A novel mechanism of resveratrol alleviates Toxoplasma gondii infection-induced pulmonary inflammation via inhibiting inflammasome activation.

BACKGROUND: Infection by Toxoplasma gondii can lead to severe pneumonia, with current treatments being highly inadequate. The NLRP3 inflammasome is one member of the NOD-like receptor family with a pyrin domain, which is crucial in the innate immune defense against T. gondii. Research has shown that resveratrol (RSV) prevents lung damage caused by this infection by inhibiting the T. gondii-derived heat shock protein 70/TLR4/NF-κB pathway, thus reducing the macrophage-driven inflammatory response. However, it should be mentioned that the participation of NLRP3 inflammasome in the immune response to the lung injuries caused by T. gondii infections is not entirely clear. PURPOSE: This study aims to clarify how RSV ameliorates lung damage triggered by Toxoplasma gondii infection, with a particular focus on the pathway involving TLR4, NF-κB, and the NLRP3 inflammasome. METHODS: Both in vitro and in vivo models of infection were developed by employing the RH strain of T. gondii in BALB/c mice and RAW 264.7 macrophage cell lines. The action mechanism of RSV was explored using techniques such as molecular docking, surface plasmon resonance, ELISA, Western blot, co-immunoprecipitation, and immunofluorescence staining. RESULTS: Findings indicate that the suppression of TLR4 or NF-κB impacts the levels of proteins associated with the NLRP3 inflammasome pathway. Additionally, a significant affinity for binding between RSV and NLRP3 was observed. Treatment with RSV led to a marked reduction in the activation and formation of the NLRP3 inflammasome within lung tissues and RAW 264.7 cells, alongside a decrease in IL-1ß concentrations in the bronchoalveolar lavage fluid. These outcomes align with those seen when using the NLRP3 inhibitor CY-09. Moreover, the application of CY-09 prior to RSV negated the latter's anti-inflammatory properties. CONCLUSION: Considering insights from previous research alongside the outcomes of the current investigation, it appears that the TLR4/NF-κB/NLRP3 signaling pathway emerges as a promising target for immunomodulation to alleviate lung injury from T. gondii infection. The evidence gathered in this study lays the groundwork for the continued exploration and potential future clinical deployment of RSV as a therapeutic agent with anti-Toxoplasma properties and the capability to modulate the inflammatory response.

RNA-binding protein-regulated fibronectin is essential for EGFR-activated metastasis of head and neck squamous cell carcinoma.

There is a higher expression level of epidermal growth factor receptor (EGFR) in up to 90% of advanced head and neck squamous cell carcinoma (HNSCC) tissue than in normal surrounding tissues. However, the role of RNA-binding proteins (RBPs) in EGFR-associated metastasis of HNSCC remains unclear. In this study, we reveal that RBPs, specifically nucleolin (NCL) and heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1), correlated with the mesenchymal phenotype of HNSCC. The depletion of RBPs significantly attenuated EGF-induced HNSCC metastasis. Intriguingly, the EGF-induced EMT markers, such as fibronectin, were regulated by RBPs through the ERK and NF-κB pathway, followed by the enhancement of mRNA stability of fibronectin through the 5' untranslated region (5'-UTR) of the gene. The upregulation of fibronectin triggered the integrin signaling activation to enhance tumor cells' attachment to endothelial cells and increase endothelial permeability. In addition, the concurrence of EGFR and RBPs or EGFR and fibronectin was associated with overall survival and disease-free survival of HNSCC. The in vivo study showed that depletion of NCL, hnRNPA2B1, and fibronectin significantly inhibited EGF-promoted extravasation of tumor cells into lung tissues. The depletion of fibronectin or treatment with integrin inhibitors dramatically attenuated EGF-induced HNSCC metastatic nodules in the lung. Our data suggest that the RBPs/fibronectin axis is essential for EGF-induced tumor-endothelial cell interactions to enhance HNSCC cell metastasis.

Coixol ameliorates Toxoplasma gondii infection-induced lung injury by interfering with T. gondii HSP70/TLR4/NF-κB signaling pathway.

Toxoplasma gondii (T. gondii) is an obligate intracellular protozoan parasite that causes pulmonary toxoplasmosis, although its pathogenesis is incompletely understood. There is no cure for toxoplasmosis. Coixol, a plant polyphenol extracted from coix seeds, has a variety of biological activities. However, the effects of coixol on T. gondii infection have not been clarified. In this study, we infected a mouse macrophage cell line (RAW 264.7) and BALB/c mice with the T. gondii RH strain to establish infection models in vitro and in vivo, respectively, to explore protective effects and potential mechanisms of coixol on lung injury caused by T. gondii infection. Anti-T. gondii effects and underlying anti-inflammatory mechanisms of coixol were investigated by real-time quantitative PCR, molecular docking, localized surface plasmon resonance, co-immunoprecipitation, enzyme-linked immunosorbent assay, western blotting, and immunofluorescence microscopy. The results show that coixol inhibits T. gondii loads and T. gondii-derived heat shock protein 70 (T.g.HSP70) expression. Moreover, coixol reduced inflammatory cell recruitment and infiltration, and ameliorated pathological lung injury induced by T. gondii infection. Coixol can directly bind T.g.HSP70 or Toll-like receptor 4 (TLR4) to disrupt their interaction. Coixol prevented overexpression of inducible nitric oxide synthase, tumor necrosis factor-α, and high mobility group box 1 by inhibiting activation of the TLR4/nuclear factor (NF)-κB signaling pathway, consistent with effects of the TLR4 inhibitor CLI-095. These results indicate that coixol improves T. gondii infection-induced lung injury by interfering with T.g.HSP70-mediated TLR4/NF-κB signaling. Altogether, these findings suggest that coixol is a promising effective lead compound for the treatment of toxoplasmosis.

Non-Singleton Type-3 Fuzzy Approach for Flowmeter Fault Detection: Experimental Study in a Gas Industry.

The main contribution of this paper is to develop a new flowmeter fault detection approach based on optimized non-singleton type-3 (NT3) fuzzy logic systems (FLSs). The introduced method is implemented on an experimental gas industry plant. The system is modeled by NT3FLSs, and the faults are detected by comparison of measured end estimated signals. In this scheme, the detecting performance depends on the estimation and modeling performance. The suggested NT3FLS is used because of the existence of a high level of measurement errors and uncertainties in this problem. The designed NT3FLS with uncertain footprint-of-uncertainty (FOU), fuzzy secondary memberships and adaptive non-singleton fuzzification results in a powerful tool for modeling signals immersed in noise and error. The level of non-singleton fuzzification and membership parameters are tuned by maximum correntropy (MC) unscented Kalman filter (KF), and the rule parameters are learned by correntropy KF (CKF) with fuzzy kernel size. The suggested learning algorithms can handle the non-Gaussian noises that are common in industrial applications. The various types of flowmeters are investigated, and the effect of common faults are examined. It is shown that the suggested approach can detect the various faults with good accuracy in comparison with conventional approaches.

Role of tool marks inside spherical mitigation pit fabricated by micro-milling on repairing quality of damaged KH2PO4 crystal.

Repairing initial slight damage site into stable structures by engineering techniques is the leading strategy to mitigate the damage growth on large-size components used in laser-driven fusion facilities. For KH2PO4 crystals, serving as frequency converter and optoelectronic switch-Pockels cell, micro-milling has been proven the most promising method to fabricate these stable structures. However, tool marks inside repairing pit would be unavoidably introduced due to the wearing of milling cutter in actual repairing process. Here we quantitatively investigate the effect of tool marks on repairing quality of damaged crystal components by simulating its induced light intensification and testing the laser-induced damage threshold. We found that due to the formation of focusing hot spots and interference ripples, the light intensity is strongly enhanced with the presence of tool marks, especially for those on rear surfaces. Besides, the negative effect of tool marks is mark density dependent and multiple tool marks would aggravate the light intensification. Laser damage tests verified the role of tool marks as weak points, reducing the repairing quality. This work offers new criterion to comprehensively evaluate the quality of repaired optical surfaces to alleviate the bottleneck issue of low laser damage threshold for optical components in laser-driven fusion facilities.

Stereotactic aspiration and thrombolysis of spontaneous intracerebellar hemorrhage.

BACKGROUND: Spontaneous intracerebellar hemorrhage (SCH) accounts for 10% of intracerebral hemorrhages. Up to now stereotactic aspiration and thrombolysis of SCH was less reported. The aim of this study was to assess the effect and feasibility of the method, and to refine the clinical protocol. METHODS: Eighteen patients with SCH were treated by stereotactic aspiration and thrombolysis and reviewed in this report. The 3-mm axial stereotactic computed tomography slices throughout the hematoma were obtained. Those images were then transferred to the workstation. The trajectory of catheter was designed to go through the main axis of the hematoma. Under local anesthesia a catheter was directed stereotactically into the hematoma through a burr hole. Hematoma thrombolysis and clot drainage was followed by instillation of urokinase (10,000 U) every 12 hours. The catheter was removed when the majority of hematoma was evacuated. RESULTS: Initial SCH volume was reduced by an average of 86% and the average final hematoma volume was 2.8 ml. At 3-month follow-up, 13 patients (72%) had achieved good recovery. At 6-month follow-up, 12 patients (67%) had achieved good recovery. CONCLUSION: Stereotactic aspiration and thrombolysis of SCH was a simple, feasible and effective method to treat moderate and some benign SCH that less respond to medical treatment.

[Effect of triptergium wilfordii polyglycosidium on content of Th1 and Th2 in child recurrent nephrotic syndrome].

OBJECTIVE: To study the effect of triptergium wilfordii polyglycosidium on the content of Th1 and Th2 in the treatment child patients of rcurrent nephrotic syndrome. METHOD: Patients were randomized into treatment group and health group. Sixty-one patients in treatment group were treated with triptergium wilfordii polyglycosidium 1 mg x kg(-1) x d(-1) orally tid for 12 weeks. However, patients in health group was not treated with any drugs. Twelve weeks constituted one course of treatment and the content of IL-12, IL-2, TNF-alpha, IL-13, IL-6, IL-4 in peripheral blood was measured before and behind therapy. RESULT: In treatment group, the content of serum cytokines behind therapy was significantly lower than that before therapy, except for IL-12. CONCLUSION: Triptergium wilfordii polyglycosidium could reduce the cytokine level (except for IL-12) of Th1 and Th2, which could lead a therapeutic effect of in the child patients of RNS.

[Effects of immunotherapy with infantile recurrent respiratory tract infection by Chinese materia medica].

OBJECTIVE: To explore the effect of Chinese materia medica on immune intervention of infantile recurrent respiratory tract infection. METHOD: Thirty-one children of recurrent respiratory tract infection were randomly divided into two groups: therapy group was treated with oral Chinese materia medica (b. i. d), control group was only treated with oral carboxymethyl liquor (< 4 years, 3 mL; 4-7 years, 5 mL; > 7 years, 7 mL, t. i. d). The change of IL-12,TNF-alpha, IL-6, IL-13, IL-6 and IL-4 in different time were observed and analyzes. RESULT: Compared with the control group, the level of IL-12 and IL-2 was significantly increased after treatment of oral Chinese materia medica (P < 0.01), however, the level of TNF-alpha, IL-13, IL-4, and IL-6 was decreased after treatment (P < 0.01). During one years follow-up study, the frequency of respiratory infection every year of therapy group was significantly decreased than that of control group. CONCLUSION: Chinese materia medica could prevent infantile recurrent respiratory tract infection effectively, increase humoral immunity function and ensure normal growth in children.

[Microstructural observation of epileptic neurons in vitro by atomic force microscopy].

OBJECTIVE: To observe the microstructure of the cell membrane of epileptic neurons using atomic force microscopy (AFM). METHODS: Model of epileptic neurons was established by subjecting the neurons culture for 14 days in vitro to magnesium-free media treatment for 3 h. Patch clamp technique was applied to record the electrophysiological activity of the epileptic neurons. AFM was performed to observe and measure the microstructure of the cell membrane of the epileptic neuron. RESULTS: After a 3-hour treatment with magnesium-free media, the epileptic neurons displayed sustained epileptiform discharge, which continued after the neurons were returned to normal medium culture on day 14. Under AFM scanning size of 80 microm x 80 microm and 2 microm x 2 microm, no obvious difference in the morphology of the cell membrane was noted between epileptic and normal neurons; under the scanning size of 500 nm x 500 nm, small pits occurred in the cell membrane in both groups, but no significant difference was found in the dimension of the pits between the two groups (the diameter and depth of the pits was 114.86-/+9.33 nm and 5.71-/+0.69 nm in epileptic neurons, and 116.4-/+9.13 nm and 5.69-/+0.71 nm in the control neurons, respectively, P>0.05). CONCLUSION: AFM provides a new method for observing neuronal membrane microstructure at nanometer resolutions. No significant alterations occur in the membrane of the neurons after a 3-hour magnesium-free media treatment.

[Clinical effect of shenbing mistura combined with glucocorticoid on recurrent nephrotic syndrome in children and levels of interleukin-6 and tumor necrosis factor-alpha in blood and urine].

OBJECTIVE: To study the effect of Shenbing Mistura (SM) combined with glucocorticoid on recurrent nephrotic syndrome (RNS) in children and levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) in blood and urine. METHODS: The treatment group was treated with SM plus glucocorticoid, the control group with glucocorticoid alone, and a healthy control group was adopted, 30 cases in each group. The clinical effect and recurrence rate were observed, and levels of IL-6 and TNF-alpha in blood and urine were determined before treatment and at the 4th, 8th, 12th week after treatment. RESULTS: Significant difference of IL-6 and TNF-alpha levels in blood and urine was found in either the pre- and post- treatment auto-control of both the treatment group and control group, or in the inter-group comparison of them (P < 0.01); clinical effect also showed remarkable difference between the two groups (P < 0.01). Furthermore, the recurrence rate of the treatment group was lower than that of the control group showed by a 18-month follow-up (P < 0.01). CONCLUSION: SM combined with glucocorticoid could significantly reduce the recurrence rate and elevate the clinical effect in children with RNS, it could also lower the levels of IL-6 and TNF-alpha in patients' blood and urine.