Extracellular vesicles derived from CD4+ T cells carry DGKK to promote sepsis-induced lung injury by regulating oxidative stress and inflammation.

BACKGROUND: Sepsis is an abnormal immune response after infection, wherein the lung is the most susceptible organ to fail, leading to acute lung injury. To overcome the limitations of current therapeutic strategies and develop more specific treatment, the inflammatory process, in which T cell-derived extracellular vesicles (EVs) play a central role, should be explored deeply. METHODS: Liquid chromatography-tandem mass spectrometry was performed for serum EV protein profiling. The serum diacylglycerol kinase kappa (DGKK) and endotoxin contents of patients with sepsis-induced lung injury were measured. Apoptosis, oxidative stress, and inflammation in A549 cells, bronchoalveolar lavage fluid, and lung tissues of mice were measured by flow cytometry, biochemical analysis, enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction, and western blot. RESULTS: DGKK, the key regulator of the diacylglycerol (DAG)/protein kinase C (PKC) pathway, exhibited elevated expression in serum EVs of patients with sepsis-induced lung injury and showed strong correlation with sepsis severity and disease progression. DGKK was expressed in CD4+ T cells under regulation of the NF-κB pathway and delivered by EVs to target cells, including alveolar epithelial cells. EVs produced by CD4+ T lymphocytes exerted toxic effects on A549 cells to induce apoptotic cell death, oxidative cell damage, and inflammation. In mice with sepsis induced by cecal ligation and puncture, EVs derived from CD4+ T cells also promoted tissue damage, oxidative stress, and inflammation in the lungs. These toxic effects of T cell-derived EVs were attenuated by the inhibition of PKC and NOX4, the downstream effectors of DGKK and DAG. CONCLUSIONS: This approach established the mechanism that T-cell-derived EVs carrying DGKK triggered alveolar epithelial cell apoptosis, oxidative stress, inflammation, and tissue damage in sepsis-induced lung injury through the DAG/PKC/NOX4 pathway. Thus, T-cell-derived EVs and the elevated distribution of DGKK should be further investigated to develop therapeutic strategies for sepsis-induced lung injury.

USP9x promotes CD8 + T-cell dysfunction in association with autophagy inhibition in septic liver injury.

Sepsis is a life-threatening condition manifested by concurrent inflammation and immunosuppression. Ubiquitin-specific peptidase 9, X-linked (USP9x), is a USP domain-containing deubiquitinase which is required in T-cell development. In the present study, we investigate whether USP9x plays a role in hepatic CD8 + T-cell dysfunction in septic mice. We find that CD8 + T cells are decreased in the blood of septic patients with liver injury compared with those without liver injury, the CD4/CD8 ratio is increased, and the levels of cytolytic factors, granzyme B and perforin are downregulated. The number of hepatic CD8 + T cells and USP9x expression are both increased 24 h after cecal ligation and puncture-induced sepsis in a mouse model, a pattern similar to liver injury. The mechanism involves promotion of CD8 + T-cell dysfunction by USP9x associated with suppression of cell cytolytic activity via autophagy inhibition, which is reversed by the USP9x inhibitor WP1130. In the in vivo studies, autophagy is significantly increased in hepatic CD8 + T cells of septic mice with conditional knockout of mammalian target of rapamycin. This study shows that USP9x has the potential to be used as a therapeutic target in septic liver injury.

U-Shaped Relationship Between Functional Outcome and Serum Uric Acid in Ischemic Stroke.

BACKGROUND/AIMS: We sought to assess a consecutive number of patients with first-ever acute ischemic stroke (AIS), the clinical relevance in regard to functional outcome of the serum uric acid (SUA) measured at admission. METHODS: In 2 prospective centers for observational study, serum concentrations of SUA were measured on admission in the serum of 710 consecutive patients with AIS. SUA concentrations were determined by high-performance liquid chromatography. SUA, NIH stroke scale (NIHSS), and conventional risk factors were evaluated to determine their value to predict functional outcome within 3 months. RESULTS: During the follow-up, an unfavorable functional outcome (defined as a mRS score > 2) was found in 219 (30.8%) patients. The unfavorable functional outcome distribution across the SUA quartiles ranged between 12.4% (third quartile) and 50.6% (first quartile). After adjusting for all other significant outcome predictors, SUA concentration remained an independent unfavorable outcome predictor with an adjusted OR of 0.996 (95% CI, 0.993-0.998; P< 0.001). CONCLUSIONS: The data show that the U-shaped nature of the exposure-risk relationship was more prominent when the data were assessed in deciles (based on the SUA values). This model predicted the lowest relative risk of unfavorable outcome in the 67th percentile (corresponding to 309 µmol/L). SUA was significantly associated with the risk of poor functional outcomes in Chinese patients with stroke.

Protective effects of syringin against lipopolysaccharide-induced acute lung injury in mice.

BACKGROUND: Syringin, a major active substance isolated from Eleutherococcus senticosus, has been found to have anti-inflammatory effect. The aim of this study was to investigate the effects and underlying mechanisms of syringin on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. METHODS: We established an LPS-induced ALI model in mice. We also detected the lung wet-to-dry ratio, myeloperoxidase activity, and inflammatory cytokines tumor necrosis factor alpha, interleukin (IL)-1ß, and IL-6 to estimate the index of lung injury in mice. Furthermore, the expression of nuclear factor-erythroid 2-related factor-2 (Nrf2), heme oxygenase-1, and nuclear factor κB (NF-κB) was detected by Western blot analysis. RESULTS: The results showed that the increases in lung wet-to-dry ratio, myeloperoxidase activity, malondialdehyde content, and levels of tumor necrosis factor alpha, IL-1ß, and IL-6 induced by LPS were significantly inhibited by treatment of syringin. The phosphorylation of IκB-α and p65 NF-κB caused by LPS was inhibited by syringin. Furthermore, syringin was found to upregulate the expression of Nrf2 and heme oxygenase 1. CONCLUSIONS: In conclusion, the results suggest that syringin protects against LPS-induced ALI by activating Nrf2 and inhibiting NF-κB signaling pathway.

Doxorubicin-loaded mesoporous silica nanoparticle composite nanofibers for long-term adjustments of tumor apoptosis.

There is a high local recurrence (LR) rate in breast-conserving therapy (BCT) and enhancement of the local treatment is promising as a way to improve this. Thus we propose a drug delivery system using doxorubicin (DOX)-loaded mesoporous silica nanoparticle composite nanofibers which can release anti-tumor drugs in two phases-burst release in the early stage and sustained release at a later stage-to reduce the LR of BCT. In the present study, we designed a novel composite nanofibrous scaffold to realize the efficient release of drugs by loading both DOX and DOX-loaded mesoporous silica nanoparticles into an electrospun PLLA nanofibrous scaffold. In vitro results demonstrated that this kind of nanomaterial can release DOX in two phases, and the results of in vivo experiments showed that this hybrid nanomaterial significantly inhibited the tumor growth in a solid tumor model. Histopathological examination demonstrated that the apoptosis of tumor cells in the treated group over a 10 week period was significant. The anti-cancer effects were also accompanied with decreased expression of Bcl-2 and TNF-α, along with up-regulation of Bax, Fas and the activation of caspase-3 levels. The present study illustrates that the mesoporous silica nanoparticle composite nanofibrous scaffold could have anti-tumor properties and could be further developed as adjuvant therapeutic protocols for the treatment of cancer.

Heterogeneity in clinical prognosis, immune infiltration and molecular characteristics of three glycolytic subtypes in lower-grade gliomas.

Background and purpose: Lower-grade gliomas (LGG) exhibit a wide range of metabolic pathway changes, and metabolic reprogramming can be largely seen as a result of oncogenic driving events. Glycolysis, an important pathway of tumor energy source, has been poorly studied in gliomas. The aim of this article is to analyze the relationship between glycolysis and lower-grade glioma development and prognosis in order to explore the heterogeneous relevance of glycolysis in lower-grade gliomas. Methods and results: Our study searched the TCGA database and identified three glycolytic subtypes with significant prognostic differences by unsupervised clustering analysis of core glycolytic genes, named C1, C2, and C3. By analysis of clinical prognosis, somatic cell variation, and immune infiltration, we found that C3 had the best prognosis with molecular features of IDHmut-codel, followed by C1 with major molecular features of IDHmut-non-codel, G -CIMP high subtype, while C2 had the worst prognosis, mainly exhibiting IDHwt, G-CIMP low and mesenchymal-like subtypes with seven important CNV features, including CDKN2A/B deletion, chr7 gain and chr10 deletion, chr19/20 co-gain, EGFR amplification and PDGFRA/B deletion phenotypes were significantly increased, with the highest level of stemness and significant T-cell depletion features. Finally, to quantify the level of abnormal glycolysis and its impact on prognosis, we developed GlySig to reflect the glycolytic activity of LGG and integrated molecular features to construct nomogram that can be independently assessed to predict prognosis. Conclusions: Our study analyzed the tumor characteristics of different glycolytic states, and our findings explain and describe the heterogeneity of glycolytic metabolism within diffuse LGGs.

Emotional and Behavioral Changes in Preschool Firstborn Children During Transition to Siblinghood: A Mixed Methods Study.

Purpose: To help firstborn children in families expecting a second child navigate the role transition more smoothly, we investigated the emotional and behavioral changes of firstborn children during the transition to siblinghood (TTS) and the factors that contribute to these changes. Patients and Methods: From March to December 2019, a total of 97 firstborn children (Mage=3.00± 0.97, and female = 51) were included in the study through a questionnaire survey of their mothers, and two follow-up visits were conducted in Chongqing, China. Individual in-depth interviews were conducted with 14 mothers. Results: Both quantitative and qualitative results suggest that emotional and behavioral problems of firstborn children tend to increase during TTS, particularly in issues such as anxiety/depression, somatic complaints, withdrawal, sleep problems, attention problems, and aggressive behavior, as well as internalization problems, externalization problems and total problems in the quantitative study (P<0.05). A poor father-child relationship may increase emotional and behavioral problems in firstborn children (P=0.05). Further qualitative analysis found that younger age and outgoing personality of the firstborn child may improve the emotional and behavioral problems. Conclusion: The firstborn children did have more emotional and behavioral problems during TTS. But these problems can be regulated by family factors and their own characteristics.

Identification of Hub Genes With Differential Correlations in Sepsis.

As a multifaceted syndrome, sepsis leads to high risk of death worldwide. It is difficult to be intervened due to insufficient biomarkers and potential targets. The reason is that regulatory mechanisms during sepsis are poorly understood. In this study, expression profiles of sepsis from GSE134347 were integrated to construct gene interaction network through weighted gene co-expression network analysis (WGCNA). R package DiffCorr was utilized to evaluate differential correlations and identify significant differences between sepsis and healthy tissues. As a result, twenty-six modules were detected in the network, among which blue and darkred modules exhibited the most significant associations with sepsis. Finally, we identified some novel genes with opposite correlations including ZNF366, ZMYND11, SVIP and UBE2H. Further biological analysis revealed their promising roles in sepsis management. Hence, differential correlations-based algorithm was firstly established for the discovery of appealing regulators in sepsis.

Resveratrol Alleviates Hepatic Fibrosis in Associated with Decreased Endoplasmic Reticulum Stress-Mediated Apoptosis and Inflammation.

Hepatic fibrosis (HF) is the typical response to chronic liver disease and is characterized by deposition of abundant extracellular matrix. The aim of the present study was to investigate the protective effect of resveratrol (RSV) in a CCl4-induced rat model of HF. We demonstrate that the administration of RSV effectively improves liver function and ameliorates liver fibrosis by reducing collagen deposition and reversing the expression of COL1A1 and PPAR-γ. Treatment efficacy of RSV could be attributed to reversed epithelial-mesenchymal transition progress with upregulated expression of E-cadherin and downregulated N-cadherin, vimentin, and α-SMA. Moreover, RSV significantly decreased the levels of endoplasmic reticulum stress (ERS)-related proteins CHOP; Bip; cleaved caspase-3, caspase-7, and caspase-12; Bax; and Bak while promotes the expression of anti-apoptosis protein Bcl2. The important role of ERS in HF was confirmed by using 4-PBA, an ERS inhibitor, which markedly ameliorated CCl4-induced HF. Further, mechanistic studies demonstrated that RSV significantly decreased CCl4-induced transforming growth factor-ß synthesis and inflammatory factor (tumor necrosis factor-α and interleukin-6) expression and reduced the inflammation of hepatic stellate cells by inhibiting the NF-κB pathway in vivo and in vitro. In conclusion, the results suggested that RSV ameliorated HF in associated with decreased ERS-induced apoptosis and inflammation in rats.

Emotional and Behavioral Changes and Related Factors of Firstborn School-Aged Compared to Same Age Only Children.

Objective: To compare the emotional and behavioral characteristics of firstborn children during the pregnancy of a second child and only children of school-age in urban districts of Chongqing, China, and to explore the influencing factors of emotional and behavioral problems. Methods: We recruited mothers of firstborn children and only children from two hospitals and one primary school using purposive sampling. Questionnaires and the Parental Child Behavior Checklist (CBCL) were used to collect basic information, family socioeconomic status, family atmosphere and emotional and behavioral characteristics of their children in the survey. Results: The sample consisted of 1,155 children, including 477 firstborn children and 678 only children. The average scores of internalizing (4.47), externalizing (6.05), total problems (22.04), and six emotional and behavioral of firstborn children were significantly lower than those of only children (p < 0.05). When adjusted for children's demographic, socioeconomic and family relationship covariates, the scores of firstborn children internalizing problems (ß = -1.423, p = 0.000), externalizing problems (ß = -0.661, p = 0.048), and total problems (ß = -4.387, p = 0.000) were also significantly lower than those of only children. All children with more difficult parenting and development temperament, greater family economic pressure, poorer relationships between mother and child, less harmonious family atmosphere and father's permissive parenting style had more internalizing problems, externalizing problems and total problems (p < 0.05). Boys had more externalizing problems (ß = 1.939, 95% CI = 1.380-2.497) and total problems (ß = 4.908, 95% CI = 3.045-6.772) than girls. Conclusion: Firstborn children had fewer emotional and behavioral problems than their counterparts who were only children. This research helps to understand the social impact of the implementation of the two-child policy in multiple dimensions.

Polycyclic aromatic hydrocarbons are associated with later puberty in girls: A longitudinal study.

The objective of this study is to explore associations between PAH exposures and puberty timing in girls. Beginning in May 2014, 734 girls age 7.2-11.8 years in Chongqing, China, were enrolled in a prospective cohort study. They were followed up every 6 months from enrollment through June 2021, at which point participants were ages 13.6-18.3 years. Metabolite concentrations of four PAHs (1-hydroxypyrene [1-OHPyr], 2-hydroxynaphthalene [2-OHNap], 2-hydroxyfluorine [2-OHFlu], and 9-hydroxyphenanthrene [9-OHPhe]) were measured in urine samples at baseline. At each follow up visit, the Tanner's Sexual Maturity Rating scale was administered. Cox proportional hazards models were used to estimate associations between four urinary PAH metabolite concentrations and four markers of puberty: menarche, breast development, pubic hair development, and axillary hair development. Geometric mean concentrations of 1-OHPyr, 2-OHNap, 2-OHFlu and 9-OHPhe in urine were 0.47 µg/L, 3.31 µg/L, 1.49 µg/L, 3.75 µg/L, respectively. There were statistically significant associations between several urinary PAH metabolite concentrations and puberty outcomes. PAH metabolite concentrations were grouped as Low (<25th percentile, referent group), Moderate (25th-75th percentile) or High (>75th). Girls with moderate levels of 1-OHPyr were at higher risk of delayed pubic hair development (hazard ratio [HR]: 0.82, 95 % confidence interval [CI]: 0.68-0.99). Delayed breast development (HR: 0.77, 95 % CI: 0.60-0.99) and pubic hair development (HR: 0.76, 95 % CI: 0.60-0.95) were associated with high 2-OHNap. High c 2-OHFlu was associated with delayed pubic hair development (HR: 0.77, 95 % CI: 0.61-0.96). Delayed breast (HR: 0.79, 95 % CI: 0.64-0.97), pubic hair (HR: 0.79, 95 % CI: 0.65-0.96) and axillary hair development (HR: 0.80, 95 % CI: 0.65-0.99) was associated with moderate 9-OHPhe. In conclusion, PAH exposure may delay puberty onset in girls.

Identification of Survival-Associated Hub Genes in Pancreatic Adenocarcinoma Based on WGCNA.

Pancreatic adenocarcinoma is one of the leading causes of cancer-related death worldwide. Since little clinical symptoms were shown in the early period of pancreatic adenocarcinoma, most patients were found to carry metastases when diagnosis. The lack of effective diagnosis biomarkers and therapeutic targets makes pancreatic adenocarcinoma difficult to screen and cure. The fundamental problem is we know very little about the regulatory mechanisms during carcinogenesis. Here, we employed weighted gene co-expression network analysis (WGCNA) to build gene interaction network using expression profile of pancreatic adenocarcinoma from The Cancer Genome Atlas (TCGA). STRING was used for the construction and visualization of biological networks. A total of 22 modules were detected in the network, among which yellow and pink modules showed the most significant associations with pancreatic adenocarcinoma. Dozens of new genes including PKMYT1, WDHD1, ASF1B, and RAD18 were identified. Further survival analysis yielded their valuable effects on the diagnosis and treatment of pancreatic adenocarcinoma. Our study pioneered network-based algorithm in the application of tumor etiology and discovered several promising regulators for pancreatic adenocarcinoma detection and therapy.

Circ-PTPDC1 promotes the Progression of Gastric Cancer through Sponging Mir-139-3p by Regulating ELK1 and Functions as a Prognostic Biomarker.

Circular RNAs (circRNAs) is a novel class of non-coding RNAs resulting from the non-canonical splicing of linear pre-mRNAs. However, the role of circRNAs in gastric cancer (GC) remains indistinct. This study aims to explore their potential modulation in GC and its prognostic value. We first screen for circRNA expression patterns in GC through GC and adjacent noncancerous tissues by microarray. Based on the bioinformatics analysis of the microarray data, we screened out a novel circRNA, circ-PTPDC1. Then we demonstrated that circ-PTPDC1 was up-regulated in GC cells, tissues, and serum. Its overexpression was positively correlated with age, invasion depth, advanced clinical stages, and worse survival in patients with GC. We further revealed that circ-PTPDC1 promotes the proliferation, migration, and invasion of GC cell lines via sponging miR-139-3p by regulating ELK1. Importantly, we identified that circ-PTPDC1 promotes tumor upgrowth and metabasis in vivo. Additionally, we established its prognostic prediction model based on the follow-up data of the patients. Our study revealed a novel regulatory mechanism and a comprehensive landscape of circ-PTPDC1 in GC, suggesting that circ-PTPDC1 has the potential to be a biomarker for early detection and prognostic prediction of GC.

miR-3613-5p enhances the metastasis of pancreatic cancer by targeting CDK6.

Pancreatic cancer (PC) is a leading cause of cancer mortality and is expected to continue increasing incidence. Abnormally expressed microRNAs have been demonstrated tightly correlated with the development and progression of PC. However, the molecular mechanisms remain largely unknown. In this study through combing both the TCGA database and our two verification PC cohorts, we found the consistent reduction of miR-3613-5p in PC tumors, which significantly correlated with reduced cumulative survival rate among PC patients. PC patients with higher lymph node metastasis rate show reduced miR-3613-5p expression. Through further mechanistic investigation, we demonstrate that miR-3613-5p down-regulated CDK6 in repressing the metastasis capacity of PC cells in vitro and in vivo. Elevated CDK6 were also found in PC samples, which also correlate with poor prognosis. Thus, our study found a novel tumor repressor miR-3613-5p in PC progression.

Long non-coding RNA PSMA3-AS1 promotes malignant phenotypes of esophageal cancer by modulating the miR-101/EZH2 axis as a ceRNA.

BACKGROUNDS: Emerging evidences has demonstrated that dysregulation of long non-coding RNAs (lncRNAs) is critically involved in esophageal squamous cell carcinoma (ESCC) progression. However, the function of lncRNA PSMA3-AS1 in ESCC is unclear. Therefore, we aimed to explore the functions and potential mechanisms of PSMA3-AS1 in ESCC cells progression. RESULTS: Here, we found that PSMA3-AS1 expression was significantly up-regulated in ESCC tissues. Forced PSMA3-AS1 expression was correlated with tumor size, distant metastasis, and poor prognosis in ESCC patients. Functionally, PSMA3-AS1-overexpression promoted ESCC cells proliferation, invasion, and migration in vitro. Mechanistically, PSMA3-AS1 up-regulated EZH2 expression by competitively binding to miR-101. CONCLUSION: PSMA3-AS1 is significantly up-regulated in ESCC tissues, and the PSMA3-AS1/miR-101/EZH2 axis plays a critical role in ESCC progression. Taken together, our results may provide promising targets for ESCC therapy. METHODS: PSMA3-AS1 and miR-101 expression were explored using qRT-PCR in ESCC tissues and cell lines. Immunohistochemistry assays were carried out to analyze EZH2 (enhancer of zeste homolog) protein expression. RIP, dual-luciferase reporter, fluorescence in situ hybridization, and biotin pull-down assays were used to detect the interactions of PSMA3-AS1, miR-101 and EZH2. The biological functions of PSMA3-AS1 in PSMA3-AS1-altered cells were explored using CCK-8, colony formation, wound healing, and transwell assays in vitro.

miR-363 promotes proliferation and chemo-resistance of human gastric cancer via targeting of FBW7 ubiquitin ligase expression.

Dysregulation of microRNA expression is involved in several pathological activities associated with gastric cancer progression and chemo-resistance. However, the role and molecular mechanisms of miR-363 in the progression and chemo-resistance of gastric cancer remain enigmatic. In this study, we validated that miR-363 expression was higher in gastric cancer tissues than in adjacent normal tissues. Multivariate analysis identifies high levels of miR-363 expression as an independent predictor for postoperative recurrence and lower overall survival. Increased miR-363 expression promotes gastric cancer cell proliferation and chemo-resistance through directly targeting the tumor suppressor F-box and WD repeat domain-containing 7 (FBW7). Clinically, our data reveal that overexpression of miR-363 correlates with the poor survival outcomes in patients with gastric cancer, and docetaxel + cisplatin + 5-FU (DCF) regimen response is impaired in patients with miR-363 overexpression. These data suggest that miR-363 may be a potential therapeutic target for gastric cancer and serve as a biomarker for predicting response to DCF regimen treatment.