Midkine (MDK) could enhance neuron survival through its endocytosis receptor, lipoprotein receptor-related protein-1 (LRP-1). This study was designed to investigate whether body weight-supported treadmill training (BWSTT) promotes motor function and ameliorates neuronal injury following T10 incomplete contusive spinal cord injury (SCI) through the MDK/LRP-1 signaling pathway. T10 incomplete contusive SCI rats underwent two weeks of BWSTT. LRP-1-siRNA was utilized during the intervention to inhibit the MDK/LRP-1 signaling pathway. The Basso, Beattie, and Bresnahan (BBB) score, three-dimensional gait analysis, Nissl and NeuN staining of the spinal cord, and protein expression of MDK/LRP-1 were evaluated. Downstream activation of PI3K/Akt and BDNF expression was analyzed in vivo and in vitro. Two weeks of BWSTT significantly improved the BBB score after spinal cord injury (SCI) and ameliorated neuronal injury in the lumbar spinal cord. Immunofluorescence co-staining of MDK with NeuN indicates that BWSTT promoted the neuronal localization of MDK. The use of LRP-1-siRNA significantly inhibited the effectiveness of exercise training in enhancing motor function and ameliorating neuronal injury. Additionally, LRP-1-siRNA also hindered the neuronal localization of MDK following exercise training. Furthermore, exercise-induced Akt activation and BDNF upregulation were diminished in vivo by LRP-1-siRNA. In vitro results demonstrated that MDK activates Akt and BDNF, while RAP, an LRP-1 inhibitor, notably inhibited this effect. The neuroprotective effect of exercise training after SCI may be mediated, at least in part, through the MDK/LRP-1 signaling pathway, which promotes Akt activation and BDNF upregulation, contributing to neuronal survival and motor recovery after BWSTT in T10 incomplete spinal cord-injured rats.

Neuromuscular electrical stimulation(NMES)is a well-established therapeutic approach for chronic wounds.Conventionally,NMES involves direct electrode contact with wounds or adjacent healthy skin;however,it is limited by the need for wound exposure and by increased pain.Our preliminary study demonstrated the innovative application of remote NMES(rNMES)to the skeletal muscle of the distal calf,which showed the potential to accelerate wound healing in remote areas.rNMES was effective in human clinical trials in our previous work,although the underlying mechanisms remain unclear.As rNMES is often used to stimulate muscle contraction in long-term bedridden patients,we analyzed data from the Gene Expression Omnibus(GEO)database and found that exercise promotes midkine(MDK)expression in muscle.MDK is a small secreted heparin-binding protein that interacts with multiple cell surface receptors to promote growth.In the present study,we found that MDK significantly enhanced macrophage efferocytosis in a low-density lipoprotein receptor-related protein 1(LRP1)-dependent manner.Our findings demonstrate that rNMES upregulates MDK expression in skeletal muscles through the AMPK-ERK axis,facilitating its delivery to wounds through the circulatory system and promoting LRP1-mediated efferocytosis of apoptotic cells,thereby expediting wound healing.

Neuropathic pain (NP) often progresses from acute to chronic, but the mechanisms driving this transition remain unclear. Microglia play a central role in spinal sensitization, yet their functional evolution during pain chronification is poorly understood. Through integrated multi-omics analysis and experimental validation, this study systematically investigates the temporal dynamics of microglial phagocytic reprogramming during the progression of neuropathic pain (NP). The results demonstrate that in the spared nerve injury (SNI) mouse model, spinal microglia undergo a dynamic evolution across three functional phases: an acute proliferative state with initial phagocytic activation (post-injury day 3, PID3), a transitional phase marked by significant activation of phagocytic pathways (PID7), and a chronic phagocytic “fatigue” state (PID14) in which autophagy- and lysosome-related pathway activity declined with a functional decoupling between phagocytosis and degradative capacity (PID14). Single-cell transcriptomic analysis further revealed functional heterogeneity among microglial subpopulations, including inflammation-regulating subsets (e.g., Micro3/Micro5) and specialized phagocytic clusters (e.g., Clusters 7). Pseudotime trajectory analysis indicated that microglia differentiate from a common progenitor state into two distinct fates: pro-inflammatory or phagocytic. Our analysis at the chronic phase (day 14 post-SNI) confirmed microglial activation, neuroinflammation, and pain hypersensitivity, alongside a novel finding of augmented microglial phagocytosis of apoptotic cells. Further research identified eight phagocytosis-related genes (such as Axl, Mfsd8, Mbtps1, and Sorl1), among which Axl showed the most significant up-regulation in the chronic phase. In vivo and in vitro experiments confirmed that inhibition of Axl not only induced mechanical allodynia but also impaired microglial phagocytic function. Furthermore, under LPS stimulation, microglial phagocytosis exhibited a biphasic response—initial enhancement followed by decline. This work provides new insights into microglial phagocytic reprogramming and suggests Axl as a promising therapeutic target for chronic neuropathic pain.

OBJECTIVE:Traumatic spinal cord injury (SCI) induces neuronal apoptosis and neuroinflammation, which exacerbate secondary damage and hinder functional recovery. Efficient clearance of apoptotic cells and modulation of the inflammatory microenvironment of spinal cord are essential for promoting tissue repair. This study aimed to investigate whether Midkine (MDK), a heparin-binding growth factor, facilitates functional recovery after SCI and explores the underlying mechanisms. METHODS:A rat model of moderate SCI was established using Allen's impact method. Lentiviral vectors were used to overexpress MDK in the spinal cord. Behavioral assessments, including BBB score and gait analysis, were performed to evaluate motor function recovery. Motor evoked potentials (MEPs) serve as a neurophysiological tool for evaluating the functional integrity of the corticospinal tract. In vivo and in vitro experiments were conducted to assess microglial efferocytosis and elucidate the underlying molecular mechanisms. RESULTS:Transcriptomic bioinformatic analysis suggests that SCI is characterized by pronounced accumulation of apoptotic cells and robust neuroinflammatory responses, whereas single-cell analysis implicates MDK as a key contributor to neurorepair after SCI. MDK expression is dynamically regulated following SCI, with an early upregulation followed by a gradual decline over time, its location predominantly observed around microglial cells. Functionally, MDK overexpression significantly enhances motor recovery after SCI, accompanied by reduced neuroinflammation, decreased neuronal apoptosis, and improved neuroprotection. Mechanistically, MDK promotes microglial efferocytosis both in vivo and in vitro, activates the AKT/mTOR signaling pathway, upregulates BDNF and LRP-1 expression, and facilitates microglial polarization toward an anti-inflammatory M2 phenotype. Notably, inhibition of LRP-1 with receptor-associated protein (RAP) abolished the efferocytic and neuroprotective effects of recombinant MDK, highlighting LRP-1 as a key mediator of MDK's actions in microglia. CONCLUSION:Our study unveils the MDK/LRP-1/efferocytosis axis as a previously unrecognized therapeutic target for SCI. By orchestrating apoptotic cell clearance, dampening neuroinflammation, and fostering neuroprotection, this axis critically shapes the post-injury microenvironment to facilitate recovery. These findings suggest that MDK-centered therapy may represent a strategy for spinal cord repair, with LRP-1 modulation offering precise control over microglial responses.

BACKGROUND:Many studies have emphasized the role of microglia-mediated neuroinflammation in spinal cord injury (SCI); however, effective clinical targets remain elusive. The growth arrest-specific 6 (Gas6)/Axl receptor tyrosine kinase (Axl) signaling pathway has been implicated in reducing inflammation, promoting tissue repair, and functional recovery. Here, we elucidate the importance of the Gas6-Axl signaling pathway in SCI repair and evaluate the role of bilirubin in modulating Gas6-Axl signaling after SCI. METHODS:SCI mice model was used to investigate the effects of bilirubin treatment on inflammation and motor function recovery. Additionally, Gas6-deficient (Gas6-/-) mice and wild-type (WT) mice were employed to examine the role of Gas6-Axl signaling in SCI recovery. Microglial cells were cultured to assess the effects of bilirubin on the activation of the Gas6-Axl-SOCS3 signaling pathway. RESULTS:Gas6-/- mice exhibited increased mortality, severe locomotor deficits, and impaired neuromuscular activity compared to WT mice. Bilirubin treatment in SCI models facilitated recovery by upregulating Gas6-Axl signaling, which in turn enhanced SOCS3 expression and suppressed the expression of pro-inflammatory mediators such as IL-1β and MMP-9. Furthermore, bilirubin treatment reduced microglial activation, highlighting its neuroprotective and anti-inflammatory properties. CONCLUSIONS:This study underscores the importance of the Gas6-Axl-SOCS3 axis in regulating functional recovery and inflammation after SCI. Activation of the Gas6-Axl pathway, particularly when combined with bilirubin treatment, represents a promising therapeutic strategy for mitigating SCI-induced damage and improving functional outcomes. Given their central role in both the pathogenesis and resolution of SCI, bilirubin treatment emerges as a promising clinical therapeutic drug for SCI.

Postmenopausal osteoporosis (PMOP) increases the risk of periodontitis (PD), yet the shared mechanisms remain unclear. Rho-signal transduction genes may play a role due to their involvement in bone remodeling. This study aimed to explore Rho-related genes as potential biomarkers linking PMOP and PD. Public transcriptomic datasets of PMOP and PD were analyzed. After PCA-based outlier removal, differentially expressed genes were identified using limma, followed by intersection analysis, KEGG enrichment, PPI network construction, and Rho pathway screening. Machine learning (Lasso, SVM-RFE) and Wilcoxon tests identified CTNNAL1 and MERTK as candidate biomarkers. GSEA, ssGSEA, and immune infiltration analyses were performed, along with construction of lncRNA/circRNA-miRNA-mRNA regulatory networks. Subcellular localization, chromosomal mapping, disease association, and molecular docking analyses were also conducted. An ovariectomy plus periodontitis (OP+PD) mouse model was used for in vivo validation. CTNNAL1 and MERTK were consistently dysregulated in both PMOP and PD datasets. They were enriched in MYC-targets-V1, allograft rejection, heme metabolism, and oxidative phosphorylation. Immune analysis revealed altered levels of CD56^bright NK cells and immature dendritic cells. Regulatory networks implicated lncRNAs such as XIST, GAS5, and NEAT1. Molecular docking indicated interactions with pinosylvin and glycitein. In vivo validation confirmed significant changes in CTNNAL1 and MERTK expression and increased bone loss and inflammation in OP+PD mice. CTNNAL1 and MERTK were identified as potential Rho-associated biomarkers showing consistent dysregulation in both PMOP and PD datasets. These biomarkers may serve as risk indicators or therapeutic candidates, warranting further validation.

OBJECTIVE:To investigate the role of telomerase reverse transcriptase (TERT) in alleviating doxorubicin (DOX)-induced cardiotoxicity. METHODS:(1) Cell experiments: rat H9c2 cardiomyocytes were divided into control group (CON group), null adenovirus transfection group (NC group), TERT overexpression adenovirus transfection group (TERT group), DOX group (treated with 1 μmol/L DOX for 12 hours), DOX+NC group, and DOX+TERT group (null adenovirus or TERT overexpression adenovirus were transfected for 24 hours and then treated with 1 μmol/L DOX for 12 hours). The mRNA expression of TERT in cardiomyocytes was detected by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR). The level of mitochondrial membrane potential was detected by immunofluorescence. The expression levels of intracellular Bax, Bcl-2, microtubule-associated protein 1 light chain 3 (LC3) and p62 were detected by Western blotting. (2) Animal experiments: male C57BL/6 mice were randomly divided into a sham operation group (Sham group), DOX group (acute cardiotoxicity model was constructed by intraperitoneal injection of DOX 15 mg/kg), DOX+NC group and DOX+TERT group (modeled after transfection with airborne adenovirus or TERT overexpression adenovirus for 7 days). After 7 days of modeling, the area of myocardial fibrosis was detected by Sirius scarlet staining, and cardiac function was detected by echocardiography. RESULTS:(1) Cellular experiments: the mRNA expression level of TERT was significantly higher in the TERT group compared with the CON and NC groups. Compared with the CON group, the TERT mRNA expression level of cardiomyocytes in the DOX group and the DOX+NC group were significantly lower, the level of mitochondrial membrane potential was significantly lower, the protein expressions of Bax and LC3 were significantly increased, and the protein expressions of Bcl-2 and p62 were significantly decreased. No significant differences were found between the DOX group and DOX+NC group. Compared with the DOX group and DOX+NC group, the TERT mRNA expression level was increased in the DOX+TERT group (relative expression: 1.02±0.10 vs. 0.61±0.05, 0.54±0.03, both P < 0.05), the level of mitochondrial membrane potential was significantly increased (1.14±0.05 vs. 0.96±0.01, 0.96±0.01, both P < 0.05), the protein expressions of Bax and LC3 were significantly decreased, and the protein expressions of Bcl-2 and p62 were significantly increased (Bax/β-actin: 0.88±0.01 vs. 1.31±0.02, 1.26±0.01; LC3-II/I: 2.16±0.05 vs. 2.64±0.06, 2.58±0.02; Bcl-2/β-actin: 0.65±0.01 vs. 0.40±0.01, 0.41±0.01; p62/β-actin: 0.45±0.01 vs. 0.23±0.02, 0.29±0.01; all P < 0.05). (2) Animal experiments: compared with the Sham group, the percentage of myocardial fibrosis area was significantly increased and left ventricular ejection fraction (LVEF) and fractional shortening (FS) were significantly decreased in the DOX group and DOX+NC group. Compared with the DOX group and DOX+NC group, the percentage of myocardial fibrotic area was significantly decreased in the DOX+TERT group (%: 2.33±0.06 vs. 3.76±0.07, 3.87±0.06, both P < 0.05), and the LVEF and FS were significantly increased [LVEF (%): 67.00±1.14 vs. 54.60±1.57, 53.40±2.18; FS (%): 38.60±0.51 vs. 30.60±1.10, 30.00±0.71; all P < 0.05]. CONCLUSION:Up-regulation of TERT expression can inhibit DOX-induced cardiomyocyte autophagy and apoptosis, attenuate DOX-induced myocardial fibrosis in mice, improve cardiac function, and thus alleviate DOX-induced cardiotoxicity.

PINK1/Parkin-mediated ubiquitin-dependent mitophagy is a critical negative regulatory machinery for browning in the inguinal white adipose tissue (iWAT). However, the precise regulatory mechanism underlying PINK1/Parkin-mediated mitophagy during browning of iWAT remains largely unknown. Here we report that PNPLA7, an Endoplasmic Reticulum and mitochondria-associated membrane (MAM) protein, inhibits browning of iWAT by promoting PINK1/Parkin-mediated mitophagy upon cold challenge or β3-adrenergic receptor agonist treatment. With genetic manipulation in mice, we show that adipose tissue overexpressing PNPLA7 induces mitophagy, abolishes iWAT browning and interrupts adaptive thermogenesis. Conversely, conditional ablation of PNPLA7 in adipose tissue promotes browning of iWAT, resulting in enhanced adaptive thermogenesis. Mechanistically, PNPLA7 interacts with Parkin to promote mitochondrial recruitment of Parkin for mitophagy activation and mitochondria degradation by disrupting PKA-induced phosphorylation of Parkin under cold challenge. Taken together, our findings suggest that PNPLA7 is a critical regulator of mitophagy that resists cold-induced browning of iWAT, thus providing a direct mechanistic link between mitophagy and browning of iWAT.

The Article Abstract is not available.

Doxorubicin-induced cardiotoxicity (DIC) is one of the most severe side effects of doxorubicin, yet the underlying mechanisms remain incompletely understood.Our results showed that Neutrophil extracellular traps (NETs) accumulated in plasma and cardiac tissue after doxorubicin treatment. The inhibition of NETs formation by Pad4 gene ablation significantly attenuated doxorubicin-induced arrhythmia, prolonged survival time and reduced the levels of Troponin T (cTnT) and creatine kinase MB (CK-MB) in mice. In addition, reductions in left ventricular fractional shortening and ejection fraction induced by doxorubicin were more severe in WT mice than in Pad4-/- mice. Immunostaining and qPCR analyses revealed that NETs activated macrophages to release pro-inflammatory cytokines such as IL-18, IL-1β, and TNF-α. IL-18, in turn, activated T cells to produce IFN-γ, which, along with TNF-α, downregulated the expression of Cx43, thereby inducing cardiac conduction abnormalities.We identify that IL-18-IFN-γ-Cx43-induced cardiac conduction abnormalities triggered by neutrophil extracellular traps is the key molecular and cellular determinants of DIC. Furthermore, targeting NETs formation using ozone therapy significantly alleviated DIC. This study highlights the critical role of NETs in the development of DIC and proposes ozone therapy as a potential therapeutic strategy for treating DIC.

This investigation elucidates the critical molecular determinants associated with the comorbidity of osteoporosis (OP) and periodontitis (PD) through proteomic profiling, while delineating the regulatory function of CD44 in experimental periodontitis in an OP murine model. Phase I involved collecting serum specimens from patients with OP+PD (n = 3) and healthy controls (n = 6) undergoing routine health evaluations at our institution for comparative proteomic analysis. Subsequent translational validation of differentially expressed genes (DEGs) and associated signaling cascades was conducted across clinical specimens and OP+PD murine models. To mechanistically characterize CD44's role in PD progression under osteoporotic conditions, an OP murine model was generated through bilateral ovariectomy, followed by experimental PD induction via ligature placement. Comprehensive assessments included histomorphometric alterations via hematoxylin-eosin staining, microarchitectural bone analysis at the maxillary first molar region using micro-CT, and immunoblotting evaluation of phosphoinositide-3-kinase (PI3K)/Akt pathway components. Parallel network pharmacological screening coupled with molecular docking simulations was executed to identify bioactive constituents of Angelica sinensis with therapeutic potential. Proteomic interrogation identified CST3, A2M, CD44, CDH13, CETP, and VWF as candidate pathogenic mediators in OP+PD pathogenesis. In our hands, gene set enrichment analysis revealed that PI3K/Akt signaling functions as a principal mediator of OP+PD disease progression. Quantitative reverse-transcription PCR-based validation confirmed significant CD44 upregulation in both clinical and experimental OP+PD cohorts. In vivo modulation via CD44 suppression significantly restored periodontal tissue integrity, reduced inflammatory cell infiltration, and strengthened alveolar bone microarchitecture in OP mice, concomitant with PI3K/Akt pathway inhibition. Network pharmacology revealed glycitein as the primary bioactive phytochemical in Angelica sinensis, with CD44 identified as its central molecular target. Glycitein improved alveolar bone structure in OP+PD mice, increasing bone volume fraction (BV/TV), trabecular thickness (Tb.Th), bone mineral density (BMD), and reducing trabecular number (Tb.N), bone surface-to-bone volume ratio (BS/BV), indicating healthier bone quality, mechanistically attributed to CD44 signaling axis attenuation.

BACKGROUND:Electroconvulsive therapy (ECT) demonstrates efficacy in treatment-resistant schizophrenia, yet the underlying metabolic mechanisms remain poorly understood. This study employed comprehensive metabolomics to elucidate the therapeutic mechanisms of ECT and identify predictive biomarkers. METHODS:We conducted untargeted metabolomics analyses (GC-MS/LC-MS) on plasma samples from 78 schizophrenia patients (pre- and post-ECT) and 76 healthy controls, followed by targeted metabolomics validation in an independent schizophrenia cohort (n = 66). Advanced bioinformatics, including WGCNA and SVM-RFE, identified treatment-responsive metabolites. RESULTS:Schizophrenia patients exhibited 542 differentially expressed metabolites compared to controls (420 downregulated, 122 upregulated), predominantly lipids involved in energy metabolism pathways. Post-ECT, 200 metabolites changed significantly (153 upregulated, 47 downregulated), primarily affecting glycolysis, ketone body metabolism, and inflammatory pathways. WGCNA revealed metabolites in the turquoise module (n = 1329) strongly correlated with symptom severity. SVM-RFE identified 10 baseline metabolites distinguishing ECT responders from non-responders (AUC = 0.724). Targeted validation confirmed 6 metabolites, with 4 showing consistent elevation in responders: N-phenylanthranilic acid, Hydroxy-alpha-sanshool and Linoelaidic acid, and Piperine. Crucially, only responders demonstrated significant post-ECT increases in Hydroxy-alpha-sanshool and Piperine, both TRPV1/TRPA1 channel agonists implicated in neuroprotection and inflammation modulation. CONCLUSIONS:This first comprehensive metabolomic investigation of ECT in schizophrenia reveals energy metabolism dysregulation as a core pathophysiological mechanism. ECT's therapeutic effects involve metabolic reprogramming and inflammation resolution, with Hydroxy-alpha-sanshool and Piperine emerging as potential predictive and therapeutic candidates. These findings advance precision psychiatry approaches and provide mechanistic insights for developing novel schizophrenia treatments targeting mitochondrial-inflammatory networks.

Spinal cord injury is followed by glial scar formation, which was long seen mainly as a physical barrier preventing axonal regeneration. Glial scar astrocytes lead to glial scar formation and produce inhibitory factors to prevent axons from growing through the scar, while inhibiting the conversion of reactive astrocytes into glial scar-forming astrocytes may represent an ideal treatment for CNS injury. Exercise is a non-invasive and effective therapeutic intervention for clinical rehabilitation of spinal cord injury. However, its precise therapeutic mechanisms still need to be continuously explored. 30 rats were randomly assigned to three groups (Sham, SCI, SCI + BWSTT; n = 10 rats per group). In this study, we employed the BBB scales and gait analysis system to examine the behavioral functions of the rats in each group. Furthermore, we utilized immunoblotting of spinal cord tissue at the injury site, in addition to histological staining and immunofluorescence staining, to explore glial scar aggregation and axonal regeneration in each group of rats. Our results revealed that hindlimb motor function was significantly improved in SCI rats after a sustained subacute period of BWSTT, accompanied by the promotion of histological repair and nerve regeneration. Subsequent immunofluorescence staining and immunoblotting showed diminished astrocyte reactivity in the region surrounding the spinal cord injury as well as reduced expression and distribution of collagen fibers near the lesion after BWSTT. Additionally, a significant decrease in the expression of MMP-2/9, which is closely related to astrocyte migration, was observed in the vicinity of spinal cord tissue lesions. Our study demonstrates that a sustained BWSTT intervention during the subacute phase of spinal cord injury can effectively reduce astrocyte reactivity and glial scarring overgrowth, thereby facilitating functional recovery after SCI.

Osteoporosis, a systemic metabolic disease, typically leads to osteogenic dysfunction with aging, which is the primary mechanism underlying the decrease in bone mass and strength. Polygonum multiflorum Thunb., a Chinese botanical drug known for kidney-tonifying and bone-fortifying effects, comprises 2,3,5,4'-Tetrahydroxy stilbene-2-O-β-d-glucoside (TSG) as its key component, which demonstrates potential for preventing and managing osteoporosis. However, its specific role in oxidative stress-induced osteoblast dysfunction remains unclear. Here, we constructed osteoblasts model of oxidative damage and a mouse model of senile osteoporosis. Alkaline phosphatase (ALP) and Alizarin Red S staining analysis, as well as histological, trabecular microstructure and indexes of bone metabolism were used to evaluate osteogenic function. Flow cytometry, western blot and qRT-PCR were employed to identify apoptosis and autophagy pathways affected by TSG. The results showed that TSG pretreatment significantly reduced apoptosis and suppressed mitochondrial apoptosis pathway proteins in H2O2-exposed osteoblasts, thereby mitigating oxidative damage. TSG also increased ALP expression, mineralization, and the expression of osteogenic factors. Furthermore, TSG aggravated autophagy induced by H2O2, while the anti-apoptotic and mineralization-promoting effects were inhibited by 3-methyladenine and enhanced by rapamycin. Mechanistically, TSG resulted in the activation of the AMPK/mTOR/ULK1 pathway, which was partially reversed by AMPK inhibition, thereby ameliorating osteoblast dysfunction. Finally, we confirmed that TSG treatment reversed bone loss by improving trabecular microstructure, balancing bone metabolic factors, and enhancing bone morphogenetic protein expression. Collectively, our findings provide a potential therapeutic strategy for alleviating osteoporosis.

Spinal cord injury (SCI) is a serious trauma of the central nervous system. The clearance of myelin debris is a critical step in the functional recovery following spinal cord injury (SCI). Recent studies have begun to reveal critical roles for professional phagocytes in the central nervous system, microglia, and their receptors in the control of myelin debris in neurodegenerative disease. Repeated trans-spinal magnetic stimulation (rTSMS) has been demonstrated as a noninvasive SCI treatment that enhances tissue repair and functional recovery. In this study, we investigated the role and molecular mechanism of rTSMS on microglial phagocytosis of myelin debris in a rat SCI model. In our studies, we found that rTSMS significantly promoted the motor function recovery of SCI rats associated with the inhibition the neuroinflammation and glia scar formation. Immunofluorescence results further showed that the rTSMS promotes the clearance of myelin debris by microglia in vivo and in vitro. Additionally, receptor-associated protein (RAP), a Low-density lipoprotein receptor-related protein-1 (LRP-1) inhibitor, could cancel the accelerated microglial phagocytosis of myelin debris after rTSMS in vitro experiments. Simultaneously, Elisa's results and western blotting respectively showed that rTSMS significantly decreased the levels of soluble LRP-1(sLRP-1) and the LRP-1 splicing enzyme of ADAM17. In conclusion, rTSMS could promote the clearance of myelin debris by microglia through LRP-1 to improve the functional recovery of SCI rats.

Background We conducted a Mendelian randomization (MR) study to elucidate the anti-infective effects of ticagrelor.Methods Single-nucleotide polymorphisms (SNPs) associated with serum levels of ticagrelor or its major metabolite AR-C124910XX (ARC) in the Platelet Inhibition and Patient Outcomes trial were selected as genetic proxies for ticagrelor exposure. Positive control analyses indicated that genetically surrogated serum ticagrelor levels (6 SNPs) but not ARC levels (2 SNPs) were significantly associated with lower risks of coronary heart disease. Therefore, the 6 SNPs were used as genetic instruments for ticagrelor exposure, and the genome-wide association study data for 5 infection outcomes were derived from the UK Biobank and FinnGen consortium.Results The 2-sample MR analyses based on inverse variance-weighted methods indicated that genetic liability to ticagrelor exposure could reduce the risk of bacterial pneumonia (odds ratio, 0.82; 95% CI, .71-.95; P = 8.75E-03) and sepsis (odds ratio, 0.83; 95% CI, .73-.94; P = 3.69E-03); however, no causal relationship was detected between ticagrelor exposure and upper respiratory infection, pneumonia, and urinary tract infection. Extensive sensitivity analyses corroborated these findings.Conclusions Our MR study provides further evidence for the preventive effects of ticagrelor on bacterial pneumonia and sepsis. The anti-infective effects of ticagrelor remain controversial. This study used 2-sample Mendelian randomization methods to determine that ticagrelor treatment was causally associated with lower risks of bacterial pneumonia and sepsis.

Acute lung injury (ALI) linked to sepsis has a high mortality rate, with limited treatment options available. In recent studies, medical ozone has shown the potential to alleviate inflammation and infection. Here, we aimed to evaluate therapeutic potential of medical ozone in a mouse model of the sepsis-induced ALI by measuring behavioral assessments, lung function, and blood flow. Protein levels were quantified by Western blotting. In vitro, we performed experiments on bone marrow-derived macrophages (BMDMs) to investigate the effect of adenosine monophosphate (AMP)-activated protein kinase (AMPK) inhibitors and agonists on their phagocytic activity. The results showed that medical ozone significantly improved the survival rate, ameliorated lung injury, and enhanced lung function and limb microcirculation in mice with ALI. Notably, medical ozone inhibited the formation of neutrophil extracellular traps (NETs), a crucial factor in the ALI development. Additionally, medical ozone counteracted the elevated levels of tissue factor, matrix metalloproteinase-9, and interleukin-1β. In the ALI mice, the effects of ozone were abolished, and BMDMs showed an impaired capacity to engulf NETs following the Sr-a1 knockout. Under normal physiological conditions, the administration of an AMPK antagonist showed similar effects on the Sr-a1 knockout, significantly inhibiting the phagocytosis of NETs by BMDMs. In contrast, AMPK agonists enhanced this phagocytic process. In conclusion, medical ozone may alleviate the sepsis-induced lung injury through the AMPK/SR-A1 pathway, thereby enhancing the phagocytosis of NETs by macrophages.

Previous studies have shown that high blood glucose-induced chronic microinflammation can cause inflammatory podocyte injury in patients with diabetic kidney disease(DKD). Therein, necroptosis is a new form of podocyte death that is closely associated with renal fibrosis(RF). To explore the effects and mechanisms in vivo of total flavones of Abelmoschus manihot(TFA), an extract from traditional Chinese herbal medicine Abelmoschus manihot for treating kidney diseases, on podocyte necroptosis and RF in DKD, and to further reveal its scientific connotation with multi-pathway and multi-target, the authors randomly divided all rats into four groups: a namely normal group, a model group, a TFA group and a rapamycin(RAP) group. After the modified DKD rat models were successfully established, four group rats were given double-distilled water, TFA suspension and RAP suspension, respectively by gavage every day. At the end of the 4th week of drug treatment, all rats were sacrificed, and the samples of their urine, blood and kidneys were collected. And then, the various indicators related to podocyte necroptosis and RF in the DKD model rats were observed, detected and analyzed, respectively. The results indicated that, general condition, body weight(BW), serum creatinine(Scr), urinary albumin(UAlb), and kidney hypertrophy index(KHI) in these modified DKD model rats were both improved by TFA and RAP. Indicators of RF, including glomerular histomorphological characteristics, fibronectin(FN) and collagen type Ⅰ(collagen Ⅰ) staining extent in glomeruli, as well as the protein expression levels of FN, collagen Ⅰ, transforming growth factor-β1(TGF-β1) and Smad2/3 in the kidneys were improved respectively by TFA and RAP. Podocyte damage, including foot process form and the protein expression levels of podocin and CD2AP in the kidneys was improved by TFA and RAP. In addition, tumor necrosis factor-α(TNF-α)-mediated podocyte necroptosis in the kidneys, including the morphological characteristics of podocyte necroptosis, the extent and levels of the protein expression of TNF-α and phosphorylated mixed lineage kinase domain like pseudokinase(p-MLKL) was improved respectively by TFA and RAP. Among them, RAP had the better effect on p-MLKL. More importantly, the activation of the receptor interacting serine/threonine protein kinase 1(RIPK1)/RIPK3/MLKL signaling axis in the kidneys, including the expression levels of its key signaling molecules, such as phosphorylated receptor interacting serine/threonine protein kinase 1(p-RIPK1), p-RIPK3, p-MLKL and cysteinyl aspartate specific proteinase-8(caspase-8) was improved respectively by TFA and RAP. Among them, the effect of TFA on p-RIPK1 was superior. On the whole, in this study, the authors demonstrated that TFA alleviates podocyte necroptosis and RF in DKD through inhibiting the activation of the TNF-α-mediated RIPK1/RIPK3/MLKL signaling axis in diabetic kidneys. The authors' findings provide new pharmacological evidence to reveal the scientific connotation of TFA in treating RF in DKD in more depth.

Di-(2-Ethylhexyl) phthalate (DEHP) and bisphenol A (BPA) present significant environmental endocrine-disrupting chemical properties. Although studies have implied reproductive impairment from exposure to BPA and DEHP, no study to date has shown the effect and mechanism of hepatic function after gestational and lactational co-exposure to DEHP and BPA in offspring. A total of 36 perinatal rats were randomly divided into four groups, DEHP (600 mg/kg/day), BPA (80 mg/kg/day), DEHP combined with BPA (600 mg/kg/day + 80 mg/kg/day), and control. Notably, 11 chemical targets were screened after identifying eight substances associated with chemically-induced hepatic damage. Molecular docking simulations revealed a high-scoring combination of eight metabolic components and targets of the PI3K/AKT/FOXO1 signaling pathway. The DEHP and BPA combination disrupted hepatic steatosis, ultimately affecting systemic the glucose and the lipid metabolic homeostasis with significant toxicity. Mechanistically, co-exposure to DEHP and BPA causes liver dysfunction and hepatic insulin resistance via PI3K/AKT/FOXO1 pathway in offspring. This is the first study of the hepatic function and mechanism of co-exposure to DEHP and BPA that combines metabolomics, molecular docking, and traditional toxicity assessment methods.

The musculoskeletal system is important for balancing metabolic activity and maintaining health. Recent studies have shown that distortions in homeostasis of the intestinal microbiota are correlated with or may even contribute to abnormalities in musculoskeletal system function. Research has also shown that the intestinal flora and its secondary metabolites can impact the musculoskeletal system by regulating various phenomena, such as inflammation and immune and metabolic activities. Most of the existing literature supports that reasonable nutritional intervention helps to improve and maintain the homeostasis of intestinal microbiota, and may have a positive impact on musculoskeletal health. The purpose of organizing, summarizing and discussing the existing literature is to explore whether the intervention methods, including nutritional supplement and moderate exercise, can affect the muscle and bone health by regulating the microecology of the intestinal flora. More in-depth efficacy verification experiments will be helpful for clinical applications.