ABSTRACT
Tumor-initiating cells (TICs) resilience and an immunosuppressive microenvironment are aggressive oncogenic phenotypes that contribute to unsatisfactory long-term outcomes in lung adenocarcinoma (LUAD) patients. The molecular mechanisms mediating the interaction between TICs and immune tolerance have not been elucidated. The role of Galectin-9 in oncogenesis and immunosuppressive microenvironment is still unknown. This study explored the potential role of galectin-9 in TIC regulation and immune modulation in LUAD. The results show that galectin-9 supports TIC properties in LUAD. Co-culture of patient-derived organoids and matched peripheral blood mononuclear cells showed that tumor-secreted galectin-9 suppressed T cell cytotoxicity and induced regulatory T cells (Tregs). Clinically, galectin-9 is upregulated in human LUAD. High expression of galectin-9 predicted poor recurrence-free survival and correlated with high levels of Treg infiltration. LGALS9, the gene encoding galectin-9, is found to be transcriptionally regulated by the nuclear factor of activated T cells 2 (NFATc2), a previously reported TIC regulator, via in silico prediction and luciferase reporter assays. Overall, the results suggest that the NFATc2/galectin-9 axis plays a dual role in TIC regulation and immune suppression.
Subject(s)
Adenocarcinoma of Lung , Galectins , Lung Neoplasms , NFATC Transcription Factors , Neoplastic Stem Cells , Humans , Adenocarcinoma of Lung/immunology , Adenocarcinoma of Lung/genetics , Adenocarcinoma of Lung/pathology , Adenocarcinoma of Lung/metabolism , Cell Line, Tumor , Galectins/genetics , Galectins/metabolism , Galectins/immunology , Lung Neoplasms/immunology , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Neoplastic Stem Cells/immunology , Neoplastic Stem Cells/metabolism , NFATC Transcription Factors/metabolism , NFATC Transcription Factors/genetics , Phenotype , Tumor MicroenvironmentABSTRACT
Glutathione S-transferase pi (GSTP1), a phase II detoxification enzyme, is known to be overexpressed and mediates chemotherapeutic resistance in lung cancer. However, whether GSTP1 supports cancer stem cells (CSCs) and the underlying mechanisms in lung adenocarcinoma (LUAD) remain largely unknown. This study unveiled that GSTP1 is upregulated in lung CSCs and supports tumor self-renewal, metastasis, and resistance to targeted tyrosine kinase inhibitors of LUAD both in vitro and in vivo. Mechanistically, CaMK2A (calcium/calmodulin-dependent protein kinase 2 isoform A)/NRF2 (nuclear factor erythroid 2-related factor 2)/GSTP1 is uncovered as a regulatory axis under hypoxia. CaMK2A increased GSTP1 expression through phosphorylating the Sersine558 residue of NRF2 and promoting its nuclear translocation, a novel mechanism for NRF2 activation apart from conventional oxidization-dependent activation. Upregulation of GSTP1 in turn suppressed reactive oxygen species levels and supported CSC phenotypes. Clinically, GSTP1 analyzed by immunohistochemistry is upregulated in a proportion of LUAD and serves as a prognostic marker for survival. Using patient-derived organoids from an ALK-translocated LUAD, the therapeutic potential of a specific GSTP1 inhibitor ezatiostat in combination treatment with the ALK inhibitor crizotinib is demonstrated. This study demonstrates GSTP1 to be a promising therapeutic target for long-term control of LUAD through targeting CSCs.
Subject(s)
Adenocarcinoma of Lung , Lung Neoplasms , Humans , Glutathione S-Transferase pi/genetics , Glutathione S-Transferase pi/metabolism , NF-E2-Related Factor 2 , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Adenocarcinoma of Lung/drug therapy , Receptor Protein-Tyrosine KinasesABSTRACT
Clear cell renal cell carcinoma (ccRCC) accounts for 80% of renal cell carcinomas (RCCs), and its morbidity and prognosis are unfavorable. Surgical resection is the first-line treatment for ccRCC, but the oncogenesis of ccRCC is very complex. With the development of high-throughput sequencing technology, it is necessary to analyze the transcriptome to determine more effective treatment methods. The tumor microenvironment (TME) is composed of tumor cells, various immune-infiltrating cells, fibroblasts, many cytokines, and catalysts. It is a complex system with a dynamic balance that plays an essential role in tumor growth, invasion, and metastasis. Previous studies have confirmed that potassium channels can affect the immune system, especially T lymphocytes that require potassium channel activation. However, the effect of potassium channels on the TME of ccRCC remains to be studied. Therefore, this study aims to construct a prognostic signature for ccRCC patients based on potassium ion channel-related genes (PCRGs), assess patient risk scores, and divide patients into high- and low-risk groups based on the cutoff value. In addition, we investigated whether there were differences in immune cell infiltration, immune activator expression, somatic mutations, and chemotherapeutic responses between the high- and low-risk groups. Our results demonstrate that the PCRG signature can accurately assess patient prognosis and the tumor microenvironment and predict chemotherapeutic responses. In summary, the PCRG signature could serve as an auxiliary tool for the precision treatment of ccRCC.
ABSTRACT
Optogenetics has become a widely used technique in neuroscience research, capable of controlling neuronal activity with high spatiotemporal precision and cell-type specificity. Expressing exogenous opsins in the selected cells can induce neuronal activation upon light irradiation, and the activation depends on the power of incident light. However, high optical power can also lead to off-target neuronal activation or even cell damage. Limiting the incident power, but enhancing power distribution to the targeted neurons, can improve optogenetic efficiency and reduce off-target effects. Here, the use of optical lenses made of polystyrene microspheres is demonstrated to achieve effective focusing of the incident light of relatively low power to neighboring neurons via photonic jets. The presence of microspheres significantly localizes and enhances the power density to the target neurons both in vitro and ex vivo, resulting in increased inward current and evoked action potentials. In vivo results show optogenetic stimulation with microspheres that can evoke significantly more motor behavior and neuronal activation at lowered power density. In all, a proof-of-concept of a strategy is demonstrated to increase the efficacy of optogenetic neuromodulation using pulses of reduced optical power.
Subject(s)
Opsins , Optogenetics , Action Potentials , Neurons/physiology , Optogenetics/methods , PhotonsABSTRACT
Objective: The beneficial effect of angiotensin(1-7) (Ang(1-7)), via the activation of its receptor, MAS-1, has been noted in diabetes treatment; however, how Ang(1-7) or MAS-1 affects insulin secretion remains elusive and whether the endogenous level of Ang(1-7) or MAS-1 is altered in diabetic individuals remains unexplored. We recently identified an important role of cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated Cl- channel, in the regulation of insulin secretion. Here, we tested the possible involvement of CFTR in mediating Ang(1-7)'s effect on insulin secretion and measured the level of Ang(1-7), MAS-1 as well as CFTR in the blood of individuals with or without type 2 diabetes. Methods: Ang(1-7)/MAS-1/CFTR pathway was determined by specific inhibitors, gene manipulation, Western blotting as well as insulin ELISA in a pancreatic ß-cell line, RINm5F. Human blood samples were collected from 333 individuals with (n = 197) and without (n = 136) type 2 diabetes. Ang(1-7), MAS-1 and CFTR levels in the human blood were determined by ELISA. Results: In RINm5F cells, Ang(1-7) induced intracellular cAMP increase, cAMP-response element binding protein (CREB) activation, enhanced CFTR expression and potentiated glucose-stimulated insulin secretion, which were abolished by a selective CFTR inhibitor, RNAi-knockdown of CFTR, or inhibition of MAS-1. In human subjects, the blood levels of MAS-1 and CFTR, but not Ang(1-7), were significantly higher in individuals with type 2 diabetes as compared to those in non-diabetic healthy subjects. In addition, blood levels of MAS-1 and CFTR were in significant positive correlation in type-2 diabetic but not non-diabetic subjects. Conclusion: These results suggested that MAS-1 and CFTR as key players in mediating Ang(1-7)-promoted insulin secretion in pancreatic ß-cells; MAS-1 and CFTR are positively correlated and both upregulated in type 2 diabetes.
ABSTRACT
Endoplasmic reticulum (ER) stress, with adaptive unfolded protein response (UPR), is a key link between obesity, insulin resistance and type 2 diabetes, all of which are often present in the most common endocrine-metabolic disorder in women of reproductive age, polycystic ovary syndrome (PCOS), which is characterized with hyperandrogenism. However, the link between excess androgen and endoplasmic reticulum (ER) stress/insulin resistance in patients with polycystic ovary syndrome (PCOS) is unknown. An unexpected role of kisspeptin was reported in the regulation of UPR pathways and its involvement in the androgen-induced ER stress in hypothalamic neuronal cells. To evaluate the relationship of kisspeptin and ER stress, we detected kisspeptin and other factors in blood plasm of PCOS patients, rat models and hypothalamic neuronal cells. We detected higher testosterone and lower kisspeptin levels in the plasma of PCOS than that in non-PCOS women. We established a PCOS rat model by dihydrotestosterone (DHT) chronic exposure, and observed significantly downregulated kisspeptin expression and activated UPR pathways in PCOS rat hypothalamus compared to that in controls. Inhibition or knockdown of kisspeptin completely mimicked the enhancing effect of DHT on UPR pathways in a hypothalamic neuronal cell line, GT1-7. Kp10, the most potent peptide of kisspeptin, effectively reversed or suppressed the activated UPR pathways induced by DHT or thapsigargin, an ER stress activator, in GT1-7 cells, as well as in the hypothalamus in PCOS rats. Similarly, kisspeptin attenuated thapsigargin-induced Ca2+ response and the DHT- induced insulin resistance in GT1-7 cells. Collectively, the present study has revealed an unexpected protective role of kisspeptin against ER stress and insulin resistance in the hypothalamus and has provided a new treatment strategy targeting hypothalamic ER stress and insulin resistance with kisspeptin as a potential therapeutic agent.
Subject(s)
Endoplasmic Reticulum Stress/genetics , Kisspeptins/blood , Neurons/metabolism , Polycystic Ovary Syndrome/genetics , Androgens/adverse effects , Animals , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/pathology , Disease Models, Animal , Endoplasmic Reticulum/metabolism , Endoplasmic Reticulum/pathology , Female , Hypothalamus/metabolism , Hypothalamus/pathology , Insulin Resistance/genetics , Kisspeptins/genetics , Neurons/pathology , Obesity/metabolism , Obesity/pathology , Polycystic Ovary Syndrome/blood , Polycystic Ovary Syndrome/pathology , Rats , Testosterone/blood , Unfolded Protein Response/geneticsABSTRACT
Ferric-carbon micro-electrolysis fillers and zeolite have been increasingly used as substrates in constructed wetlands due to their good wastewater pollution-removal efficiencies. To explore the effects of different fillers on wastewater treatment in constructed wetlands, four constructed wetlands were examined with vertical subsurface flow areas filled with ferric-carbon micro-electrolysis filler+gravel (CW-A), ferric-carbon micro-electrolysis filler+zeolite (CW-B), zeolite (CW-C), and gravel (CW-D). In addition, intermittent aeration was used to improve the dissolved oxygen (DO) environment. The results showed that, compared with CW-D, the ferric-carbon micro-electrolysis filler significantly increased the dissolved oxygen (DO, P<0.05) and pH (P<0.05) of the effluent from the wetlands. The mean removal efficiency of chemical oxygen demand (COD) in the four constructed wetlands were more than 95% (P>0.05). For TN, the mean removal efficiency of CW-A,-B, and-C was 7.94% (P<0.05), 9.29% (P<0.05), and 3.63% (P<0.05) higher than that of CW-D, respectively. The contribution of ferric-carbon micro-electrolysis filler and zeolite to improving the TN removal efficiency of the constructed wetlands was 73.55% and 26.45%, respectively. The mean removal efficiency of NH4+ in the four wetlands ranged from 67.93% to 76.90%, and compared with CW-D, the other treatments significantly improved the removal efficiency of NH4+ (P<0.05). The ferric-carbon micro-electrolysis filler had an excellent removal effect on NO3-, with a removal efficiency of more than 99%, which was significantly higher than the constructed wetlands without ferric-carbon micro-electrolysis (P<0.05). Considering the treatment effect of the organic pollutants and the nitrogen-containing pollutants, CW-B achieved the best removal efficiency in constructed wetlands with intermittent aeration.
ABSTRACT
Investigate the effects of plastic film mulching on CH4 and N2O emissions from a vegetable field, a one-year in situ field observation was conducted using a static opaque chamber in a pepper-radish cropping system at the Key Field Station for Monitoring of Eco-Environment of Purple Soil of the Ministry of Agriculture of China at Southwest University, Chongqing. Two treatments (conventional and film mulching) were used to study the influence of film mulching on CH4 and N2O emissions. The results showed that mulching significantly increased the annual average soil pH (P<0.01), annual surface and subsurface (5 cm) temperature (P<0.05), and soil moisture content during the radish-growing season (P<0.05). The mulching also significantly reduced CH4 emissions in the field ridges (P<0.05); the average CH4 flux from ridges during the pepper-growing season was 0.110 mg·(m2·h)-1 and 0.028 mg·(m2·h)-1, and 0.011 mg·(m2·h)-1 and -0.019 mg·(m2·h)-1 during the radish-growing season, under the conventional and film mulching treatments, respectively. However, across the entire experiment, CH4 flux from field furrows was not significantly different between the two mulching treatments (P>0.05), with mean flux values during the pepper-growing season of 0.058 mg·(m2·h)-1 and 0.057 mg·(m2·h)-1, and 0.083 mg·(m2·h)-1 and 0.092 mg·(m2·h)-1 during the radish-growing season, for conventional and plastic film mulching, respectively. Except for the conventional treatment during the pepper-growing season, CH4 emissions from ridges were significantly higher than from furrows, but for other treatments, including conventional and film mulching treatments during radish-growing season and film mulching treatment during the pepper-growing season, the CH4 emissions from furrows were all significantly higher than those from ridges. This was related to the stable anoxic environment created in furrows under high rainfall conditions in Southwest China. The N2O emission flux from the ridges during the pepper-growing season was 65.41 µg·(m2·h)-1 and 68.39 µg·(m2·h)-1 under the conventional and film mulching treatments, respectively, and the N2O emission flux during the radish-growing season was 78.43 µg·(m2·h)-1 and 66.19 µg·(m2·h)-1, respectively. The N2O flux between conventional treatment and film mulching treatment in ridges or furrows were not significantly different (P>0.05), while the N2O emissions from the ridges were significantly higher than that from the furrows. CH4 emission flux was significantly positively correlated with surface and subsurface temperature, while N2O emission flux was only significantly positively correlated with alkaline nitrogen and ammonium nitrogen content.
ABSTRACT
The abnormal proliferation of vascular smooth muscle cells (VSMCs) is crucial in the atherosclerosis. Although long noncoding RNAs (lncRNAs) are implicated in a variety of diseases, their roles in activation of VSMCs proliferation and vascular disorder diseases are not well understood. In addition, heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2/B1) was reported to participate in lncRNAs-mediated function. Herein, we propose to investigate the role of lncRNA AC105942.1 and hnRNPA2/B1 in pathological VSMCs proliferation and the possible mechanisms in vitro. We have identified that lncRNA AC105942.1 was downregulated and hnRNPA2/B1 was upregulated in atherosclerotic plaques compared with normal artery tissues. Enhanced lncRNA AC105942.1 could noticeably inhibit Ang II-induced VSMCs proliferation. Further investigation suggested that lncRNA AC105942.1 could downregulate the expression of hnRNPA2/B1 and then regulate the level of CDK4 and p27. Taken together, our study indicated that lncRNA AC105942.1 downregulated hnRNPA2B1 to protect against the atherosclerosis by suppressing VSMCs proliferation. LncRNA AC105942.1 and hnRNPA2/B1 could represent potential therapeutic and diagnostic targets to atherosclerosis-related diseases.
Subject(s)
Down-Regulation/genetics , Heterogeneous-Nuclear Ribonucleoprotein Group A-B/genetics , Muscle, Smooth, Vascular/cytology , Myocytes, Smooth Muscle/cytology , Myocytes, Smooth Muscle/metabolism , RNA, Long Noncoding/metabolism , Angiotensin II , Cell Proliferation/genetics , Gene Knockdown Techniques , Heterogeneous-Nuclear Ribonucleoprotein Group A-B/metabolism , Humans , Models, Biological , Plaque, Atherosclerotic/genetics , Plaque, Atherosclerotic/pathology , RNA, Long Noncoding/geneticsABSTRACT
To understand the atmospheric quality of the Beibei District of Chongqing, using the simultaneous observation data of aerosol optical depth and particulate matter concentration in 2014, we analyzed the characteristics of aerosol optical depth (AOD) in the urban area of Beibei and its correlation with particle concentration. The results showed that the annual average of AOD500nm in Beibei District is 1.46±0.69, which varies significantly by month. The highest value in November was 2.90±1.85, and the lowest in September was 0.54±0.05. There is particulate matter pollution in Beibei District. The annual average values of PM2.5 and PM10 are (62±40)µg·m-3 and (94±51)µg·m-3, respectively, which exceed the secondary standard of GB 3095-2012 Ambient Air Quality Standard. The limit values, the daily average over-standard rates of PM2.5 and PM10, are 26% and 15%, respectively. There was significant correlation between fine particle PM2.5 and PM10 concentration of respirable particulate matter. The annual coefficient of determination R2 could reach 0.95 (P<0.01). The correlation between AOD and PM2.5 and PM10 was positive throughout the year. The coefficient of determination R2 was 0.48 and 0.46, respectively, and the coefficient of determination and correlation function were different in different seasons, among which the correlation in winter was the best and the correlation in summer was the worst. AOD and air quality index showed positive correlation characteristics throughout the year, and the coefficient of determination R2 was 0.15 (P<0.05). The AOD value was affected by the comprehensive effects of weather elements. The temperature, humidity, water vapor, and other factor data should also be collected synchronously during the observation period.
ABSTRACT
BACKGROUND: Streptococcus agalactiae (GBS) is the causative pathogen of puerperal sepsis in pregnant women and pneumonia, sepsis and meningitis in infants. Infection of GBS is responsible for the increased morbidity in pregnant women and the elderly, and bring challenges to clinical diagnosis and treatment. However, culture-based approaches to detect S.agalactiae is time-consuming with limited sensitivity. Besides, real-time quantitative PCR demands expensive instruments with tedious steps. Thus, we aim to establish a new detection method for more accurate and rapid detection of S.agalactiae. RESULTS: The ddPCR primer targeted the CpsE gene showed better amplified efficiency in the reaction. The limit of detection for GBS DNA with ddPCR was able to reach 5 pg/µL. Moreover, no positive amplified signals could be detected in the reactions which served 11 non-GBS strains DNA as templates. Furthermore, the coefficient of variation of this method was 4.5%, indicating excellent repeatability of ddPCR assay. CONCLUSIONS: In our study, ddPCR was performed as a rapid detection of S.agalactiae with high sensitivity and specificity. This technique can promote the accuracy of the diagnosis of GBS infection and provide a scientific basis for clinical treatment.
Subject(s)
Bacterial Proteins/genetics , Polymerase Chain Reaction/methods , Streptococcal Infections/diagnosis , Streptococcus agalactiae/isolation & purification , DNA Primers/genetics , Early Diagnosis , Humans , Limit of Detection , Streptococcus agalactiae/geneticsABSTRACT
Rationale: Abnormal Wnt/ß-catenin signaling in the endometrium can lead to both embryo implantation failure and severe pathogenic changes of the endometrium such as endometrial cancer and endometriosis. However, how Wnt/ß-catenin signaling is regulated in the endometrium remains elusive. We explored possible regulation of Wnt/ß-catenin signaling by multi-drug resistance protein 4 (MRP4), a potential target in cancer chemotherapy, and investigated the mechanism. Methods: Knockdown of MRP4 was performed in human endometrial cells in vitro or in a mouse embryo-implantation model in vivo. Immunoprecipitation, immunoblotting and immunofluorescence were used to assess protein interaction and stability. Wnt/ß-catenin signaling was assessed by TOPflash reporter assay and quantitative PCR array. Normal and endometriotic human endometrial tissues were examined. Data from human microarray or RNAseq databases of more than 100 participants with endometriosis, endometrial cancer or IVF were analyzed. In vitro and in vivo tumorigenesis was performed. Results: MRP4-knockdown, but not its transporter-function-inhibition, accelerates ß-catenin degradation in human endometrial cells. MRP4 and ß-catenin are co-localized and co-immunoprecipitated in mouse and human endometrium. MRP4-knockdown in mouse uterus reduces ß-catenin levels, downregulates a series of Wnt/ß-catenin target genes and impairs embryo implantation, which are all reversed by blocking ß-catenin degradation. Analysis of human endometrial biopsy samples and available databases reveals significant and positive correlations of MRP4 with ß-catenin and Wnt/ß-catenin target genes in the receptive endometrium in IVF, ectopic endometriotic lesions and endometrial cancers. Knockdown of MRP4 also inhibits in vitro and in vivo endometrial tumorigenesis. Conclusion: A previously undefined role of MRP4 in stabilizing ß-catenin to sustain Wnt/ß-catenin signaling in endometrial cells is revealed for both embryo implantation and endometrial disorders, suggesting MRP4 as a theranostic target for endometrial diseases associated with Wnt/ß-catenin signaling abnormality.
Subject(s)
Endometrial Neoplasms/metabolism , Endometriosis/metabolism , Multidrug Resistance-Associated Proteins/metabolism , Pregnancy/metabolism , Wnt Signaling Pathway , Adult , Animals , Cell Line, Tumor , Endometrium/metabolism , Female , Humans , Mice , Mice, Inbred ICR , Mice, Nude , Multidrug Resistance-Associated Proteins/genetics , beta Catenin/metabolismABSTRACT
OBJECTIVE: To measure blood and follicular antimüllerian hormone (AMH) levels in women with polycystic ovary syndrome (PCOS) undergoing assisted reproductive technologies (ART) and to examine the direct action of insulin on AMH expression in human granulosa cells. DESIGN: Prospective clinical and experimental study. SETTING: University Hospital-based laboratory. PATIENT(S): Women with (n = 86) and without (n = 172) PCOS in ART. INTERVENTION(S): Blood, follicular fluid, and luteinized granulosa cells were collected from PCOS and non-PCOS women in ART. MAIN OUTCOME MEASURE(S): Hormone levels in blood and fluid, and gene expression in granulosa cells. RESULT(S): Serum levels of AMH were elevated and inversely correlated with embryo cleavage rate in PCOS women in ART. Significant higher levels of AMH were also found in small and large follicles collected from PCOS women compared with non-PCOS women. Luteinized granulosa cells from PCOS women showed higher expression of AMH and its receptor AMHR2. Direct effect of insulin in increasing the expression of AMH in the isolated luteinized granulosa cells was observed, with the PCOS granulosa cells responding to a high dose of insulin. Cotreatment with AMH attenuated insulin-induced aromatase expression in the luteinized granulosa cells. CONCLUSION(S): These results suggest that insulin may contribute to AMH elevation in PCOS and that AMH counteracts insulin-promoted aromatase expression in granulosa cells.
Subject(s)
Anti-Mullerian Hormone/metabolism , Granulosa Cells/metabolism , Insulin/administration & dosage , Polycystic Ovary Syndrome/metabolism , Reproductive Techniques, Assisted , Adult , Anti-Mullerian Hormone/blood , Biomarkers/blood , Biomarkers/metabolism , Cells, Cultured , Dose-Response Relationship, Drug , Female , Granulosa Cells/drug effects , Humans , Ovulation Induction/methods , Ovulation Induction/trends , Polycystic Ovary Syndrome/diagnosis , Prospective Studies , Reproductive Techniques, Assisted/trends , Young AdultABSTRACT
Aim: Particulate matter 2.5 (PM2.5) exposure is high risk to cardiovascular diseases. We investigated the influence of PM2.5 exposure on pulmonary arterial hypertension (PAH) murine model induced by left ventricular (LV) failure. Methods: Thirty 10 weeks old C57BL/6 mice were randomised to four groups: sham group, sham + PM2.5 group, TAC group, and TAC + PM2.5 group. Eight weeks post TAC surgery, right ventricular (RV) and lung remodelling (Sirius Red staining and WGA Staining), heart and lung function (EF and RVSBP), and fibrotic genes (TGF-ti mRNA expression and collagen III protein level in lung tissue were measured. Results: Exposure to PM2.5 augments TAC induced PAH as evidenced by decreased EF value and increased RVSBP, RV cardiomyocytes size, RV and lung fibrosis, and upregulated expression of collagen III and TGF-a in comparison to TAC group in lung tissues. Even the LV EF value was deceased from 79.3 ± 3.4% to 63.4 ± 2.1% when sham group exposed to PM2.5, PM2.5 exposure had no effect on RVSBP, RV cardiomyocytes' size, RV weight/tibia length, RV and lung fibrosis, and expression of collagen III and TGF-a in sham surgery mice. Conclusions: Exposure to PM2.5 aggravates deterioration of LV failure induced PAH.
Subject(s)
Air Pollutants/toxicity , Air Pollution/adverse effects , Arterial Pressure , Heart Failure/complications , Particulate Matter/toxicity , Pulmonary Arterial Hypertension/etiology , Pulmonary Artery/physiopathology , Ventricular Dysfunction, Left/complications , Ventricular Function, Left , Animals , Collagen Type III/metabolism , Disease Models, Animal , Disease Progression , Heart Failure/physiopathology , Hypertrophy, Right Ventricular/etiology , Hypertrophy, Right Ventricular/physiopathology , Inhalation Exposure , Lung/metabolism , Lung/pathology , Mice, Inbred C57BL , Pulmonary Arterial Hypertension/physiopathology , Pulmonary Fibrosis/etiology , Pulmonary Fibrosis/metabolism , Pulmonary Fibrosis/pathology , Transforming Growth Factor beta/metabolism , Ventricular Dysfunction, Left/physiopathologyABSTRACT
The shift of cytokine profile from anti- to pro-inflammatory is the most recognizable sign of labor, although the underlying mechanism remains elusive. Here, we report that the epithelial sodium channel (ENaC) is upregulated and activated in the uterus at labor in mice. Mechanical activation of ENaC results in phosphorylation of CREB and upregulation of pro-inflammatory cytokines as well as COX-2/PGE2 in uterine epithelial cells. ENaC expression is also upregulated in mice with RU486-induced preterm labor as well as in women with preterm labor. Interference with ENaC attenuates mechanically stimulated uterine contractions and significantly delays the RU486-induced preterm labor in mice. Analysis of a human transcriptome database for maternal-fetus tissue/blood collected at onset of human term and preterm births reveals significant and positive correlation of ENaC with labor-associated pro-inflammatory factors in labored birth groups (both term and preterm), but not in non-labored birth groups. Taken together, the present finding reveals a pro-inflammatory role of ENaC in labor at term and preterm, suggesting it as a potential target for the prevention and treatment of preterm labor.
Subject(s)
Cytokines/metabolism , Epithelial Cells/metabolism , Epithelial Sodium Channels/metabolism , Labor, Obstetric , Animals , Female , Gene Expression Profiling , Humans , Mice , Models, Animal , Pregnancy , Uterus/physiologyABSTRACT
Multi-drug resistance protein 4 (MRP4), a potential chemotherapeutic target as well as a transporter for endogenous signaling molecules (e.g. prostaglandins), is known to be expressed in the endometrium, although its possible role(s) in the physiology of the endometrium remains unknown. Here, we show that MRP4 is upregulated at implantation window and localized to the basolateral membrane of the endometrial epithelium, the interface between the epithelium and stroma in mice. In human endometrial epithelial cells, MRP4 expression is upregulated by ENaC activation and the inhibition of MRP4 blocks ENaC-dependent PGE2 release as well as phosphorylation of CREB. Intrauterine injection of MRP4 inhibitor in mice prior to implantation significantly downregulated implantation markers COX-2, Claudin4 and Lif, and reduced implantation rate. These results in together have revealed a previously undefined role of MRP4 in mediating ENaC-dependent CREB/COX-2/PGE2 signaling essential to embryo implantation with implication in cancer progression as well.
ABSTRACT
Cystic fibrosis transmembrane conductance regulator (CFTR), known as a cAMP-activated Cl- channel, is widely expressed at the apical membrane of epithelial cells in a wide variety of tissues. Of note, despite the abundant expression of CFTR in mammalian kidney, the role of CFTR in kidney disease development is unclear. Here, we report that CFTR expression is downregulated in the UUO (unilateral ureteral obstruction)-induced kidney fibrosis mouse model and human fibrotic kidneys. Dysfunction or downregulation of CFTR in renal epithelial cells leads to alteration of genes involved in Epithelial-Mesenchymal Transition (EMT) and kidney fibrosis. In addition, dysregulation of CFTR activates canonical Wnt/ß-catenin signaling pathways, whereas the ß-catenin inhibitor reverses the effects of CFTR downregulation on EMT marker. More interestingly, CFTR interacts with Dishevelled 2 (Dvl2), a key component of Wnt signaling, thereby suppressing the activation of ß-catenin. Compared to wild type, deltaF508 mice with UUO treatment exhibit significantly higher ß-catenin activity with aggregated kidney fibrogenesis, which is reduced by forced overexpression of CFTR. Taken together, our study reveals a novel mechanism by which CFTR regulates Wnt/ß-catenin signaling pertinent to progression of kidney fibrosis and indicates a potential treatment target.
Subject(s)
Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Fibrosis/pathology , Kidney Diseases/pathology , Mutation , beta Catenin/metabolism , Animals , Cystic Fibrosis Transmembrane Conductance Regulator/antagonists & inhibitors , Cystic Fibrosis Transmembrane Conductance Regulator/metabolism , Epithelial Cells , Epithelial-Mesenchymal Transition , Female , Fibrosis/genetics , Fibrosis/metabolism , Humans , Kidney Diseases/genetics , Kidney Diseases/metabolism , Male , Mice , Mice, Inbred C57BL , Wnt Signaling Pathway , beta Catenin/geneticsABSTRACT
OBJECTIVE: To design and develop new types of health education materials which are suitable for fishermen and boatmen in endemic areas of marshland and lake regions, and to observe their application effects. METHODS: A total of 292 adult fishmen and boatmen who lived in Houshan Village, Yugan County, the schistosomiasis endemic area of Poyang Lake Region, were selected randomly and investigated by questionnaires to understand the status of their knowledge, attitudes, practices on schistosomiasis control as well as the channels for getting information on schistosomiasis control and the materials that they were willing to accept. Then the information and materials suitable for the target population were developed together by the researchers and the volunteers of the villagers through focus group discussions, personal interviews and the Delphi method. RESULTS: A series of participatory health education materials of schistosomiasis control targeted to the fishmen and boatmen were developed, including 2 live posters, 2 picture puzzles, 2 short opusculums and one song about schistosomiasis control. The field application showed that 98.97%, 84.38%, 78.35% and 80.93% of the participants considered those materials had scientificity, intelligibility, interestingness and practicability, respectively. CONCLUSION: The participatory health education materials of schistosomiasis control is suitable for fishmen and boatmen, which can be used for reference by other endemic areas in marshland and lake regions.