Airways epithelial exposure to Streptococcus pneumoniae in the presence of the alarmin IL-33 induces a novel subset of pro-inflammatory ILC2s promoting a mixed inflammatory response.

BACKGROUND: We have previously shown that asthma-like airways inflammation may be induced by topical exposure to respiratory tract pathogens such as S. pneumoniae (SP) in concert with epithelial alarmins such as IL-33. Details of the pathogenesis of this murine surrogate remain however unexplored. METHODS: Airways inflammation was induced by repeated, intranasal exposure of Il-4-/-, Rag1-/- and Rag2-/-Il2rg-/- mice (in which B lymphocyte IgE switching, adaptive and innate immunity are respectively ablated) as well as wild type mice to inactivated SP, IL-33 or both. Airways pathological changes were analysed, and the subsets and functions of locally accumulated ILC2s investigated by single cell RNA sequencing and flow cytometry. RESULTS: In the presence of IL-33, repeated exposure of the airways to inactivated SP caused marked eosinophil- and neutrophil-rich inflammation and local accumulation of ILC2s, which was retained in the Il-4-/- and Rag1-/- deficient mice but abolished in the Rag2-/-Il2rg-/- mice, an effect partly reversed by adoptive transfer of ILC2s. Single cell sequencing analysis of ILC2s recruited following SP and IL-33 exposure revealed a Klrg1+Ly6a+subset, expressing particularly elevated quantities of the pro-inflammatory cytokine IL-6, type 2 cytokines (IL-5 and IL-13) and MHC class II molecules, promoting type 2 inflammation as well as involved in neutrophil-mediated inflammatory responses. CONCLUSION: Local accumulation of KLRG1+Ly6a+ ILC2s in the lung tissue is a critical aspect of the pathogenesis of airways eosinophilic and neutrophil-rich inflammation induced by repeated exposure to SP in the presence of the epithelial alarmin IL-33.

Node features of chromosome structure networks and their connections to genome annotation.

The 3D conformations of chromosomes can encode biological significance, and the implications of such structures have been increasingly appreciated recently. Certain chromosome structural features, such as A/B compartmentalization, are frequently extracted from Hi-C pairwise genome contact information (physical association between different regions of the genome) and compared with linear annotations of the genome, such as histone modifications and lamina association. We investigate how additional properties of chromosome structure can be deduced using an abstract graph representation of the contact heatmap, and describe specific network properties that can have a strong connection with some of these biological annotations. We constructed chromosome structure networks (CSNs) from bulk Hi-C data and calculated a set of site-resolved (node-based) network properties. These properties are useful for characterizing certain aspects of chromosomal structure. We examined the ability of network properties to differentiate several scenarios, such as haploid vs diploid cells, partially inverted nuclei vs conventional architecture, depletion of chromosome architectural proteins, and structural changes during cell development. We also examined the connection between network properties and a series of other linear annotations, such as histone modifications and chromatin states including poised promoter and enhancer labels. We found that semi-local network properties exhibit greater capability in characterizing genome annotations compared to diffusive or ultra-local node features. For example, the local square clustering coefficient can be a strong classifier of lamina-associated domains. We demonstrated that network properties can be useful for highlighting large-scale chromosome structure differences that emerge in different biological situations.

Biomechanism of abnormal stress on promoting osteoarthritis of temporomandibular joint through Piezo1 ion channel.

OBJECTIVE: This study aimed to investigate whether flow fluid shear stress (FFSS)-mediated signal transduction affects the function of Piezo1 ion channel in chondrocyte and to further explore the role of mechanical overloading in development of temporomandibular joint osteoarthritis (TMJ OA). METHODS: Immunohistochemical staining was used to determine the expression of Piezo1 in TMJ OA tissue collected from rat unilateral anterior crossbite (UAC) models. Chondrocytes harvested from normal adult SD rats were treated with FFSS (0, 4, 8, 12 dyn/cm2) in vitro. Immunofluorescent staining, real-time polymerase chain reaction, western blotting, flow cytometry and phalloidin assay were performed to detect the changes of cellular morphology as well as the expression of Piezo1 and certain pro-inflammatory and degradative factors in chondrocyte. RESULTS: Immunohistochemical analysis revealed that significantly increased Piezo1 expression was associated with UAC stimulation (p < .05). As applied FFSS escalated (4, 8 and 12 dyn/cm2), the expression levels of Piezo1, ADAMTS-5, MMP-13 and Col-X gradually increased, compared with the non-FFSS group (p < .05). Administering Piezo1 ion channel inhibitor to chondrocytes beforehand, it was observed that expression of ADAMTS-5, MMP-13 and Col-X was substantially decreased following FFSS treatment (p < .05) and the effect of cytoskeletal thinning was counteracted. The activated Piezo1 ion channel enhanced intracellular Ca2+ excess in chondrocytes during abnormal mechanical stimulation and the increased intracellular Ca2+ thinned the cytoskeleton of F-actin. CONCLUSIONS: Mechanical overloading activates Piezo1 ion channel to promote pro-inflammation and degradation and to increase Ca2+ concentration in chondrocyte, which may eventually result in TMJ OA.

Sex Differences in Prognosis of Childhood Arterial Ischemic Stroke: Results From Chinese Pediatric Ischemic Stroke Registry Multicenter Registry.

BACKGROUND: Current studies on the impact of sex in the prognosis of childhood arterial ischemic stroke (AIS) are limited. We aimed to explore the sex differences in outcomes in patients with childhood AIS. METHODS: A retrospective analysis was conducted using the prospective data from the Chinese Pediatric Ischemic Stroke Registry. Baseline characteristics between sexes were compared in the total population cohort, propensity score (PS)-matched cohort, and inverse probability of treatment weighting cohort. Multivariate logistic regression and ordinal regression were used to analyze the association of sex with outcomes. Mixed-effects regression model was applied to further analyze the improvement in pediatric modified Rankin Scale (mRS) scores between sexes from 90 days to one year. Survival analysis was used to estimate the recurrence rates during the follow-up period. RESULTS: A total of 468 patients were finally included. Multivariate logistic regression showed that there were no significant differences between females and males in achieving favorable outcome (odds ratio [OR] 1.04, 95% confidence interval [CI] 0.63 to 1.72), functional independence (OR 0.98, 95% CI 0.59 to 1.63), or shift to worse pediatric mRS scores (OR 0.83, 95% CI 0.59 to 1.17) at 90-day. Mixed-effects regression and survival analysis indicated that females and males exhibited comparable functional recovery from 90 days to one year and had similar recurrent risk during the follow-up period. CONCLUSIONS: This nationally-representative observational study indicated that both male and female pediatric patients with AIS exhibited comparable similar clinical outcomes at 90 days, as well as similar improvements and risks of recurrence during the follow-up period.

Total glucosides of paeony alleviates cGAS-STING-mediated diseases by blocking the STING-IRF3 interaction.

In the realm of autoimmune and inflammatory diseases, the cyclic GMP-AMP synthase (cGAS) stimulator of interferon genes (STING) signaling pathway has been thoroughly investigated and established. Despite this, the clinical approval of drugs targeting the cGAS-STING pathway has been limited. The Total glucosides of paeony (TGP) is highly anti-inflammatory and is commonly used in the treatment of rheumatoid arthritis (RA), emerged as a subject of our study. We found that the TGP markedly reduced the activation of the cGAS-STING signaling pathway, triggered by various cGAS-STING agonists, in mouse bone marrow-derived macrophages (BMDMs) and Tohoku Hospital Pediatrics-1 (THP-1) cells. This inhibition was noted alongside the suppression of interferon regulatory factor 3 (IRF3) phosphorylation and the expression of interferon-beta (IFN-ß), C-X-C motif chemokine ligand 10 (CXCL10), and inflammatory mediators such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). The mechanism of action appeared to involve the TGP's attenuation of the STING-IRF3 interaction, without affecting STING oligomerization, thereby inhibiting the activation of downstream signaling pathways. In vivo, the TGP hindered the initiation of the cGAS-STING pathway by the STING agonist dimethylxanthenone-4-acetic acid (DMXAA) and exhibited promising therapeutic effects in a model of acute liver injury induced by lipopolysaccharide (LPS) and D-galactosamine (D-GalN). Our findings underscore the potential of the TGP as an effective inhibitor of the cGAS-STING pathway, offering a new treatment avenue for inflammatory and autoimmune diseases mediated by this pathway.

[Mechanism of total glucosides of White Paeony Capsules in ameliorating acute lung injury based on NLRP3 inflammasome].

This study deciphered the ameliorating effect and molecular mechanism of the total glucosides of White Paeony Capsules(TGP) in the treatment of mice model with acute lung injury(ALI) via NOD-like receptor thermal protein domain associated protein 3(NLRP3) signaling pathway of the inflammasome. The study established an inflammasome activation model of primed bone marrow-derived macrophages(BMDMs), and its molecular mechanism was investigated by Western blot(WB), immunofluorescence staining, enzyme-linked immunosorbent assay(ELISA), and flow cytometry. C57BL/6J mice were randomly divided into a blank control group, a TGP group, a model group(LPS group), LPS+low-and high-dose TGP groups, LPS+MCC950 group, and LPS+MCC950+TGP group, with eight mice per group. The ALI model was induced in mice. Finally, bronchoalveolar lavage fluid(BALF) and lung tissue were collected. Lung index and lung weight wet-to-dry ratio were determined for each group of mice. The pathological changes in lung tissue were observed through hematoxylin-eosin(HE) staining. The number of neutrophils in the BALF of each group was detected using flow cytometry. The levels of interleukin(IL)-1ß, IL-6, and tumor necrosis factor(TNF)-α in the BALF were determined by ELISA. The expressions of IL-1ß, IL-18, IL-6, and TNF-α in the lung tissue were determined by real-time quantitative PCR(RT-qPCR). This study demonstrated that TGP dramatically blocked the activation of the NLRP3 inflammasome by inhibiting the production of upstream mitochondrial reactive oxygen species(mtROS) and the subsequent oligomerization of apoptosis-associated specks(ASC). Additionally, in the ALI mice model, compared with the blank control group, the model group showed alveolar structure rupture, thic-kening of alveolar septa, and dramatically increased lung index, lung weight wet-to-dry ratio in lung tissue, neutrophil count, and inflammatory factor levels. Compared with the model group, the pathological morphology of lung tissue was significantly ameliorated in the TGP and MCC950 groups, and the lung index and lung weight wet-to-dry ratio were significantly reduced. Neutrophil counts were reduced, and levels of inflammatory factors were significantly downregulated. Notably, compared with the MCC950 group, there was no significant difference in effect in the MCC950+TGP group. Collectively, the study reveals that TGP may ameliorate ALI in mice by inhibiting the activation of NLRP3 inflammasome, providing a safe and effective drug candidate for the prevention or treatment of ALI/ARDS.

Proteomic Analysis of Milk Fat Globule Membrane Protein Modulation of Differently Expressed Proteins in Lactobacillus plantarum under Bile Salt Stress.

Tolerance to bile stress is a crucial property for lactic acid bacteria (LAB) to survive in the gastrointestinal tract and exert their beneficial effects. Whey powder enriched with milk fat globule membrane proteins (M-WPI) as a functional component is protective for strains under stress conditions. The current study investigated the key mechanisms of action involved in Lactobacillus plantarum (L. plantarum) CGMCC 23701 survival in the presence of bile and the protective mechanism of M-WPI. According to proteomic analysis (proteomics), there could be several reasons for the greater protective effect of M-WPI. These include promoting the synthesis of fatty acids and peptidoglycans to repair the structure of the cell surface, regulating the metabolism of carbohydrates and amino acids to release energy and produce a range of precursors, enabling the expression of the repair system to repair damaged DNA, and promoting the expression of proteins associated with the multidrug efflux pump, which facilitates the exocytosis of intracellular bile salts. This study helps us to better understand the changes in proteome of L. plantarum CGMCC 23701 under bile salt stress and M-WPI protection, which will provide a new method for the protection and development of functional LAB.

CircPHGDH downregulation decreases papillary thyroid cancer progression through miR-122-5p/PKM2 axis.

BACKGROUND: Although papillary thyroid carcinoma (PTC) has a favorable prognosis, it could affect patient life quality and become a serious threat because of invasion and metastasis. Many investigations have suggested that circular RNAs (circRNAs) are involved in different cancer regulations. Nevertheless, circRNAs role in invasive PTC remains unclear. METHODS: In the present investigation, next-generation sequencing was applied to explore abnormal circRNA expression. The expression of circRNA phosphoglycerate dehydrogenase (circPHGDH) in PTC cell lines and tissues were examined. Then, we investigated regulatory mechanism and circPHGDH downstream targets using bioinformatics analysis and luciferase reporting analysis. Then transwell migration, Cell Counting Kit-8 (CCK8) and 5-ethynyl-2'-deoxyuridine (EdU) assays were used for cells migration and proliferation analysis. In vivo metastasis and tumorigenesis assays were also employed to evaluate the circPHGDH role in PTC. RESULTS: The data showcased that circPHGDH expression increased in both PTC cell lines and tissues, which suggested that circPHGDH functions in PTC progression. circPHGDH downregulation suppressed PTC invasion and proliferation in both in vivo and in vitro experiments. Bioinformatics and luciferase reporter results confirmed that both microRNA (miR)-122-5p and pyruvate kinase M2 subtype (PKM2) were downstream targets of circPHGDH. PKM2 overexpression or miR-122-5p suppression reversed PTC cell invasion and proliferation post silencing circPHGDH by restoring aerobic glycolysis. CONCLUSION: Taken together, our research found that circPHGDH downregulation reduced PTC progression via miR-122-5p/PKM2 axis regulation mediated by aerobic glycolysis.

ASCOD phenotyping of acute vertebrobasilar artery occlusion treated by mechanical thrombectomy: insight from the PERSIST registry.

OBJECTIVE: Determining the underlying etiology of acute vertebrobasilar artery occlusion (VBAO) is crucial for selecting an appropriate treatment approach. The authors aimed to investigate the distribution of etiology and the association with functional outcomes in patients with acute VBAO who underwent endovascular treatment in which atherosclerosis, small-vessel disease, cardiac pathology, other causes, and dissection (ASCOD) phenotyping was used. METHODS: A retrospective study was conducted at 21 centers in China, involving patients with VBAO who received endovascular treatment within 24 hours of the estimated occlusion time. In the ASCOD phenotyping, each phenotype is graded based on the following categories: 1, likely to be causal; 2, uncertain if causal; and 3, unlikely to be causal. The authors defined a single possible cause as a cause graded 1 in a single domain, and multiple possible causes were graded 1 or 2 regardless of overlap. The primary outcome was unfavorable outcome (modified Rankin Scale [mRS] score of 3-6) at 90 days. The secondary outcomes included shift of mRS score at 90 days, 90-day mortality, successful reperfusion, and National Institutes of Health Stroke Scale score at 24 hours. Multivariable regression analysis was used to assess the association between etiological subtypes and functional outcomes. Multivariate competing-risk regression analysis was performed to analyze the association between etiological subtypes and the risk of recurrent stroke. RESULTS: A total of 577 patients were included in this study. Of these, 521 (90%) had a single possible cause. The most common etiology was A1 (382 cases, 73%), followed by C1 (111 cases, 21%) and O1 (28 cases, 5%-in this study the other causes and dissection subtypes were categorized under the umbrella term of "O" causes). Similar patterns were observed in the multiple possible causes. In the baseline characteristics of the cohort, as rescue therapy, stenting was more frequently used in patients in the A1 group than in the C1 group (53.2% vs 41.7%; p < 0.01). The proportion of atherosclerosis-type etiology increased when the occlusion was located more proximally (p < 0.01). Compared to the A1 group, patients in the C1 group had a lower incidence of unfavorable outcome (OR 0.42, 95% CI 0.24-0.73), which was less likely to shift to a worse mRS score (OR 0.60, 95% CI 0.39-0.91). The O1 subtype was not associated with unfavorable outcome (OR 1.35, 95% CI 0.46-4.01), whereas patients with the O1 subtype were more likely to shift to worse mRS score (OR 2.39, 95% CI 1.09-5.25) and to have a higher 90-day mortality rate (OR 2.60, 95% CI 1.07-6.31). Furthermore, there was no significant association between single etiological subtypes and stroke recurrence within 1 year. CONCLUSIONS: The most common etiology in patients with VBAO was atherosclerosis, followed by cardiac pathology and other. Compared to the A1 subgroup, the C1 subgroup showed better functional outcomes, whereas the O1 subgroup showed worse outcomes. Additionally, there was no statistically significant difference in the recurrence risk.

Does the active hydrogen atom in the hydantoin anion affect the physical properties, CO2 capture and conversion of ionic liquids?

Compared to the effect of the active hydrogen atom in the cation in protic ionic liquids (ILs) on their properties and applications, there are very few reports on the role of the active hydrogen atom in the anion. In order to better understand the role of the active hydrogen atom in the anion, the physical properties, CO2 capture and conversion of three hydantoin-based anion-functionalized ILs ([P4442][Hy], [P4442]2[Hy], and [HDBU][Hy]) have been investigated via experiments, spectroscopy, and DFT calculations in this work. The results show that the active hydrogen atom in the anion can form anionic hydrogen bonding networks, which significantly increase the melting point and viscosity and decrease the basicity of the IL, thereby weakening its ability to capture and convert CO2. Interestingly, [P4442][Hy] undergoes a solid/liquid two-phase transition during CO2 absorption/desorption due to the formation of quasi-intramolecular hydrogen bonding between the active hydrogen atom and the O- atom of the absorbed CO2, suggesting that the presence of the active hydrogen atom gives [P4442][Hy] the potential to be an excellent molecular switch. As there is no active hydrogen atom in the anion of [P4442]2[Hy], it shows excellent CO2 capture and conversion performance through the double-site interaction. [HDBU][Hy] shows the weakest catalytic CO2 conversion due to the presence of active hydrogen atoms on both its anion and cation. Therefore, the active hydrogen atom in the anion may play a more important role in the properties and potential applications of ILs than the active hydrogen atom in the cation.

TCEB3 initiates ovarian cancer apoptosis by mediating ubiquitination and degradation of MCL-1.

Platinum resistance remains a major contributor to the poor prognosis of ovarian cancer. Anti-apoptotic protein myeloid cell leukemia-1 (MCL-1) has emerged as a promising target for overcoming drug resistance, but different cancer cells utilize distinct protein degradation pathways to alter MCL-1 level. We systematically investigated E3 ligases to identify novel candidates that mediate platinum resistance in ovarian cancer. Transcription Elongation Factor B (TCEB3) has been identified as a novel E3 ligase recognition subunit that targets MCL-1 in the cytoplasm during platinum treatment other than its traditional function of targeting the Pol II in the nuclear compartment. TCEB3 expression is downregulated in platinum-resistant cell lines and this low expression is associated with poor prognosis. The ubiquitination of MCL-1 induced by TCEB3 leads to cell death in ovarian cancer. Moreover, platinum treatment increased the cytoplasm proportion of TCEB3, and the cytoplasm localization of TCEB3 is important for its targeting of MCL-1. This study emphasizes the dual function of TCEB3 in homeostasis maintenance and in cell fate determination under different conditions, and provides a new insight into drug resistance in ovarian cancer.

The masking phenomenon of microplastics additives on oxidative stress responses in freshwater food chains.

The variability and intrinsic mechanisms of oxidative stress induced by microplastics at different trophic levels in freshwater food chains are not well understood. To comprehensively assess the oxidative stress induced by polystyrene microplastics (PS-MPs) in freshwater food chains, the present study first quantified the oxidative stress induced by PS-MPs in organisms at different trophic levels using factorial experimental design and molecular dynamics methods. Then focuses on analyzing the variability of these responses across different trophic levels using mathematical statistical analysis. Notably, higher trophic level organisms exhibit diminished responses under PS-MPs exposure. Furthermore, the coexistence of multiple additives was found to mask these responses, with antioxidant plastic additives significantly influencing oxidative stress responses. Mechanism analysis using computational chemistry simulation determines that protein structure and amino acid characteristics are key factors driving PS-MPs induced oxidative stress variation in freshwater organisms at different nutrient levels. Increased hydrophobic additives induce protein helicalization and amino acid residue aggregation. This study systematically reveals the variability of biological oxidative stress response under different nutrient levels, emphasizing the pivotal role of chemical additives. Overall, this study offers crucial insights into PS-MPs' impact on oxidative stress responses in freshwater ecosystems, informing future environmental risk assessment.

Improved microalgae carbon fixation and microplastic sedimentation in the lake through in silico method.

The impact of microplastics in lake water environments on microalgae carbon fixation and microplastic sedimentation has attracted global attention. The molecular dynamic simulation method was used to design microplastic additive proportioning schemes for improving microalgae carbon fixation and microplastic sedimentation. Results showed that the harm of microplastics can be effectively alleviated by adjusting the proportioning scheme of plastic additives. Besides, the decabromodiphenyl oxide (DBDPO) was identified as the main additive that affect the microalgae carbon fixation and microplastic sedimentation. Thus, a molecular modification based on CiteSpace visual analysis was firstly used and 12 DBDPO derivatives were designed. After the screening, DBDPO-2 and DBDPO-5 became the environmentally friendly DBDPO alternatives, with the highest microalgae carbon fixation and microplastic sedimentation ability enhancement of over 25 %. Compared to DBDPO, DBDPO derivatives were found easier to stimulate the adsorption and binding ability of surrounding hotspot amino acids to CO2 and ribulose-5-phosphate, increasing the solvent-accessible surface area of microplastics, thus improving the microalgae carbon fixation and microplastic sedimentation ability. This study provides theoretical support for simultaneously promoting the microalgae carbon fixation and microplastic sedimentation in the lake water environment and provides scientific basis for the protection and sustainable development of lake water ecosystem.

Calcitonin Inhibits Phenotypic Switching of Aortic Smooth Muscle Cells and Neointimal Hyperplasia through the AMP-Activated Protein Kinase/Mechanistic Target of Rapamycin Pathway.

Calcitonin (CT) is a peptide hormone secreted by the parafollicular C cells of the thyroid gland, salmon calcitonin was originally extracted from the hind cheek of salmon. Neointimal hyperplasia refers to the excessive proliferation and migration of vascular smooth muscle cells (VSMCs). In this study, a rat model of restenosis was employed to explore the impact of calcitonin on neointima proliferation. Calcitonin was administered via continuous injections for a duration of 14 days postsurgery, and the expression of proteins associated with proliferation, migration, and phenotypic switching was assessed using the vascular smooth muscle cells. Additionally, metabolomic analyses were conducted to shed light on the mechanisms that underlie the role of calcitonin in the development of cardiovascular disease. In our study, we found that calcitonin possesses the capability to dispute the proliferation, migration, and phenotypic transformation of VSMCs induced by platelet-derived growth factor-BB (PDGF-BB) and 15% fetal bovine serum in vitro. Calcitonin has demonstrated a favorable impact on smooth muscle cells, both in vitro and in vivo. More specifically, it has been observed to mitigate phenotypic switching, proliferation, and migration of these cells. Moreover, calcitonin has been identified as a protective factor against phenotypic switching and the formation of neointima, operating through the AMP-activated protein kinase/mechanistic target of rapamycin (mTOR) pathway.

The combination of Schisandrin C and Luteolin synergistically attenuates hepatitis B virus infection via repressing HBV replication and promoting cGAS-STING pathway activation in macrophages.

BACKGROUND: HBV infection can result in severe liver diseases and is one of the primary causes of liver cell carcinoma-related mortality. Liuwei Wuling tablet (LWWL) is a traditional Chinese medicine formula, with a protecting liver and decreasing enzyme activity, usually used to treat chronic hepatitis B with NAs in clinic. However, its main active ingredients and mechanism of action have not been fully investigated. Hence, we aimed to screen the active ingredient and effective ingredient combinations from Liuwei Wuling tablet to explore the anti-herpatitis B virus activity and mechanism. METHODS: Analysis and screening of effective antiviral components in LWWL by network pharmacology, luteolin (Lut) may be a compound with significant antiviral activity. The mechanism of antiviral action of Lut was also found by real-time PCR detection and western blotting. Meanwhile, we established a co-culture model to investigate the antiviral mechanism of Schisandrin C (SC), one of the main active components of Schisandra chinensis fructus (the sovereign drug of LWWL). Next, HBV-infected mice were established by tail vein injection of pAAV-HBV1.2 plasmid and administered continuously for 20 days. And their antiviral capacity was evaluated by checking serum levels of HBsAg, HBeAg, levels of HBV DNA, and liver levels of HBcAg. RESULTS: In this study, we conducted network pharmacology analysis on LWWL, and through in vitro experimental validation and data analysis, we found that luteolin (Lut) possessed obviously anti-HBV activity, inhibiting HBV replication by downregulating hepatocyte nuclear factor 4α (HNF4α) via the ERK pathway. Additionally, we established a co-culture system and proved that SC promoted activation of cGAS-STINIG pathway and IFN-ß production in THP-1 cells to inhibit HBV replication in HepG2.2.15 cells. Moreover, we found the combination of SC and Lut shows a greater effect in inhibiting HBV compared to SC or Lut alone in HBV-infected mice. CONCLUSION: Taken together, our study suggests that combination of SC and Lut may be potential candidate drug for the prevention and treatment of chronic hepatitis B.

Bacterial antigens and asthma: a comparative study of common respiratory pathogenic bacteria.

Objective: In a previous study we have shown that, in the presence of interleukin (IL)-33, repeated, per-nasal challenge of murine airways with Streptococcus pneumoniae (S. pneumoniae) organisms induces human asthma-like airways inflammation. It is not clear, however, whether this effect is unique or manifest in response to other common respiratory pathogens.Methods: To explore this, airways of BALB/c mice were repeatedly challenged per-nasally with formaldehyde-inactivated bacterial bodies in the presence or absence of murine recombinant IL-33. Serum concentrations of S.pneumoniae, Moraxella catarrhalis (M.catarrhalis) and Haemophilus influenzae (H.influenzae) lysates-specific IgE were measured in patients with asthma and control subjects.Results: We showed that in the presence of IL-33, repeated, per-nasal airways exposure to the bodies of these bacteria induced airways hyperresponsiveness (AHR) in the experimental mice. This was accompanied by cellular infiltration into bronchoalveolar lavage fluid (BALF), eosinophilic infiltration and mucous hypertrophy of the lung tissue, with elevated local expression of some type 2 cytokines and elevated, specific IgG and IgE in the serum. The precise characteristics of the inflammation evoked by exposure to each bacterial species were distinguishable.Conclusions: These results suggest that in the certain circumstances, inhaled or commensal bacterial body antigens of both Gram-positive (S. pneumoniae) and Gram-negative (M. catarrhalis and H. influenzae) respiratory tract bacteria may initiate type 2 inflammation typical of asthma in the airways. In addition, we demonstrated that human asthmatic patients manifest elevated serum concentrations of M.catarrhalis- and H.influenzae-specific IgE.

Comparison of the medial midline and the anterolateral portal in ankle arthroscopy for the treatment of osteochondral lesions of the medial talus.

PURPOSE: To compare the clinical efficacy and complication rates between the medial midline and anterolateral portals in ankle arthroscopy for treating medial osteochondral lesions of the talus (OLTs). METHODS: We retrospectively analyzed patients with medial OLTs who underwent either a dual medial approach (via the medial midline and anteromedial portal) or a traditional approach (via the anterolateral and anteromedial portal) between June 2017 and January 2023. The degree of injury was evaluated by radiographs, computed tomography, and magnetic resonance imaging. Clinical outcomes were assessed using the visual analog scale (VAS), the American Orthopaedic Foot and Ankle Society (AOFAS) score, and the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) scoring system. The incidence of postoperative complications, including superficial peroneal nerve (SPN) injury, was evaluated in all patients. RESULTS: There were 39 patients in total; 16 patients underwent the dual medial approach, and 23 patients underwent the traditional approach. The mean age was 39.4 ± 9.0 years, and the mean follow-up duration was 18.7 ± 6.4 months. The clinical outcomes improved significantly in both groups (*P < 0.05), but there was no significant difference between the two groups (P > 0.05). Postoperative complications were mainly SPN injury. The incidence of SPN injury was 13.0% in the traditional approach group and 0% in the dual medial approach group, with no significant difference between the two groups (P > 0.05), but a trend of reduction in SPN injury was observed in the dual medial approach group. CONCLUSION: The dual medial approach can also treat medial OLTs well, providing clear visualization and more convenient operation and reducing the possibility of injury to the SPN compared with the traditional approach. Therefore, we consider that the MM portal would be a good alternative to the anterolateral portal in treating medial OLTs.

Flavonoid extracted from Epimedium attenuate cGAS-STING-mediated diseases by targeting the formation of functional STING signalosome.

Hyperactivation of the cyclic-GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signalling pathway has been shown to be associated with the development of a variety of inflammatory diseases, and the discovery of an inhibitor of the cGAS-STING signalling pathway holds great promise in the therapeutic interventions. Epimedium flavonoid (EF), a major active ingredient isolated from the medicinal plant Epimedium, has been reported to have good anti-inflammatory activity, but its exact mechanism of action remains unclear. In the present study, we found that EF in mouse bone marrow-derived macrophages (BMDMs), THP-1 (Tohoku Hospital Pediatrics-1) as well as in human peripheral blood mononuclear cells (hPBMC) inhibited the activation of the cGAS-STING signalling pathway, which subsequently led to a decrease in the expression of type I interferon (IFN-ß, CXCL10 and ISG15) and pro-inflammatory cytokines (IL-6 and TNF-α). Mechanistically, EF does not affect STING oligomerization, but inhibits the formation of functional STING signalosome by attenuating the interaction of interferon regulatory factor 3 (IRF3) with STING and TANK-binding kinase 1 (TBK1). Importantly, in vivo experiments, EF has shown promising therapeutic effects on inflammatory diseases mediated by the cGAS-STING pathway, which include the agonist model induced by DMXAA stimulation, the autoimmune inflammatory disease model induced by three prime repair exonuclease 1 (Trex1) deficiency, and the non-alcoholic steatohepatitis (NASH) model induced by a pathogenic amino acid and choline deficiency diet (MCD). To summarize, our study suggests that EF is a potent potential inhibitor component of the cGAS-STING signalling pathway for the treatment of inflammatory diseases mediated by the cGAS-STING signalling pathway.

New Local Composition Model for Correlating of the Molar Conductivity of Ionic Liquid-Solvent Systems over the Whole Concentration Range.

Considering that traditional electrolyte models are limited to use in the solvent-rich region, the development of new models to describe the molar conductivity (Λm) over the whole concentration range of ionic liquid (IL)-solvent systems is a meaningful study. Based on the idea of local composition and the law of independent ion migration, a new model is proposed in this study and used to successfully correlate the relationship between Λm and composition over the whole concentration range for 18 IL-solvent systems with satisfactory fitting accuracy. Meanwhile, the electrical conductivity (κ) of the systems is estimated using the calculated Λm. Moreover, the strength of anion-cation, anion-solvent, and cation-solvent interactions in the systems is explored by the obtained energy parameters, and the effect of the solvent on the interactions is investigated. The proposed model provides a new method to accurately describe the conductivity property of IL-solvent systems over the whole concentration range.