ABSTRACT
Dihydro-nicotinamide adenine dinucleotide (NADH) detection is crucial since it is a vital coenzyme in organism metabolism. Compared to the traditional method based on natural NADH oxidase (NOX), nanozymes with multienzyme-like activity can catalyze multistage reactions in a singular setup, simplifying detection processes and enhancing sensitivity. In this study, an innovative NADH detection method was developed using iron-doped carbon (Fe@C) nanozyme synthesized from metal-organic frameworks with in situ reduced Pt clusters. This nanozyme composite (Pt/Fe@C) demonstrated dual NOX and peroxidase-like characteristics, significantly enhancing the catalytic efficiency and enabling NADH conversion to NAD+ and H2O2 with subsequent detection. The collaborative research involving both experimental and theoretical simulations has uncovered the catalytic process and the cooperative effect of Fe and Pt atoms, leading to enhanced oxygen adsorption and activation, as well as a decrease in the energy barrier of the key step in the H2O2 decomposition process. These findings indicate that the catalytic performance of Pt/Fe@C in NOX-like and POD-like reactions can be significantly improved. The colorimetric sensor detects NADH with a limit of detection as low as 0.4 nM, signifying a breakthrough in enzyme-mimicking nanozyme technology for precise NADH measurement.
Subject(s)
Carbon , Metal-Organic Frameworks , NAD , Platinum , NAD/chemistry , Metal-Organic Frameworks/chemistry , Platinum/chemistry , Carbon/chemistry , Iron/chemistry , Hydrogen Peroxide/chemistry , Colorimetry/methods , Humans , Catalysis , Multienzyme Complexes/chemistry , Multienzyme Complexes/metabolism , Biomimetic Materials/chemistry , Limit of Detection , NADH, NADPH OxidoreductasesABSTRACT
Alloy-type antimony (Sb) and conversion-type molybdenum (Mo) anodes have attracted extensive attention in the application of lithium-ion batteries (LIBs) owing to their high theoretical capacity. In this study, Sb2MoO6 nanowires are prepared via a hydrothermal method and assessed their thermal behavior upon heat treatment, observing an intriguing transformation from nanowire to Sb2O3/MoOx nanosheets. To enhance structure stability, the Sb2MoO6 nanowires are successfully coated with a polyphosphazene layer (referred to as PZS@Sb2MoO6), which not only preserved the nanowires form but also yielded N/S co-doped carbon-coated SbPO4/MoOx (NS-C@SbPO4/MoOx) nanowires following annealing in an inert environment. This composite benefits from the stable PO4 3- anion that serve as a buffer against volume expansion and form a Li3PO4 matrix during cycling, both of which substantially bolster ion transport and cycle endurance. Doping with heteroatoms introduces numerous oxygen vacancies, augmenting the number of electrochemically active sites, and carbon integration considerably enhances the electronic conductivity of the electrode and alleviates the volume-change-induced electrode pulverization. Employed as anode materials in LIBs, the NS-C@SbPO4/MoOx electrode exhibits remarkable cycling performance (449.8 mA h g-1 at 1000 mA g-1 over 700 cycles) along with superior rate capability (394.2 mA h g-1 at 2000 mA g-1).
ABSTRACT
Although ALK tyrosine kinase inhibitors (ALK-TKIs) have shown remarkable benefits in EML4-ALK positive NSCLC patients compared to conventional chemotherapy, the optimal sequence of ALK-TKIs treatment remains unclear due to the emergence of primary and acquired resistance and the lack of potential prognostic biomarkers. In this study, we systematically explored the validity of sequential ALK inhibitors (alectinib, lorlatinib, crizotinib, ceritinib and brigatinib) for a heavy-treated patient with EML4-ALK fusion via developing an in vitro and in vivo drug testing system based on patient-derived models. Based on the patient-derived models and clinical responses of the patient, we found that crizotinib might inhibit proliferation of EML4-ALK positive tumors resistant to alectinib and lorlatinib. In addition, NSCLC patients harboring the G1269A mutation, which was identified in alectinib, lorlatinib and crizotinib-resistant NSCLC, showed responsiveness to brigatinib and ceritinib. Transcriptomic analysis revealed that brigatinib suppressed the activation of multiple inflammatory signaling pathways, potentially contributing to its anti-tumor activity. Moreover, we constructed a prognostic model based on the expression of IL6, CXCL1, and CXCL5, providing novel perspectives for predicting prognosis in EML4-ALK positive NSCLC patients. In summary, our results delineate clinical responses of sequential ALK-TKIs treatments and provide insights into the mechanisms underlying the superior effects of brigatinib in patients harboring ALKG1269A mutation and resistant towards alectinib, lorlatinib and crizotinib. The molecular signatures model based on the combination of IL6, CXCL1 and CXCL5 has the potential to predict prognosis of EML4-ALK positive NSCLC patients.
Subject(s)
Adenocarcinoma of Lung , Antineoplastic Agents , Lung Neoplasms , Oncogene Proteins, Fusion , Organophosphorus Compounds , Protein Kinase Inhibitors , Pyrimidines , Humans , Organophosphorus Compounds/therapeutic use , Organophosphorus Compounds/pharmacology , Pyrimidines/therapeutic use , Pyrimidines/pharmacology , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Oncogene Proteins, Fusion/genetics , Oncogene Proteins, Fusion/metabolism , Animals , Adenocarcinoma of Lung/drug therapy , Adenocarcinoma of Lung/genetics , Adenocarcinoma of Lung/pathology , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/pharmacology , Prognosis , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/pharmacology , Drug Resistance, Neoplasm , Lactams/therapeutic use , Carbazoles/therapeutic use , Carbazoles/pharmacology , Sulfones/therapeutic use , Sulfones/pharmacology , Crizotinib/therapeutic use , Crizotinib/pharmacology , Cell Line, Tumor , Piperidines/therapeutic use , Piperidines/pharmacology , Female , Mice , Inflammation/drug therapy , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Pyrazoles/therapeutic use , Pyrazoles/pharmacology , Male , Anaplastic Lymphoma Kinase/genetics , Anaplastic Lymphoma Kinase/antagonists & inhibitors , Anaplastic Lymphoma Kinase/metabolism , Cell Proliferation/drug effects , Mutation , Aminopyridines/therapeutic use , Aminopyridines/pharmacologyABSTRACT
Inflammation and ferroptosis crosstalk complexly with immune microenvironment of hepatocellular carcinoma (HCC), thus affecting the efficacy of immunotherapy. Herein, our aim was to identify the inflammation-associated ferroptosis (IAF) biomarkers for contributing HCC. A total of 224 intersecting DEGs identified from different inflammation- and ferroptosis-subtypes were set as IAF genes. Seven of them including ADH4, APOA5, CFHR3, CXCL8, FTCD, G6PD and PON1 were used for construction of a risk model which classified HCC patients into two groups (high and low risk). HCC patients in the high-risk group exhibited shorter survival rate and higher immune score, and were predicted to have higher respond rate in immune checkpoint inhibition (ICI) therapy. Levels of the seven genes were significantly changed in HCC tissues in comparison to adjacent tissues. After inserting the gene expression into the risk model, we found that the risk model exhibited the higher diagnostic value for distinguish HCC tissues compared each single gene. Furthermore, HCC tissues from our research group with high-risk score exhibited more cases of microsatellite instability (MSI), heavier tumour mutational burden (TMB), higher expression level of PDL1 and cells with CD8. Knockdown of APOA5 reduced HCC cell proliferation combining with elevating inflammation and ferroptosis levels. In conclusion, we considered APOA5 maybe a novel target for suppressing HCC via simultaneously elevating inflammation and ferroptosis levels, and signature constructed by seven IAF genes including ADH4, APOA5, CFHR3, CXCL8, FTCD, G6PD and PON1 can act as a biomarker for optimising the diagnosis, prognosis evaluation and immunotherapy options in HCC patients.
Subject(s)
Carcinoma, Hepatocellular , Ferroptosis , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/diagnosis , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/therapy , Ferroptosis/genetics , Liver Neoplasms/diagnosis , Liver Neoplasms/genetics , Liver Neoplasms/therapy , Immunotherapy , Inflammation/genetics , Tumor Microenvironment/genetics , AryldialkylphosphataseABSTRACT
Objective: To investigate the correlations between APACHE-II score and pressure parameters of mechanical ventilation in patients with acute respiratory distress syndrome (ARDS) and their value in prognostic evaluation. Methods: This was a retrospective study. The clinical data of 79 patients with ARDS treated in Shengzhou Hospital of Traditional Chinese Medicine from April 2020 to April 2022 were analyzed retrospectively. According to whether their APACHE-II scores were higher than 15, they were divided into low score group (n= 20) and high score group (n= 59). The plateau pressure (Pplat), driving pressure(ΔP) and mean airway pressure (Pmean) were compared. The correlation between APACHE-II score and pressure parameters of mechanical ventilation was analyzed. Based on the follow-up of 28-d survival, their Pplat, ΔP, Pmean and APACHE-II scores were compared. The value of APACHE-II score and pressure parameters in the prognostic evaluation of ARDS patients was analyzed. Results: Pplat, ΔP and Pmean in the low score group were significantly lower than those in the high score group(P<0.05). Pplat, ΔP, Pmean and APACHE-II score in the survival group were significantly lower than those in the control group(P<0.05). APACHE-II score showed significantly positive correlations with Pplat, ΔP and Pmean. The AUC of Pmean, Pplat, ΔP and APACHE-II score in predicting the prognosis and diagnosis of ARDS patients was 0.761, 0.833, 0.754 and 0.832, respectively. Conclusion: APACHE-II score of ARDS patients shows significantly positive correlations with pressure parameters of mechanical ventilation, and has diagnostic value for the prognosis of ARDS patients.
ABSTRACT
Hyperactive signal transducer and activator of transcription 3 (STAT3) signaling is frequently detected in human triple-negative breast cancer (TNBC) and gastric cancer, leading to uncontrolled tumor growth, resistance to chemotherapy, and poor prognosis. Thus, inhibition of STAT3 signaling is a promising therapeutic approach for both TNBC and gastric cancer, which have high incidences and mortality and limited effective therapeutic approaches. Here, we report a small molecule, WZ-2-033, capable of inhibiting STAT3 activation and dimerization and STAT3-related malignant transformation. We present in vitro evidence from surface plasmon resonance analysis that WZ-2-033 interacts with the STAT3 protein and from confocal imaging that WZ-2-033 disrupts HA-STAT3 and Flag-STAT3 dimerization in intact cells. WZ-2-033 suppresses STAT3-DNA-binding activity but has no effect on STAT5-DNA binding. WZ-2-033 inhibits the phosphorylation and nuclear accumulation of pY705-STAT3 and consequently suppresses STAT3-dependent transcriptional activity and the expression of STAT3 downstream genes. Moreover, WZ-2-033 significantly inhibited the proliferation, colony survival, migration, and invasion of TNBC cells and gastric cancer cells with aberrant STAT3 activation. Furthermore, administration of WZ-2-033 in vivo induced a significant antitumor response in mouse models of TNBC and gastric cancer that correlated with the inhibition of constitutively active STAT3 and the suppression of known STAT3 downstream genes. Thus, our study provides a novel STAT3 inhibitor with significant antitumor activity in human TNBC and gastric cancer harboring persistently active STAT3.
Subject(s)
Stomach Neoplasms , Triple Negative Breast Neoplasms , Animals , Cell Line, Tumor , Cell Proliferation , Heterografts , Humans , Mice , STAT3 Transcription Factor/metabolism , Stomach Neoplasms/drug therapy , Triple Negative Breast Neoplasms/pathologyABSTRACT
BACKGROUND: Septic heart failure accounts for high mortality rates globally. With a strong reducing capacity, zero-valent iron nanoparticles (nanoFe) have been applied in many fields. However, the precise roles and mechanisms of nanoFe in septic cardiomyopathy remain unknown. RESULTS: NanoFe was prepared via the liquid-phase reduction method and functionalized with the biocompatible polymer sodium carboxymethylcellulose (CMC). We then successfully constructed a mouse model of septic myocardial injury by challenging with cecal ligation and puncture (CLP). Our findings demonstrated that nanoFe has a significant protective effect on CLP-induced septic myocardial injury. This may be achieved by attenuating inflammation and oxidative stress, improving mitochondrial function, regulating endoplasmic reticulum stress, and activating the AMPK pathway. The RNA-seq results supported the role of nanoFe treatment in regulating a transcriptional profile consistent with its role in response to sepsis. CONCLUSIONS: The results provide a theoretical basis for the application strategy and combination of nanoFe in sepsis and septic myocardial injury.
Subject(s)
Heart Failure , Heart Injuries , Nanoparticles , Sepsis , Animals , Heart Failure/metabolism , Iron , Mice , Myocardium/metabolism , Sepsis/metabolismABSTRACT
BACKGROUND: Pubic ramus fracture was an injury of anterior pelvic ring, the anterior pelvic ring plays an important role in maintaining the stability of the pelvis. The purpose of this study was to investigate the effect and indication of percutaneous retrograde pubic screw fixation assisted by hollow pedicle finder for pubic ramus fractures. METHODS: The clinical data of 68 patients with pubic ramus fracture treated with cannulated screw from March 2008 to March 2020 were retrospectively analyzed. According to the surgical methods, they were divided into traditional surgery group (32 cases in group A, with traditional retrograde pubic screw fixation) and modified surgery group (36 cases in group B, with percutaneous retrograde pubic screw fixation assisted by hollow open circuit device). Operation time, blood loss, incision length, screw length and complications were recorded and compared between the two groups. On the second day after surgery, the maximum fracture displacement over plain radiographs, entrance radiographs and exit radiographs of the pelvis was evaluated according to Matta criteria to evaluate the postoperative fracture reduction. Majeed score was used to evaluate the hip function at 12 months after surgery. RESULTS: The operations were successfully completed in both groups. The operation time, blood loss and incision length in group B were significantly less than those in group A (P < 0.05). There was no significant difference in screw length between the two groups (t = 0.797, P = 0.431). All patients were followed up for 8-38 months (mean 21.8 months). There were no vascular and nerve injury, fracture of internal fixator, screw entry into joint cavity, fracture nonunion and other complications in both groups. The fracture healing time of the two groups was 23.1 ± 2.1 weeks in group A while 22.7 ± 2.1 weeks in group B, respectively, and there was no statistical difference in the fracture healing time between the two groups (P > 0.05). In group A, there were 3 cases of incision infection, 1 case of incision fat liquefaction and 2 cases of lower extremity deep venous thrombosis, and the complication rate was 18.8%. There was only 1 case of lower extremity deep vein thrombosis in group B, and the complication rate was 2.8%, which was significantly lower than that in group A. The fracture in one case after surgery was found to be displaced in group A and no fracture was found in group B. There was no significant difference between the two groups in Matta imaging evaluation on the next day after surgery and Majeed function evaluation at 12 months after surgery (P > 0.05). CONCLUSION: Percutaneous retrograde pubic ramus screw fixation assisted by hollow pedicle finder is effective in the treatment of pelvic pubic ramus fracture. It has the advantages of less incision, shorter operation time, less blood loss and lower incidence of complications compared with traditional methods. However, correct surgical indications should be required when we apply this surgical method.
Subject(s)
Fractures, Bone , Pelvic Bones , Spinal Fractures , Bone Screws , Fracture Fixation, Internal/methods , Fractures, Bone/surgery , Humans , Pelvic Bones/injuries , Pelvic Bones/surgery , Retrospective Studies , Treatment OutcomeABSTRACT
Enzyme engineering toward catalytic-tetrad residues usually results in activity loss. Unexpectedly, we found that a directed evolution campaign yielded a beneficial residue A100 in KmCR (a carbonyl reductase from Kluyveromyces marxianus ZJB14056), which is a residue of catalytic tetrad and conserved according to multiple sequence alignment. Inspired by this finding, we performed saturation mutagenesis on all the four residues of catalytic tetrad of KmCR. A number of variants with improved enzymatic activities were obtained. Among them, the variant KmCR_A100S exhibited increased catalytic efficiency (kcat /KM = 47.3 s-1 ·mM-1 ), improved stereoselectivity (from moderate selectivity (deP = 66.7%) to strict (S)-selectivity (deP > 99.5%)), and extended substrate scope, compared to those of KmCR_WT. In silico analysis showed that a relay system was rebuilt in KmCR via the beneficial residue S100. Furthermore, comparison of 11 protein engineering campaigns indicated that the beneficial position is easily overlooked due to the long distance (>10 Å) from ketone substrates. Since CRs share similar catalytic mechanism, the knowledge gained from this study has universal significance to CR engineering.
Subject(s)
Alcohol Oxidoreductases , Catalytic Domain/genetics , Protein Engineering/methods , Alcohol Oxidoreductases/chemistry , Alcohol Oxidoreductases/genetics , Alcohol Oxidoreductases/metabolism , Biocatalysis , Escherichia coli/genetics , Fungal Proteins/chemistry , Fungal Proteins/genetics , Fungal Proteins/metabolism , Kluyveromyces/enzymology , Kluyveromyces/genetics , Molecular Docking Simulation , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/metabolismABSTRACT
This study focused on the ameliorative effects of gypenosides(GPS) on insulin sensitivity and inflammatory factors in rats with type 2 diabetes mellitus(T2 DM) and explored their possible molecular mechanisms. After the successful establishment of T2 DM model, diabetic rats were randomly divided into four groups, including model group, GPS groups(200, 100 mg·kg~(-1)) and metformin group(100 mg·kg~(-1)), with healthy rats serving as the control. After 6-week intragastric administration, fasting blood glucose(FBG) and oral glucose tolerance were examined. The levels of insulin, C-peptide, tumor necrosis factor-α(TNF-α), interleukin-1ß(IL-1ß), interleukin-6(IL-6) and C-reactive protein(CRP) in serum were examined. Then the homeostasis model assessment of insulin resistance(HOMA-IR) and insulin sensitivity index(ISI) were calculated. The protein expression levels of phosphorylated insulin receptor substrate-1(p-IRS-1) and phosphorylated protein kinase B(p-Akt) in skeletal muscle were measured by Western blot, as well as those of phosphorylated inhibitor of nuclear factor-κB(NF-κB) kinase ß(p-IKKß), phosphorylated alpha inhibitor of NF-κB(p-IκBα) and phosphorylated p65 subunit of NF-κB(p-p65) in adipose tissue. The relative expression levels of glucose transporter 4(GLUT4) mRNA in skeletal muscle and NF-κB mRNA in adipose tissue were measured by qRT-PCR, and the morphological changes of pancreatic tissue were observed. Compared with the model group, the GPS groups witnessed significant decrease in FBG, marked amelioration of impaired oral glucose tolerance and significant increase in ISI. Further, the high-dose GPS group saw significantly reduced HOMA-IR, TNF-α, IL-1ß and CRP, significantly increased expression levels of p-IRS-1(Tyr), p-Akt and GLUT4, and markedly inhibited p-IRS-1(Ser), p-IKKß, p-IκBα, p-p65 and NF-κB. The concentration of CRP and the expression levels of p-IRS-1(Ser), p-IKKß, p-IκBα and NF-κB were remarkably reduced in the low-dose GPS group. However, GPS was found less effective in the regulation of serum insulin, C-peptide and IL-6 levels and the alleviation of pancreatic islet injury. The results indicated that GPS can reduce FBG and improve insulin sensitivity in diabetic rats possibly by regulating the NF-κB signaling pathway, inhibiting inflammation, and thereby regulating the expression of key proteins in the insulin signaling pathway.
Subject(s)
Diabetes Mellitus, Experimental , Diabetes Mellitus, Type 2 , Insulin Resistance , Animals , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/genetics , Gynostemma , Insulin , NF-kappa B/genetics , NF-kappa B/metabolism , Plant Extracts , Rats , Signal TransductionABSTRACT
Abscisic acid (ABA) signaling is a vital plant signaling pathway for plant responses to stress conditions. ABA treatment can alter global gene expression patterns and cause significant phenotypic changes. We investigated the responses to ABA treatment during flowering in Arabidopsis thaliana. Dipping the flowers of CARK3 T-DNA mutants in ABA solution, led to less reduction of pollen fertility than in the wild type plants (Col-0). We demonstrated that PMEIL, a gene located downstream of CARK3, directly affects pollen fertility. Due to the close arrangement of CARK3 and PMEIL, CARK3 expression represses transcription of PMEIL in an ABA-dependent manner through transcriptional interference. Our study uncovers a molecular mechanism underlying ABA-mediated pollen sterility and provides an example of how transcriptional interference caused by close arrangement of genes may mediate stress responses during plant reproduction.
Subject(s)
Abscisic Acid/metabolism , Arabidopsis Proteins/genetics , Arabidopsis/genetics , Intracellular Signaling Peptides and Proteins/genetics , Plant Growth Regulators/physiology , Plant Infertility/genetics , Pollen/genetics , Protein Serine-Threonine Kinases/genetics , Arabidopsis/physiology , Arabidopsis Proteins/physiology , Gene Order/genetics , Gene Order/physiology , Germination , Intracellular Signaling Peptides and Proteins/physiology , Plant Growth Regulators/metabolism , Plant Infertility/physiology , Pollen/physiology , Protein Serine-Threonine Kinases/physiologyABSTRACT
The polyethyleneimine (PEI)-based antigen delivery system has been proved valuable for therapeutic vaccines. However, the previous bulk mixing method is not ideal to prepare PEI-base antigen- containing nanoparticles. The wide-size distribution and poor reproducibility limit its further application. In this research, we developed a microfluidic method to prepare nanopolyplexes on chips with Tesla structure to improve the fabrication. The structure and bioactivity of protein were not hampered by the shearing force in microfluidics. Comparison between physiochemical parameters suggested that the polyplexes prepared by Tesla chips were more uniform than those prepared by bulk mixing and non-Tesla chips. The reproducibility was improved obviously. The preparation was not influence much by the operating parameters such as flow rates, reagents concentration, and switching of inlets. The results indicated that it was a robust and reliable method. The data that were obtained from BMDC model demonstrated that the nanopolyplexes with optimal weight ratio had higher antigen cross-presentation efficiency than those in free antigen group. In conclusion, Tesla structured microfluidics offers a better method over bulk mixing in the preparation of PEI-based antigen-containing nanopolyplexes. It greatly expands the scope of our study and increases the potential of PEI-based antigen delivery system.
Subject(s)
Drug Carriers/chemistry , Lab-On-A-Chip Devices , Microfluidic Analytical Techniques/methods , Nanoparticles/chemistry , Animals , Antigens/chemistry , Cell Line , Male , Mice , Mice, Inbred C57BL , Particle Size , Polyethyleneimine/chemistryABSTRACT
Mangrove wetlands are important coastal ecosystems in tropical and subtropical regions, and mangrove sediments and tissues often are the pollutant sinks due to their high organic matter contents. Polycyclic aromatic hydrocarbons (PAHs) in the mangrove sediments and tissues of nine species from three typical mangrove wetlands of Hainan Island were studied. The average concentration of PAHs in all mangrove tissues was 403 ng g-1 dw, with PAHs concentrations in leaf, branch, root, and fruit of 566, 335, 314, and 353 ng g-1 dw, respectively. PAHs levels were much higher in leaf than in other mangrove tissues, which may be caused partly by atmospheric deposition of PAHs. The dominant individual PAH compounds in mangrove tissues were phenanthrene (41.3%), fluoranthene (14.7%), and pyrene (11.4%), while in sediments were naphthalene (73.4%), phenanthrene (3.9%), and pyrene (3.6%), respectively. The biota-sediment accumulation factors of PAH congeners in the mangrove wetlands showed different patterns, with the most predominant of phenanthrene. The cycling of PAHs in the mangrove wetlands of Hainan Island also were estimated, and the results showed that the standing accumulation, the annual absorption, the annual net retention, the annual return, and the turnover period in all mangrove tissues of the community were 2228 µg m-2, 869 µg m-2 a-1, 206 µg m-2 a-1, 663 µg m-2 a-1, and 3.4 a, respectively. These results indicated that mangroves are playing an important role in retaining PAHs.
Subject(s)
Plants/chemistry , Polycyclic Aromatic Hydrocarbons/analysis , Water Pollutants, Chemical/analysis , Wetlands , Biota , China , Ecosystem , Environmental Monitoring/methods , Geologic Sediments , Phenanthrenes/analysis , Phenanthrenes/pharmacokinetics , Plants/drug effects , Plants/metabolism , Polycyclic Aromatic Hydrocarbons/pharmacokinetics , Pyrenes/analysis , Pyrenes/pharmacokinetics , Water Pollutants, Chemical/pharmacokineticsABSTRACT
EDP-239, a novel hepatitis C virus (HCV) inhibitor targeting nonstructural protein 5A (NS5A), has been investigated in vitro and in vivo EDP-239 is a potent, selective inhibitor with potency at picomolar to nanomolar concentrations against HCV genotypes 1 through 6. In the presence of human serum, the potency of EDP-239 was reduced by less than 4-fold. EDP-239 is additive to synergistic with other direct-acting antivirals (DAAs) or host-targeted antivirals (HTAs) in blocking HCV replication and suppresses the selection of resistance in vitro Furthermore, EDP-239 retains potency against known DAA- or HTA-resistant variants, with half-maximal effective concentrations (EC50s) equivalent to those for the wild type. In a phase I, single-ascending-dose, placebo-controlled clinical trial, EDP-239 demonstrated excellent pharmacokinetic properties that supported once daily dosing. A single 100-mg dose of EDP-239 resulted in reductions in HCV genotype 1a viral RNA of >3 log10 IU/ml within the first 48 h after dosing and reductions in genotype 1b viral RNA of >4-log10 IU/ml within 96 h. (This study has been registered at ClinicalTrials.gov under identifier NCT01856426.).
Subject(s)
Antiviral Agents/pharmacology , Benzimidazoles/pharmacology , Hepacivirus/drug effects , Hepatitis C, Chronic/drug therapy , Valine/analogs & derivatives , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/pharmacokinetics , Carbamates , Cell Line , Drug Evaluation, Preclinical/methods , Drug Resistance, Viral/drug effects , Drug Resistance, Viral/genetics , Drug Therapy, Combination , Female , Hepacivirus/genetics , Humans , Imidazoles/pharmacology , Male , Pyrrolidines , RNA, Viral/blood , Valine/pharmacology , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/metabolism , Virus Replication/drug effectsABSTRACT
BACKGROUND: Assessment of immunoglobulin A (IgA) antibody responses to Epstein-Barr virus (EBV) antigen is important for the early diagnosis of nasopharyngeal carcinoma (NPC). EBV glycoprotein gp42 has been shown to play an essential role in membrane fusion with B cells. The aim of the present study was to assess whether the antibodies to EBV glycoprotein gp42 in serum could be a novel marker for diagnosis of NPC. METHODS: EBV glycoprotein gp42 expressed in the recombinant baculovirus system was used in an enzyme-linked immunosorbent assay (ELISA) to detect antibodies to gp42 in serum. The blood samples were obtained from 406 participants (n = 208 patients with NPC and 198 healthy controls). Receiver operating characteristics (ROC) was used to calculate diagnostic accuracy. RESULTS: The ROC curves showed that IgA-gp42 ELISA had a sensitivity of 76.4%, specificity of 78.3% and an area under the curve (AUC) of 0.856 (95% CI, 0.82 - 0.891) to diagnose NPC. Furthermore, gp42 maintained diag- nostic capacity in NPC patients who were IgA-viral capsid antigen (VCA) negative (87.5%, 64.1% and 0.844 [95% CI, 0.776 - 0.912]). Combining gp42 and VCA improved the diagnostic capacity compared with the individual tests (89.9%, 94.4% and 0.973 [95% CI, 0.959 - 0.9871). CONCLUSIONS: The EBV glycoprotein complex gp42 acts as a novel biomarker for diagnosis of NPC and improves identification of patients with VCA-negative NPC.
Subject(s)
Antibodies, Viral/blood , Glycoproteins/immunology , Nasopharyngeal Neoplasms/diagnosis , Viral Proteins/immunology , Adult , Biomarkers , Capsid Proteins/analysis , Carcinoma , Female , Humans , Immunoglobulin A/blood , Logistic Models , Male , Middle Aged , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms/virology , ROC CurveABSTRACT
Bioaccumulation and trophic transfer of mercury (Hg) both in the natural marine ecosystem and the mariculture ecosystem were studied at Daya Bay, a subtropical bay in Southern China. Averaged Hg concentrations in sediment, phytoplankton, macrophyte, shrimp, crab, shellfish, planktivorous fish, carnivorous fish, farmed pompano, farmed snapper, compound feed and trash fish were 0.074, 0.054, 0.044, 0.098, 0.116, 0.171, 0.088, 0.121, 0.210, 0.125, 0.038 and 0.106 µg g(-1) dw, respectively. These Hg levels were at the low-middle ends of the global range. Positive correlation between Hg concentrations in farmed fish and fish weights/sizes was observed, whereas no clear correlation between Hg concentrations and lipid contents was found. Hg concentrations followed macrophyte < phytoplankton < sediment < planktivorous fish < shrimp < crab < carnivorous fish < shellfish, and commercial feed < trash fish < farmed fish. Hg was biomagnified along the marine food chain in the ecosystem of Daya Bay. Hg levels in the farmed fish were higher than those in the wild fish primarily because of the higher Hg level in fish feed and the smaller size of marine wild fish.
Subject(s)
Bays/chemistry , Food Chain , Geologic Sediments/analysis , Mercury/metabolism , Water Pollutants, Chemical/metabolism , Animals , Animals, Wild/metabolism , Aquaculture , China , Environmental Monitoring , Mercury/analysis , Water Pollutants, Chemical/analysisABSTRACT
Neuromyelitis optica spectrum disorder-related optic neuritis (NMOSD-ON) is an autoimmune disease that affects the astrocytes. NMOSD-ON is one of the core clinical phenotypes of neuromyelitis optica spectrum disorder and its most-common initial symptom. NMOSD-ON is characterized by severe vision loss, poor prognosis and high recurrence, mainly affecting young and middle-aged individuals. It is a challenge to know how to improve patients' visual outcomes. In this report, we present a refractory case of NMOSD-ON treated with satralizumab after multiple conventional therapies proved ineffective. Satralizumab was found to effectively control relapses in this patient and visual improvement was found after 18 months of treatment. Given to that, satralizumab may have a potential longitudinal effect on visual improvement in NMOSD-ON.
ABSTRACT
In order to obtain high yield pomelo peel pectin with better physicochemical properties, four pectin extraction methods, including hot acid extraction (HAE), microwave-assisted extraction (MAE), ultrasound-assisted extraction, and enzymatic assisted extraction (EAE) were compared. MAE led to the highest pectin yield (20.43%), and the lowest pectin recovery was found for EAE (11.94%). The physicochemical properties of pomelo peel pectin obtained by different methods were also significantly different. Pectin samples obtained by MAE had the highest methoxyl content (8.35%), galacturonic acid content (71.36%), and showed a higher apparent viscosity, thermal and emulsion stability. The pectin extracted by EAE showed the highest total phenolic content (12.86%) and lowest particle size (843.69 nm), showing higher DPPH and ABTS scavenging activities than other extract methods. The pectin extracted by HAE had the highest particle size (966.12 nm) and degree of esterification (55.67%). However, Fourier-transform infrared spectroscopy showed that no significant difference occurred among the different methods in the chemical structure of the extracted pectin. This study provides a theoretical basis for the industrial production of pomelo peel pectin.
Subject(s)
Citrus , Hexuronic Acids , Pectins , Pectins/chemistry , Pectins/isolation & purification , Citrus/chemistry , Viscosity , Particle Size , Microwaves , Spectroscopy, Fourier Transform Infrared , Plant Extracts/chemistry , Plant Extracts/isolation & purification , Chemical Fractionation/methods , Chemical Phenomena , Fruit/chemistry , Antioxidants/chemistry , Antioxidants/isolation & purification , Antioxidants/pharmacology , Phenols/analysis , Phenols/chemistry , Phenols/isolation & purification , EsterificationABSTRACT
Seawater warming, ocean acidification and chemical pollution are the main threats to coral growth and even survival. The legacy persistent organic contaminants (POCs), such as polycyclic aromatic hydrocarbons (PAHs), organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs), and the emerging contaminants, including polybrominated diphenyl ethers (PBDEs), dechlorane plus (DPs) and novel brominated flame retardants (NBFRs) were studied in corals from Luhuitou fringing reef in Sanya Bay and Yongle atoll in Xisha Islands, the South China Sea (SCS). Total average concentrations of ∑16PAHs, ∑23OCPs, ∑34PCBs, ∑8PBDEs, ∑2DPs and ∑5NBFRs in 20 coral species (43 samples) from the SCS were 40.7 ± 34.6, 5.20 ± 5.10, 0.197 ± 0.159, 3.30 ± 3.70, 0.041 ± 0.042 and 36.4 ± 112 ng g-1 dw, respectively. PAHs and NBFRs were the most abundant compounds and they are likely to be dangerous pollutants for future coral growth. Compared to those found in other coral reef regions, these pollutants concentrations in corals were at low to median levels. Except for PBDEs, POCs in massive Porites were significantly higher than those in branch Acropora and Pocillopora (p < 0.01), as large, closely packed corals may be beneficial for retaining more pollutant. The current study contributes valuable data on POCs, particularly for halogenated flame retardants (HFRs, including PBDEs, DPs and NBFRs), in corals from the SCS, and will improve our knowledge of the occurrence and fate of these pollutants in coral reef ecosystems.