Lysine acetyltransferase 14 mediates TGF-ß-induced fibrosis in ovarian endometrioma via co-operation with serum response factor.

BACKGROUND: Fibrogenesis within ovarian endometrioma (endometrioma), mainly induced by transforming growth factor-ß (TGF-ß), is characterized by myofibroblast over-activation and excessive extracellular matrix (ECM) deposition, contributing to endometrioma-associated symptoms such as infertility by impairing ovarian reserve and oocyte quality. However, the precise molecular mechanisms that underpin the endometrioma- associated fibrosis progression induced by TGF-ß remain poorly understood. METHODS: The expression level of lysine acetyltransferase 14 (KAT14) was validated in endometrium biopsies from patients with endometrioma and healthy controls, and the transcription level of KAT14 was further confirmed by analyzing a published single-cell transcriptome (scRNA-seq) dataset of endometriosis. We used overexpression, knockout, and knockdown approaches in immortalized human endometrial stromal cells (HESCs) or human primary ectopic endometrial stromal cells (EcESCs) to determine the role of KAT14 in TGF-ß-induced fibrosis. Furthermore, an adeno-associated virus (AAV) carrying KAT14-shRNA was used in an endometriosis mice model to assess the role of KAT14 in vivo. RESULTS: KAT14 was upregulated in ectopic lesions from endometrioma patients and predominantly expressed in activated fibroblasts. In vitro studies showed that KAT14 overexpression significantly promoted a TGF-ß-induced profibrotic response in endometrial stromal cells, while KAT14 silencing showed adverse effects that could be rescued by KAT14 re-enhancement. In vivo, Kat14 knockdown ameliorated fibrosis in the ectopic lesions of the endometriosis mouse model. Mechanistically, we showed that KAT14 directly interacted with serum response factor (SRF) to promote the expression of α-smooth muscle actin (α-SMA) by increasing histone H4 acetylation at promoter regions; this is necessary for TGF-ß-induced ECM production and myofibroblast differentiation. In addition, the knockdown or pharmacological inhibition of SRF significantly attenuated KAT14-mediating profibrotic effects under TGF-ß treatment. Notably, the KAT14/SRF complex was abundant in endometrioma samples and positively correlated with α-SMA expression, further supporting the key role of KAT14/SRF complex in the progression of endometrioma-associated fibrogenesis. CONCLUSION: Our results shed light on KAT14 as a key effector of TGF-ß-induced ECM production and myofibroblast differentiation in EcESCs by promoting histone H4 acetylation via co-operating with SRF, representing a potential therapeutic target for endometrioma-associated fibrosis.

Glycemic load, but not glycemic index, is associated with an increased risk of ovarian cancer: A systematic review and meta-analysis.

The association between glycemic index (GI),glycemic load (GL) and ovarian cancer risk remains unclear. Carbohydrate intake promotes insulin secretion, leading to cell proliferation and invasion. We hypothesized that high GI and GL intake may increase ovarian cancer risk. Therefore, we conducted a meta-analysis after systematically searching PubMed, Embase, Web of Science, and Cochrane Library from inception to December 2022. Fixed- or random-effect models calculated the pooled relative risks (RRs) and corresponding 95% confidence intervals (CIs). Subgroup, sensitivity, publication bias analysis, and dose-response analysis were performed. Nine original studies were included, involving 4716 cases and 119,960 controls. No significant association was observed between GI or GL and ovarian cancer risk (GI: RR = 1.02 [95% CI, 0.83-1.26]; GL: RR = 1.11 [95% CI, 0.84-1.47]). Subgroup analysis suggested the results were not significantly modified by any group. Sensitivity analysis identified the sources of heterogeneity. No publication bias was observed. A linear positive dose-response relationship was observed between dietary GL and ovarian cancer risk after removing heterogeneous sources (RR = 1.11 [95% CI, 1.05-1.17], I2 = 32.9%, P = .23 at 50 U/d; RR = 1.04 [95% CI, 1.02-1.07], I2 = 19.1%, P = .29 at 20 U/d). These outcomes suggest that high dietary GL, but not GI, is associated with significantly increased ovarian cancer risk. Thus, sufficient intake of a low dietary GL is important for reducing ovarian cancer risk.

The Gene Expression Profiles Associated with Maternal Nicotine Exposure in the Liver of Offspring Mice.

This study aims to investigate the effect of maternal nicotine exposure on the gene expression profiles in the liver of offspring mice. Pregnant mice were subcutaneously injected with either saline vehicle or nicotine twice a day on gestational days 11-21. Total RNA from the liver samples which collected from the offspring mice of postnatal day 7 and 21 was subjected to RNA sequencing. Gene Ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway enrichment analysis were conducted to identify the functions of differentially expressed genes (DEGs). Four genes were selected for further validation by quantitative reverse transcription polymerase chain reaction (qRT-PCR). A total of 448 DEGs and 186 DEGs were identified on postnatal day 7 and 21, respectively. GO analysis revealed that the DEGs on postnatal day 7 mainly participated in the biological functions of cell growth and proliferation, and the DEGs on postnatal day 21 mainly participated in ion transport/activity. KEGG enrichment analysis showed that the DEGs on postnatal day 7 were mainly enriched in the cell cycle, cytokine-cytokine receptor interactions, hypertrophic cardiomyopathy, and the p53 signaling pathway, while the DEGs on postnatal day 21 were mainly enriched in neuroactive ligand-receptor interactions, the calcium signaling pathway, retinol metabolism, and axon guidance. The qRT-PCR results were consistent with the RNA sequencing data. The DEGs may affect the growth of liver in early postnatal period while may affect ion transport/activity in late postnatal period.

Phenotype plasticity and altered sensitivity to chemotherapeutic agents in aggressive prostate cancer cells.

In 2023, approximately 288,300 new diagnoses of prostate cancer will occur, with 34,700 disease-related deaths. Death from prostate cancer is associated with metastasis, enabled by progression of tumor phenotypes and successful extracapsular extension to reach Batson's venous plexus, a specific route to the spine and brain. Using a mouse-human tumor xenograft model, we isolated an aggressive muscle invasive cell population of prostate cancer, called DU145J7 with a distinct biophysical phenotype, elevated histone H3K27, and increased matrix metalloproteinase 14 expression as compared to the non-aggressive parent cell population called DU145WT. Our goal was to determine the sensitivities to known chemotherapeutic agents of the aggressive cells as compared to the parent population. High-throughput screening was performed with 5,578 compounds, comprising of approved and investigational drugs for oncology. Eleven compounds were selected for additional testing, which revealed that vorinostat, 5-azacitidine, and fimepinostat (epigenetic inhibitors) showed 2.6-to-7.5-fold increases in lethality for the aggressive prostate cancer cell population as compared to the parent, as judged by the concentration of drug to inhibit 50% cell growth (IC50). On the other hand, the DU145J7 cells were 2.2-to-4.0-fold resistant to mitoxantrone, daunorubicin, and gimatecan (topoisomerase inhibitors) as compared to DU145WT. No differences in sensitivities between cell populations were found for docetaxel or pirarubicin. The increased sensitivity of DU145J7 prostate cancer cells to chromatin modifying agents suggests a therapeutic vulnerability occurs after tumor cells invade into and through muscle. Future work will determine which epigenetic modifiers and what combinations will be most effective to eradicate early aggressive tumor populations.

Pyroptosis is involved in maternal nicotine exposure-induced metabolic associated fatty liver disease progression in offspring mice.

We have investigated whether inflammasomes and pyroptosis are activated in maternal nicotine exposure (MNE) offspring mice and whether they are involved in MNE-promoted metabolic associated fatty liver disease (MAFLD) in adult offspring. We injected pregnant mice subcutaneously with saline vehicle or nicotine twice a day on gestational days 11-21. Offspring mice from both groups were fed with a normal diet (ND) or a high-fat diet (HFD) for 6 months at postnatal day 21 to develop the MAFLD model. Serum biochemical indices were analyzed, and liver histology was performed. The expression levels of inflammasome and pyroptosis proteins were detected by western blot. We found MNE significantly aggravated the injury of MAFLD in adult offspring mice. MNE activated inflammasomes and pyroptosis in both infant and adult offspring mice. HFD treatment activated inflammasomes but not pyroptosis at 3 months, while it showed no effect at 6 months. However, pyroptosis was more severe in MNE-HFD mice than in MNE-ND mice at 6 months. Taken together, our data suggest MNE promotes MAFLD progression in adult offspring mice. MNE also induces NLRP3 and NLRP6 inflammasome activation and pyroptosis in both infant and adult offspring mice, which may be involved in MNE-promoted progression of MAFLD.

[Expression and prognostic value of IL-6 and ß-catenin in oral squamous cell carcinoma].

PURPOSE: To investigate the expression of interleukin-6 (IL-6) and ß-catenin in oral squamous cell carcinoma (OSCC) and its clinicopathological significance. METHODS: The serum IL-6 concentration in 110 OSCC patients and 109 healthy controls were determined by chemiluminescence analysis. IL-6 and ß-catenin expression levels in 68 tumor specimens of OSCC patients undergoing surgical treatment and 6 normal mucosal tissues were determined by immunohistochemistry method. The correlation between IL-6 and ß-catenin and clinicopathological parameters and their prognostic value were analyzed. SPSS 22.0 software package was used for data analysis. RESULTS: Chemiluminescence method showed that the serum IL-6 content of OSCC patients was significantly increased (P＜0.001). Immunohistochemical results demonstrated that high expression of IL-6 in OSCC tissues was remarkably associated with cervical lymph node metastasis(P=0.017), pathological differentiation(P=0.014), recurrence and distant metastasis (P=0.048). OSCC patients with high IL-6 expression showed a poor prognosis by Kaplan-Meier survival analysis. Multivariate Cox regression analysis showed that high expression of IL-6 was an independent risk factor affecting the prognosis of patients with OSCC(P＜0.05). ß-catenin hyperexpression was associated with pathological differentiation(P=0.006) and overall poor survival in OSCC patients. Spearman correlation analysis showed a positive correlation between IL-6 and ß-catenin expression in OSCC (P＜0.001). CONCLUSIONS: Serum IL-6 is expected to be a biomarker for detection of OSCC, and IL-6 and ß-catenin expression in tumour tissues can be used as markers to evaluate the poor prognosis of OSCC.

Lowered expression level of INSC predicts poor prognosis in patients with colon cancer.

The aim of this study was to investigate the prognostic value of inscuteable spindle orientation adaptor protein (INSC) in colon cancer (CC). Firstly, transcriptional change of INSC was analysed using the data from public databases. Next, INSC protein expression was assessed by immunohistochemistry. Its correlation with clinicopathological features and the prognostic values of patients were also investigated. Then, an INSC-based nomogram was built to predict CC prognosis. Compared to normal tissues, INSC was significantly downregulated at the transcriptional level in CC tissues. A low INSC mRNA level not only positively correlated with TNM stage (tumour-nodus-metastases), advanced T stage, and N stage, but also with the shorter 5- and 8-year overall survival (OS) and disease-specific survival. Concerning protein level, INSC downregulation was confirmed in CC samples. In terms of the correlation with N stage and 5- and 8-year OS, it was also consistent with mRNA levels. Cox regression analysis indicated that INSC protein expression was an independent prognostic factor for OS. The nomogram showed better prognostic accuracy and clinical net benefit for 5-year OS than TNM staging. Altogether, downregulation of INSC is related to inferior clinicopathological features and patient outcomes, and it may be a novel independent prognostic biomarker in CC.

MCP-4 and Eotaxin-3 Are Novel Biomarkers for Chronic Obstructive Pulmonary Disease.

The aim of our study was to examine the production of monocyte chemoattractant protein (MCP-4) and eotaxin-3 during the onset and progression of COPD. The expression levels of MCP-4 and eotaxin-3 were evaluated in COPD samples and healthy controls using immunostaining and ELISA. The relationship between the clinic pathological features in the participants and the expression of MCP-4 and eotaxin-3 were evaluated. The association of MCP-4/eotaxin-3 production in COPD patients was also determined. The results revealed enhanced production of MCP-4 and eotaxin-3 in COPD patients especially the cases with AECOPD in both bronchial biopsies and bronchial washing fluid samples. Furthermore, the expression signatures of MCP-4/eotaxin-3 show high AUC values in distinguishing COPD patients and healthy volunteers and AECOPD and stable COPD cases, respectively. Additionally, the number of MCP-4/eotaxin-3 positive cases was notably increased in AECOPD patients compared to those with stable COPD. Moreover, the expression of MCP-4 and eotaxin-3 was positively correlated in COPD and AECOPD cases. In addition, the levels of MCP-4 and eotaxin-3 could be increased in HBEs stimulated with LPS, which is a risk factor of COPD. Moreover, MCP-4 and eotaxin-3 may exert their regulatory functions in COPD by regulating CCR2, 3, and 5. These data indicated that MCP-4 and eotaxin-3 were potential markers for the clinical course of COPD, which could provide guidance for accurate diagnosis and treatment for this disease in future clinical practice.

A digital multimeter-based portable photoelectrochemical immunoassay for the detection of cardiac troponin I with enzymatic biocatalytic precipitation.

Early diagnosis of acute myocardial infarction (AMI) can significantly reduce mortality, which can be achieved by the highly sensitive detection of AMI-specific cardiac troponin I (cTnI) biomarkers. Herein a highly sensitive and portable photoelectrochemical (PEC) immunoassay for the detection of cTnI was innovatively fabricated based on an efficient photocurrent response of Cu2O coupling with a split-type enzymatic biocatalytic precipitation reaction with a digital multimeter readout. Initially, Cu2O cubic nanomaterials with a good photocurrent response were obtained by facile green room temperature synthesis and dropped on fluorine-doped tin oxide (FTO) plates as photoactive materials (Cu2O/FTO). In the presence of target cTnI, horseradish peroxidase (HRP) on the detection antibody catalyzes the substrate 4-chloro1-naphthol (4-CN) to produce insoluble precipitates of benzo-4-chlorohexadienone (4-CD) on Cu2O/FTO with the assistance of H2O2, resulting in a decrease in the photocurrent of the Cu2O/FTO electrode. To make the whole inspection process more concise and efficient, we used a flashlight and a digital multimeter as the excitation light source and reading device for the PEC sensing system, respectively. Under the optimal conditions of immunoreaction time, pH, and loading, the photocurrent of Cu2O/FTO decreased with increasing target cTnI concentration with a limit of detection (LOD) of 4.7 pg mL-1 in the operating range of 0.01-10 ng mL-1. It is of interest that the developed portable PEC immunoassay is also capable of detecting cTnI in human serum samples with acceptable accuracy compared to the reference cTnI enzyme-linked immunosorbent assay (ELISA) method while maintaining portability and sensitivity.

Dynamic Service Function Chain Deployment and Readjustment Method Based on Deep Reinforcement Learning.

With the advent of Software Defined Network (SDN) and Network Functions Virtualization (NFV), network operators can offer Service Function Chain (SFC) flexibly to accommodate the diverse network function (NF) requirements of their users. However, deploying SFCs efficiently on the underlying network in response to dynamic SFC requests poses significant challenges and complexities. This paper proposes a dynamic SFC deployment and readjustment method based on deep Q network (DQN) and M Shortest Path Algorithm (MQDR) to address this problem. We develop a model of the dynamic deployment and readjustment of the SFC problem on the basis of the NFV/SFC network to maximize the request acceptance rate. We transform the problem into a Markov Decision Process (MDP) and further apply Reinforcement Learning (RL) to achieve this goal. In our proposed method (MQDR), we employ two agents that dynamically deploy and readjust SFCs collaboratively to enhance the service request acceptance rate. We reduce the action space for dynamic deployment by applying the M Shortest Path Algorithm (MSPA) and decrease the action space for readjustment from two dimensions to one. By reducing the action space, we decrease the training difficulty and improve the actual training effect of our proposed algorithm. The simulation experiments show that MDQR improves the request acceptance rate by approximately 25% compared with the original DQN algorithm and 9.3% compared with the Load Balancing Shortest Path (LBSP) algorithm.

Is lymphatic invasion of microrectal neuroendocrine tumors an incidental event?: A case report.

BACKGROUND: A rectal neuroendocrine tumor (rNET) is a malignant tumor originating from neuroendocrine cells. Currently, tumor size is the primary basis for assessing tumor risk. CASE SUMMARY: This article reports the case of a 46-year-old male patient who underwent a colonoscopy that found a 3 mm rectal polypoid bulge. The pathological examination of a sample collected with biopsy forceps revealed a neuroendocrine tumor. Further endoscopic submucosal dissection rescue therapy was used. The presence of lymphatic vessels indicated that the tumor had infiltrated the negative resection margin. The lesion was located in the distal rectum near the anal canal. Therefore, to ensure the patient's quality of life, follow-up observation was conducted after full communication with the patient. No tumor recurrence or distant metastasis has been found during the 13-mo follow-up after surgery. CONCLUSION: Despite the presence of lymphatic invasion and extremely small diameter rNETs in our case, this phenomenon may not imply a higher risk of distant lymph node and organ metastasis.

Association of platelet-to-neutrophil ratios with 1-year outcome and mortality in patients with acute ischemic stroke.

BACKGROUND: Platelet-neutrophil crosstalk is being increasingly recognized as a driver of inflammation and thrombosis in patients with ischemic stroke. The aim of this study was to investigate the potential of PNR value in predicting the long-term prognosis and evaluate whether or not an available and routine blood cell biomarker could help predict the long-term neurological function and mortality in AIS patients. METHODS: A total of 718 patients with suspected acute ischemic stroke were involved and followed up for 1 year by standard telephone interview or reexamination. Kaplan-Meier curve, Univariate and Multivariate Cox Regression were analyzed using Statistical Packages for Social Sciences. RESULTS: ROC curve for PNR to evaluate 1-year outcomes was analyzed and the area under the curve (AUC) was 0.659 (P < 0.001). The cutoff point was observed at 38.30, with a sensitivity of 53.09 % and a specificity of 71.25 %. Moreover, patients in PNR ≤ 38.30 were more likely to have more serious NIHSS on admission, 1-year mRS and higher 1-year mortality (P < 0.001, respectively). The 1-year mortality in the low PNR group was significantly higher than that of the high PNR group (log-rank tests: P < 0.0001). Age, NIHSS, RBC and PNR were combined into model B which significantly increased the AUC value from 0.736 to 0.888 compared to model A (including Age, NIHSS and RBC). CONCLUSION: PNR may serve as a readily assessable biomarker for early predicting neurological deterioration and the long-term prognosis of AIS. The nomogram that included age, NIHSS, PNR and RBC may be a useful predictive tool for 1-year mortality.

PCDH20 inhibits esophageal squamous cell carcinoma proliferation and migration by suppression of the mitogen-activated protein kinase 9/AKT/ß-catenin pathway.

Aberrant protocadherins (PCDHs) expression trigger tumor invasion and metastasis. PCDH20 anti-tumor functions in various tumor have been identified. Tumor suppression is due to Wnt/ß-catenin pathway antagonism and may be suppressed caused by PCDH20 downregulation through promotor methylation, whereas PCDH20 effects and regulation mechanism in esophageal squamous cell carcinoma (ESCC) remains elusive. We analyzed PCDH20 effects on ESCC and underlying action mechanisms for PCDH20. We test PCDH20 expression in ESCC tissues and cells by semi-quantitative PCR (RT-PCR) and q-PCR (real-time quantitative polymerase chain reaction). MSP (methylation-specific PCR) was carried out to assess the methylation of PCDH20 in ESCC cells and tissues. Anti-tumor effects of PCDH20 in vitro were assessed by clone formation assay, CCK8 assay, Transwell assay, and flow cytometry. Nude mice tumorigenicity was used to assess PCDH20 anti-tumor effect in vivo. Online database, qPCR, and Western blotting were used to identify the downregulation of MAP3K9 by PCDH20, associated with AKT/ß-catenin signaling inactivation. We found that PCDH20 expression was dramatically attenuated in esophageal cancer tissues and cells, maybe due to promotor methylation, and ectopic PCDH20 expression suppressed ESCC malignant biological phenotypes. PCDH20 exerted anti-tumor effects by MAP3K9 downregulation, which suppressed AKT/ß-catenin signaling in ESCC cells. Conclusion: PCDH20 was a tumor suppressor gene, which antagonized AKT/ß-catenin signaling pathway in ESCC by decreasing MAP3K9.

Dietary glycemic index, glycemic load intake, and risk of lung cancer: A meta-analysis of observational studies.

This meta-analysis evaluated the relationship between dietary glycemic index (GI), glycemic load (GL), and lung cancer risk, which has been controversial in previous studies. We searched PubMed, Embase, Web of Science, and Cochrane Library databases for relevant studies from inception to October 2021 in English only. We included case-control and cohort studies that reported relative risks (RRs) and 95% confidence intervals (CI) between dietary GI or GL intake and lung cancer risk. Either a fixed- or random-effects model was used to estimate pooled RRs. Subgroup analysis, sensitivity analysis, meta-regression, publication bias test, and dose-response meta-analysis were performed. We identified nine studies eligible for meta-analysis with 32810 cases and 351013 controls. The pooled RR for highest versus lowest intake was 1.14 (95% CI: 1.03-1.26, I2=64.8%, P=0.002) for GI and 0.93 (95% CI: 0.84-1.02, I2=42.3%, P=0.076) for GL. Subgroup analysis showed that the associations between GI or GL and lung cancer were similar between groups. Sensitivity analysis revealed reduced heterogeneity among GL-related studies when one particular study was excluded. There was no evidence of publication bias. A linear association between GI intake and lung cancer risk was observed. The present meta-analysis suggests that high dietary GI intake is associated with a significantly increased risk of lung cancer in a linear fashion. However, no significant association was observed between GL and lung cancer risk.

Catalytic Asymmetric Benzylation of Azomethine Ylides Enabled by Synergistic Lewis Acid/Palladium Catalysis.

The synergistic chiral Lewis acid/achiral Pd catalyst system was successfully applied in the enantioselective benzylation of various imine esters, giving a range of α-benzyl-substituted α-amino acid derivatives in satisfactory yield with excellent enantioselectivity. It is worth noting that this strategy exhibits good tolerance for bicyclic and monocyclic benzylic electrophiles. Furthermore, the utility of this synthetic protocol was demonstrated by the expedient preparation of enantioenriched antihypertensive drug α-methyl-l-dopa.

Exercise-Mediated Alteration of miR-192-5p Is Associated with Cognitive Improvement in Alzheimer's Disease.

INTRODUCTION: Physical exercise is an important component of managing Alzheimer's disease (AD). miRNAs can be modulated by exercise intervention. OBJECTIVE: The study explored the involvement and potential mechanism of miR-192-5p in the protective effect of physical exercise on AD. METHODS: Ninety AD patients were enrolled, in which 45 cases accepted cycling training for continuous 3 months. The expression changes of miR-192-5p before and after exercise were analyzed by reverse transcription-quantitative PCR. 8-month-old APP/PS1 double Tg mice were used as the AD animal model. Mice in the voluntary exercise (VE) group received VE for 4 weeks. Morris water maze (MWM) test was used to evaluate the learning and memory function. Enzyme-linked immunosorbent assay was used to calculate the level of IL-1ß, IL-6, and TNF-α. RESULTS: AD patients showed elevated MMSE scores, decreased ADAS-cog and NPI-Q scores after 3 months of exercise. miR-192-5p was downregulated in the serum of AD patients and correlated with the levels of MMSE score, ADAS-cog, and NPI-Q score. A positive association was detected between serum miR-192-5p with TNF-α, IL-6, and IL-1ß levels. MiR-192-5p is downregulated in the hippocampus tissues of mice after VE. Overexpression of miR-192-5p reversed the neuroprotective effect of exercise on AD in mice and promoted the inflammatory response of AD mice. CONCLUSION: MiR-192-5p can be modulated by the exercise intervention and involved in the protective effect of exercise on AD.

Targeting Neuregulin 1 (NRG1): A Novel Biomarker for Non-Small-Cell Lung Cancer.

The aim of this study was to identify the roles of neuregulin 1 (NRG1) during the tumor progression in non-small-cell lung cancer (NSCLC). NSCLC patients with lung squamous cell carcinoma and lung adenocarci-noma were enrolled in this study. The expression of NRG1, vascular endothelial growth factor (VEGF) and surviving in clinical specimens was examined using immunohistochemistry analysis. The cytokine production in plasma was evaluated by ELISA. The levels of NRG1-associated molecules were determined using western blotting. The proliferation and apoptosis of cells with NRG1 knockdown were accessed by CCK-8 assay and flow cytometry. Upregulation of NRG1 as well as tumor-associated angiogenesis markers VEGF and survivin was detected in tissue and serum samples of NSCLC patients compared with the control. Furthermore, positive correlation with NSCLC levels and VEGF/survivin was also found in NSCLC specimens. In addition, upregulation of NRG1, VEGF and survivin was associated with poor overall survival in NSCLC patients. Moreover, enhanced production of NRG1 was detected in serum samples from NSCLC patients compared with healthy donors, and ROC analysis revealed the importance of NRG1 levels on distinguishing NSCLC samples and the controls. These findings suggested the novel diagnostic value of NRG1 in NSCLC. Additionally, upregulated protein levels of NRG1 and its target genes were also found in tissues samples of NSCLC patients compared with normal controls. These data indicated that NRG1 was a promising marker NSCLC, and it could be involved in tumor progression by targeting its downstream target including ErbB-Akt axis. Furthermore, the growth of lung cancer cells was suppressed by the knockdown of NRG1. Our findings could provide guidance for more accurate diagnosis for NSCLC, and future therapeutic approaches might be developed by better understanding of NRG-1-modulated molecular mechanisms during the tumor development in NSCLC.

Maternal nicotine exposure aggravates metabolic associated fatty liver disease via PI3K/Akt signaling in adult offspring mice.

AIM: The aim of this study is to investigate the effect of maternal nicotine exposure (MNE) on the development of metabolic associated fatty liver disease (MAFLD) in adulthood offspring and the underlying mechanism. METHODS: Pregnant mice (n = 22) were subcutaneously injected with either saline vehicle (n = 11) or nicotine (n = 11) twice a day on gestational days 11-21. Offspring mice (n = 176) from both groups were weaned at postnatal day 21, and for 6 months after postnatal day 21, 96 mice were fed either a standard chow diet (n = 48) or a high-fat diet (n = 48). Serum lipid indicators, liver function indicators, insulin, and liver mitochondrial respiration were analyzed. The expression levels of fibrosis-related proteins, phosphorylated PI3K, phosphorylated Akt, sterol regulatory element-binding transcription factor 1 (SREBP1c), and peroxisome proliferator-activated receptor alpha (PPAR-α) were detected in the liver by immunohistochemistry and Western blotting. RESULTS: MNE significantly decreased the weight of both maternal and offspring mice (~30%) and inhibited organ growth in offspring mice (P < .05). MNE also significantly increased serum levels of total bile acid, triglycerides, total cholesterol, glucose, alanine aminotransferase, aspartate aminotransferase, low-density lipoprotein, and insulin while decreasing serum high-density lipoprotein levels and mitochondrial respiration activity in mice fed either the normal diet or high-fat diet (all P < .05). These effects of MNE on lipid metabolism and insulin resistance were mediated via PI3K and Akt phosphorylation and down-regulation of SREBP1c and PPAR-α. CONCLUSION: Our data indicate MNE induces lipid metabolism disorder and insulin resistance to promote MAFLD progression in adult offspring through activation of PI3K/Akt signaling and suppression of SREBP1c and PPARα protein expression.

Seeking sustainable development policies at the municipal level based on the triad of city, economy and environment: evidence from Hunan province, China.

Keeping urbanization, economy and eco-environment in harmony is a core issue for attaining Sustainable Development Goals (SDGs) in any complex geographical regions. Previous studies mainly focused on seeking the balance between urban expansion levels, eco-environment quality and socioeconomic degree. But the challenges still exist in solving the negative influence of urban expansion that affects eco-environmental and economic development. Based on the Environmental Kuznets Curve theory, we involved inclusive indexes to analyze the interlinkages of eco-environment quality, economic level, and urban expansion degree, which closely relate to urban sustainable development goals and spatial complexity, as well as using available data corresponding to waterfront cities. Cities in Hunan were taken as a study-case, and the study period of 2006-2016 covers the last 10 years of the millennium development goals agenda and the first 2 years of SDGs agenda. The key indicators of city-economy-environment relationships were different at the provincial level, urban level and urbanization grade. According to the regression models and inverted N shape curve, urban expansion resulted in high positive effects on economic development level and negative effects on ecological environment quality, partically higher at high urbanization level than that of the low ones. But the overall trends were that the environmental quality of the cities was undergoing slowly improving processes both at low and high urban expansion levels. Promoting adaptations with the eco-environmental capacity when formulating policies and taking actions is necessary for realizing sustainable cities and communities (SDG11), life on land (SDG15), decent work and economic growth (SDG8) and responsible consumption and production (SDG12) at the same time. Regulating citizens' density, urban expansion speed in area, the quantity of enterprises with heavy pollution, and the structure of industry to the suitable urbanization stages is an important way for achieving SDGs at provincial and municipal levels.

LncRNA SUMO1P3 regulates the invasion, migration and cell cycle of gastric cancer cells through Wnt/ß-catenin signaling pathway.

OBJECTIVE: To investigate the regulatory effect of long non-coding RNA (lncRNA) SUMO1P3 on invasion, migration and cell cycle of gastric cancer (GC) cells through Wnt/ß-catenin signaling pathway. METHODS: Tumor tissues and adjacent normal tissues from the GC patients were collected, and human normal gastric epithelial cells GES1 and GC cells SGC-7901, MKN45, HGC-27 and AGS were selected for study. The expression of SUMO1P3 in GC tissues and cells were detected by RT-qPCR. The effects of SUMO1P3 on the proliferation, invasion and migration of SGC-7901 and MKN45 cells were detected by CCK-8, transwell and wound healing assay respectively, and the effects of SUMO1P3 on apoptosis and cycle progression of SGC-7901 and MKN45 cells were detected by flow cytometry. The expressions of Wnt/ß-catenin pathway-related and cell cycle-related proteins were detected by Western blot. RESULTS: The expression of SUMO1P3 was significantly upregulated in GC tissues and cell lines. Downregulation of SUMO1P3 significantly inhibited the SGC-7901 and MKN45 cell proliferation, invasion, migration, and cycle progression and promoted the cell apoptosis, while overexpression of SUMO1P3 showed the opposite effect. Further study showed that downregulation of SUMO1P3 significantly reduced the expressions of Wnt1, ß-catenin, c-myc, and Cyclin D1 in SGC-7901 and MKN45 cells. CONCLUSION: SUMO1P3 may promote invasion, migration, and cycle progression of SGC-7901 and MKN45 cells by enhancing the Wnt/ß-catenin pathway.