Substance P Increases STAT6-Mediated Transcription Activation of Lymphocyte Cytosolic Protein 2 to Sustain M2 Macrophage Predominance in Pediatric Asthma.

Substance P (SP) is a neuropeptide released by neurons and participates in various biological processes, including inflammation. M2 macrophages are major immune cells associated with type 2 inflammation in asthma. This study investigated the effect of SP on macrophage phenotype in pediatric asthma and the underpinning factors. Asthmatic children exhibited an increased level of SP, along with a higher proportion of M2 macrophages in their bronchoalveolar lavage fluid. Flow cytometry revealed that SP treatment enhanced the M2 polarization of 12-O-tetradecanoylphorbol 13-acetate-treated THP-1 cells (macrophages) in vitro. By contrast, the administration of a neutralizing antibody of SP reduced the M2 macrophage population, mitigated inflammatory cell infiltration in mouse lung tissues, and decreased the population of immune cells in the mouse bronchoalveolar lavage fluid. SP up-regulated the expression of STAT6, which, in turn, activated the transcription of lymphocyte cytosolic protein 2 (LCP2). The population of macrophages and allergic inflammatory responses in mice were reduced by STAT6 inhibition but restored by LCP2 overexpression. Collectively, the present study demonstrated that SP sustains M2 macrophage predominance and allergic inflammation in pediatric asthma by enhancing STAT6-dependent transcription activation of LCP2.

SNHG4-mediated PTEN destabilization confers oxaliplatin resistance in colorectal cancer cells by inhibiting ferroptosis.

Oxaliplatin resistance poses a significant challenge in colorectal cancer (CRC) therapy, necessitating further investigation into the underlying molecular mechanisms. This study aimed to elucidate the regulatory role of SNHG4 in oxaliplatin resistance and ferroptosis in CRC. Our findings revealed that treatment with oxaliplatin led to downregulation of SNHG4 expression in CRC cells, while resistant CRC cells exhibited higher levels of SNHG4 compared to parental cells. Silencing SNHG4 attenuated oxaliplatin resistance and reduced the expression of resistance-related proteins MRD1 and MPR1. Furthermore, induction of ferroptosis effectively diminished oxaliplatin resistance in both parental and resistant CRC cells. Notably, ferroptosis induction resulted in decreased SNHG4 expression, whereas SNHG4 overexpression suppressed ferroptosis. Through FISH, RIP, and RNA pull-down assays, we identified the cytoplasmic localization of both SNHG4 and PTEN, establishing that SNHG4 directly targets PTEN, thereby reducing mRNA stability in CRC cells. Silencing PTEN abrogated the impact of SNHG4 on oxaliplatin resistance and ferroptosis in CRC cells. In vivo experiments further validated the influence of SNHG4 on oxaliplatin resistance and ferroptosis in CRC cells through PTEN regulation. In conclusion, SNHG4 promotes resistance to oxaliplatin in CRC cells by suppressing ferroptosis through instability of PTEN, thus serves as a target for patients with oxaliplatin-base chemoresistance.

Plant economics spectrum governs leaf nitrogen and phosphorus resorption in subtropical transitional forests.

BACKGROUND: Leaf nitrogen (N) and phosphorus (P) resorption is a fundamental adaptation strategy for plant nutrient conservation. However, the relative roles that environmental factors and plant functional traits play in regulating N and P resorption remain largely unclear, and little is known about the underlying mechanism of plant functional traits affecting nutrient resorption. Here, we measured leaf N and P resorption and 13 plant functional traits of leaf, petiole, and twig for 101 representative broad-leaved tree species in our target subtropical transitional forests. We integrated these multiple functional traits into the plant economics spectrum (PES). We further explored whether and how elevation-related environmental factors and these functional traits collectively control leaf N and P resorption. RESULTS: We found that deciduous and evergreen trees exhibited highly diversified PES strategies, tending to be acquisitive and conservative, respectively. The effects of PES, rather than of environmental factors, dominated leaf N and P resorption patterns along the elevational gradient. Specifically, the photosynthesis and nutrient recourse utilization axis positively affected N and P resorption for both deciduous and evergreen trees, whereas the structural and functional investment axis positively affected leaf N and P resorption for evergreen species only. Specific leaf area and green leaf nutrient concentrations were the most influential traits driving leaf N and P resorption. CONCLUSIONS: Our study simultaneously elucidated the relative contributions of environmental factors and plant functional traits to leaf N and P resorption by including more representative tree species than previous studies, expanding our understanding beyond the relatively well-studied tropical and temperate forests. We highlight that prioritizing the fundamental role of traits related to leaf resource capture and defense contributes to the monitoring and modeling of leaf nutrient resorption. Therefore, we need to integrate PES effects on leaf nutrient resorption into the current nutrient cycling model framework to better advance our general understanding of the consequences of shifting tree species composition for nutrient cycles across diverse forests.

Non-native plants tend to be phylogenetically distant but functionally similar to native plants under intense disturbance at the Three Gorges Reservoir Area.

Darwin's two opposing hypotheses, proposing that non-native species closely or distantly related to native species are more likely to succeed, are known as 'Darwin's Naturalization Conundrum'. Recently, invasion ecologists have sought to unravel these hypotheses. Studies that incorporate rich observational data in disturbed ecosystems that integrate phylogenetic and functional perspectives have potential to shed light on the conundrum. Using 313 invaded plant communities including 46 invasive plant species and 531 native plant species across the Three Gorges Reservoir Area in China, we aim to evaluate the coexistence mechanisms of invasive and native plants by integrating phylogenetic and functional dimensions at spatial and temporal scales. Our findings revealed that invasive plants tended to co-occur more frequently with native plant species that were phylogenetically distant but functionally similar in the reservoir riparian zone. Furthermore, our study demonstrated that the filtering of flood-dry-flood cycles played a significant role in deepening functional similarities of native communities and invasive-native species over time. Our study highlights the contrasting effects of phylogenetic relatedness and functional similarity between invasive and native species in highly flood-disturbed habitats, providing new sights into Darwin's Naturalization Conundrum.

The protease corin regulates electrolyte homeostasis in eccrine sweat glands.

Sweating is a basic skin function in body temperature control. In sweat glands, salt excretion and reabsorption are regulated to avoid electrolyte imbalance. To date, the mechanism underlying such regulation is not fully understood. Corin is a transmembrane protease that activates atrial natriuretic peptide (ANP), a cardiac hormone essential for normal blood volume and pressure. Here, we report an unexpected role of corin in sweat glands to promote sweat and salt excretion in regulating electrolyte homeostasis. In human and mouse eccrine sweat glands, corin and ANP are expressed in the luminal epithelial cells. In corin-deficient mice on normal- and high-salt diets, sweat and salt excretion is reduced. This phenotype is associated with enhanced epithelial sodium channel (ENaC) activity that mediates Na+ and water reabsorption. Treatment of amiloride, an ENaC inhibitor, normalizes sweat and salt excretion in corin-deficient mice. Moreover, treatment of aldosterone decreases sweat and salt excretion in wild-type (WT), but not corin-deficient, mice. These results reveal an important regulatory function of corin in eccrine sweat glands to promote sweat and salt excretion.

Disentangling the role of environmental filtering and biotic resistance on alien invasions in a reservoir area.

Large-scale water conservancy projects benefit human life but have modified the landscape and provided opportunities for alien plant invasions. Understanding the environmental (e.g., climate), human-related (e.g., population density, proximity to human activities), and biotic (e.g., native plant, community structure) factors driving invasions is essential in the management of alien plants and biodiversity conservation in areas with intense human pressure. To this end, we investigated the spatial patterns of alien plant species distribution in the Three Gorges Reservoir Area (TGRA) of China and distinguished the role of the external environment and community characteristics in determining the occurrence of alien plants with differing levels of known invasion impacts in China using random forest analyses and structural equation models. A total of 102 alien plant species belonging to 30 families and 67 genera were recorded, the majority being annual and biennial herbs (65.7%). The results showed a negative diversity-invasibility relationship and supported the biotic resistance hypothesis. Moreover, percentage coverage of native plants was found to interact with native species richness and had a predominant role in resisting alien plant species. We found alien dominance was mainly the result of disturbance (e.g., changes in hydrological regime), which drove native plant loss. Our results also demonstrated that disturbance and temperature were more important for the occurrence of malignant invaders than all alien plants. Overall, our study highlights the importance of restoring diverse and productive native communities in resistance to invasion.

A synthetic TLR4 agonist significantly increases humoral immune responses and the protective ability of an MDCK-cell-derived inactivated H7N9 vaccine in mice.

Antigenically divergent H7N9 viruses pose a potential threat to public health, with the poor immunogenicity of candidate H7N9 vaccines demonstrated in clinical trials underscoring the urgent need for more-effective H7N9 vaccines. In the present study, mice were immunized with various doses of a suspended-MDCK-cell-derived inactivated H7N9 vaccine, which was based on a low-pathogenic H7N9 virus, to assess cross-reactive immunity and cross-protection against antigenically divergent H7N9 viruses. We found that the CRX-527 adjuvant, a synthetic TLR4 agonist, significantly enhanced the humoral immune responses of the suspended-MDCK-cell-derived H7N9 vaccine, with significant antigen-sparing and immune-enhancing effects, including robust virus-specific IgG, hemagglutination-inhibiting (HI), neuraminidase-inhibiting (NI), and virus-neutralizing (VN) antibody responses, which are crucial for protection against influenza virus infection. Moreover, the CRX-527-adjuvanted H7N9 vaccine also elicited cross-protective immunity and cross-protection against a highly pathogenic H7N9 virus with a single vaccination. Notably, NI and VN antibodies might play an important role in cross-protection against lethal influenza virus infections. This study showed that a synthetic TLR4 agonist adjuvant has a potent immunopotentiating effect, which might be considered worth further development as a means of increasing vaccine effectiveness.

Collateral-Pricking and Bloodletting Cupping Combined with Electroacupuncture for Postherpetic Neuralgia: A Meta-Analysis.

Background: Acupuncture therapy has demonstrated significant efficacy in the treatment of postherpetic neuralgia, effectively alleviating pain intensity and enhancing patients' quality of life. However, the effectiveness of collateral-pricking and bloodletting cupping combined with electroacupuncture in the treatment of postherpetic neuralgia remains a subject of controversy. We aimed to assess the efficacy and safety of collateral-pricking and bloodletting cupping combined with electroacupuncture for postherpetic neuralgia. Methods: We identified relevant randomized controlled trials by conducting a comprehensive search in multiple databases: China National Knowledge Infrastructure, China Biomedical Literature, Wanfang Data, PubMed, Cochrane Central Register of Controlled Trials, Embase, and Web of Science. The outcome included efficacy rate, visual analog scale (VAS)scores and pittsburgh sleep quality index (PSQI) scores. We meticulously assessed the risk of bias in the included trials and performed a meta-analysis. Results: We analyzed 9 randomized controlled trials involving 639 patients. Collateral-pricking and bloodletting cupping combined with electroacupuncture achieved a significantly higher efficacy rate (risk ratio, 1.22 [95% CI, 1.13-1.31]; P < .001), reduced theVAS scores (standardized mean difference, -1.52 [95% CI, -2.26 to -0.79]; P < .001), and improved the PSQI scores (standardized mean difference, -2.31 [95% CI, -3.97 to -0.64]; P = .007) compared with the control groups. The subgroup analysis revealed that the combined treatment of collateral-pricking and bloodletting cupping and electroacupuncture had a significantly higher total effective rate compared with the carbamazepine, electroacupuncture, and pregabalin groups (P < .05). The total efficacy rate of the collateral-pricking and bloodletting cupping combined with electroacupuncture group was superior to that of the control group, irrespective of whether 2 or 3 courses were administered (P < .05). Conclusion: Existing evidence suggests that the combination of collateral-pricking and bloodletting cupping and electroacupuncture demonstrates efficacy in pain relief, improvement of sleep quality, and enhanced therapeutic outcomes for patients with postherpetic neuralgia. However, further validation through large-scale multicenter randomized controlled trials is warranted due to the limited quantity and quality of the included literature in this study.

Identification of necroptosis-related gene expression and the immune response in polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common reproductive and endocrine disorder; however, the understanding of the pathogenesis of PCOS remains unclear. Necroptosis is a newly discovered mechanism of cell death, and it is closely related to reproductive endocrine-related diseases. This study aimed to investigate the hub necroptosis-related genes in PCOS patients and its correlation with immune cell infiltration by bioinformatics methods. METHOD: The gene expression chip result matrix and the annotation matrix files of the GSE34526, GSE8157, and GSE5090 datasets were downloaded from the GEO database. We analyzed the expression and correlation of the necroptosis-related genes in all samples, constructed a diagnostic model based on all necroptosis-related genes and genes with significant differences, performed unsupervised clustering of samples and gene enrichment analysis, and evaluated the correlations between the hub gene and immune cell infiltration levels by the R packages GSVA and CIBERSORT. Finally, PPI networks were constructed using the Cytoscape software GeneMANIA plug-in, and the miRNA, transcription factors, RBP, and drugs were predicted. CONCLUSION: Necroptosis-related genes have important relationships in the development of PCOS and are potentially associated with immune infiltration in PCOS patients.

Mechanism of Treadmill Exercise Combined with Rich Environmental Stimulation to Improve Depression in Post-stroke Depression Model Rats.

BACKGROUND: Post-stroke depression (PSD) is a common complication, occurring in approximately one-third of these patients. The neurological symptoms of PSD affect patients' daily life and subsequent recovery. Analyzing the pathogenesis of post-stroke depression from a psychological perspective, it was found that PSD patients often feel despair and anxiety, and it is crucial to explore non-pharmacological ways to improve post-stroke depressive symptoms. A combination of exercise and rich environmental stimulation (RES) has been found effective in improving post-stroke depressive symptoms. Therefore, this study aimed to explore the effects of exercise and rich environmental stimulation on PSD in rats and their potential underlying mechanisms and to provide a theoretical basis for managing PSD. METHODS: The PSD rat model was constructed, and the depression-like behaviors of rats in each group were evaluated using the open field test (OFT), sucrose preference test (SPT), and forced swimming test (FST). Moreover, changes in the morphological behavior of rat hippocampus were observed using hematoxylin-eosin (HE) staining and Nissl staining. The expression levels of 5-hydroxytryptamine (5-HT) and norepinephrine (NE) in hippocampus tissues were assessed using enzyme linked immunosorbent assay (ELISA), and the levels of tryptophan-related proteins were determined employing western blot analysis. Additionally, a kynurenine-3-monooxygenase (KMO) inhibitor was administered to the combined stimulation group, and the levels of tryptophan (TRP), 5-HT, kynurenine (KYN), 3-hydroxy-kynurenine (3-HK), and quinolinic acid (QA) were evaluated using liquid chromatography mass spectrometry/mass spectrometry (LC-MS/MS). RESULTS: Treadmill exercise combined with rich environmental stimulation significantly reduced the immobility time in the FST (p < 0.01), increased the exploratory behavior in the OFT (p < 0.05), and increased the sucrose water consumption in the SPT (p < 0.01), indicating that the depression-like behavior was improved. Treadmill exercise combined with rich environmental stimulation also improved the shape of the damaged hippocampus and increased the number of neurons in the hippocampus. Additionally, treadmill exercise combined with rich environmental stimulation significantly increased the levels of 5-HT and NE in hippocampus tissues (p < 0.01) and decreased KMO protein level (p < 0.01). In the KMO inhibitor group, the neural function was efficiently restored, the levels of 3-HK, QA, and KMO in the hippocampus were substantially reduced (p < 0.01), and the expression level of 5-HT was increased (p < 0.01). CONCLUSIONS: Exercise stimulation combined with enriched environmental stimuli alleviates post-stroke depression in rats, and the underlying mechanisms may be related to TRP/KYN/3-HK/QA excitotoxicity pathways and increased 5-hydroxytryptamine levels.

Loss of SPRY2 contributes to cancer-associated fibroblasts activation and promotes breast cancer development.

The communication between tumor cells and tumor microenvironment plays a critical role in cancer development. Cancer-associated fibroblasts (CAFs) are the major components of the tumor microenvironment and take part in breast cancer formation and progression. Here, by comparing the gene expression patterns in CAFs and normal fibroblasts, we found SPRY2 expression was significantly decreased in CAFs and decreased SPRY2 expression was correlated with worse prognosis in breast cancer patients. SPRY2 knockdown in fibroblasts promoted tumor growth and distant metastasis of breast cancer in mice. Loss of stromal SPRY2 expression promoted CAF activation dependent on glycolytic metabolism. Mechanically, SPRY2 suppressed Y10 phosphorylation of LDHA and LDHA activity by interfering with the interaction between LDHA and SRC. Functionally, SPRY2 knockdown in fibroblasts enhanced the stemness of tumor cell dependent on glycolysis in fibroblasts. Collectively, this work identified SPRY2 as a negative regulator of CAF activation, and SPRY2 in CAFs may potentially be therapeutically targeted in breast cancer treatment.

Melatonin Alleviates Acute Respiratory Distress Syndrome by Inhibiting Alveolar Macrophage NLRP3 Inflammasomes Through the ROS/HIF-1α/GLUT1 Pathway.

Sepsis-induced acute respiratory distress syndrome (ARDS) is a devastating clinically severe respiratory disorder, and no effective therapy is available. Melatonin (MEL), an endogenous neurohormone, has shown great promise in alleviating sepsis-induced ARDS, but the underlying molecular mechanism remains unclear. Using a lipopolysaccharide (LPS)-treated mouse alveolar macrophage cell line (MH-S) model, we found that MEL significantly inhibited NOD-like receptor protein 3 (NLRP3) inflammasome activation in LPS-treated macrophages, whereas this inhibitory effect of MEL was weakened in MH-S cells transfected with glucose transporter 1 (GLUT1) overexpressing lentivirus. Further experiments showed that MEL downregulated GLUT1 via inhibition of hypoxia-inducible factor 1 (HIF-1α). Notably, hydrogen peroxide (H2O2), a donor of reactive oxygen species (ROS), significantly increased the level of intracellular ROS and inhibited the regulatory effect of MEL on the HIF-1α/GLUT1 pathway. Interestingly, the protective effect of MEL was attenuated after the knockdown of melatonin receptor 1A (MT1) in MH-S cells. We also confirmed in vivo that MEL effectively downregulated the HIF-1α/GLUT1/NLRP3 pathway in the lung tissue of LPS-treated mice, as well as significantly ameliorated LPS-induced lung injury and improved survival in mice. Collectively, these findings revealed that MEL regulates the activation of the ROS/HIF-1α/GLUT1/NLRP3 pathway in alveolar macrophages via the MT1 receptor, further alleviating sepsis-induced ARDS.

Anthropogenic activities explained the difference in exotic plants invasion between protected and non-protected areas at a northern subtropics biodiversity hotspot.

Biological invasion poses a major threat to biodiversity and conservation efforts in protected areas. The Greater Shennongjia Area (GSA) is one of China's 16 key areas for biodiversity, as stated in the China National Biodiversity Conservation Strategy and Action Plan. However, the local authorities lack appropriate data on the extent and impact of exotic species in protected areas, as well as lack the capacity and motivation to properly plan for exotic species strategy and action plan to support both prevention, control as well as management of exotic plants in their jurisdiction. In addition, while most previous studies have focused on exotic species in protected areas, little effort has been devoted to specifying which environmental factors contribute to the difference between protected and non-protected areas. Here, we explored the current distribution pattern of the richness and abundance of exotic species in relation to environmental variables within the GSA. In total, we found 84 exotic plant species, of which 41 exotic species within the protected areas, in 64 genera and 27 families, predominately from Asteraceae, Fabaceae, and Poaceae. The generalized linear mixed models (GLMMs) revealed that the protection status and the distance to human settlements were the most important predictors of exotic plant richness and abundance in the GSA. Our results showed that the average exotic plant richness and coverage in the protected areas were 22% and 31% lower than outside the protected areas, respectively. Such differences were probably the result of anthropogenic activities (e.g., proximity to human settlements and the proportion of cropland). Although protected areas provide an important barrier against plant invasions, invasion may be a tricky issue for protected area management in the future. The Alliance of Protected areas in Western Hubei and Eastern Chongqing will need to further consider stringent control and management strategies for the entry of exotic species into protected areas to effectively maintain the continuity and integrity of the GSA's biodiversity and ecosystems. Our results provided guidance and support to enhance the capacity of scientific and effective management and sustainable development of the Shennongjia World Natural Heritage Site and other protected areas.

One Versatile Cas9-Integrated Single-Tube Duplex Quantitative Real-Time PCR System for Rapid Analysis of CRISPR/Cas-Induced Mutants.

Clustered regularly interspersed short palindromic repeat (CRISPR)/Cas9 gene editing has become a common tool for rapid crop and animal breeding, but efficiently screening out and genotyping for the CRISPR/Cas9-induced mutant lines at a low cost remains challenging. Using rice (Oryza sativa L.) samples genetically edited at the Waxy locus as an example, we developed a single-tube duplex quantitative real-time PCR assisted by an in vitro CRISPR/Cas9 cleavage (Cc-qPCR) method to screen for expected genetically edited lines, identify genotypes, and evaluate gene-editing frequency. In Cc-qPCR, genomic DNA is first cleaved at the target site by the single-guide RNA (sgRNA)/Cas9 complex and then quantified with qPCR to assess for the presence of a mutant and identify sample genotypes. Our findings suggest that Cc-qPCR can successfully identify mutants with small insertions or deletions (indels), even in mutant lines with single-base indels or substitutions. Cc-qPCR was also able to successfully identify heterozygous and homozygous mutants. The sensitivity of Cc-qPCR was determined to be as low as 0.5%, indicating that the method could be used to evaluate the editing efficiency of gene-editing systems. After testing our novel method on Waxy locus-edited rice offspring, our results show that Cc-qPCR is an accurate and effective approach to rapidly identify expected mutants and their genotypes and to evaluate editing efficiency. This method will prove useful for increasing the efficiency and range of molecular breeding techniques.

Comparison of model-specific histopathology in mouse models of COVID-19.

A novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been identified as the causative agent of the current coronavirus disease 2019 pandemic. Development of animal models that parallel the clinical and pathologic features of disease are highly essential to understanding the pathogenesis of SARS-CoV-2 infection and the development of therapeutics and prophylactics. Several mouse models that express the human angiotensin converting enzyme 2 (hACE2) have been created, including transgenic and knock-in strains, and viral vector-mediated delivery of hACE2. However, the comparative pathology of these mouse models infected with SARS-CoV-2 are unknown. Here, we perform systematic comparisons of the mouse models including K18-hACE2 mice, KI-hACE2 mice, Ad5-hACE2 mice and CAG-hACE2 mice, which revealed differences in the distribution of lesions and the characteristics of pneumonia induced. Based on these observations, the hACE2 mouse models meet different needs of SARS-CoV-2 researches. The similarities or differences among the model-specific pathologies may help in better understanding the pathogenic process of SARS-CoV-2 infection and aiding in the development of effective medications and prophylactic treatments for SARS-CoV-2.

Edaravone Dexborneol Downregulates Neutrophil Extracellular Trap Expression and Ameliorates Blood-Brain Barrier Permeability in Acute Ischemic Stroke.

Background: Our previous work has shown that inflammatory processes play a detrimental role in the pathophysiology of acute ischemic stroke (AIS). Neutrophil extracellular traps (NETs) have been recognized as a key contributor to the proinflammatory response in AIS and could aggravate blood-brain barrier (BBB) damage. Recently, experimental and clinical researches showed that Edaravone Dexborneol (Eda.B), which is comprised of two active ingredients, Edaravone and (+)-Borneol, was effective in treatment of AIS. However, it is not clear whether the effects of Eda.B against AIS are related to NETs and BBB permeability. Methods: Experiment 1 was to detect the effects of Eda.B in AIS patients. Serum samples of volunteers and AIS patients were collected before and 3 days after Edaravone Dexborneol treatment. Markers of NETs and occludin were detected by ELISA kit. Experiment 2 was to explore the effects of Eda.B on experimental stroke mice. Male C57BL/6 mice were subjected to distal middle cerebral artery occlusion (MCAO) and treated with vehicle, Eda.B, or DeoxyribonueleaseI (DNase I). After stroke, the neurobehavioral tests, infarct volume, and cerebral blood flow evaluation were determined. Leakage of Evans blue was to assess the integrity of BBB. Western blot, real-time quantitative polymerase chain reaction (RT-qPCR), and immunofluorescence were used to examine the expression of NETs and tight junction- (TJ-) associated proteins. Results: Eda.B significantly improved neurological function and cerebral blood flow but reduced infarct volume after experimental stroke. Eda.B downregulated level of NETs in serum samples of AIS patients and tissue samples of MCAO mouse cortex. Eda.B and DNase I alleviated BBB permeability by upregulating TJ-associated proteins. Conclusion: NETs are related to the early stage of AIS. Eda.B exerted neuroprotective effects and ameliorated BBB permeability after AIS.

Image quality improvement in low-dose chest CT with deep learning image reconstruction.

OBJECTIVES: To investigate the clinical utility of deep learning image reconstruction (DLIR) for improving image quality in low-dose chest CT in comparison with 40% adaptive statistical iterative reconstruction-Veo (ASiR-V40%) algorithm. METHODS: This retrospective study included 86 patients who underwent low-dose CT for lung cancer screening. Images were reconstructed with ASiR-V40% and DLIR at low (DLIR-L), medium (DLIR-M), and high (DLIR-H) levels. CT value and standard deviation of lung tissue, erector spinae muscles, aorta, and fat were measured and compared across the four reconstructions. Subjective image quality was evaluated by two blind readers from three aspects: image noise, artifact, and visualization of small structures. RESULTS: The effective dose was 1.03 ± 0.36 mSv. There was no significant difference in CT values of erector spinae muscles and aorta, whereas the maximum difference for lung tissue and fat was less than 5 HU among the four reconstructions. Compared with ASiR-V40%, the DLIR-L, DLIR-M, and DLIR-H reconstructions reduced the noise in aorta by 11.44%, 33.03%, and 56.1%, respectively, and had significantly higher subjective quality scores in image artifacts (all p < 0.001). ASiR-V40%, DLIR-L, and DLIR-M had equivalent score in visualizing small structures (all p > 0.05), whereas DLIR-H had slightly lower score. CONCLUSIONS: Compared with ASiR-V40%, DLIR significantly reduces image noise in low-dose chest CT. DLIR strength is important and should be adjusted for different diagnostic needs in clinical application.

LncRNA SNHG6 promotes breast cancer progression and epithelial-mesenchymal transition via miR-543/LAMC1 axis.

PURPOSE: Breast cancer (BC) is the most prevalent cancer in women with an estimated incidence of 10% and the leading cause of mortality due to its heterogenous property and high metastasis rate. Development of novel therapy is very necessary and requires an understanding of molecular mechanisms. We investigated the function of SNHG6/miR-543/LAMC1 axis in BC. METHODS: Human BC tissues were obtained from diagnosed patients. BC cell lines and normal breast cells were used. QRT-PCR and Western blotting were employed to measure expression levels of SNHG6, miR-543, LAMC1, EMT-related proteins, and PI3K/AKT pathway. Dual-luciferase assay was performed to validate interactions of SNHG6/miR-543 and miR-543/LAMC1. Colony formation assay, flow cytometry, scratch wound healing assay, and transwell assay were utilized to assess the proliferation, apoptosis, migration, and invasion of BC cells. Nude mouse xenograft model was used the evaluate the function of SNHG6/miR-543 in tumor growth in vivo. RESULTS: SNHG6 and LAMC1 were elevated, but miR-543 was reduced in BC tissues and cells. SNHG6 interacted directly with miR-543, while miR-543 targeted LAMC1. Knockdown of SNHG6 suppressed BC cell proliferation, migration, invasion, EMT, and PI3K/AKT pathway, but promoted cell apoptosis, while miR-543 inhibitor or overexpression of LAMC1 reversed those effects. Overexpression of LAMC1 also blocked the effects of miR-543 on BC cell proliferation, migration, invasion, and EMT. Knockdown of SNHG6 restrained BC growth in vivo, while miR-543 inhibitor inhibited that suppression. CONCLUSION: SNHG6 promoted EMT and BC cell proliferation and migration by acting as a miR-543 sponge and disinhibiting LAMC1/PI3K/AKT pathway. SNHG6/miR-543/LAMC1 axis could serve as candidates for the development of therapeutic strategies for BC.

H. pylori infection induces CXCL8 expression and promotes gastric cancer progress through downregulating KLF4.

Tumour-derived CXCL8 facilitates the movement of myeloid-derived suppressor cells, which are able to restrain antitumour immune responses to the tumour microenvironment. Kruppel-like factor 4 (KLF4) is a potential tumour suppressor in gastric cancer (GC). However, knowledge regarding correlations between KLF4 and CXCL8 in GC is limited. We use cellular and molecular biological methods to assess whether these two factors interact in GC. Expression CXCL8 and KLF4 was altered in human GC tissues compared to normal gastric tissues in opposite ways. Additionally, cytotoxin-associated gene A protein (CagA) gene transduction or Helicobacter pylori (H. pylori) infection upregulated CXCL8 expression. Knockdown of KLF4 expression increased CXCL8 protein and RNA expression, whereas its overexpression had the opposite effect. CXCL8-mediated enhancement of GC cell migration and proliferation was reversed by upregulation of KLF4 expression. Further mechanistic research revealed that KLF4 binds the CXCL8 promoter, suppressing CXCL8 transcription. Moreover, CXCL8 stimulation reduced KLF4 protein expression and promoted GC cell proliferation and migration, eventually promoting neoplasm growth in vivo. Together, our findings demonstrate that CagA promotes CXCL8 and inhibits KLF4. CXCL8 is a decisive downstream target gene of KLF4, and KLF4 negatively regulates CXCL8 in GC. Furthermore, CXCL8's negative regulation of KLF4 in vivo and in vitro, indicates that CagA may downregulate KLF4 by inducing CXCL8 expression, low expression of KLF4 further promotes that of CXCL8, forming a vicious circle in GC. Targeted KLF4 activation might improve the immunosuppressive microenvironment through direct negative regulation of CXCL8, providing a new potential target to strengthen the efficacy of immunotherapy in GC patients.

The Edwardsiella piscicida thioredoxin-like protein inhibits ASK1-MAPKs signaling cascades to promote pathogenesis during infection.

It is important that bacterium can coordinately deliver several effectors into host cells to disturb the cellular progress during infection, however, the precise role of effectors in host cell cytosol remains to be resolved. In this study, we identified a new bacterial virulence effector from pathogenic Edwardsiella piscicida, which presents conserved crystal structure to thioredoxin family members and is defined as a thioredoxin-like protein (Trxlp). Unlike the classical bacterial thioredoxins, Trxlp can be translocated into host cells, mimicking endogenous thioredoxin to abrogate ASK1 homophilic interaction and phosphorylation, then suppressing the phosphorylation of downstream Erk1/2- and p38-MAPK signaling cascades. Moreover, Trxlp-mediated inhibition of ASK1-Erk/p38-MAPK axis promotes the pathogenesis of E. piscicida in zebrafish larvae infection model. Taken together, these data provide insights into the mechanism underlying the bacterial thioredoxin as a virulence effector in downmodulating the innate immune responses during E. piscicida infection.