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A new series of usnic acid (UA) monoesterified derivatives 2-15 were designed and synthesised using UA (1) as starting material. The structural characterisation of all compounds was elucidated using 1H-NMR and 13C-NMR spectral data. In vitro studies demonstrated thatmost UA derivatives exhibited higher inhibitory activity against Candida albicans and Staphylococcus aureus. Among them, compound 7 displayed the highest inhibitory activity against C. albicans with a minimum inhibitory concentration (MIC) of 32 µg/mL. Compounds 5, 8, 9, 11and 13 demonstrated superior inhibition of S. aureus (MIC, 16 µg/mL) and biofilm formation in a concentration-dependent manner. With the exception of 11, compounds 5, 8, 9 and 13 were all more effective than UA in inhibiting S. aureus biofilms. This research highlights the potential of UA monoesterified derivatives for the development of dual antimicrobial and antibiofilm agents.
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The infant sleep-wake behavior is an essential indicator of physiological and neurological system maturity, the circadian transition of which is important for evaluating the recovery of preterm infants from inadequate physiological function and cognitive disorders. Recently, camera-based infant sleep-wake monitoring has been investigated, but the challenges of generalization caused by variance in infants and clinical environments are not addressed for this application. In this paper, we conducted a multi-center clinical trial at four hospitals to improve the generalization of camera-based infant sleep-wake monitoring. Using the face videos of 64 term and 39 preterm infants recorded in NICUs, we proposed a novel sleep-wake classification strategy, called consistent deep representation constraint (CDRC), that forces the convolutional neural network (CNN) to make consistent predictions for the samples from different conditions but with the same label, to address the variances caused by infants and environments. The clinical validation shows that by using CDRC, all CNN backbones obtain over 85% accuracy, sensitivity, and specificity in both the cross-age and cross-environment experiments, improving the ones without CDRC by almost 15% in all metrics. This demonstrates that by improving the consistency of the deep representation of samples with the same state, we can significantly improve the generalization of infant sleep-wake classification.
Subject(s)
Intensive Care Units, Neonatal , Sleep , Video Recording , Humans , Infant, Newborn , Video Recording/methods , Sleep/physiology , Monitoring, Physiologic/methods , Male , Female , Infant, Premature/physiology , Neural Networks, Computer , Wakefulness/physiology , Infant , Image Processing, Computer-Assisted/methodsABSTRACT
Electroplating sludge is extensively produced in chemical precipitation-based treatment of electroplating wastewater. It poses a huge threat to environmental safety if not properly disposed, ascribed to its high contents of heavy metals. An innovative metallurgical approach was proposed a to recycle Cu, Cr, and Ni from it. Ammonia leaching was firstly performed to selectively leach Cu from Cr, in which the Cu oxide and sulfide were leached into the leachate while the Cr oxide and Ni carbide (NiCx) retained in the residue. (NH4)2SO4 increased the Cu leaching rate via increasing the dissolved oxygen amount in the ammonia leachate and converting CuS to Cu2+. Under the optimal conditions, the leaching efficiency of Cu achieved 96.5 % while that of Cr was only 0.1 %. In the followed aluminothermic reduction, C in the leaching residue could be effectively removed via a thermal oxidation, which in turn decreased the formation of a C-containing compound of high melting point and benefited the Cr and Ni recovery. Cr and Ni from the residue were reduced and recovered in a Cr-Ni alloy, and the reductant of Al first changed to a refractory Al2O3 and then transformed to a low melting point 12CaO·7Al2O3 with the additive of CaO. This transformation increased the molten slag fluidity and promoted the separation of Cr-Ni alloy from slag. Moreover, the excessive Al increased the Cr and Ni yields and concentrated all of them to be together. Partial Al was used as reductant, and the other Al transferred into Cr-Ni alloy to decrease its melting point. Cr and Ni contents in the smelting slag could be decreased to 0.11 wt% and 0.12 wt% respectively, showing an efficient recovery. This work provided a high efficiency method to recover Cu, Cr, and Ni from waste electroplating sludge.
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ETHNOPHARMACOLOGICAL RELEVANCE: Aromatic and medicinal plants continue to be a major component of alternative and traditional medicine in the developing countries. Eucalyptus globulus (Labill.) is being employed to cultivation and production in China. However, few studies have reported the chemical composition and anti-inflammatory activity of Eucalyptus globulus (Labill.) leaf essential oil (E. globulus leaf EO) extracted from Eucalyptus globulus. AIM OF THE STUDY: This study aimed to assess the composition of E. globulus leaf EO and identify its bacteriostatic action as well as anti-inflammatory activity. Importantly, we evaluated the effect of E. globulus leaf EO on neurological impairment and neuroinflammation in experimental stroke mice. MATERIALS AND METHODS: Gas Chromatography-Mass Spectrometer (GC-MS) analyses was employed to evaluate the chemical components of E. globulus leaf EO, and the relative content of each component was determined by area normalization method. The antimicrobial activity of E. globulus leaf EO was determined by Oxford cup method and microbroth dilution assay. Cytotoxic activity of E. globulus leaf EO on THP-1 cells or BV2 cells in vitro was determined by CCK8 assay. In addition, the lipopolysaccharide (LPS)/ATP-induced inflammation model in THP-1 cells or BV2 cells were established, and the relative expression of TNF-α, IL-1ß, MCP-1and IL-6 were confirmed by RT-PCR. Furthermore, the expression of protein GSDMD, IL-lß, NLRP3 and NFκB signaling pathway were assessed by immunoblotting. In vivo,the experimental stroke model constructed by middle cerebral artery occlusion/reperfusion (MCAO/R) in mice was employed and subsequently treated with E. globulus leaf EO (50,100 mg/kg, subcutaneous injection) for 3 days to assess neurological impairment and neuroinflammation. Behavioral and neuronal damage were assessed using grip strength test, rod trarod test, and Nissl staining. Pro-inflammatory factors in serum or ischemic brain tissue was detected by ELISA kits. RESULTS: GC-MS analyses revealed that the major compound in E. globulus leaf EO was eudesmol (71.967%). E. globulus leaf EO has antimicrobial activity against Staphylococcus aureus (gram positive bacteria, MIC = 0.0625 mg/mL), Escherichia coli (gram negative bacteria, MIC = 1 mg/mL), and Candida albicans (MIC = 4 mg/mL). E. globulus leaf EO (0.5312, 1.0625, and 2.15 mg/mL) significantly decreased the expression of inflammation-related genes, including IL-1ß, TNF-α, MCP-1, and IL-6. Furthermore, reduced levels of TLR4, Myd88, phosphorylated NF-κB P65, and IκBα were found in the E. globulus leaf EO group for BV2 cells (1.025, and 2.125 mg/mL). In addition, the expression levels of GSDMD, NLRP3, IL-1ß and AIM2 were significantly decreased in the E. globulus leaf EO group when compared with the LPS -stimulated group, regulating GSDMD-mediated pyroptosis. In vivo, E. globulus leaf EO improved neurological functional deficits, inhibited excessive activation of microglia, and reduced the secretion of pro-inflammatory factors IL-1ß, TNF-α in the ischemic tissue and serum after MCAO/R. CONCLUSION: E. globulus leaf EO has strong antibacterial and anti-inflammatory activity, which has been implicated in blocking GSDMD-mediated pyroptosis. Moreover, E. globulus leaf EO could exert neuroprotective effect on cerebral ischemia-reperfusion injury.
Subject(s)
Anti-Infective Agents , DNA-Binding Proteins , Stroke , Rats , Mice , Animals , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Rats, Sprague-Dawley , Neuroinflammatory Diseases , Tumor Necrosis Factor-alpha/metabolism , Interleukin-6/metabolism , Pyroptosis , Lipopolysaccharides/pharmacology , Stroke/drug therapy , Infarction, Middle Cerebral Artery/drug therapy , Infarction, Middle Cerebral Artery/metabolism , Inflammation/drug therapy , Inflammation/metabolism , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Anti-Inflammatory Agents/metabolism , Plant Leaves/metabolism , Anti-Infective Agents/pharmacology , NF-kappa B/metabolism , MicrogliaABSTRACT
Effects of low hydraulic loading rate (HLR) in dry weather and high HLR in wet weather on pollutant removal, microbial community, and sludge properties of a full-scale wastewater treatment plant (WWTP) were extensively studied to explore the risk of under-loaded operation for overflow pollution control. Long-term low HLR operation had an insignificant effect on the pollutant removal performance of the full-scale WWTP, and the system could withstand high-load shocks in wet weather. Low HLR resulted in higher oxygen and nitrate uptake rate due to the storage mechanism under the alternating feast/famine condition, and lower nitrifying rate. Low HLR operation enlarged particle size, deteriorated floc aggregation and sludge settleability, and reduced sludge viscosity due to the overgrowth of filamentous bacteria and inhibition of floc-forming bacteria. The remarkable increase in Thuricola and the contract morphology of Vorticella in microfauna observation confirmed the risk of flocs disintegration in low HLR operation.
Subject(s)
Environmental Pollutants , Microbiota , Sewage/microbiology , Waste Disposal, Fluid/methods , Anaerobiosis , WeatherABSTRACT
Bronchopulmonary dysplasia (BPD) is a common chronic respiratory disease in preterm infants caused by multifactorial etiology. Genetic factors are involved in the occurrence of BPD, but studies have found that candidate genes have poor reproducibility and are influenced by ethnic heterogeneity; therefore, more exploration is still needed. We performed whole-exon sequencing in 34 preterm infants with BPD and 32 non-BPD control neonates. The data were analyzed and interpreted by Fisher difference comparison, PLINK and eQTL association analysis, KEGG and GO enrichment analysis, STRING tool, Cytoscape software, ProtParam tool, HOPE online software, and GEOR2 analysis on NCBI GEO dataset. BPD has a highly heterogeneity in different populations, and we found 35 genes overlapped with previous whole-exon sequencing studies, such as APOB gene. Arterial and epithelial cell development and energy metabolism pathways affect BPD. In this study, 24 key genes were identified, and BIVM rs3825519 mutation leads to prolonged assisted ventilation in patients with BPD. A novel DDAH1 mutation site (NM_012137: exon1: c.89 T > G: p.L30R) was found in 9 BPD patients. CONCLUSION: BIVM gene rs3825519 mutation may play a role in the pathogenesis of BPD by affecting cilia movement, and the DDAH1 and APOB genes mutations may have a pathogenic role in BPD. WHAT IS KNOWN: ⢠Genetic factors are involved in the occurrence of bronchopulmonary dysplasia. ⢠The candidate genes have poor reproducibility and are influenced by ethnic heterogeneity, therefore, more exploration is still needed. WHAT IS NEW: ⢠We identified the role of susceptible SNPs in BPD in Shenzhen, China, and identified 24 key genes that influence the pathogenesis of BPD, and also found 35 genes overlapped with previous whole exon sequencing studies, such as APOB gene. ⢠We found that BIVM and DDAH1 genes may play a pathogenic role in the pathogenesis of BPD.
Subject(s)
Bronchopulmonary Dysplasia , Infant, Premature , Infant , Infant, Newborn , Humans , Bronchopulmonary Dysplasia/genetics , Bronchopulmonary Dysplasia/epidemiology , Genetic Predisposition to Disease , Exome Sequencing , Reproducibility of Results , Apolipoproteins B/geneticsABSTRACT
Animal models play a key role in life science research, especially in the study of human disease pathogenesis and drug screening. Because of the closer proximity to humans in terms of genetic evolution, physiology, immunology, biochemistry, and pathology, nonhuman primates (NHPs) have outstanding advantages in model construction for disease mechanism study and drug development. In terms of animal model construction, gene editing technology has been widely applied to this area in recent years. This review summarizes the current progress in the establishment of NHPs using gene editing technology, which mainly focuses on rhesus and cynomolgus monkeys. In addition, we discuss the limiting factors in the applications of genetically modified NHP models as well as the possible solutions and improvements. Furthermore, we highlight the prospects and challenges of the gene-edited NHP models.
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A comparative study was conducted between an anaerobic side-stream reactor (ASSR) process and a sludge process reduction (SPR) activated sludge (SPRAS) process for uncovering crucial metabolic mechanisms governing sludge reduction. Both of two processes were efficient in removing pollutants, while the SPRAS (62.3 %) obtained much higher sludge reduction than the ASSR (27.9 %). The highest rate coefficients of sludge decay, heterotroph lysis and particles hydrolysis were 0.106, 0.219 and 0.054 d-1 in the SPR module, followed by ASSR with coefficients of 0.060, 0.135 and 0.047 d-1. The SPR module achieved an 81.9 % higher sludge decay mass with a 32.8 % smaller volume than the ASSR module. The SPR module preferentially enriched hydrolytic/fermentative and slow-growing bacteria. Metagenomic analysis revealed that SPR strengthened the key hydrolases and L-lactate dehydrogenase in the glycolysis pathways and weakened the citrate cycle, inducing metabolic uncoupling due to the reduced biosynthesis of ATP. Inserting ASSR only altered the ATP biosynthesis pathway, but maintenance metabolism was dominant for sludge reduction, with a long sludge retention time prolonging the food chain for predation.
Subject(s)
Environmental Pollutants , Sewage , Sewage/microbiology , Waste Disposal, Fluid , Bioreactors , Anaerobiosis , Kinetics , L-Lactate Dehydrogenase , Hydrolases , Citrates , Adenosine TriphosphateABSTRACT
Patients with Hantavirus-caused epidemic hemorrhagic fever (EHF) are at risk of contracting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there is currently no validated EHF/SARS-CoV-2 strategy. Several studies have recently shown Puerarin, a natural product, has potent antiviral properties. The goal of present study was to determine the mechanism of puerarin in patients with EHF/COVID-19. We use network pharmacology and bioinformatics to investigate the possible pharmacological targets, bioactivities, and molecular mechanisms of puerarin in the treatment of patients with EHF/SARS-CoV-2. The study investigated the pathogenesis of COVID-19 and EHF and the signaling pathway impacted by puerarin. 68 common genes linked to puerarin and EHF/SARS-CoV-2 were discovered during the investigation. By using protein-protein interaction (PPI) network, we identified RELA, JUN, NF-B1, NF-B2, and FOS as potential therapeutic targets. The bioactivity and signaling pathways of puerarin have also been demonstrated in the treatment of EHF and COVID-19. According to present study, puerarin could reduce excessive immune responses and inflammation through the NF-B, TNF, and HIF-1 signaling pathways. This study explored the potential therapeutic targets and mechanisms of Puerarin in the treatment of EHF/COVID-19.
Subject(s)
COVID-19 Drug Treatment , Coinfection , Hantavirus Infections , Orthohantavirus , Humans , Isoflavones , SARS-CoV-2ABSTRACT
Endometriosis (EMs) is a common benign gynecological disease in women of childbearing age, which usually causes pelvic pain, secondary dysmenorrhea, and infertility. EMs has been linked to recurrent pregnancy loss (RPL) in epidemiological data. The relationship of both, however, remains unknown. The purpose of this study is to explore the underlying pathological mechanisms between EMs and RPL. We searched Gene Expression Omnibus (GEO) database to obtain omics data of EMs and RPL. Co-expression modules for EMs and RPL were investigated by using weighted gene co-expression network analysis (WGCNA). The intersections of gene modules with the strong correlation to EMs or RPL obtained by WGCNA analysis were considered as shared genes. MicroRNAs (miRNAs) and their corresponding target genes linked to EMs and RPL were found though the Human MicroRNA Disease Database (HMDD) and the miRTarbase database. Finally, we constructed miRNAs-mRNAs regulatory networks associated with the two disorders by using the intersection of previously obtained target genes and shared genes. We discovered as significant modules for EMs and RPL, respectively, by WGCNA. The energy metabolism might be the common pathogenic mechanism of EMs and RPL, according to the findings of a Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. We discovered several target genes that might be linked to these two disorders, as well as the potential mechanisms. RAB8B, GNAQ, H2AFZ, SUGT1, and LEO1 could be therapeutic candidates for RPL and EMs. The PI3K-Akt signaling pathway and platelet activation were potentially involved in the mechanisms of EM-induced RPL. Our findings for the first time revealed the underlying pathological mechanisms of EM-induced RPL and identified several useful biomarkers and potential therapeutic targets.
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Objectives: In this research, we aim to explore the bioinformatic mechanism of infertile endometriosis in order to identify new treatment targets and molecular mechanism. Methods: The Gene Expression Omnibus (GEO) database was used to download MRNA sequencing data from infertile endometriosis patients. The "limma" package in R software was used to find differentially expressed genes (DEGs). Weighted gene co-expression network analysis (WGCNA) was used to classify genes into modules, further obtained the correlation coefficient between the modules and infertility endometriosis. The intersection genes of the most disease-related modular genes and DEGs are called gene set 1. To clarify the molecular mechanisms and potential therapeutic targets for infertile endometriosis, we used Gene Ontology (GO), Kyoto Gene and Genome Encyclopedia (KEGG) enrichment, Protein-Protein Interaction (PPI) networks, and Gene Set Enrichment Analysis (GSEA) on these intersecting genes. We identified lncRNAs and miRNAs linked with infertility and created competing endogenous RNAs (ceRNA) regulation networks using the Human MicroRNA Disease Database (HMDD), mirTarBase database, and LncRNA Disease database. Results: Firstly, WGCNA enrichment analysis was used to examine the infertile endometriosis dataset GSE120103, and we discovered that the Meorangered1 module was the most significantly related with infertile endometriosis. The intersection genes were mostly enriched in the metabolism of different amino acids, the cGMP-PKG signaling pathway, and the cAMP signaling pathway according to KEGG enrichment analysis. The Meorangered1 module genes and DEGs were then subjected to bioinformatic analysis. The hub genes in the PPI network were performed KEGG enrichment analysis, and the results were consistent with the intersection gene analysis. Finally, we used the database to identify 13 miRNAs and two lncRNAs linked to infertility in order to create the ceRNA regulatory network linked to infertile endometriosis. Conclusion: In this study, we used a bioinformatics approach for the first time to identify amino acid metabolism as a possible major cause of infertility in patients with endometriosis and to provide potential targets for the diagnosis and treatment of these patients.
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OBJECTIVES: To elucidate breastfeeding patterns, the reasons for stopping exclusive breastfeeding, and the sociodemographic characteristics associated with exclusive breastfeeding of full-term infants during the 6 months after discharge from a neonatal unit in China. METHODS: This cross-sectional study included mothers of full-term infants who were discharged from the 40-bed neonatal unit (level IIA) of a tertiary hospital in Hunan province, China between August 2019 and September 2020. Information on breastfeeding patterns was collected through telephone interviews with the mothers 6 months after their infants had been discharged from the neonatal unit. Binary logistic regression was used to determine the factors associated with exclusive breastfeeding. RESULTS: This study included 489 mother-infant dyads. At 6 months after discharge, 51.5% of mothers were exclusively breastfeeding, 29.0% of mothers were partially breastfeeding, and 19.4% of mothers were not breastfeeding. The most common reason for stopping breastfeeding was "poor milk supply" (81.2%). Factors associated with exclusive breastfeeding included multiparity, exclusive breastfeeding before the hospitalization, providing breast milk to the hospitalized infant, and a high level of maternal education. CONCLUSIONS: In the Chinese culture, mothers who experienced multiparity and higher-level education were more likely to breastfeed their infants to 6 months after discharge from the neonatal unit. In addition, infants who were exclusively breastfed before and during hospitalization were also more likely to be exclusively breastfed after discharge. The results will help inform future research aimed at identifying interventions to reduce early breastfeeding cessation.
Subject(s)
Breast Feeding , Cross-Sectional Studies , Female , Humans , Infant , Infant, Newborn , Milk, Human , Mothers , Patient DischargeABSTRACT
BACKGROUND: Necrotizing enterocolitis (NEC) remains a life-threatening disease in neonates. Numerous studies have shown a correlation between the intestinal microbiota and NEC, but the causal link remains unclear. This study aimed to demonstrate the causal role of gut microbiota in NEC and explore potential mechanisms involved. METHODS: Eighty-one fecal samples from patients with NEC and eighty-one matched controls (matched to the NEC infants by gestational age, birth weight, date of birth, mode of delivery and feeding patterns) were collected. To explore if altered gut microbiota contributes to the pathogenesis of NEC, fecal microbiota transplantation (FMT) was carried out in germ-free (GF) mice prior to a NEC-induction protocol that included exposure to hypoxia and cold stress. Butyric acid was also administered to demonstrate its role in NEC. The fecal microbiota from patients and mice were analyzed by 16S rRNA gene sequencing analysis. Short chain fatty acid (SCFA) levels were measured by gas chromatography-mass spectrometry (GC-MS). The ontogeny of T cells and regulatory T cells (Tregs) in lamina propria mononuclear cells (LPMC) from the ileum of patients and mice were isolated and analyzed by flow cytometry.The transcription of inflammatory cytokines was quantified by qRT-PCR. RESULTS: NEC patients had increased Proteobacteria and decreased Firmicutes and Bacteroidetes compared to fecal control samples, and the level of butyric acid in the NEC group was lower than the control group. FMT in GF mice with samples from NEC patients achieved a higher histological injury scores when compared to mice that received FMT with control samples. Alterations in microbiota and butyrate levels were maintained in mice following FMT. The ratio of Treg/CD4+T (Thelper) cells was reduced in both NEC patients and mice modeling NEC following FMT. CONCLUSIONS: The microbiota was found to have NEC and the microbial butyrate-Treg axis was identified as a potential mechanism for the observed effects.
Subject(s)
Enterocolitis, Necrotizing , Microbiota , Animals , Butyrates , Enterocolitis, Necrotizing/microbiology , Humans , Infant, Newborn , Mice , RNA, Ribosomal, 16S/genetics , T-Lymphocytes, RegulatoryABSTRACT
This study was for verifying that transfecting colon cancer cells (CCCs) with lncRNA NEAT1 packed with siRNA chitosan nanoparticles (CNPs) can suppress lncRNA NEAT1 and biological behaviors of the cells. siRNA targeting lncRNA NEAT1 expression vector was constructed and then transfected into CCCs after being packed with CNPs. Subsequently, the impact of the transfection on biological behaviors of the cells was evaluated. As a result, with high expression in CCCs, NEAT1 was negatively bound up with miR-377-3p in cases with colon cancer (CC), and dual luciferase reporter assay confirmed the potential binding region. Additionally, after downregulating NEAT1 in CCCs, transfection of NEAT1 siRNA packed with CNPs brought a great inhibition on cell proliferation and a promotion on apoptosis, and inhibiting miR-377-3p was able to offset the role of silencing NEAT1 in CCCs. Therefore, in our opinion, NEAT1 siRNA packed with CNPs can hinder the growth and metastasis of CCCs by knocking down NEAT1 in CC, and its mechanism may be achieved by targeting miR-377-3p, which offers a novel direction for treating CC.
Subject(s)
Chitosan/chemistry , Colonic Neoplasms/drug therapy , Nanoparticles/chemistry , RNA, Long Noncoding/pharmacology , RNA, Small Interfering/pharmacology , Apoptosis , Cell Line, Tumor , Cell Proliferation , Colon , Down-Regulation , Humans , MicroRNAs/genetics , RNA, Long Noncoding/genetics , RNA, Small Interfering/genetics , TransfectionABSTRACT
Autophagy is a conservative lysosomal catabolic pathway commonly seen in eukaryotic cells. It breaks down proteins and organelles by forming a two-layer membrane structure of autophagosomes and circulating substances and maintaining homeostasis. Autophagy can play a dual role in viral infection and serve either as a pro-viral factor or an antiviral defense element dependent on the virus replication cycle. Recent studies have suggested the complicated and multidirectional role of autophagy in the process of virus infection. On the one hand, autophagy can orchestrate immunity to curtail infection. On the other hand, some viruses have evolved strategies to evade autophagy degradation, facilitating their replication. In this review, we summarize recent progress of the interaction between autophagy and viral infection. Furthermore, we highlight the link between autophagy and SARS-CoV-2, which is expected to guide the development of effective antiviral treatments against infectious diseases.
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OBJECTIVE: To investigate the effects of nicotinamide phosphoribosyl transferase (NAMPT) inhibitor FK866 on polymicrobial sepsis-induced liver injury in mice. METHODS: Eighty-four healthy male C57BL/6J mice were divided into four groups by random number table method (n = 21): sham group, sepsis-induced liver injury model by cecal ligation and perforation group (CLP group), vehicle+CLP group and FK866+CLP group. FK866 (10 mg/kg) or same volume dimethyl sulfoxide were given intraperitoneally into mice 24, 12 and 0.5 hours prior to CLP in the FK866+CLP group or the vehicle+CLP group, respectively. Fifteen mice in each group were used to observe the 48-hour survival after operation. The remaining 6 mice were sacrificed 20 hours after operation to harvest venous blood and liver tissue samples for index detection. The levels of serum alanine transaminase (ALT) and aspartate aminotransferase (AST) were measured by colorimetry; the levels of serum NAMPT, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were measured by enzyme linked immunosorbent assay (ELISA); the mRNA expressions of TNF-α and IL-6 were measured by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR); the protein expressions of hepatic NAMPT, cytoplasmic IκBα and nuclear factor-κB (NF-κB) were measured by Western Blot. RESULTS: Compared with the sham group, the 48-hour survival in the CLP group was significantly decreased; serum and liver NAMPT protein levels were significantly increased, serum ALT, AST, TNF-α, IL-6 levels and mRNA expressions of TNF-α, IL-6 in liver tissue were significantly increased; the expression of cytoplasmic IκBα protein was significantly decreased, and the expression of nuclear NF-κB protein was significantly increased; which indicated that CLP induced NF-κB activation, inflammation and liver injury. There was no significant difference between the vehicle+CLP group and the CLP group. Compared with the vehicle+CLP group, the 48-hour survival in FK866+CLP group was significantly increased (53.33% vs. 26.67%); serum ALT, AST, TNF-α, IL-6 levels and mRNA expressions of TNF-α, IL-6 in liver tissue were significantly decreased [serum ALT (U/L): 128.94±32.48 vs. 237.24±58.61, serum AST (U/L): 289.89±68.74 vs.468±82.17, serum TNF-α (pg/L): 65.17±18.74 vs.127.64±48.18, serum IL-6 (ng/L): 31.78±5.23 vs. 60.87±13.12, liver TNF-α mRNA (2-ΔΔCt): 8.37±4.17 vs. 18.24±6.12, liver IL-6 mRNA (2-ΔΔCt): 18.58±7.12 vs.34.24±6.71], the expression of cytoplasmic IκBα protein was significantly increased (IκBα/GAPDH: 0.23±0.03 vs. 0.12±0.04), while expression of nuclear NF-κB protein was significantly decreased (NF-κB/Lamin B1: 0.25±0.04 vs. 0.42±0.05), with statistically significant differences (all P < 0.05). CONCLUSIONS: NAMPT inhibitor FK866 protects polymicrobial sepsis-induced liver injury via the inhibition of NF-κB activation and inflammation.
Subject(s)
Liver/injuries , Sepsis , Animals , Aspartate Aminotransferases , Interleukin-6 , Male , Mice , Mice, Inbred C57BL , Tumor Necrosis Factor-alphaABSTRACT
Liver dysfunction has been known to occur frequently in cases of sepsis. Excessive inflammation and apoptosis are pathological features of acute liver failure. Recent studies suggest that activation of glycogen synthase kinase- (GSK-) 3ß is involved in inflammation and apoptosis. We aimed to investigate the protective effects of GSK-3ß inhibition on polymicrobial sepsis-induced liver injury and to explore the possible mechanisms. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP), and SB216763 was used to inhibit GSK-3ß in C57BL/6 mice. GSK-3ß was activated following CLP. Administration of SB216763 decreased mortality, ameliorated liver injury, and reduced hepatic apoptosis. The inhibition of GSK-3ß also reduced leukocyte infiltration and hepatic inflammatory cytokine expression and release. Moreover, GSK-3ß inhibition suppressed the transcriptional activity of nuclear factor-kappa B (NF-κB) but enhanced the transcriptional activity of cAMP response element binding protein (CREB) in the liver. In in vitro studies, GSK-3ß inhibition reduced inflammatory cytokine production via modulation of NF-κB and CREB signaling pathways in lipopolysaccharide-stimulated macrophages. In conclusion, these findings suggest that GSK-3ß blockade protects against CLP-induced liver via inhibition of inflammation by modulating NF-κB and CREB activity and suppression of hepatic apoptosis.
Subject(s)
Apoptosis , Glycogen Synthase Kinase 3/metabolism , Inflammation/metabolism , Liver/pathology , Animals , Cell Line , Cytokines/metabolism , Enzyme-Linked Immunosorbent Assay , Glycogen Synthase Kinase 3 beta , Immunohistochemistry , Indoles/chemistry , Interleukin-6/metabolism , Leukocytes/cytology , Liver/injuries , Liver/metabolism , Male , Maleimides/chemistry , Mice , Mice, Inbred C57BL , NF-kappa B/metabolism , Peroxidase/metabolism , Signal TransductionABSTRACT
Iron is essential for nearly all biological events. Siderophores are indispensable for most organisms to obtain iron from iron-limiting milieus. This holds particularly true for pathogens such as the causative agent of tuberculosis - Mycobacterium tuberculosis. The categories of mycobacterial siderophores, their biosynthesis and regulation are summarized here. The siderophore biosynthesis and regulation differences between the pathogenic and non-pathogenic mycobacteria are highlighted from comparative genomic perspective, with an aim to find clues for drug or drug target within siderophore metabolism.
Subject(s)
Mycobacterium/metabolism , Siderophores/biosynthesis , Comparative Genomic Hybridization , Iron/metabolism , Multigene Family , Mycobacterium/classification , Mycobacterium/genetics , Polyketide Synthases/genetics , Polyketide Synthases/metabolismABSTRACT
PURPOSE: To investigate the influence of the peroxisome proliferator activated receptor gamma (PPAR-γ) Pro12Ala polymorphism on the susceptibility of polycystic ovary syndrome (PCOS) and body mass index (BMI), fast insulin levels, homeostasis model assessment of insulin resistance (HOMA-IR) in PCOS patients. METHODS: PubMed, EMBASE, MEDLINE and CENTRAL databases were searched to identify eligible studies. We then conducted a meta-analysis to examine the association between Pro12Ala polymorphism and PCOS. RESULTS: Seventeen eligible studies, including 2,149 patients and 2,124 controls were enrolled in this meta-analysis. Pro12Ala polymorphism was significantly associated with the susceptibility of PCOS (odds ratio [OR] 0.74, 95 % confidence interval [CI] [0.61, 0.90] for allele; OR 0.70, 95 % CI [0.57, 0.86] for genotype). In the European subgroup of PCOS, the X/Ala genotype was associated with lower BMI (mean difference [MD] -1.08, 95 % CI [-2.08, -0.09]) and fast insulin levels (MD -19.82, 95 % CI [-34.07, -5.58]). However, this polymorphism did not display an impact on HOMA-IR in PCOS patients. CONCLUSIONS: Ala variant would decrease the risk of PCOS and result in lower BMI and fast insulin levels in a European population, but had no impact on HOMA-IR in PCOS patients. Further studies are required to elucidate these associations more clear.