSCs can be used as an approach for the translational therapy of SOP.

Physiologically aged lungs are prone to senescence-associated pulmonary diseases (SAPD). This study aimed to determine the mechanism and subtype of aged T cells affecting alveolar type II epithelial (AT2) cells, which promote the pathogenesis of senescence-associated pulmonary fibrosis (SAPF). Cell proportions, the relationship between SAPD and T cells, and the aging- and senescence-associated secretory phenotype (SASP) of T cells between young and aged mice were analyzed using lung single-cell transcriptomics. SAPD was monitored by markers of AT2 cells and found to be induced by T cells. Furthermore, IFNγ signaling pathways were activated and cell senescence, SASP, and T cell activation were shown in aged lungs. Physiological aging led to pulmonary dysfunction and TGF-β1/IL-11/MEK/ERK (TIME) signaling-mediated SAPF, which was induced by senescence and SASP of aged T cells. Especially, IFNγ was produced by the accumulated CD4+ effector memory T (TEM) cells in the aged lung. This study also found that physiological aging increased pulmonary CD4+ TEM cells, IFNγ was produced mainly by CD4+ TEM cells, and pulmonary cells had increased responsiveness to IFNγ signaling. Specific regulon activity was increased in T cell subclusters. IFNγ transcriptionally regulated by IRF1 in CD4+ TEM cells promoted the epithelial-to-mesenchymal transition by activating TIME signaling and cell senescence of AT2 cells with aging. Accumulated IRF1+CD4+ TEM produced IFNγ in lung with aging and anti-IRF1 primary antibody treatment inhibited the expression of IFNγ. Aging might drive T cell differentiation toward helper T cells with developmental trajectories and enhance cell interactions of pulmonary T cells with other surrounding cells. Thus, IFNγ transcribed by IRF1 in CD4+ effector memory T cells promotes SAPF. IFNγ produced by CD4+ TEM cells in physiologically aged lungs could be a therapeutic target for preventing SAPF.

The blood-spinal cord barrier (BSCB) is a physical barrier between the blood and the spinal cord parenchyma. Current evidence suggests that the disruption of BSCB integrity after spinal cord injury can lead to secondary injuries such as spinal cord edema and excessive inflammatory response. Regulatory T (Treg) cells are effective anti-inflammatory cells that can inhibit neuroinflammation after spinal cord injury, and their infiltration after spinal cord injury exhibits the same temporal and spatial characteristics as the automatic repair of BSCB. However, few studies have assessed the relationship between Treg cells and spinal cord injury, emphasizing BSCB integrity. This study explored whether Treg affects the recovery of BSCB after SCI and the underlying mechanism. We confirmed that spinal cord angiogenesis and Treg cell infiltration occurred simultaneously after SCI. Furthermore, we observed significant effects on BSCB repair and motor function in mice by Treg cell knockout and overexpression. Subsequently, we demonstrated the presence and function of exosomes in vitro. In addition, we found that Treg cell-derived exosomes encapsulated miR-2861, and miR-2861 regulated the expression of vascular tight junction (TJs) proteins. The luciferase reporter assay confirmed the negative regulation of IRAK1 by miR-2861, and a series of rescue experiments validated the biological function of IRAKI in regulating BSCB. In summary, we demonstrated that Treg cell-derived exosomes could package and deliver miR-2861 and regulate the expression of IRAK1 to affect BSCB integrity and motor function after SCI in mice, which provides novel insights for functional repair and limiting inflammation after SCI.

Sarcopenia increases with age, and an underlying mechanism needs to be determined to help with designing more effective treatments. This study aimed to determine whether 1,25(OH)(2)D-3 deficiency could cause cellular senescence and a senescence-associated secretory phenotype (SASP) in skeletal muscle cells to induce sarcopenia, whether GATA4 could be upregulated by 1,25(OH)(2)D-3 deficiency to promote SASP, and whether Bmi-1 reduces the expression of GATA4 and GATA4-dependent SASP induced by 1,25(OH)(2)D-3 deficiency in skeletal muscle cells. Bioinformatics analyses with RNA sequencing data in skeletal muscle from physiologically aged and young mice were conducted. Skeletal muscles from 2-month-old young and 2-year-old physiologically aged wild-type (WT) mice and 8-week-old WT, Bmi-1 mesenchymal transgene (Bmi-1(Tg)), Cyp27b1 homozygous (Cyp27b1(-/-)), and Bmi-1(Tg)Cyp27b1(-/-) mice were observed for grip strength, cell senescence, DNA damage, and NF-kappa B-mediated SASP signaling of skeletal muscle. We found that muscle-derived Bmi-1 and vitamin D receptor (VDR) decreased with physiological aging, and DNA damage and GATA4-dependent SASP activation led to sarcopenia. Furthermore, 1,25(OH)(2)D-3 deficiency promoted DNA damage-induced GATA4 accumulation in muscles. GATA4 upregulated Rela at the region from -1448 to -1412 bp at the transcriptional level to cause NF-kappa B-dependent SASP for aggravating cell senescence and muscular dysfunction and sarcopenia. Bmi-1 overexpression promoted the ubiquitination and degradation of GATA4 by binding RING1B, which prevented cell senescence, SASP, and dysfunctional muscle, and improved sarcopenia induced by 1,25(OH)(2)D-3 deficiency. Thus, Bmi-1 overexpression improves sarcopenia induced by 1,25(OH)(2)D-3 deficiency, downregulates GATA4-dependent Rela transcription, and sequentially inhibits GATA4-dependent SASP in muscle cells. Therefore, Bmi-1 overexpression could be used for translational gene therapy for the ubiquitination of GATA4 and prevention of sarcopenia. (c) 2023 American Society for Bone and Mineral Research (ASBMR).

目的 探索甲状旁腺素相关肽(PTHrP)核定位序列(NLS)与C末端在肾发育中的作用.方法 按照小鼠基因型进行分组,同窝野生型(WT)小鼠为对照组;PTHrP Knock In-/-小鼠为实验组.观察2组小鼠体型、肾的形态与结构;采用Masson染色、免疫组织化学、免疫荧光染色、TUNEL染色、蛋白质印迹法比较分析2组小鼠肾纤维化、增殖、凋亡与衰老相关指标,及炎症反应相关分子的表达变化.结果 对照组和实验组小鼠的体质量分别为(5.61±0.15)和(2.07±0.11)g;肾质量分别为(35.50±1.59)和(16.18±1.06)mg;Masson染色纤维化面积百分比分别为(1.30±0.15)％和(5.28±0.81)％;PCNA阳性细胞数百分比分别为(12.75±1.95)％和(5.82±0.85)％;TUNEL染色阳性细胞数百分比分别为(2.05±0.50)％和(7.20±1.06)％;p16蛋白相对表达水平分别为0.45±0.11和1.01±0.07;IL-1β 阳性面积百分比分别为(6.67±2.01)％和(35.74±3.83)％;实验组的上述指标与对照组相比,差异均有统计学意义(均P<0.05).结论 PTHrP NLS和C末端缺失可通过抑制肾细胞增殖、促进肾细胞凋亡,上调炎症因子的表达而导致肾发育异常.

Recent progress on the central lymphatic system has greatly increased our understanding of how the brain maintains its own waste homeostasis. Here, we showed that perivascular spaces and meningeal lymphatic vessels form a functional route for clearance of senescent astrocytes from the aging brain. Blocking meningeal lymphatic drainage by ligation of the deep cervical lymph nodes impaired clearance of senescent astrocytes from brain parenchyma, subsequently increasing neuroinflammation in aged mice. By contrast, enhancing meningeal lymphatic vessel diameter by a recombinant adeno-associated virus encoding mouse vascular endothelial growth factor-C (VEGF-C) improved clearance of senescent astrocytes and mitigated neuroinflammation. Mechanistically, VEGF-C was highly expressed in senescent astrocytes, contributing themselves to migrate across lymphatic vessels along C-C motif chemokine ligand 21 (CCL21) gradient by interacting with VEGF receptor 3. Moreover, intra-cisternal injection of antibody against CCL21 hampered senescent astrocytes into the lymphatic vessels and exacerbated short memory defects of aged mice. Together, these findings reveal a new perspective for the meningeal lymphatics in the removal of senescent astrocytes, thus offering a valuable target for therapeutic intervention.