Catalpol ameliorates liver fibrosis via inhibiting aerobic glycolysis by EphA2/FAK/Src signaling pathway.

BACKGROUND: Hepatic fibrosis is a pathological process in a variety of acute or chronic liver injuries. Catalpol (CAT), an iridoid glycoside found in Rehmannia glutinosa, has several pharmacological properties, including anti-inflammatory, antidiabetic and anti-fibrotic effects. Nevertheless, there is currently no report on whether CAT regulates the aerobic glycolysis of hepatic stellate cells (HSCs) to inhibit liver fibrosis. OBJECTIVE: This study aimed to investigate the protective effects of CAT on hepatic fibrosis and elucidate its underlying mechanisms. METHODS: To explore whether CAT improved liver fibrosis in vivo and in vitro, hepatic fibrosis was induced to mice by intraperitoneally injecting carbon tetrachloride (CCl4). Additionally, LX-2 cells were stimulated with transforming growth factor-ß (TGF-ß) to simulate fibrosis in vitro. Serum markers of liver injury were examined by using an automatic biochemical analyzer. Histopathological staining, Immunofluorescence (IF) staining, Western blot (WB) analysis, co-immunoprecipitation (Co-IP), drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), etc. were employed to identify the targeting between CAT and EphA2 and detect the expression of aerobic glycolysis related proteins, fiber markers and signaling pathways that are responsible for CAT's anti-fibrotic effects of CAT. RESULTS: Results showed that CAT significantly inhibited hepatic injury, fibrogenesis and inflammation in mice treated with CCl4. This was demonstrated by the enhancement of fibrosis markers, liver function indices, and histopathology. In addition, CAT significantly inhibited the activation of HSCs in TGF-ß-induced LX-2 cells, as indicated by decreased proliferation, migration, and expression of collagen I and a-SMA. The study results also suggested that CAT may exert anti-fibrotic effects by inhibiting glycolysis in activated HSCs and in CCl4-treated mice. Mechanistically, CAT directly targets Ephrin type-A receptor 2 (EphA2) to reduce binding with focal adhesion kinases (FAK) and significantly inhibits the FAK/Src pathway. In addition, the pharmacological inhibition of EphA2 cannot further increase the therapeutic effects of CAT on liver fibrosis in vivo and in vitro. CONCLUSION: The study findings generally demonstrated that CAT presented a novel therapeutic method to treat hepatic fibrosis; this method which inhibits the aerobic glycolysis of activated HSCs through the EphA2/FAK/Src signaling pathway.

Quantitative Electroencephalography for Predication of Neurological Dysfunction in Type A Aortic Dissection: A Prospective Observational Study.

BACKGROUND: Type A aortic dissection presents challenges with postoperative cerebral complications, and this study evaluates the predictive value of quantitative electroencephalography for perioperative brain function prognosis. METHODS AND RESULTS: Amplitude-integrated electroencephalography (aEEG) processes raw signals through filtering, amplitude integration, and time compression, displaying the data in a semilogarithmic format. Using this method, postoperative relative band power (post-RBP) α% and dynamic aEEG (ΔaEEG) grade were significantly associated with neurological dysfunction in univariate and multivariable analyses, with area under the receiver operating characteristic curve of 0.876 (95% CI, 0.825-0.926) for the combined model. Postoperative relative band power α% and ΔaEEG were significantly associated with adverse outcomes, with area under the receiver operating characteristic curve of 0.903 (95% CI, 0.835-0.971) for the combined model. Postoperative relative band power α% and ΔaEEG were significantly associated with transient neurological dysfunction and stroke, with areas under the receiver operating characteristic curve of 0.818 (95% CI, 0.760-0.876) and 0.868 (95% CI, 0.810-0.926) for transient neurological dysfunction, and 0.815 (95% CI, 0.743-0.886) and 0.831 (95% CI, 0.746-0.916) for stroke. Among 56 patients, the Alberta Stroke Program Early Computed Tomography score was superior to ΔaEEG in predicting neurological outcomes (area under the receiver operating characteristic curve of 0.872 versus 0.708 [95% CI, 0.633-0.783]; P<0.05). CONCLUSIONS: Perioperative quantitative electroencephalography monitoring offers valuable insights into brain function changes in patients with type A aortic dissection. ∆aEEG grades can aid in early detection of adverse outcomes, while postoperative relative band power and ∆aEEG grades predict transient neurological dysfunction. Quantitative electroencephalography can assist cardiac surgeons in assessing brain function and improving outcomes in patients with type A aortic dissection. REGISTRATION: URL: https://www.chictr.org.cn; Unique identifier: ChiCTR2200055980.

Predictive value of white matter hyperintensity burden combined with collateral circulation in mechanical thrombectomy for acute anterior circulation large vessel occlusion.

OBJECTIVE: To investigate the correlation and predictive value of white matter hyperintensity (WMH) burden in conjunction with collateral circulation during mechanical thrombectomy (MT) for acute anterior circulation occlusion. METHODS: A database comprising consecutive registrations of patients who underwent mechanical thrombectomy for acute anterior circulation large vessel occlusive cerebral infarction at Nanjing Drum Tower Hospital from January 2018 to December 2021 was analyzed. Collateral circulation was assessed using the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) scoring criteria. The good collateral group included ASITN/SIR grades 3 and 4, while the poor collateral group included grades 1 and 2. Additionally, white matter hyperintensity burden was evaluated using white matter hyperintensity volume and the Fazekas scoring system. A favorable functional outcome was defined as a modified Rankin scale (mRS) of 0-2 at 90 days. Multivariable logistic regression analyses and Spearman correlation analysis were employed to assess the correlation between white matter hyperintensity burden and unfavorable outcomes in mechanical thrombectomy. RESULTS: A total of 123 patients who underwent mechanical thrombectomy for acute anterior circulation occlusion were included (56.9 % male). Favorable outcomes were observed in 45.5 % (56/123) of cases. Those with a low ASITN/SIR scale (r = -1.33, 95 % CI: 0.26 (0.09-0.78), P=0.01; cutoff value = 2.5), low low-density lipoprotein cholesterol (LDL-C) level (r = -1.00, 95 % CI: 0.37 (0.15-0.92), P=0.03; cutoff value = 2.26), and high white matter hyperintense volume (r = 0.28, 95 % CI: 1.33 (1.03-1.71), P=0.03; cutoff value = 10.03) were more likely to experience unfavorable outcomes. Moreover, when compared to ASITN/SIR scale (AUC=89.6, 95 % CI: 0.09-0.78) and LDL level (AUC=62.8, 95 % CI: 0.15-0.92), white matter hyperintense volume demonstrated greater accuracy in predicting poor outcomes (AUC=94.4, 95 % CI: 1.03-1.71). Importantly, white matter hyperintense volume showed a positive correlation with the modified Rankin Scale (mRS) Score (r = 0.8289, P<0.0001). In brief, the burden of white matter hyperintensity is negatively correlated with collateral circulation in mechanical thrombectomy for acute anterior circulation occlusion. CONCLUSIONS: The higher the burden of white matter hyperintensity, the worse the collateral circulation in mechanical thrombectomy for acute anterior circulation occlusion. The combination of high white matter hyperintensity volume and poor collateral circulation enhances might predict a worse clinical outcome of mechanical thrombectomy with acute anterior circulation occlusion.

Comparative quantitative phosphoproteomic and parallel reaction monitoring analysis of soybean roots under aluminum stress identify candidate phosphoproteins involved in aluminum resistance capacity.

Aluminum (Al) toxicity adversely impacts soybean (Glycine max) growth in acidic soil. Reversible protein phosphorylation plays an important role in adapting to adverse environmental conditions by regulating multiple physiological processes including signal transduction, energy coupling and metabolism adjustment in higher plant. This study aimed to reveal the Al-responsive phosphoproteins to understand their putative function and involvement in the regulation of Al resistance in soybean root. We used immobilized metal affinity chromatography to enrich the key phosphoproteins from soybean root apices at 0, 4, or 24 h Al exposure. These phosphoproteins were detected using liquid chromatography-tandem mass spectrometry measurement, verified by parallel reaction monitoring (PRM), and functionally characterized via overexpression in soybean hairy roots. A total of 638 and 686 phosphoproteins were identified as differentially enriched between the 4-h and 0-h, and the 24-h and 0-h Al treatment comparison groups, respectively. Typically, the phosphoproteins involved in biological processes including cell wall modification, and RNA and protein metabolic regulation displayed patterns of decreasing enrichment (clusters 3, 5 and 6), however, the phosphoproteins involved in the transport and metabolic processes of various substrates, and signal transduction pathways showed increased enrichment after 24 h of Al treatment. The enrichment of phosphoproteins in organelle organization bottomed after 4 h of Al treatment (cluster 1). Next, we selected 26 phosphoproteins from the phosphoproteomic profiles, assessed their enrichment status using PRM, and detected enrichment patterns similar to those observed via phosphoproteomic analysis. Among them, 15 phosphoproteins were found to reduce the accumulation of Al and callose in Al-stressed soybean root apices when their corresponding genes were individually overexpressed in soybean hairy roots. In summary, the findings of this study facilitated a comprehensive understanding of the protein phosphorylation events involved in Al resistance responses and revealed some critical phosphoproteins that enhance Al resistance in soybean roots.

Mechanisms of the effect of high-performance ester composite materials on plant growth under soilless conditions.

The utilization of high-performance ester materials in addressing soil erosion and conserving water remains a crucial area of research in soil remediation. Currently, however, the mechanism underlying the role of these materials in vegetation restoration remains unclear, hampering the accurate determination of the optimal ratio of high-performance ester composite materials for soil enhancement. To address this issue, this study examines the mechanism of how high-performance ester composite materials affect the germination and growth of plant seeds through soilless cultivation experiments. The results revealed that the high-performance ester composite materials significantly enhanced seed germination ability and fostered plant seedling growth. Notably, the promotional effects of the ester adhesive and water-retaining materials within the high-performance ester composite varied. Specifically, the adhesive material significantly spurred radicle development, while the water-retaining material significantly accelerated germ growth. Varying concentrations of adhesive materials exerted distinct effects on plant growth. In particular, a small amount of adhesive materials enhanced seed germination, whereas excessive amounts exhibited inhibitory effects. Consequently, the optimal adhesive materials dosage conducive to plant growth and the optimal weight ratio of adhesive to water-retaining materials were ascertained. Additionally, the underlying mechanism of high-performance ester composite materials influence plant growth was elucidated. Overall, this research offers a theoretical foundation for the optimal ratio adjustment of high-performance ester composite materials to optimize soil improvement efforts.

Network pharmacology and transcriptomic profiling elucidate the therapeutic effects of Ranunculus ternatus Thunb on liver fibrosis via MK3-NF-κB inhibition.

Activation of hepatic stellate cells (HSCs) is critical in the progression of liver fibrosis and is a promising target for anti-hepatic fibrosis drug development. Moreover, effective pharmacological interventions targeting this pathomechanism are scarce. Our study confirms the therapeutic value of ß-sitosterol, a major constituent of Ranunculus ternatus Thunb, in hepatic fibrosis and identifies its underlying mechanisms. After treatment with ß-sitosterol, CCL4-induced hepatic fibrosis was reversed in mice, while inflammatory and hepatic fibrosis indices were improved. Meanwhile, we explored the molecular mechanism of ß-sitosterol treatment for hepatic fibrosis and, based on RNA-seq results, found that the ameliorative effect of ß-sitosterol on hepatic fibrosis was associated with the MK3 and NF-κB signalling pathways. MK3, an important kinase in the MAPK pathway, plays a role in transmitting upstream and downstream signals, whereas the NF-κB signalling pathway has been shown to be associated with HSC activation. We verified the interaction between MK3 and IκB in HSC cells using endogenous Co-IP, whereas ß-sitosterol reduced the binding of MK3 to IκB and the activation of the NF-κB signalling pathway. Our findings reveal the mechanism of ß-sitosterol in the treatment of liver fibrosis, suggesting that ß-sitosterol may be a promising drug for the treatment of liver fibrosis and deserves further investigation.

IL11-mediated stromal cell activation may not be the master regulator of pro-fibrotic signaling downstream of TGFß.

Fibrotic diseases, such as idiopathic pulmonary fibrosis (IPF) and systemic scleroderma (SSc), are commonly associated with high morbidity and mortality, thereby representing a significant unmet medical need. Interleukin 11 (IL11)-mediated cell activation has been identified as a central mechanism for promoting fibrosis downstream of TGFß. IL11 signaling has recently been reported to promote fibroblast-to-myofibroblast transition, thus leading to various pro-fibrotic phenotypic changes. We confirmed increased mRNA expression of IL11 and IL11Rα in fibrotic diseases by OMICs approaches and in situ hybridization. However, the vital role of IL11 as a driver for fibrosis was not recapitulated. While induction of IL11 secretion was observed downstream of TGFß signaling in human lung fibroblasts and epithelial cells, the cellular responses induced by IL11 was quantitatively and qualitatively inferior to that of TGFß at the transcriptional and translational levels. IL11 blocking antibodies inhibited IL11Rα-proximal STAT3 activation but failed to block TGFß-induced profibrotic signals. In summary, our results challenge the concept of IL11 blockade as a strategy for providing transformative treatment for fibrosis.

Arterial transit artifact as a short-term prognostic indicator in acute ischemic stroke.

BACKGROUND: Arterial transit artifact (ATA) observed on arterial spin labeling (ASL) was recently suggested to be associated with improved functional outcomes following acute ischemic stroke (AIS). AIS is a heterogeneous disease with diverse pathogenic mechanisms depending on the stroke subtype. This study aimed to investigate the association between ATA and 3-month functional outcomes in AIS patients according to etiology subtypes. METHODS: Consecutive patients with AIS were included. All patients underwent ASL MRI with postlabeling delay (PLD) of 1.5 and 2.5 s. ATA was assessed from the ASL images of both PLDs. Stroke etiologic subtypes were determined according to the modified TOAST (Trial of ORG 10172 in Acute Stroke Treatment) classification. Short-term functional outcomes were evaluated using the 3-month modified Rankin scale (mRS). Log-binomial regression was applied to analyze the association between ATA and functional outcomes at 3 months after stroke. RESULTS: Ninety-eight AIS patients (62.73 ± 13.05 years; 68 men) were finally included. ATA was detected in forty-six patients and most frequently seen in the large-artery atherosclerosis (LAA) subtype (35/46). The ATA group exhibited a lower percentage of patients with mRS > 2 compared to the group without ATA (36.5% vs. 19.6%; P < 0.001). ATA was independently associated with better 3-month clinical outcomes (adjusted risk ratio, 0.35[95% CI, 0.16-0.74]) in the multivariate log-binomial regression model. After stratification by TOAST subtypes, a significant association was found between ATA and better outcomes in the LAA subtype (adjusted risk ratio, 0.20[ 95% CI, 0.05-0.72]) but not in cardioembolism and small artery occlusion (SVO) subtype. CONCLUSION: ATA is associated with better outcomes at 3 months in patients with AIS, especially in the LAA subtype, but this association attenuated in the cardioembolism and SVO subtypes.

Echinatin protects from ischemic brain injury by attenuating NLRP3-related neuroinflammation.

BACKGROUND: Microglia-mediated neuroinflammation is the major contributor to the secondary brain injury of ischemic stroke. NLRP3 is one of the major components of ischemia-induced microglial activation. Echinatin, a chalcone found in licorice, was reported to have the activity of anti-inflammation and antioxidant. However, the relative study of echinatin in microglia or ischemic stroke is still unclear. METHODS: We intravenously injected echinatin or vehicle into adult ischemic male C57/BL6J mice induced by 60-min transient middle cerebral artery occlusion (tMCAO). The intraperitoneal injection was performed 4.5 h after reperfusion and then daily for 2 more days. Infarct size, blood brain barrier (BBB) leakage, neurobehavioral tests, and microglial-mediated inflammatory reaction were examined to assess the outcomes of echinatin treatment. LPS and LPS/ATP stimulation on primary microglia were used to explore the underlying anti-inflammatory mechanism of echinatin. RESULTS: Echinatin treatment efficiently decreased the infarct size, alleviated blood brain barrier (BBB) damage, suppressed microglial activation, reduced the production of inflammatory factors (e.g., IL-1ß, IL-6, IL-18, TNF-α, iNOS, COX2), and relieved post-stroke neurological defects in tMCAO mice. Mechanistically, we found that echinatin could suppress the NLRP3 assembly and reduce the production of inflammatory mediators independently of NF-κB and monoamine oxidase (MAO). CONCLUSION: Based on our study, we have identified echinatin as a promising therapeutic strategy for the treatment of ischemic stroke.

Bile acids induce liver fibrosis through the NLRP3 inflammasome pathway and the mechanism of FXR inhibition of NLRP3 activation.

BACKGROUND: Altered patterns of bile acids (BAs) are frequently present in liver fibrosis, and BAs function as signaling molecules to initiate inflammatory responses. Therefore, this study was conducted to uncover the notably altered components of BAs and to explore the pathway of altered BA induced inflammation in the development of liver fibrosis. METHODS: Bile acids were quantified by ultraperformance liquid chromatography coupled to mass spectrometry (UPLC‒MS/MS). Cell Counting Kit-8 assays were used to determine the proliferative capacity of HSCs. Transwell assays and wound healing assays were used to determine the migratory capacity of LX2 cells. Protein expression was evaluated by western blotting. RESULTS: Plasma bile acid analysis showed higher levels of GCDCA, TCDCA, GCA and TCA in patients with liver fibrosis than in normal controls. The AUC of GCDCA was the highest. Western blotting showed that GCDCA treatment increased the expression of NLRP3-related proteins and collagen1 in vitro and significantly increased LX2 cells proliferation and migration. Furthermore, knockdown of NLRP3 or overexpression of FXR in LX2 cells decreased the expression of the above proteins, and FXR inhibited NLRP3 (ser 295) phosphorylation in vitro and vivo. In vivo, HE, Masson's trichrome, and Sirius Red staining showed that GCDCA increased collagen fibers in the mouse liver, and the expression of NLRP3-related proteins, collagen 1, and α-SMA in the liver increased significantly. However, the knockout of NLRP3 reversed these patterns. CONCLUSION: (1) Primary conjugated bile acids increased in patients with liver fibrosis; (2) GCDCA induce hepatic fibrosis via the NLRP3 inflammasome pathway; (3) FXR inhibits NLRP3 activity by restraining its phosphorylation; (4) knockdown or knockout of NLRP3 may relieve the onset of hepatic fibrosis.

Linarin ameliorates ischemia-reperfusion injury by the inhibition of endoplasmic reticulum stress targeting AKR1B1.

Due to various factors, there is still a lack of effective neuroprotective agents for ischemic stroke in clinical practice. Neuroinflammation and neuronal apoptosis mediated by endoplasmic reticulum stress are some of the important pathological mechanisms in ischemic stroke. Linarin has been reported to have anti-inflammation, antioxidant, and anti-apoptotic effects in myocardial ischemia, osteoarthritis, and kidney disease. Whether it exerts neuroprotective functions in ischemic stroke has not been investigated. The results showed that linarin could reduce the infarct volume in cerebral ischemia animal models, improve the neurological function scores and suppress the expression of inflammatory factors mediating the NF-κB. Meanwhile, it could protect the neurons from OGD/R-induced-apoptosis, which was related to the PERK-eIF2α pathway. Our results suggested linarin could inhibit neuronal inflammation and apoptosis induced by endoplasmic reticulum stress. Furthermore, the neuroprotective effect of linarin may be related to the inhibition of AKR1B1. Our study offers new insight into protecting against ischemia-reperfusion injury by linarin treatment in stroke.

Correlation between Carotid Blood Flow Velocity and Total Magnetic Resonance Imaging Burden of Cerebral Small Vessel Disease in Patients with Recent Small Subcortical Infarcts.

BACKGROUND: The common and internal carotid arteries are the upstream vessels of the small cerebral vessels. The relationship between hemodynamic changes in the significant cervical vessels and cerebral small vessel disease (CSVD) remains uncertain. This research sought to analyze the correlation between carotid blood flow velocity and the total magnetic resonance imaging (MRI) burden of CSVD in patients with recent small subcortical infarcts (RSSIs). METHODS: Data were gathered from individuals diagnosed with RSSIs admitted to Changzhou Second People's Hospital between January 2022 and June 2023. Brain MRI was performed on every patient to determine the overall MRI burden of CSVD, along with carotid duplex ultrasound to evaluate carotid blood flow velocity and pulsatility index (PI) of the common carotid (CCA) and internal carotid (ICA) arteries. The association between carotid blood flow velocity and the total MRI load of CSVD was examined using univariate and multivariate analyses. RESULTS: For our investigation, 272 individuals with RSSIs were screened. 82 individuals had a moderate to severe load of CSVD, while 190 participants showed a mild burden. Patients with moderate to severe burden of CSVD had lower end-diastolic velocity (EDV) and higher PI in CCA and ICA than those with mild load (P < 0.001). After adjusting for variables like age, hypertension, systolic blood pressure, and blood homocysteine levels, multivariate logistic regression analysis showed that EDV in CCA (OR, 0.894; P = 0.011), PI in CCA (OR, 5.869; P = 0.017), EDV in ICA (OR, 0.909; P = 0.008), and PI in ICA (OR, 5.324; P = 0.041) were independently related to moderate to severe CSVD burden. Spearman correlation analysis showed that EDV in CCA and ICA was negatively related to the total MRI load of CSVD in patients with RSSIs (P < 0.001). PI in CCA and ICA was positively associated with the whole MRI load of CSVD (P < 0.001). CONCLUSION: Low carotid blood flow velocity and high carotid pulsatility index are independently associated with moderate to severe burden of CSVD.

Association of tirofiban with improvement of functional outcomes of direct thrombectomy for acute anterior circulation occlusion: a retrospective, nonrandomized, multicenter, real-world study.

OBJECTIVE: Although tirofiban and endovascular thrombectomy have been widely used in the treatment of acute ischemic stroke (AIS) patients, the effectiveness of their combined application remains a subject of debate. This study aimed to assess the efficacy and safety of tirofiban in direct thrombectomy for AIS with anterior circulation vessel occlusion. METHODS: A total of 204 patients undergoing direct thrombectomy between January 2020 and December 2021 for AIS with anterior circulation vessel occlusion from four hospitals were included in this study. Patients at high risk of reocclusion with severe atherosclerosis, those who achieved successful recanalization for ≥ 3 stent retriever passes, or those who underwent emergency stenting or balloon angioplasty for severe residual stenosis were treated with tirofiban. Following a low-dose intra-arterial bolus (0.25-1 mg) immediately after endovascular treatment, tirofiban was administered continuously through intravenous infusion (0.1 µg/kg/min) for 12-24 hours. The primary efficacy outcome was evaluated using the 90-day modified Rankin Scale score. The safety outcome was assessed using symptomatic intracerebral hemorrhage (sICH) and mortality rates. RESULTS: The tirofiban group and nontirofiban group each included 102 patients. The favorable outcome rate in the tirofiban group was significantly higher than that in the nontirofiban group (53.9% vs 35.3%, p = 0.007). However, the sICH and 90-day mortality rates were lower in the tirofiban group, despite a lack of statistical significance (sICH: 15.7% vs 16.7%, p = 0.849; 90-day mortality: 16.67% vs 24.51%, p = 0.166). Finally, it was found that older patients (> 72 years), male patients, patients with admission National Institutes of Health Stroke Scale scores > 14, patients with a time from onset to reperfusion > 327 minutes, and patients with a medical history of diabetes tend to benefit from tirofiban treatment. CONCLUSIONS: This study suggests that tirofiban combined with direct thrombectomy improves functional outcomes of AIS and reduces the 90-day mortality rate. Therefore, it could be considered as a suitable treatment option for AIS patients with anterior circulation vessel occlusion.

Interpretable Machine Learning Model Predicting Early Neurological Deterioration in Ischemic Stroke Patients Treated with Mechanical Thrombectomy: A Retrospective Study.

Early neurologic deterioration (END) is a common and feared complication for acute ischemic stroke (AIS) patients treated with mechanical thrombectomy (MT). This study aimed to develop an interpretable machine learning (ML) model for individualized prediction to predict END in AIS patients treated with MT. The retrospective cohort of AIS patients who underwent MT was from two hospitals. ML methods applied include logistic regression (LR), random forest (RF), support vector machine (SVM), and extreme gradient boosting (XGBoost). The area under the receiver operating characteristic curve (AUC) was the main evaluation metric used. We also used Shapley Additive Explanation (SHAP) and Local Interpretable Model-Agnostic Explanations (LIME) to interpret the result of the prediction model. A total of 985 patients were enrolled in this study, and the development of END was noted in 157 patients (15.9%). Among the used models, XGBoost had the highest prediction power (AUC = 0.826, 95% CI 0.781-0.871). The Delong test and calibration curve indicated that XGBoost significantly surpassed those of the other models in prediction. In addition, the AUC in the validating set was 0.846, which showed a good performance of the XGBoost. The SHAP method revealed that blood glucose was the most important predictor variable. The constructed interpretable ML model can be used to predict the risk probability of END after MT in AIS patients. It may help clinical decision making in the perioperative period of AIS patients treated with MT.

Bone marrow mesenchymal stem cell-derived exosomes alleviate skin fibrosis in systemic sclerosis by inhibiting the IL-33/ST2 axis via the delivery of microRNA-214.

Interleukin (IL)- 33 is a tissue-derive proinflammatory cytokine that promotes fibrosis in systemic sclerosis (SSc). microRNA (miR)- 214 expression has been elaborated to be downregulated in SSc patients and exert anti-fibrotic and anti-inflammatory effects. This study elucidates the role of bone marrow mesenchymal stem cell-derived exosome (BMSC-Exos)-delivered miR-214 in SSc and the relationship between this miR and IL-33/ST2 axis. SSc clinical samples were obtained to evaluate levels of miR-214, IL-33, and ST2. Primary fibroblasts and BMSC-Exos were extracted, followed by the co-culture of PKH6-labeled BMSC-Exos and fibroblasts. Subsequently, Exos extracted from miR-214 inhibitor-transfected BMSCs were co-cultured with TGF-ß1-stimulated fibroblasts, after which the expression of fibrotic markers, miR-214, IL-33, and ST2, as well as fibroblast proliferation and migration, was determined. A skin fibrosis mouse model was induced with bleomycin (BLM) and treated with BMSC-Exos. Collagen fiber accumulation, collagen content, α-SMA expression, and IL-33 and ST2 levels were examined in BLM-treated or IL-33-knockout mice. IL-33 and ST2 were upregulated and miR-214 was downregulated in SSc patients. Mechanistically, miR-214 targeted IL-33 and blocked the IL-33/ST2 axis. BMSC-Exos delivering miR-214 inhibitor augmented proliferation, migration, and fibrotic gene expression in TGF-ß1-stimulated fibroblasts. Similarly, IL-33 induced migration, proliferation, and fibrotic gene expression in fibroblasts via ST2. In BLM-treated mice, IL-33 knockout suppressed skin fibrosis, and BMSC-Exos delivered miR-214 to suppress the IL-33/ST2 axis, thus mitigating skin fibrosis. Conclusively, BMSC-Exos alleviate skin fibrosis through the blockade of the IL-33/ST2 axis by delivering miR-214.

Stattic alleviates pulmonary fibrosis in a mouse model of rheumatoid arthritis-relevant interstitial lung disease.

Approximately 20% of rheumatoid arthritis (RA) patients have RA-related interstitial lung disease (RA-ILD). Stattic, an STAT3 inhibitor, has been confirmed to be relevant to both RA and ILD. Therefore, this study explored the effect of Stattic on the progression of joint disease and pulmonary fibrosis in zymosan-treated female SKG mice, an established model for autoimmune arthritis. The experimental mice developed pulmonary interstitial pneumonia, which is similar to human cellular and fibrotic nonspecific interstitial pneumonia. Oral gavage of Stattic (60 mg/kg/d) was initiated 10 weeks after zymosan injection. Arthritis and lung fibrosis outcome scores decreased significantly following Stattic treatment. An obvious decrease in lung collagen levels, measured using hydroxyproline level determination and collagen staining, was detected after 6 weeks in Stattic-exposed mice with established disease. Stattic also dramatically restricted arthritis progression, based on joint evaluation. Transforming growth factor beta 1 (TGF-ß1) is a pivotal fibrosis-causing cytokine, used here to treat myofibroblasts, thereby establishing a lung fibrosis cell model. Stattic treatment can mitigate the TGF-ß1-triggered inflammatory response, myofibroblast activation, oxidative stress, and hyperproliferation by modulating the JAK1/STAT3 pathway. Our observations support a direct role of Stattic-inhibited STAT3 activation in lung fibrosis, which may be particularly relevant in the RA-ILD context.

Blocking postsynaptic density-93 binding to C-X3-C motif chemokine ligand 1 promotes microglial phenotypic transformation during acute ischemic stroke.

We previously reported that postsynaptic density-93 mediates neuron-microglia crosstalk by interacting with amino acids 357-395 of C X3 C motif chemokine ligand 1 (CX3CL1) to induce microglia polarization. More importantly, the peptide Tat-CX3CL1 (comprising amino acids 357-395 of CX3CL1) disrupts the interaction between postsynaptic density-93 and CX3CL1, reducing neurological impairment and exerting a protective effect in the context of acute ischemic stroke. However, the mechanism underlying these effects remains unclear. In the current study, we found that the pro-inflammatory M1 phenotype increased and the anti-inflammatory M2 phenotype decreased at different time points. The M1 phenotype increased at 6 hours after stroke and peaked at 24 hours after perfusion, whereas the M2 phenotype decreased at 6 and 24 hours following reperfusion. We found that the peptide Tat-CX3CL1 (357-395aa) facilitates microglial polarization from M1 to M2 by reducing the production of soluble CX3CL1. Furthermore, the a disintegrin and metalloprotease domain 17 (ADAM17) inhibitor GW280264x, which inhibits metalloprotease activity and prevents CX3CL1 from being sheared into its soluble form, facilitated microglial polarization from M1 to M2 by inhibiting soluble CX3CL1 formation. Additionally, Tat-CX3CL1 (357-395aa) attenuated long-term cognitive deficits and improved white matter integrity as determined by the Morris water maze test at 31-34 days following surgery and immunofluorescence staining at 35 days after stroke, respectively. In conclusion, Tat-CX3CL1 (357-395aa) facilitates functional recovery after ischemic stroke by promoting microglial polarization from M1 to M2. Therefore, the Tat-CX3CL1 (357-395aa) is a potential therapeutic agent for ischemic stroke.

Characterization of GmMATE13 in its contribution of citrate efflux and aluminum resistance in soybeans.

Citrate exudation mediated by a citrate transporter of the MATE protein family is critical for resisting aluminum (Al) toxicity in soybeans. However, the expression patterns of citrate transporter genes differ under Al stress. Thus, exploring the responsive pattern of GmMATEs in response to Al stress is of great importance to understand the Al resistance mechanism in soybeans. In the present study, the phylogenetic analysis, transcriptionally expressed pattern, and function of GmMATE13 were investigated. The results show that soybean GmMATE13 is highly homologous to known citrate transporter proteins from other plants. Under Al exposure, the transcript abundance of GmMATE13 was increased during a 24 h Al treatment period. The expression of GmMATE13 is specifically induced by Al exposure, but not by the status of Fe, Cu, Cd, or La. Moreover, it was also highly increased when soybean seedlings were grown on acidic soil with a high Al content. Subcellular localization showed that GmMATE13 was localized on the plasma membrane when it was transiently expressed in Arabidopsis protoplasts. Investigation of tissue localization of GmMATE13 expression by investigating GUS activity staining under control of the GmMATE13 promoter showed that it was mainly expressed in the central cylinder in the root tips of the soybean under Al-free conditions, yet extended to cortical and epidermis cells under Al stress. Finally, overexpressing GmMATE13 in soybean hairy roots enhanced Al resistance by increasing citrate efflux. Collectively, we conclude that GmMATE13 is a promising candidate to improve the resistance of soybean to Al toxicity in acidic soil.

Mechanical properties and mechanism of soil treated with nano-aqueous adhesive (NAA).

The loose structure and low mechanical strength of the surface soil make it vulnerable to damage under erosion conditions. Slope ecological protection is one of the effective methods to improve the stability of slope soil. Although it has been proved that polymer modified materials can effectively improve the soil properties and the environmental protection effect of slope, so far, the improvement mechanism has not been fully understood, especially the chemical mechanism of the material on the enhancement of soil mechanical properties is not clear. In the present study, the effects of nano-aqueous adhesive (NAA) on unconfined compressive strength, shear strength and aggregate characteristics of soil were studied by a series of laboratory experiments. The results show that NAA can increase the strength, aggregate number and stability of the soil, to effectively improve the stability of surface soil. In addition, through infrared spectroscopy and SEM test, it was found that NAA molecules were mainly distributed in the interlayer position of flaky clay minerals, mainly connected with clay minerals through hydrogen bonds, thereby effectively enhancing the cohesion of soil particles.

The LncRNA AK018453 regulates TRAP1/Smad signaling in IL-17-activated astrocytes: A potential role in EAE pathogenesis.

The pro-inflammatory cytokine interleukin 17 (IL-17), that is mainly produced by Th17 cells, has been recognized as a key regulator in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). Reactive astrocytes stimulated by proinflammatory cytokines including IL-17 are involved in blood brain barrier destruction, inflammatory cells infiltration and spinal cord injury. However, the role of long non-coding RNAs (lncRNAs) induced by IL-17 in the pathogenesis of MS and EAE remains unknown. Herein, we found that an IL-17-induced lncRNA AK018453 promoted TGF-ß receptor-associated protein 1 (TRAP1) expression and Smad-dependent signaling in mouse primary astrocytes. Knockdown of AK018453 significantly suppressed astrocytosis, attenuated the phosphorylation of Smad2/3, reduced NF-κB p65 and CBP/P300 binding to the TRAP1 promoter, and diminished pro-inflammatory cytokine production in the IL-17-treated astrocytes. AK018453 knockdown in astrocytes by a lentiviral vector in vivo dramatically inhibited inflammation and prevented the mice from demyelination in the spinal cord during the progression of EAE. Together, these results suggest that AK018453 regulates IL-17-dependent inflammatory response in reactive astrocytes and potentially promotes the pathogenesis of EAE via the TRAP1/Smad pathway. Targeting this pathway may have a therapeutic potential for intervening inflammatory demyelinating diseases.