Association between glymphatic dysfunction and neurocognitive decline in patients with frontal lobe epilepsy.

Background: The glymphatic system is essential for the maintenance of brain homeostasis. It may be impaired in patients with epilepsy, but its association with neurocognitive function remains unknown. In this study, we aimed to elucidate the association between changes in the glymphatic system and neurocognitive function in individuals diagnosed with frontal lobe epilepsy (FLE). Methods: This retrospective case-control research engaged a group of patients with FLE and age-, sex-, and education-matched healthy volunteers. All participants were subjected to extensive neurocognitive assessments, complemented by structural and diffusion-weighted imaging. The "diffusion tensor imaging analysis along the perivascular space" (DTI-ALPS) index was computed to ascertain differences in glymphatic system function between the groups. Univariate and multivariate analyses were conducted to explore associations between DTI-ALPS, clinical characteristics in patients with FLE, and the neurocognitive test outcomes for both groups. Results: Twenty-five patients [mean age ± standard deviation (SD): 26.28±8.12 years, 10 females] with FLE and 22 healthy control (HC) participants (average age ± SD: 25.86±6.15 years, 11 females) were included. The average ALPS-index in FLE group was significantly lower than that in HC group (1.387±0.127 vs. 1.468±0.114, P=0.026). Further, significant neurocognitive difference was noted in Trail Making Test (TMT), Stroop Color and Word Test (SCWT), Digit Span Test (DST) and similarity test (ST) between the two groups. ALPS-index scores exhibited a negative correlation with disease duration in patients with FLE (r=-0.415, P=0.039), and positive correlations with the Forward Digit Span Test (FDST, r=0.399, P=0.005) and Similarity Test (ST, r=0.395, P=0.006) in both groups. After adjusting for potential confounders, DTI-ALPS maintained a significant independent association with FDST and ST. Conclusions: The findings of the current study suggest a possible association between impairment in glymphatic function and FLE. Furthermore, results indicate that glymphatic dysfunction, as assessed via DTI-ALPS index, appears to be related to neurocognitive decline in FLE.

Bromadiolone may cause severe acute kidney injury through severe disorder of coagulation: a case report.

BACKGROUND: Bromadiolone is a wide-use long-acting anticoagulant rodenticide known to cause severe coagulation dysfunction. At present, there have been no detailed reports of acute kidney injury (AKI) resulting from bromadiolone poisoning. CASE PRESENTATION: A 27-year-old woman was admitted to the hospital due to severe coagulopathy and severe AKI. Coagulation test revealed a prothrombin time exceeding 120 s and an international normalized ratio (INR) greater than 10. Further examination for coagulation factors showed significantly reduced level of factors II, VII, IX and X, indicating a vitamin K deficiency. The AKI was non-oliguric and characterized by gross dysmorphic hematuria. Following the onset of the disease, the patient's serum creatinine rose from 0.86 to 6.96 mg/dL. Suspecting anticoagulant rodenticide poisoning, plasma bromadiolone was identified at a concentration of 117 ng/mL via gas chromatography/mass spectrometry. All other potential causes of AKI were excluded, except for the presence of a horseshoe kidney. The patient's kidney function fully recovered after the coagulopathy was corrected with high doses of vitamin K and plasma transfusion. At a follow-up 160 days post-discharge, the coagulation function had normalized, and the serum creatinine had returned to 0.51 mg/dL. CONCLUSION: Bromadiolone can induce AKI through a severe and prolonged coagulation disorder. Kidney function can be restored within days following treatment with high-dose vitamin K1.

Icariside II modulates pulmonary fibrosis via PI3K/Akt/ß-catenin pathway inhibition of M2 macrophage program.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a debilitating interstitial lung disorder characterized by its limited therapeutic interventions. Macrophages, particularly the alternatively activated macrophages (M2 subtype), have been acknowledged for their substantial involvement in the development of pulmonary fibrosis. Hence, targeting macrophages emerges as a plausible therapeutic avenue for IPF. Icariside II (ISE II) is a natural flavonoid glycoside molecule known for its excellent anti-tumor and anti-fibrotic activities. Nevertheless, the impact of ISE II on pulmonary fibrosis and the intricate mechanisms through which it operates have yet to be elucidated. OBJECTIVE: To scrutinize the impact of ISE II on the regulation of M2 macrophage polarization and its inhibitory effect on pulmonary fibrosis, as well as to delve deeper into the underlying mechanisms of its actions. METHODS: The effect of ISE II on proliferation and apoptosis in RAW264.7 cells was assessed through the use of EdU-488 labeling and the Annexin V/PI assay. Flow cytometry, western blot, and qPCR were employed to detect markers associated with the M2 polarization phenotype. The anti-fibrotic effects of ISE II in NIH-3T3 cells were investigated in a co-culture with M2 macrophages. Si-Ctnnb1 and pcDNA3.1(+)-Ctnnb1 plasmid were used to investigate the mechanism of targeted intervention. The murine model of pulmonary fibrosis was induced by intratracheal administration of bleomycin (BLM). Pulmonary function, histopathological manifestations, lung M2 macrophage infiltration, and markers associated with pulmonary fibrosis were evaluated. Furthermore, in vivo transcriptomics analysis was employed to elucidate differentially regulated genes in lung tissues. Immunofluorescence, western blot, and immunohistochemistry were conducted for corresponding validation. RESULTS: Our investigation demonstrated that ISE II effectively inhibited the proliferation of RAW264.7 cells and mitigated the pro-fibrotic characteristics of M2 macrophages, exemplified by the downregulation of CD206, Arg-1, and YM-1, Fizz1, through the inhibition of the PI3K/Akt/ß-catenin signaling pathway. This impact led to the amelioration of myofibroblast activation and the suppression of nuclear translocation of ß-catenin of NIH-3T3 cells in a co-culture. Consequently, it resulted in decreased collagen deposition, reduced infiltration of profibrotic macrophages, and a concurrent restoration of pulmonary function in mice IPF models. Furthermore, our RNA sequencing results showed that ISE II could suppress the expression of genes related to M2 polarization, primarily by inhibiting the PI3K/Akt and ß-catenin signaling pathway. In essence, our findings suggest that ISE II holds potential as an anti-fibrotic agent by orchestrating macrophage polarization. This may have significant implications in clinical practice. CONCLUSION: This study has provided evidence that ISE II exerts a significant anti-fibrotic effect by inhibiting macrophage M2 polarization through the suppression of the PI3K/Akt/ß-catenin signaling pathway. These findings underscore the potential of ISE II as a promising candidate for the development of anti-fibrotic pharmaceuticals in the future.

Spatiotemporal differentiation and driving mechanisms of high-level Grade A tourist attractions in the Yangtze River Delta City Cluster.

Herein, the spatial evolution characteristics of high-level Grade A tourist attractions in the Yangtze River Delta (YRD) urban agglomeration, from 2001 to 2021, are studied by comprehensively applying the nearest neighbor index, kernel density analysis, standard deviation ellipse, and spatial autocorrelation. High-level Grade A tourist attractions are investigated using the random forest model as the driving mechanism of the spatial pattern. Results show that 1) the spatial distribution of high-level Class A tourist attractions in the YRD city cluster has grown to be an agglomeration, and the high-density areas have evolved from "point-like dispersion to regiment-like combination," gradually forming a B-shaped core density structure. 2) The spatial distribution comprises an overall "northwest-southeast" direction, a small counterclockwise rotation, the distribution of the center of gravity to the southwest migration, and the center of gravity from the territory of Suzhou City to the territory of Huzhou City. 3) The high-level Class A tourist attractions in the YRD city cluster as a whole show a strong positive spatial correlation, and the significantly clustered areas include three types: high-high (H-H), low-low (L-L), and low-high (L-H). 4) The spatial distribution of high, A-level tourist attractions in the YRD city cluster results from the combined action of the natural environment, resource endowment, socioeconomy, and policy background. Each element has a nonlinear and complex influence on the distribution of scenic spots.

Amphiphilic polymeric nanodrug integrated with superparamagnetic iron oxide nanoparticles for synergistic antibacterial and antitumor therapy of colorectal cancer.

Colorectal cancer (CRC) is one of the most prevalent and deadly malignancies that can be influenced by Fusobacterium nucleatum (Fn), a bacterium that promotes tumor development and chemoresistance, resulting in limited therapeutic efficacy. Traditional antibiotics cannot effectively eliminate Fn at tumor site due to issues like biofilm formation, while chemotherapy alone fails to suppress tumor progression. Therefore, the development of new methods to eliminate Fn and promote antitumor efficacy is of great significance for improving the outcome of CRC treatment. Herein, we developed a nanodrug (OPPL) that integrates oleic acid-modified superparamagnetic iron oxide nanoparticles (O-SPIONs) and an amphiphilic polymer (PPL) to deliver the platinum prodrug and antimicrobial lauric acid (LA) for enhancing the treatment of CRC. We demonstrated that OPPL can synergistically enhance antibacterial and biofilm disruption activities against Fn along with the antimicrobial LA by producing reactive oxygen species (ROS) through its peroxidase-like activity. Furthermore, the OPPL nanodrug can increase intracellular ROS, promote lipid peroxides and deplete glutathione, leading to ferroptosis. By combining chemotherapy and induced ferroptosis, the OPPL nanodrug exhibited high cytotoxicity against CRC cells. In vivo studies showed that the OPPL nanodrug could enhance tumor accumulation, enable magnetic resonance imaging, suppresse tumor growth, and inhibit growth of intratumor Fn. These results suggest that OPPL is an effective and promising candidate for the treatment of Fn-infected CRC. STATEMENT OF SIGNIFICANCE: The enrichment of Fusobacterium nucleatum (Fn) in colorectal cancer is reported to exacerbate tumor malignancy and is particularly responsible for chemoresistance. To this respect, we strategically elaborated multifaceted therapeutics, namely OPPL nanodrug, combining oleic acid-modified superparamagnetic iron oxide nanoparticles (O-SPIONs) with a polymer containing a platinum prodrug and antimicrobial lauric acid. The O-SPION components exert distinctive peroxidase-like activity, capable of stimulating Fenton reactions selectively in the tumor microenvironment, consequently accounting for the progressive production of reactive oxygen species. Hence, O-SPIONs have been demonstrated to not only supplement the antimicrobial activities of lauric acid in overcoming Fn-induced chemoresistance but also stimulate potent tumor ferroptosis. Our proposed dual antimicrobial and chemotherapeutic nanodrug provides an appreciable strategy for managing challenging Fn-infected colorectal cancer.

Proteomic analysis reveals the molecular mechanism of Astragaloside in the treatment of non-small cell lung cancer by inducing apoptosis.

BACKGROUND: Astragaloside III (AS III), a saponin-like metabolite derived from the traditional Chinese medicine Astragali Radix, has been shown to be effective in the treatment of cancer and heart failure, and a variety of digestive disorders. However, its molecular mechanism in the treatment of non-small cell lung cancer (NSCLC) is unknown. METHODS: Human lung cancer A549 cells and NCI-H460 cells and a normal human lung epithelial cell BEAS-2B were treated with different concentrations of AS III. CCK-8 and EdU staining were used to determine the anti-proliferative effects of AS III in vitro. Quantitative proteomic analysis was performed on A549 cells treated with the indicated concentrations of AS III, and the expression levels of apoptosis-related proteins were examined by Western blotting. RESULTS: AS III treatment significantly inhibited proliferation and increased apoptosis in A549 and H460 cells and modulated functional signaling pathways associated with apoptosis and metabolism. At the molecular level, AS III promoted a reduction in the expression of ANXA1 (p < 0.01), with increased levels of cleaved Caspase 3 and PARP 1. In addition, AS III treatment significantly decreased the LC3-I/LC3-II ratio. The results of experiment in vitro showed that AS III promoted NSCLC apoptosis by down-regulating the phosphorylation levels of P38, JNK, and AKT (p < 0.01), inhibiting the expression of Bcl-2 (p < 0.01), and up-regulating the expression of Bax (p < 0.01). CONCLUSION: These findings provide a mechanism whereby AS III treatment induces apoptosis in NSCLC cells, which may be achieved in part via modulation of the P38, ERK and mTOR signaling pathways.

Facile filter cloth brush-coating of large-area uniform silver nanowire conductive films for paper-based heater.

Filter cloth brush-coating (FCBC), using soft filter cloth as a brush-coating medium, in conjunction with viscous silver nanowire (AgNW) conductive solution, is used to prepare AgNW conductive films. The density and uniformity of AgNWs deposited on the substrate are controlled by the interplay between the filter cloth aperture, the conductive solution viscosity, and the brush-coating speed. Further, with appropriate AgNW concentration and flow rate, uniform AgNW transparent conductive film with sheet resistance of 18 Ω sq-1and transmittance of 94% at 550 nm is acquired by FCBC. Due to the precise control of the coating process in FCBC, large-area uniform AgNW conductive film fabricated on printing paper has a low non-uniformity factor of 1.2% at a sheet resistance of 19.0 Ω sq-1. The resultant paper-based AgNW film heater shows sensitive and stable heating performance. FCBC shows great potential in producing large-area uniform AgNW films on various substrates.

Nitrite stimulates HONO and NOx but not N2O emissions in Chinese agricultural soils during nitrification.

The long-lived greenhouse gas nitrous oxide (N2O) and short-lived reactive nitrogen (Nr) gases such as ammonia (NH3), nitrous acid (HONO), and nitrogen oxides (NOx) are produced and emitted from fertilized soils and play a critical role for climate warming and air quality. However, only few studies have quantified the production and emission potentials for long- and short-lived gaseous nitrogen (N) species simultaneously in agricultural soils. To link the gaseous N species to intermediate N compounds [ammonium (NH4+), hydroxylamine (NH2OH), and nitrite (NO2-)] and estimate their temperature change potential, ex-situ dry-out experiments were conducted with three Chinese agricultural soils. We found that HONO and NOx (NO + NO2) emissions mainly depend on NO2-, while NH3 and N2O emissions are stimulated by NH4+ and NH2OH, respectively. Addition of 3,4-dimethylpyrazole phosphate (DMPP) and acetylene significantly reduced HONO and NOx emissions, while NH3 emissions were significantly enhanced in an alkaline Fluvo-aquic soil. These results suggested that ammonia-oxidizing bacteria (AOB) and complete ammonia-oxidizing bacteria (comammox Nitrospira) dominate HONO and NOx emissions in the alkaline Fluvo-aquic soil, while ammonia-oxidizing archaea (AOA) are dominant in the acidic Mollisol. DMPP effectively mitigated the warming effect in the Fluvo-aquic soil and the Ultisol. In conclusion, our findings highlight NO2- significantly stimulates HONO and NOx emissions from dryland agricultural soils, dominated by nitrification. In addition, subtle differences of soil NH3, N2O, HONO, and NOx emissions indicated different N turnover processes, and should be considered in biogeochemical and atmospheric chemistry models.

Ultrasound diagnosis of renal cell carcinoma associated with Xp11.2 translocation/TFE3 gene fusion in children and adolescents.

BACKGROUND: Many studies have reported Xp 11.2 translocation renal cancer in radioimaging,but there is little literature on the evaluation of Xp11.2 translocation renal cell carcinoma by ultrasound. OBJECTIVE: To investigate the ultrasonographic features and diagnostic value of renal cell carcinoma associated with Xp11.2 translocation/TFE3 gene fusion in children and adolescents. MATERIALS AND METHODS: The clinical and ultrasonographic data of 10 patients with renal cell carcinoma associated with Xp11.2 translocation/TFE3 gene fusion confirmed by pathology in our hospital were analyzed retrospectively. The age ranged from 3 to 18 years old, including 7 males and 3 females. The tumor location, size, boundary, echo, hemorrhage, cystic change, calcification, blood flow, lymph node status and metastasis were mainly observed, and the results were compared with the pathological results. RESULTS: There were 10 masses in 10 cases of renal cell carcinoma associated with Xp11.2 translocation/TFE3 gene fusion, including 4 in the right kidney and 6 in the left kidney; the maximum diameter line is 5-23cm; 9 cases had clear mass boundary (90%); 9 masses (90%) showed mixed cystic and solid masses with high echo of solid components, and 1 mass (10%) showed huge multilocular cystic mass with multiple septations; necrosis and cystic changes were seen in all 10 masses (100%); calcification in 5 masses (50%); blood flow signals were seen in the solid components of the mass (100%). CONCLUSION: Renal cell carcinoma associated with Xp11.2 translocation/TFE3 gene fusion in children and adolescents are mostly large cystic and solid mixed echo masses, with high echo of solid components, and often accompanied by cystic changes and calcification. Its ultrasonic manifestations have certain characteristics. Color Doppler ultrasound has a certain diagnostic value for this disease.

Icariside â ¡ attenuates bleomycin-induced pulmonary fibrosis by modulating macrophage polarization.

ETHNOPHARMACOLOGICAL RELEVANCE: Numerous studies have provided evidence supporting the significant roles of icariin, in the prevention of multiple chronic diseases like diabetes, liver fibrosis, cardiac fibrosis, renal fibrosis, and pulmonary fibrosis. In particular, Icariside II (ISE II), a prominent flavonoid glycoside derived from Epimedium brevicornum Maxim, the principal metabolite of icariin, has demonstrated noteworthy anti-inflammatory and anti-oxidant properties, along with its ability to protect against lung remodeling. However, the research exploring ISE Ⅱ's application in treating pulmonary fibrosis remains limited. AIM OF THE STUDY: The aim of this study was to assess the therapeutic efficacy of ISE II in models of pulmonary fibrosis, while also investigating its potential mechanisms of action in cell signaling pathways. MATERIALS AND METHODS: An in vitro model of pulmonary fibrosis was established by treating NIH-3T3 cells with transforming growth factor-ß1 (TGF-ß1). Western blot, RT-qPCR, and scratch test were performed to assess the effect of ISE Ⅱ. In addition, a murine model of pulmonary fibrosis was induced by intratracheal instillation of bleomycin, and the therapeutic effect of ISE Ⅱ was tested by orally administering ISE Ⅱ at a dose of 10 mg/kg. Three weeks later, lung function, micro-CT, hydroxyproline content, pathological staining, and cytokines detection of BALF or serum were used to assess the anti-fibrosis effects of ISE Ⅱ. Next, immunofluorescence staining, flow cytometry, and in vivo transcriptomics were used to investigate the underlying mechanisms of action. RESULTS: Our data revealed a significant inhibitory effect of ISE Ⅱ on the upregulation of α-smooth muscle actin (α-SMA) and collagen production induced by TGF-ß1 in fibroblasts. Meanwhile, ISE Ⅱ exerted a therapeutic effect against bleomycin-induced pulmonary fibrosis in mice by improving lung function, decreasing collagen deposition, and reducing the expression of interleukin (IL)-1ß, tumor necrosis factor α (TNF-α), TGF-ß1 and platelet-derived growth factor (PDGF) in serum and bronchoalveolar lavage fluid (BALF). Additionally, ISE Ⅱ treatment effectively attenuated the infiltration of M2 macrophages, concurrently downregulating the expression level of M2 marker genes, such as CD206, arginase-1(Arg-1), and Chitinase-Like Protein 3 (YM-1). Importantly, we observed a statistically significant reduction in the M2 phenotype of interstitial macrophages (IMs). However, the impact of ISE Ⅱ on the M2 polarization of alveolar macrophages (AMs) did not reach statistical significance. Lastly, transcriptome sequencing results suggested that the anti-pulmonary fibrosis effects of ISE Ⅱ may be mediated by the suppression of the WNT/ß-catenin signaling pathway, which modulated M2 polarization in macrophages and contributed to the amelioration of pulmonary fibrosis. By immunohistochemical analysis, it was verified that ISE Ⅱ treatment dramatically inhibited the activation of ß-catenin in fibrosis murine. CONCLUSION: Our findings indicated that ISE Ⅱ exerted anti-fibrotic effects by inhibiting pro-fibrotic macrophage polarization. The underlying mechanism of action might be mediated by modulating the WNT/ß-catenin signaling pathway to inhibit the M2 program in IMs.

Transcriptomics reveals apigenin alleviates airway inflammation and epithelial cell apoptosis in allergic asthma via MAPK pathway.

Persistent chronic inflammation of the lungs and airway remodeling are important pathological features that cannot be ignored in patients with chronic asthma. Apigenin (API) is a natural small molecule compound with good anti-inflammatory and antioxidant activity that has been widely reported in recent years, but its role in chronic asthma is not well defined. Our study began with oral gavage intervention using API (10, 20 mg/kg) or dexamethasone (DEX, 2 mg/kg) in a BALB/c mouse model of ovalbumin (OVA) sensitization. Different doses of API intervention effectively reduced airway resistance in the administered group. Additionally, inflammation was downregulated, mucus secretion was reduced, and airway remodeling was inhibited in the API intervention group compared with the model group. Asthma-related inflammatory cytokines, such as IgE, IL-4, IL-5, IL-13, and IL-17, were downregulated in alveolar lavage fluid. Moreover, the apoptosis level of the administered group was found to be lower than that of the model group in the Tunel staining experiment. By analyzing transcriptome sequencing results, we found that API may exert anti-inflammatory and anti-apoptotic effects by inhibiting the MAPK pathway. Our subsequent results supported this conclusion, showing that the phosphorylation levels of ERKs, JNKs, and p38 MAPKs were inhibited in the administered group relative to the model group. Downstream expression of the apoptosis-related protein B-cell lymphoma-2 (Bcl-2) was upregulated, and the expression of Bcl-2-associated × protein (Bax) and cleaved caspase-3 was downregulated. To further investigate the specific mechanism by which API acted, we established an in vitro model with house dust mite (HDM) stimulation, using API (10, 20 µM) for administration intervention. The results showed that API was able to improve cell viability, inhibit ROS production, and reverse HDM-induced decreases in mitochondrial membrane potential (MMP) and apoptosis in airway epithelial cells via the MAPK pathway.

Topological abnormality of structural covariance network in MRI-negative frontal lobe epilepsy.

Background: Frontal lobe epilepsy (FLE) is the second most common type of focal epilepsy, however, imaging studies of FLE have been far less than Temporal lobe epilepsy (TLE) and the structural findings were not consistent in previous literature. Object: Investigate the changes in cortical thickness in patients with FLE and the alteration of the structural covariance networks (SCNs) of cortical thickness with graph-theory. Method: Thirty patients with FLE (18 males/12 females; 28.33 ± 11.81 years) and 27 demographically matched controls (15 males/12 females; 29.22 ± 9.73 years) were included in this study with high-resolution structural brain MRI scans. The cortical thickness was calculated, and structural covariance network (SCN) of cortical thickness were reconstructed using 68 × 68 matrix and analyzed with graph-theory approach. Result: Cortical thickness was not significantly different between two groups, but path length and node betweenness were significantly increased in patients with FLE, and the regional network alterations were significantly changed in right precentral gyrus and right temporal pole (FDR corrected, p < 0.05). Comparing to HC group, network hubs were decreased and shifted away from frontal lobe. Conclusion: The topological properties of cortical thickness covariance network were significantly altered in patients with FLE, even without obvious surface-based morphological damage. Graph-theory based SCN analysis may provide sensitive neuroanatomical biomarkers for FLE.

Albumin-based formononetin nanomedicines for lung injury and fibrosis therapy via blocking macrophage pyroptosis.

Pulmonary fibrosis that occurs following lung injury is a progressive and fatal disease since continual damage to lung tissue triggers the dysregulated inflammation response and accompanying abnormal healing process. Pyroptosis of alveolar macrophages has been found to play an essential role in the deterioration of lung injury and fibrosis. However, the lack of inhibitors against this inflammatory cell death in macrophages and the dense stroma pose major barriers to lung injury and fibrosis treatment. Herein, we developed an albumin-based nanoformulation to realize active delivery of formononetin (FMN) to improve the treatment of lung injury and fibrosis. The obtained nanoparticle, FMN@BSA NPs, could efficiently accumulate at the impaired lesion benefiting from the leaky vasculatures and the affinity between albumin and the overexpressed SPARC protein. Through blocking the NLRP3 inflammasome-involved pyroptosis process of macrophages, FMN@BSA NPs remarkably improved lung function and prolonged animal survival in the bleomycin (BLM)-induced lung injury and fibrosis model without noticeable side effects. Meanwhile, we proved FMN as a pyroptosis inhibitor and the corresponding lipid metabolism-related mechanisms through multi-omics analysis. This study first employed an albumin-based nanoparticle to deliver the pyroptosis inhibitor to the impaired lung tissue actively, providing a promising strategy for lung injury and fibrosis treatment.

Network pharmacology and experiments in vivo and in vitro reveal that the Jia-Wei-Bu-Shen-Yi-Qi formula (JWBSYQF) and its active ingredient baicalein ameliorate BLM-induced lung fibrosis in mice via PI3K/Akt signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Jia-Wei-Bu-Shen-Yi-Qi formula (JWBSYQF), a classical traditional Chinese herbal formula consisting of five herbs, is used clinically in China to treat inflammatory lung diseases, including asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Its mechanism for treating asthma and COPD has been reported, however, how it works against IPF remains unclear. RESEARCH PURPOSE: Our study aims to observe the therapeutic effect of JWBSYQF on pulmonary fibrosis and further identify the potential active ingredients and molecular pathways. RESEARCH METHODS: In this study, we used a bleomycin-induced mouse model to investigate the therapeutic effect of JWBSYQF on pulmonary fibrosis. To further explore the potential effective ingredients and molecular pathways, we used the network pharmacology approach to construct a drug-ingredient-target network of JWBSYQF. Then, the common target set was established for JWBSYQF, fibroblast, and lung fibrosis. Analyses of the KEGG pathway, GO enrichment, and network topology were performed to identify key biological processes and molecular pathways for the common targets. Finally, a TGF-ß-induced NIH/3T3 proliferation and activation model was used to validate the possible active ingredients and signaling pathways. RESEARCH RESULTS: JWBSYQF reversed BLM-induced balf leukocyte levels, pulmonary inflammatory lesions and fibrotic collagen deposition in mice and reduced the levels of a-SMA, Col1a1 and TGF-ß. A total of 86 active ingredients were identified, 12 of which were considered as potential effective ingredients, while only baicalein effectively improved TGF-ß-induced proliferation and activation of NIH/3T3. KEGG results showed that PI3K/Akt signaling pathway may be the potential action mechanism, and Western Blot demonstrated that both JWBSYQF and baicalein downregulated the protein levels of p-PI3K and p-Akt. The molecular docking results suggest that baicalein may have a direct effect on the catalytic and regulatory subunits of P13K, which is stronger than direct binding to Aktl. CONCLUSIONS: Our study revealed that baicalein may be the material basis for JWBSYQF in the treatment of pulmonary fibrosis, and the PI3K/Akt signaling pathway may be a common pathway of action for JWBSYQF and baicalein.

Radiation-induced glymphatic dysfunction in patients with nasopharyngeal carcinoma: a study using diffusion tensor image analysis along the perivascular space.

Radiation encephalopathy (RE) refers to radiation-induced brain necrosis and is a life-threatening complication in patients with nasopharyngeal carcinoma (NPC) after radiotherapy (RT), and radiation-induced pre-symptomatic glymphatic alterations have not yet been investigated. We used diffusion tensor image analysis along the perivascular space (DTI-ALPS) index to examine the pre-symptomatic glymphatic alterations in NPC patients following RT. A total of 109 patients with NPC consisted of Pre-RT (n = 35) and Post-RT (n = 74) cohorts were included. The post-RT NPC patients, with normal-appearing brain structure at the time of MRI, were further divided into Post-RT-RE- (n = 58) and Post-RT-RE+ (n = 16) subgroups based on the detection of RE in follow-up. We observed lower DTI-ALPS left index, DTI-ALPS right index and DTI-ALPS whole brain index in post-RT patients than that in pre-RT patients (p < 0.05). We further found that post-RT-RE+ patients demonstrated significantly lower DTI-ALPS right (p = 0.013), DTI-ALPS whole brain (p = 0.011) and marginally lower DTI-ALPS left (p = 0.07) than Post-RT non-RE patients. Significant negative correlations were observed between the maximum dosage of radiation-treatment (MDRT) and DTI-ALPS left index (p = 0.003) as well as DTI-ALPS whole brain index (p = 0.004). Receiver operating characteristic (ROC) curve analysis showed that DTI-ALPS whole brain index exhibited good performance (AUC = 0.706) in identifying patients more likely developing RE. We concluded that glympathic function was impaired in NPC patients following RT and DTI-ALPS index may serve as a novel imaging biomarker for diagnosis of RE.

Alteration in topological organization characteristics of gray matter covariance networks in patients with prediabetes. / ç³–å°¿ç— å‰æœŸæ‚£è€ ç°è´¨åå˜ç½‘ç»œæ‹“æ‰‘ç»„ç»‡ç‰¹æ€§çš„æ”¹å˜.

OBJECTIVES: Prediabetes is associated with an increased risk of cognitive impairment and neurodegenerative diseases. However, the exact mechanism of prediabetes-related brain diseases has not been fully elucidated. The brain structure of patients with prediabetes has been damaged to varying degrees, and these changes may affect the topological characteristics of large-scale brain networks. The structural covariance of connected gray matter has been demonstrated valuable in inferring large-scale structural brain networks. The alterations of gray matter structural covariance networks in prediabetes remain unclear. This study aims to examine the topological features and robustness of gray matter structural covariance networks in prediabetes. METHODS: A total of 48 subjects were enrolled in this study, including 23 patients with prediabetes (the PD group) and 25 age-and sex-matched healthy controls (the Ctr group). All subjects' high-resolution 3D T1 images of the brain were collected by a 3.0 Tesla MR machine. Mini-mental state examination was used to evaluate the cognitive status of each subject. We calculated the gray matter volume of 116 brain regions with automated anatomical labeling (AAL) template, and constructed gray matter structural covariance networks by thresholding interregional structural correlation matrices as well as graph theoretical analysis. The area under the curve (AUC) in conjunction with permutation testing was employed for testing the differences in network measures, which included small world parameter (Sigma), normalized clustering coefficient (Gamma), normalized path length (Lambda), global efficiency, characteristic path length, local efficiency, mean clustering coefficient, and network robustness parameters. RESULTS: The network in both groups followed small-world characteristics, showing that Sigma was greater than 1, the Lambda was much higher than 1, and Gamma was close to 1. Compared with the Ctr group, the network of the PD group showed increased Sigma, Lambda, and Gamma across a range of network sparsity. The Gamma of the PD group was significantly higher than that in the Ctr group in the network sparsity range of 0.12-0.16, but there was no difference between the 2 groups (all P>0.05). The grey matter network showed an increased characteristic path length and a decreased global efficiency in the PD group, but AUC analysis showed that there was no significant difference between groups (all P>0.05). For the network separation measures, the local efficiency and mean clustering coefficient of the gray matter network in the PD group were significantly increased and AUC analysis also confirmed it (P=0.001 and P=0.004, respectively). In addition, network robustness analysis showed that the grey matter network of the PD group was more vulnerable to random damage (P=0.001). CONCLUSIONS: The prediabetic gray matter network shows an increased average clustering coefficient and local efficiency, and is more vulnerable to random damage than the healthy control, suggesting that the topological characteristics of the prediabetes grey matter covariant network have changed (network separation enhanced and network robustness reduced), which may provide new insights into the brain damage relevant to the disease.

Evaluation of the efficacy of transcatheter arterial embolization combined with apatinib on rabbit VX2 liver tumors by intravoxel incoherent motion diffusion-weighted MR imaging.

Background and purpose: It is crucial to evaluate the efficacy, recurrence, and metastasis of liver tumors after clinical treatment. This study aimed to investigate the value of Introvoxel Incoherent Motion (IVIM) imaging in the evaluation of rabbit VX2 liver tumors treated with Transcatheter Arterial Embolization (TAE) combined with apatinib. Methods: Twenty rabbit VX2 liver tumor models were established and randomly divided into either the experimental group (n=15) or the control group (n=5). The experimental group was treated with TAE combined with oral apatinib after successful tumor inoculation, while no treatment was administered following inoculation in the control group. IVIM sequence scan was performed in the experimental group before treatment, at 7 and 14 days after treatment. All rabbits were sacrificed after the last scan of the experimental group. Marginal tissues from the tumors of both groups were excised for immunohistochemical analysis to observe and compare the expression of microvessel density (MVD). The alterations of IVIM-related parameters of tumor tissues in the experimental group, including Apparent Diffusion Coefficient (ADC), True Diffusion Coefficient (D), Pseudodiffusion Coefficient (D*), and Perfusion Fraction (f) were compared at different periods, and the correlation between these parameters and MVD was analyzed. Results: After treatment, ADC and D values significantly increased, whereas D* and f values both decreased, with statistically significant differences.(P<0.05). The average tumor MVD of the experimental group after TAE combined with apatinib ((33.750 ± 6.743) bars/high power field (HPF)) was significantly lower than that in the control group ((64.200 ± 10.164) bars/HPF)). Moreover, D and f were positively correlated with tumor MVD in the experimental group (r=0.741 for D and r=0.668 for f, P<0.05). However, there was no significant correlation between ADC and D* values of the experimental group and tumor MVD (r=0.252 for ADC and r=0.198 for D*, P>0.05). Conclusion: IVIM imaging can be employed to evaluate the efficacy of TAE combined with apatinib in rabbit VX2 liver tumors. Alterations in D and f values were closely related to the MVD of liver tumor tissues.

A Sensor and Machine Learning-Based Sensory Management Recommendation System for Children with Autism Spectrum Disorders.

Sensory processing issues are one of the most common issues observed in autism spectrum disorders (ASD). Technologies that could address the issue serve a more and more important role in interventions for ASD individuals nowadays. In this study, a sensory management recommendation system was developed and tested to help ASD children deal with atypical sensory responses in class. The system employed sensor fusion and machine learning techniques to identify distractions, anxious situations, and the potential causes of these in the surroundings. Another novelty of the system included a sensory management strategy making a module based on fuzzy logic, which generated alerts to inform teachers and caregivers about children's states and risky environmental factors. Sensory management strategies were recommended to help improve children's attention or calm children down. The evaluation results suggested that the use of the system had a positive impact on children's performance and its design was user-friendly. The sensory management recommendation system could work as an intelligent companion for ASD children that helps with their in-class performance by recommending management strategies in relation to the real-time information about the children's environment.

Integrated systems pharmacology and transcriptomics to dissect the mechanisms of Loki Zupa decoction in the treatment of murine allergic asthma.

ETHNOPHARMACOLOGICAL RELEVANCE: Loki zupa (LKZP) decoction, a traditional Uyghur medicine prescription, has been commonly used to treat numerous respiratory ailments in the Xinjiang region of western China, especially chronic airway inflammatory diseases such as allergic asthma. Due to its complex chemical composition, however, the mechanism of action of LKZP has yet to be fully elucidated. AIM OF THE STUDY: Based on the balanced regulation theory of pro-inflammation and anti-inflammation, we tried to investigate the effectiveness of LKZP on asthma and its related protective mechanisms. MATERIALS AND METHODS: In this study, an experimental model of asthma was established using ovalbumin (OVA) in BALB/c mice to assess the effects of LKZP. The potential mechanism of LKZP anti allergic asthma were researched by the combination of in silico systems pharmacology and in vivo transcriptomics. RESULTS: Our data revealed that LKZP exerted a therapeutic effect against OVA-induced asthma by reducing airway hyperresponsiveness (AHR), peribronchial inflammation, and mucus hypersecretion. Meanwhile, LKZP downregulated the expression of OVA-induced IgE, interleukin (IL)-4, IL-5, IL-13, and tumor necrosis factor (TNF)-α and concurrently promoted the expression of interferon (IFN)-γ in serum and bronchoalveolar lavage fluid (BALF). Systems pharmacology analysis identified 10 core bioactive ingredients and 26 hub targets of LKZP against asthma. Transcriptomic analysis confirmed 246 differentially expressed genes (DEGs) after LKZP treatment. These were mainly expressed in cytokine-cytokine receptor interactions and immune and inflammatory response-related signaling pathways. Additionally, the real-time quantitative PCR (qPCR) results for the nine selected DEGs matched those of the RNA-seq analysis. Nuclear factor (NF)-κB and hypoxia-inducible factor (HIF)-1 signaling pathways were identified as candidate targets involved in the action of LKZP on allergic asthma, which was highly consistent with the findings in silico. By qPCR, Western blot, and immunohistochemical analysis, it was verified that LKZP treatment dramatically inhibited the activation of NF-κB p65 and HIF-1α stimulated by OVA in asthmatic mice. CONCLUSIONS: Taken together, our experimental data revealed that LKZP could be a candidate for the treatment of allergic asthma via NF-κB and HIF-1 signaling pathways.

Climate warming, but not Spartina alterniflora invasion, enhances wetland soil HONO and NOx emissions.

Climate warming and invasive plant growth (plant invasion) may aggravate air pollution by affecting soil nitrogen (N) cycling and the emissions of reactive N gases, such as nitrous acid (HONO) and nitrogen oxides (NOx). However, little is known about the response of soil NOy (HONO + NOx) emissions and microbial functional genes to the interaction of climate warming and plant invasion. Here, we found that experimental warming (approximately 1.5 °C), but not Spartina alterniflora invasion, increased NOy emissions (0-140 ng N m-2 s-1) of treated wetland soils by 4-10 fold. Warming also decreased soil archaeal and fungal richness and diversity, shifted their community structure (e.g., decreased the archaeal classes Thermoplasmata and Iainarchaeia, and increased the archaeal genus Candidatus Nitrosoarchaeum, and the fungal classes Saccharomycetes and Tritirachiomycetes), and decreased the overall abundance of soil N cycling genes. Structural equation modeling revealed that warming-associated changes in edaphic factors and the microbial N cycling potential are responsible for the observed increase in soil NOy emissions. Collectively, the results showed that climate warming accelerates soil N cycling by stimulating large soil HONO and NOx emissions, and influences air quality by contributing to atmospheric reactive N and ozone cycling.