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BACKGROUND: The pathogenesis of acute lung injury (ALI) involves a severe inflammatory response, leading to significant morbidity and mortality. N6-methylation of adenosine (m6A), an abundant mRNA nucleotide modification, plays a crucial role in regulating mRNA metabolism and function. However, the precise impact of m6A modifications on the progression of ALI remains elusive. METHODS: ALI models were induced by either intraperitoneal injection of lipopolysaccharide (LPS) into C57BL/6 mice or the LPS-treated alveolar type II epithelial cells (AECII) in vitro. The viability and proliferation of AECII were assessed using CCK-8 and EdU assays. The whole-body plethysmography was used to record the general respiratory functions. M6A RNA methylation level of AECII after LPS insults was detected, and then the "writer" of m6A modifications was screened. Afterwards, we successfully identified the targets that underwent m6A methylation mediated by METTL3, a methyltransferase-like enzyme. Last, we evaluated the regulatory role of METTL3-medited m6A methylation at phosphatase and tensin homolog (Pten) in ALI, by assessing the proliferation, viability and inflammation of AECII. RESULTS: LPS induced marked damages in respiratory functions and cellular injuries of AECII. The m6A modification level in mRNA and the expression of METTL3, an m6A methyltransferase, exhibited a notable rise in both lung tissues of ALI mice and cultured AECII cells subjected to LPS treatment. METTL3 knockdown or inhibition improved the viability and proliferation of LPS-treated AECII, and also reduced the m6A modification level. In addition, the stability and translation of Pten mRNA were enhanced by METTL3-mediated m6A modification, and over-expression of PTEN reversed the protective effect of METTL3 knockdown in the LPS-treated AECII. CONCLUSIONS: The progression of ALI can be attributed to the elevated levels of METTL3 in AECII, as it promotes the stability and translation of Pten mRNA through m6A modification. This suggests that targeting METTL3 could offer a novel approach for treating ALI.
Subject(s)
Acute Lung Injury , Alveolar Epithelial Cells , Cell Proliferation , Methyltransferases , Mice, Inbred C57BL , PTEN Phosphohydrolase , RNA, Messenger , Animals , Acute Lung Injury/chemically induced , Acute Lung Injury/metabolism , Acute Lung Injury/genetics , Acute Lung Injury/pathology , PTEN Phosphohydrolase/metabolism , PTEN Phosphohydrolase/genetics , Methyltransferases/metabolism , Methyltransferases/genetics , Mice , Cell Proliferation/drug effects , Alveolar Epithelial Cells/metabolism , Alveolar Epithelial Cells/drug effects , Alveolar Epithelial Cells/pathology , Male , RNA, Messenger/metabolism , Cell Survival/physiology , Cell Survival/drug effects , Methylation , Adenosine/analogs & derivatives , Adenosine/metabolism , Lipopolysaccharides/toxicity , RNA Stability , Cells, CulturedABSTRACT
BACKGROUND: Acute lung injury (ALI) is manifested by increased blood vessel permeability within the lungs and subsequent impairment of alveolar gas exchange. Methylprednisolone (MP) is commonly used as a treatment for ALI to reduce inflammation, yet its molecular mechanism remains unclear. This study aims to explore the underlying mechanisms of MP on ALI in a model induced by lipopolysaccharide (LPS). MATERIAL AND METHODS: The proliferation, viability, apoptosis, and miR-151-5p expression of alveolar type II epithelial cells (AECII) were detected using the cell EdU assay, Annexin V/PI Apoptosis Kit, counting kit-8 (CCK-8) assay, and RT-qPCR. Western blot analysis was used to detect the Usp38 protein level. IL-6 and TNF-α were measured by ELISA. The combination of miR-151-5p and USP38 was determined by chromatin immunoprecipitation (ChIP)-PCR and dual-luciferase reporter assay. RESULTS: MP greatly improved pulmonary function in vivo, reduced inflammation, and promoted the proliferation of the alveolar type II epithelial cells (AECII) in vitro. By comparing the alterations of microRNAs in lung tissues between MP treatment and control groups, we found that miR-151-5p exhibited a significant increase after LPS-treated AECII, but decreased after MP treatment. Confirmed by a luciferase reporter assay, USP38, identified as a downstream target of miR-151-5p, was found to increase after MP administration. Inhibition of miR-151-5p or overexpression of USP38 in AECII significantly improved the anti-inflammatory, anti-apoptotic, and proliferation-promotive effects of MP. CONCLUSION: In summary, our data demonstrated that MP alleviates the inflammation and apoptosis of AECII induced by LPS, and promotes the proliferation of AECII partially via miR-151-5p suppression and subsequent USP38 activation.
Subject(s)
Acute Lung Injury , Apoptosis , Lipopolysaccharides , Methylprednisolone , MicroRNAs , Sepsis , MicroRNAs/metabolism , MicroRNAs/genetics , Methylprednisolone/therapeutic use , Methylprednisolone/pharmacology , Animals , Acute Lung Injury/drug therapy , Acute Lung Injury/pathology , Acute Lung Injury/metabolism , Sepsis/drug therapy , Sepsis/metabolism , Apoptosis/drug effects , Male , Cell Proliferation/drug effects , Signal Transduction/drug effects , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Mice , Mice, Inbred C57BL , Ubiquitin-Specific Proteases/metabolism , Ubiquitin-Specific Proteases/genetics , Humans , Alveolar Epithelial Cells/drug effects , Alveolar Epithelial Cells/metabolism , Disease Models, AnimalABSTRACT
Adequate drug delivery across the blood-brain barrier (BBB) is a critical factor in treating central nervous system (CNS) disorders. Inspired by swimming fish and the microstructure of the nasal cavity, this study is the first to develop swimming short fibrous nasal drops that can directly target the nasal mucosa and swim in the nasal cavity, which can effectively deliver drugs to the brain. Briefly, swimming short fibrous nasal drops with charged controlled drug release were fabricated by electrospinning, homogenization, the π-π conjugation between indole group of fibers, the benzene ring of leucine-rich repeat kinase 2 (LRRK2) inhibitor along with charge-dipole interaction between positively charged poly-lysine (PLL) and negatively charged surface of fibers; this enabled these fibers to stick to nasal mucosa, prolonged the residence time on mucosa, and prevented rapid mucociliary clearance. In vitro, swimming short fibrous nasal drops were biocompatible and inhibited microglial activation by releasing an LRRK2 inhibitor. In vivo, luciferase-labelled swimming short fibrous nasal drops delivered an LRRK2 inhibitor to the brain through the nasal mucosa, alleviating cognitive dysfunction caused by sepsis-associated encephalopathy by inhibiting microglial inflammation and improving synaptic plasticity. Thus, swimming short fibrous nasal drops is a promising strategy for the treatment of CNS diseases.
Subject(s)
Administration, Intranasal , Nasal Mucosa , Animals , Administration, Intranasal/methods , Nasal Mucosa/metabolism , Nasal Mucosa/drug effects , Blood-Brain Barrier/metabolism , Blood-Brain Barrier/drug effects , Drug Delivery Systems/methods , Mice , Nasal Cavity/drug effects , Nasal Cavity/metabolism , Polylysine/chemistry , Polylysine/analogs & derivatives , Swimming , Male , Brain/metabolism , Brain/drug effects , Brain/pathology , Mucociliary Clearance/drug effects , Microglia/drug effects , Microglia/metabolism , HumansABSTRACT
Sepsis-associated liver dysfunction (SALD) aggravates the disease progression and prognosis of patients. Macrophages in the liver play a crucial role in the occurrence and development of SALD. Human umbilical cord mesenchymal stem cells (MSCs), by secreting extracellular vesicles (EVs), show beneficial effects in various inflammatory diseases. However, whether MSC-derived EVs (MSC-EVs) could ameliorate the inflammatory response in liver macrophages and the underlying mechanisms remain unclear. In this study, a mouse model of sepsis induced by lipopolysaccharide (LPS) challenge was used to investigate the immunomodulatory functions of MSC-EVs in SALD. LPS-stimulated primary Kupffer cells (KCs) and Raw264.7 were used to further explore the potential mechanisms of MSC-EVs in regulating the inflammatory response of macrophages. The results showed that MSC-EVs alleviated liver tissue injury and facilitated the polarization of M1 to M2 macrophages. Further in vitro studies confirmed that MSC-EVs treatment significantly downregulated the expression of several enzymes related to glycolysis and reduced the glycolytic flux by inhibiting hypoxia-inducible factor 1α (HIF-1α) expression, thus effectively inhibiting the inflammatory responses of macrophages. These findings reveal that the application of MSC-EVs might be a potential therapeutic strategy for treating SALD.
Subject(s)
Extracellular Vesicles , Liver Diseases , Mesenchymal Stem Cells , Sepsis , Mice , Animals , Humans , Lipopolysaccharides/metabolism , Macrophages/metabolism , Liver Diseases/metabolism , Mesenchymal Stem Cells/metabolism , Extracellular Vesicles/metabolism , Sepsis/metabolismABSTRACT
INTRODUCTION: This research is aimed to evaluate the correlation between Th9-associated cytokine levels in MM patients, clinical features, and therapy. METHODS: Peripheral blood samples were taken in 52 MM patients and 20 healthy volunteers matched by sex and age. The patients with MM were separated into two groups: the untreated group (27) and the remission group (25). An enzyme-linked immunosorbent assay (ELISA) was used to measure the IL-9 plasma levels. The levels of Th9-associated cytokines' mRNA expression (IL-9, PU.1, and IRF4) were measured in RT-qPCR. We also analyzed the correlations between the IL-9 plasma levels and the clinical parameters of newly diagnosed MM patients. RESULTS: The IL-9 plasma levels and the Th9-associated cytokines (IL-9, PU.1, and IRF4) mRNA levels in newly diagnosed MM patients were significantly elevated than those in healthy volunteers and significantly decreased after achieving remission. Moreover, PU.1 and IRF4 had a positive correlation with the IL-9 mRNA expression. Then, we found that the upregulation of IL-9 plasma levels correlates with the severity of anemia and decreased albumin Levels. CONCLUSION: The results demonstrate that Th9/IL-9 may be involved in the pathogenesis of MM and is correlated with worse patient conditions such as lower hemoglobin and serum albumin. More work is necessary to confirm whether they might serve as a useful therapeutic target and prognostic marker for MM.
Subject(s)
Interleukin-9 , Multiple Myeloma , Humans , Interleukin-9/genetics , Interleukin-9/metabolism , T-Lymphocytes, Helper-Inducer/metabolism , T-Lymphocytes, Helper-Inducer/pathology , Multiple Myeloma/diagnosis , Multiple Myeloma/genetics , Multiple Myeloma/pathology , Cytokines/metabolism , RNA, Messenger/geneticsABSTRACT
Alectinib is an ALK tyrosine kinase inhibitor, which is mainly used in patients with crizotinib-resistant nonsmall cell lung cancer. Alectinib has attracted much clinical attention for its longest progression-free survival time and the best therapeutic effect. The chemical adsorption of Au nanoclusters (AuNPs) with alectinib molecules is studied by density functional theory (DFT) and surface-enhanced Raman scattering spectroscopy (SERS) experiments. DFT/B3LYP-D3/6-311G** was used for optimization and vibration analysis of alectinib-Au6 complexes, as well as molecular electrostatic potential, frontier molecular orbital, and electro-optic-based charge transfer descriptors. Comparing the results of the DFT theory and SERS experiment, alectinib and AuNPs can form Au-N6 bonds primarily through chemical adsorption of N6 atoms, and the experimental results showed that the enhancement factor (EFCHEM) could reach 4.27. The results provide a theoretical basis for exploring the mechanism of chemical enhancement between AuNPs and alectinib.
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OBJECTIVE: To investigate the mechanism of action of Srg3 in acute lung injury caused by sepsis. METHODS: First, a sepsis-induced acute lung injury rat model was established using cecal ligation and puncture (CLP). RNA sequencing (RNA-seq) was used to screen for highly expressed genes in sepsis-induced acute lung injury (ALI), and the results showed that Srg3 was significantly upregulated. Then, SWI3-related gene 3 (Srg3) was knocked down using AAV9 vector in vivo, and changes in ALI symptoms in rats were analyzed. In vitro experiments were conducted by establishing a cell model using lipopolysaccharide (LPS)-induced BEAS-2B cells and coculturing them with phorbol 12-myristate 13-acetate (PMA)-treated THP-1 cells to analyze macrophage polarization. Next, downstream signaling pathways regulated by Srg3 and transcription factors involved in regulating Srg3 expression were analyzed using the KEGG database. Finally, gain-of-loss functional validation experiments were performed to analyze the role of downstream signaling pathways regulated by Srg3 and transcription factors involved in regulating Srg3 expression in sepsis-induced acute lung injury. RESULTS: Srg3 was significantly upregulated in sepsis-induced acute lung injury, and knocking down Srg3 significantly improved the symptoms of ALI in rats. Furthermore, in vitro experiments showed that knocking down Srg3 significantly weakened the inhibitory effect of LPS on the viability of BEAS-2B cells and promoted alternative activation phenotype (M2) macrophage polarization. Subsequent experiments showed that Srg3 can regulate the activation of the NF-κB signaling pathway and promote ferroptosis. Specific activation of the NF-κB signaling pathway or ferroptosis significantly weakened the effect of Srg3 knockdown. It was then found that Srg3 can be transcriptionally activated by interferon regulatory factor 7 (Irf7), and specific inhibition of Irf7 significantly improved the symptoms of ALI. CONCLUSIONS: Irf7 transcriptionally activates the expression of Srg3, which can promote ferroptosis and activate classical activation phenotype (M1) macrophage polarization by regulating the NF-κB signaling pathway, thereby exacerbating the symptoms of septic lung injury.
Subject(s)
Acute Lung Injury , Ferroptosis , Sepsis , Animals , Rats , Acute Lung Injury/genetics , Acute Lung Injury/metabolism , Interferon Regulatory Factor-7/metabolism , Lipopolysaccharides/pharmacology , NF-kappa B/metabolism , Sepsis/complications , Transcription Factors/metabolismABSTRACT
Cognitive control is adaptive in that it rapidly adjusts attention in response to changing contexts and shifting goals. Research provides evidence that cognitive control can rapidly adjust attention to focus on task-relevant information based on prior conflict experience. Neural encoding of goal-related information is critical for goal-directed behaviour; however, the empirical evidence on how conflict experience affects the encoding of cognitive conflict in the brain is rather weak. In the present fMRI study, a Stroop task with different proportions of incongruent trial was used to investigate the neural encoding of cognitive conflict in the environment with changing conflict experience. The results showed that the anterior cingulate cortex, dorsolateral prefrontal cortex, and intraparietal sulcus played a pivotal role in the neural encoding of cognitive conflict. The classification in anterior cingulate cortex was significantly above chance in the high-proportion, moderate-proportion, and low-proportion conflict conditions conducted separately, suggesting that neural encoding of cognitive conflict in this region was not altered based on proportion of conflict. The dorsolateral prefrontal cortex and intraparietal sulcus showed significant above-chance classification in the moderate-proportion and low-proportion conflict conditions, but not in the high-proportion conflict condition. These findings provide direct evidence that conflict experience modulates the neural encoding of cognitive conflict.
ABSTRACT
This study used a femtosecond laser to ablate a Cu sample, forming a micro/nanostructural layer on the surface. And the effect of this structural layer on nanosecond laser-induced breakdown spectroscopy (LIBS) was discussed. Firstly, the effect of the micro/nanostructural layer on the intensity of laser-induced Cu plasma spectra was investigated. The micro/nanostructure could significantly enhance the spectral intensity of the Cu plasma by 82.5 times at 13.3 mJ laser energy. Secondly, the Cu plasma temperature and electron density were calculated. The micro/nanostructures could significantly increase Cu plasma temperature and electron density. Finally, the effect of micro/nanostructure surface on the spectral intensities of Pb and Cr elements in water was investigated for LIBS analysis. It was found that the detection limit of Pb and Cr trace metal elements in water was 1.85 ng/mL and 0.51 ng/mL at a lower laser energy (13.3 mJ), which was significantly better than other LIBS methods reported so far. The results show that the micro/nanostructure enhanced LIBS is a more sensitive method for detecting trace metal elements in the water.
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The increasing number of regions have begun to construct age-friendly medical institutions to further promote the "successful aging" of the elderly in mainland China. This study deeply analyzes the development status of age-friendly medical institutions abroad and describes the policies, research, evaluation, and certification of different countries. This study focuses on the current construction status of age-friendly medical institutions in mainland China. With the issuing of several national policies, mainland China has established a top-down system for the construction of age-friendly medical institutions, which has been gradually implemented in the actions of medical institutions. On the whole, the goal and evaluation standard are clear and the action is rapid. However, it also faces many challenges and problems. This study puts forward various suggestions for the construction of age-friendly medical institutions, such as increasing manpower and financial investment and carrying out evidence-based research. In particular, we should pay attention to promoting a bottom-up construction system, understand the actual needs of the elderly, pay attention to the personal experience of the elderly, and fully mobilize the active and full participation of the whole society.
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BACKGROUND AND AIMS: Wilson's disease (WD) is an inherited disorder of copper metabolism with predominant hepatic manifestations. Left untreated, it can be fatal. Current therapies focus on treating copper overload rather than targeting the pathophysiology of copper-induced liver injuries. We sought to investigate whether liposome-encapsulated curcumin (LEC) could attenuate the underlying pathophysiology of WD in a mouse model of WD. APPROACH AND RESULTS: Subcutaneous administration in a WD mouse model with ATP7B knockout (Atp7b-/-) resulted in robust delivery of LEC to the liver as determined by in-vitro and in-vivo imaging. Treatment with LEC attenuated hepatic injuries, restored lipid metabolism and decreased hepatic inflammation and fibrosis, and thus hepatosplenomegaly in Atp7b-/- mice. Mechanistically, LEC decreased hepatic immune cell and macrophage infiltration and attenuated the hepatic up-regulation of p65 by preventing cellular translocation of high-mobility group box-1 (HMGB-1). Moreover, decreased translocation of HMGB1 was associated with reduced splenic CD11b+/CD43+/Ly6CHi inflammatory monocyte expansion and circulating level of proinflammatory cytokines. Nevertheless there was no change in expression of oxidative stress-related genes or significant copper chelation effect of LEC in Atp7b-/- mice. CONCLUSION: Our results indicate that treatment with subcutaneous LEC can attenuate copper-induced liver injury in an animal model of WD via suppression of HMGB1-mediated hepatic and systemic inflammation. These findings provide important proof-of-principle data to develop LEC as a novel therapy for WD as well as other inflammatory liver diseases.
Subject(s)
Curcumin , HMGB1 Protein , Hepatolenticular Degeneration , Adenosine Triphosphatases/metabolism , Animals , Copper/metabolism , Curcumin/metabolism , Curcumin/pharmacology , Disease Models, Animal , Fibrosis , HMGB1 Protein/metabolism , Hepatolenticular Degeneration/drug therapy , Hepatolenticular Degeneration/genetics , Hepatolenticular Degeneration/metabolism , Inflammation/metabolism , Liposomes , Liver/metabolism , MiceABSTRACT
ABSTRACT: Acute lung injury (ALI) is characterized by excessive production of inflammatory factors and alveolar epithelial damage, type II alveolar epithelial (ATII) cells participate in the repairment of the damaged lung tissue in ALI. Recently, microRNAs (miRNAs) have been found to play crucial roles in the amelioration of various inflammation-induced diseases, including ALI. However, the biological function and the mechanisms of action of miRNAs in the regulation of inflammation, and how ATII cells repair damaged lung tissue in ALI remain unknown. In this study, a model of ALI was established using LPS, and ATII cells were isolated and treated with LPS. Hematoxylin and eosin staining revealed the injury to lung tissues. In this study we found that miR-541-5p expression was significantly decreased in ALI tissue and in the LPS-induced ATII cell model. Additionally, the LPS-induced model showed suppression of ATII cell proliferation and activity. Furthermore, overexpression of miR-541-5p was found to promote cell activity and proliferation in the LPS-induced ATII cell model. Moreover, a luciferase assay illustrated that HMGB1 is a target of miR-541-5p, HMGB1 knockdown blocked the inhibitory effect of miR-541-5p on LPS-induced ATII cells. Ultimately, our study demonstrated that expression of p38, JNK, and ERK in LPS-induced ATII cells increased significantly. These results suggest that miR-541-5p is a key effector in ALI tissue, and that LPS-induced ATII cells act by regulating HMGB1 expression. This effect may be related to excessive activation of the JNK/ERK/p38 signaling pathway.
Subject(s)
Acute Lung Injury , HMGB1 Protein , MicroRNAs , Acute Lung Injury/metabolism , Alveolar Epithelial Cells/metabolism , Cell Proliferation/genetics , HMGB1 Protein/genetics , HMGB1 Protein/metabolism , Humans , Inflammation/metabolism , Lipopolysaccharides/pharmacology , MicroRNAs/genetics , MicroRNAs/metabolism , Signal TransductionABSTRACT
This study presents a thorough investigation of the relationship between the coronavirus disease 2019 (COVID-19) and daily stock price changes. We use several types of COVID-19 patients as indicators for exploring whether stock prices are significantly affected by COVID-19's impact. In addition, using the Chinese stock market as an example, we are particularly interested in the psychological and industrial impacts of COVID-19 on the financial market. This study makes two contributions to the literature. First, from a theoretical perspective, it shows a novel quantitative relationship between the psychological response to the pandemic and stock prices. In addition, it depicts the mechanism of the shock to the stock market by pointing out the specific functional expression of the impulse reaction. To our knowledge, this is the first theoretical calculation of the impulse of a shock to the financial market. Second, this study empirically estimates the marginal effect of the COVID-19 pandemic on fluctuations in stock market returns. By controlling for stock fundamentals, this study also estimates diverse industrial responses to pandemic stock volatility. We confirm that the COVID-19 pandemic has caused panic in the stock market, which not only depresses stock prices but also inflates volatility in daily returns. Regarding the impulse of the shock, we identify the cumulative level of the pandemic variables as well as their incremental differences. As shown by our empirical results, the terms for these differences will eventually dominate the marginal effect, which confirms the fading impulse of the shock. Finally, this study highlights some important policy implications of stock market volatility and returns to work in the industry.
ABSTRACT
MicroRNAs (miRNAs), are a novel class of gene expression regulators, that have been found to participate in regulating host-virus interactions. However, the function of insect-derived miRNAs in response to virus infection is poorly understood. We analyzed miRNA expression profiles in the fat bodies of Helicoverpa armigera (H. armigera) infected with Mamestra brassicae multiple nucleopolyhedroviruses (MbMNPV). A total of 52 differentially expressed miRNAs (DEmiRNAs) were filtered out through RNA-seq analysis. The targets of 52 DEmiRNAs were predicted and 100 miRNA-mRNA interaction pairs were obtained. The predicted targets of DEmiRNAs were mainly enriched in the Wnt signaling pathway, phagosome, and mTOR signaling pathway, which are related to the virus infection. Real-time PCR was used to verify the RNA sequencing results. ame-miR-317-3p, mse-miR-34, novel1-star, and sfr-miR-6094-5p were shown to be involved in the host response to MbMNPV infection. Results suggest that sfr-miR-6094-5p can negatively regulate the expression of four host genes eIF3-S7, CG7583, CG16901, and btf314, and inhibited MbMNPV infection significantly. Further studies showed that RNAi-mediated knockdown of eIF3-S7 inhibited the MbMNPV infection. These findings suggest that sfr-miR-6094-5p inhibits MbMNPV infection by negatively regulating the expression of eIF3-S7. This study provides new insights into MbMNPV and H. armigera interaction mechanisms.
Subject(s)
MicroRNAs , Moths , Animals , MicroRNAs/genetics , MicroRNAs/metabolism , Fat Body , Eukaryotic Initiation Factor-3/genetics , Moths/genetics , RNA, Messenger/genetics , Gene Expression ProfilingABSTRACT
The surprising spread speed of the COVID-19 pandemic creates an urgent need for investigating the transmission chain or transmission pattern of COVID-19 beyond the traditional respiratory channels. This study therefore examines whether human feces and public toilets play a critical role in the transmission of COVID-19. First, it develops a theoretical model that simulates the transmission chain of COVID-19 through public restrooms. Second, it uses stabilized epidemic data from China to empirically examine this theory, conducting an empirical estimation using a two-stage least squares (2SLS) model with appropriate instrumental variables (IVs). This study confirms that the wastewater directly promotes the transmission of COVID-19 within a city. However, the role of garbage in this transmission chain is more indirect in the sense that garbage has a complex relationship with public toilets, and it promotes the transmission of COVID-19 within a city through interaction with public toilets and, hence, human feces. These findings have very strong policy implications in the sense that if we can somehow use the ratio of public toilets as a policy instrument, then we can find a way to minimize the total number of infections in a region. As shown in this study, pushing the ratio of public toilets (against open defecation) to the local population in a city to its optimal level would help to reduce the total infection in a region.
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BACKGROUND: The purpose of this study was to determine whether elevated glucose can induce a dermal microvascular endothelial cell metabolic memory, thus affecting angiogenesis in the repair process of mammalian cutaneous wound. We hypothesized that transient elevated glucose levels cause sustained alteration of endothelial cell responses to injury and persistent epigenetic changes in gene expression. METHODS: Human dermal microvascular endothelial cells were exposed to experimental conditions with or without 30 mM D-glucose. The control group was maintained at 5 mM D-glucose; while in the transient glucose group, after being exposed to 30 mM D-glucose for two days, then being put under the control conditions during the experiment. Besides, in the whole process of the experiment, the chronic glucose group was kept in the condition with 30 mM D-glucose. Proliferation, migration, tube formation, gene expression and histone methylation were assessed for individual conditions. RESULTS: Transient elevated glucose caused sustained effects on endothelial cell migration, tube formation and TIMP3 gene expression. The effects on TIMP3 expression were associated with persistent changes in histone modification at the 5' end of the TIMP3 gene, suggesting an epigenetic effect. CONCLUSIONS: Hyperglycemia induced metabolic memory could promote the regulation of TIMP3, and it can be used as a possible innovative molecular target for therapeutic intervention in the treatment of chronic non-healing diabetic wounds.
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Pancreatic ductal adenocarcinoma (PDAC) is almost universally lethal. A critical unmet need exists to explore essential susceptibilities in PDAC and to identify druggable targets to improve PDAC treatment. KRAS mutations dominate the genetic landscape of PDAC and lead to activation of multiple downstream pathways and cellular processes. Here, we investigated the requirement of these pathways for tumor maintenance using an inducible KrasG12D -driven PDAC mouse model (iKras model), identifying that RAF-MEK-MAPK signaling is the major effector for oncogenic KRAS-mediated tumor maintenance. However, consistent with previous studies, MEK inhibition had minimal therapeutic effect as a single agent for PDAC in vitro and in vivo. Although MEK inhibition partially downregulated transcription of glycolysis genes, it failed to suppress glycolytic flux in PDAC cells, which is a major metabolic effector of oncogenic KRAS. Accordingly, an in vivo genetic screen identified multiple glycolysis genes as potential targets that may sensitize tumor cells to MEK inhibition. Inhibition of glucose metabolism with low-dose 2-deoxyglucose in combination with a MEK inhibitor induced apoptosis in KrasG12D -driven PDAC cells in vitro. The combination also inhibited xenograft PDAC tumor growth and prolonged overall survival in a genetically engineered PDAC mouse model. Molecular and metabolic analyses indicated that co-targeting glycolysis and MAPK signaling results in apoptosis via induction of lethal endoplasmic reticulum stress. Together, our work suggests that combined inhibition of glycolysis and the MAPK pathway may serve as an effective approach to target KRAS-driven PDAC. SIGNIFICANCE: This study demonstrates the critical role of glucose metabolism in resistance to MAPK inhibition in KRAS-driven pancreatic cancer, uncovering a potential therapeutic approach for treating this aggressive disease.
Subject(s)
Adenocarcinoma/drug therapy , Carcinoma, Pancreatic Ductal/drug therapy , Glucose/metabolism , Protein Kinase Inhibitors/therapeutic use , Animals , Humans , Mice , Protein Kinase Inhibitors/pharmacologyABSTRACT
Fluorescence quenching of rhodamine 6G by graphene oxide (GO) was investigated using steady-state fluorescence spectroscopy and ultrafast time-resolved absorption spectroscopy. The steady-state fluorescence spectra showed that rhodamine 6G fluorescence was effectively quenched by titrating the GO to the rhodamine 6G solutions. For lower GO concentrations, transient dynamic curves followed two-exponential decay parameters. For higher GO concentrations, the dynamic curves could not be fitted well, and three-exponential decay parameters were appropriate. The results indicated that there was a new transition process (electron transfer) in the exited rhodamine 6G and GO solution.
Subject(s)
Graphite , Rhodamines , Spectrometry, FluorescenceABSTRACT
This paper studies the analysis of Na element concentration in NaCl aqueous solution using laser-induced breakdown spectroscopy (LIBS). The NaCl solution is transformed to a thin water film. The water film can provide a stable liquid surface, and overcome the disadvantage that laser focusing position cannot be fixed due to liquid level fluctuation (when nanosecond laser is used as the excitation light source, there is serious liquid splash phenomenon, which affects the signal stability). And, femtosecond pulse laser is used to excite the water film to produce the plasma, avoiding liquid splashing. The measured emission lines are Na (I) at 589.0 nm and 589.6 nm. The calibration curves of sodium are plotted by measuring different concentrations of NaCl solution. The linear correlation coefficients of Na (I) lines at 589.0 nm and 589.6 nm are 0.9928 and 0.9914, respectively. In addition, the relative standard deviation is also calculated; its range is from 1.5% to 4.5%. The results indicate that the combination of femtosecond laser and water film can significantly improve the signal stability for liquid analysis in LIBS.
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The network security situation of campus networks on CERNET (China Education and Research Network) has received great concern. However, most network managers have no complete picture of the network security because of its special management and the rapid growth of network assets. In this investigation, the security of campus networks belonging to seven universities in Wuhan was investigated. A tool called "WebHunt" was designed for campus networks, and with its help, the network security risks were found. Differently from existing tools for network probing, WebHunt can adopt the network scale and special rules of the campus network. According to the characteristics of campus websites, a series of functions were integrated into WebHunt, including reverse resolution of domain names, active network detection and fingerprint identification for software assets. Besides, WebHunt builds its vulnerability intelligence database with a knowledge graph structure and locates the vulnerabilities through matching knowledge graph information. Security assessments of seven universities presents WebHunt's applicability for campus networks. Besides, it also shows that many security risks are concealed in campus networks, such as non-compliance IP addresses and domain names, system vulnerabilities and so on. The security reports containing risks have been sent to the relevant universities, and positive feedback was received.