Peroxynitrite-activated fluorescent probe with two reaction triggers for pathological diagnosis and therapeutic evaluation of inflammation.

Excessive peroxynitrite (ONOO-) is closely related to the occurrence and progression of inflammation. Therefore, the development of an efficacious ONOO- activatable probe holds great potential for the early diagnosis of pathological inflammation, and the direct evaluation of the therapeutic efficacy of active protectants. In this work, a new ONOO--activated fluorescent probe (SZP) which greatly improved the specificity and sensitivity (LOD = 8.03 nM) with large Stokes shift (150 nm) through introducing two reaction triggers (diphenyl phosphinate moiety, CC unsaturated bond) was rationally designed for rapid detecting ONOO- (within 2 min). The excellent properties of probe SZP enable it to realize the fluorescence-guided diagnosis of inflammation. More importantly, probe SZP has also been utilized to assess the anti-inflammatory efficacy of traditional Chinese medicines (TCMs) active ingredients for the remediation of inflammation by monitoring ONOO- fluctuation for the first time.

A new dyslipidemia-based scoring model to predict transplant-free survival in patients with hepatitis E-triggered acute-on-chronic liver failure.

BACKGROUND/AIMS: Hepatitis E virus (HEV)-triggered acute-on-chronic liver failure (ACLF) has unacceptably high short-term mortality. However, it is unclear whether the existing predictive scoring models are applicable to evaluate the prognosis of HEV-triggered ACLF. METHODS: We screened datasets of patients with HEV-triggered ACLF from a regional tertiary hospital for infectious diseases in Shanghai, China, between January 2011 and January 2021. Clinical and laboratory parameters were recorded and compared to determine a variety of short-term mortality risk factors, which were used to develop and validate a new prognostic scoring model. RESULTS: Out of 4952 HEV-infected patients, 817 patients with underlying chronic liver disease were enrolled in this study. Among these, 371 patients with HEV-triggered ACLF were identified and allocated to the training set (n = 254) and test set (n = 117). The analysis revealed that hepatic encephalopathy (HE), ascites, triacylglycerol and apolipoprotein A (apoA) were associated with 90-day mortality (P < 0.05). Based on these significant indicators, we designed and calculated a new prognostic score = 0.632 × (ascites: no, 1 point; mild to moderate, 2 points; severe, 3 points) + 0.865 × (HE: no, 1 point; grade 1-2, 2 points; grade 3-4, 3 points) - 0.413 × triacylglycerol (mmol/L) - 2.171 × apoA (g/L). Compared to four well-known prognostic models (MELD score, CTP score, CLIF-C OFs and CLIF-C ACLFs), the new scoring model is more accurate, with the highest auROCs of 0.878 and 0.896, respectively, to predict 28- and 90-day transplantation-free survival from HEV-triggered ACLF. When our model was compared to COSSH ACLF IIs, there was no significant difference. The test data also demonstrated good concordance. CONCLUSIONS: This study is one of the first to address the correlation between hepatitis E and serum lipids and provides a new simple and efficient prognostic scoring model for HEV-triggered ACLF.

[Comparison of distribution of eight components from Liangxue Tuizi Mixture between normal and Henoch-Schonlein purpura rats].

This study used UPLC-TQ-MS technology to replicate a Henoch-Schonlein purpura(HSP) model in rats by administering warm drugs by gavage and injecting ovalbumin with Freund's complete adjuvant emulsion. The distribution differences and characteristics of eight major components(ferulic acid, caffeic acid, neochlorogenic acid, cryptochlorogenic acid, benzoyl oxypaeoniflorin, tracheloside, loganin, and paeoniflorin) in rat liver, lung, heart, spleen, and kidney tissues were determined after oral administration of the Liangxue Tuizi Mixture at a dose of 42 g·kg~(-1) in both normal physiological and HSP states at 0.5, 1, 2, 6, and 12 hours. The results showed that the distribution patterns of the eight components of Liangxue Tuizi Mixture in the tissues of normal and HSP model rats were different. The main component, paeoniflorin, in Moutan Cortex and Paeoniae Radix Alba had higher content in all tissues. The eight components were predominantly distributed in the liver, lung, and kidney tissues, followed by spleen and heart tissues.

[Potential components and mechanism of Liangxue Tuezi Mixture in treating Henoch-Schönlein purpura based on network pharmacology and metabolomics].

Ultra-performance liquid chromatography-quadrupole time of fight/mass spectrometry(UPLC-Q-TOF-MS) and UNIFI were employed to rapidly determine the content of the components in Liangxue Tuizi Mixture. The targets of the active components and Henoch-Schönlein purpura(HSP) were obtained from SwissTargetPrediction, Online Mendelian Inheritance in Man(OMIM), and GeneCards. A "component-target-disease" network and a protein-protein interaction(PPI) network were constructed. Gene Ontology(GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis were performed for the targets by Omishare. The interactions between the potential active components and the core targets were verified by molecular docking. Furthermore, rats were randomly assigned into a normal group, a model group, and low-, medium-, and high-dose Liangxue Tuizi Mixture groups. Non-targeted metabolomics was employed to screen the differential metabolites in the serum, analyze possible metabolic pathways, and construct the "component-target-differential metabolite" network. A total of 45 components of Liangxue Tuizi Mixture were identified, and 145 potential targets for the treatment of HSP were predicted. The main signaling pathways enriched included resistance to epidermal growth factor receptor tyrosine kinase inhibitors, phosphatidylinositol 3-kinase/protein kinase B(PI3K-AKT), and T cell receptor. The results of molecular docking showed that the active components in Liangxue Tuizi Mixture had strong binding ability with the key target proteins. A total of 13 differential metabolites in the serum were screened out, which shared 27 common targets with active components. The progression of HSP was related to metabolic abnormalities of glycerophospholipid and sphingolipid. The results indicate that the components in Liangxue Tuizi Mixture mainly treats HSP by regulating inflammation and immunity, providing a scientific basis for rational drug use in clinical practice.

Selectivity mechanism of BCL-XL/2 inhibition through in silico investigation.

The BCL-XL protein is among the most important members of the anti-apoptotic subfamily of the BCL-2 protein family, and is currently a promising new target for anti-tumor drug research. However, the BCL-XL/2 proteins have similar structures and functions, which could lead to undesirable side effects because of inhibitors that can bind to both BCL-XL and BCL-2. Therefore, it is crucial to expound on the structural basis of the selective mechanism towards BCL-XL/2 inhibition. In the current study, we employed hybrid computational methods including molecular docking and dynamics simulation, MM/GBSA energy calculation, alanine scanning mutagenesis and Hirshfeld surface analysis to comprehensively reveal the selectivity mechanism towards BCL-XL/2 from multiple perspectives, revealing the significant effects of the BCL-XL residues SER106 and LEU108 as well as the BCL-2 residue ASP103 on the inhibitory selectivity. Overall, our findings provide useful references for the rational design of BCL-XL/2 selective inhibitors with better affinity.

Selectivity mechanism of muscarinic acetylcholine receptor antagonism through in silico investigation.

Structures of muscarinic acetylcholine receptors illustrate the strikingly high degree of homology of the residues among isoforms, thus leading to difficulty in achieving subtype selectivity when targeting these receptors and causing undesired side effects when treating the corresponding diseases. Considering the urgent need for more selective and potency therapies, this study is aimed at revealing the selectivity mechanism against M4/5 via in silico strategies, revealing crucial molecular interactions such as hydrogen bonds and pi-cation interaction formed between the key residues TYR416, ASN417, and TRP435 of M4, respectively, hydrophobic pocket formed by the key residues, especially CYS484 of M5. Besides, the water around TYR416M4 and ASN459M5, which can be replaced by substituent groups which can form the hydrogen bond interaction network by simulated bridging water and the water around ASP112M4, whose replacement maybe not contribute to the increase in binding affinity of the compound, may affect the inhibitory selectivity among M4/5 in the aspect of the solvent. Moreover, from the point of inhibitors, compounds with a positively ionizable group could selectively bind to M4 receptors, while hydrophobic molecules may bind preferably to M5. We believe that the current study would provide a basis for the design of subsequent M4/5 selective antagonists.

Epidemiology of suspected life-threatening perioperative anaphylaxis: a cross-sectional multicentre study in China.

BACKGROUND: Perioperative anaphylaxis is relatively rare but can be life-threatening. The incidence in China is unknown and may differ from other global geographic regions. This study was therefore designed to understand the incidence of perioperative anaphylaxis in China. METHODS: We enrolled 112 tertiary care hospitals from seven distinct geographic areas in mainland China. We collected information about Ring and Messmer III and IV reactions from September 2018 to August 2019. A collaborative educational learning network was used to reduce diagnostic errors. Information about patient characteristics, clinical features, treatment, and clinical outcomes were recorded and analysed. RESULTS: A total of 447 cases of 5 078 118 surgical procedures met inclusion criteria. The incidence of suspected perioperative anaphylaxis throughout China was one in 11 360 anaesthetics (95% confidence interval [CI], with a range of 1:12 521 to 1:10 397). The incidence in South China was higher (one in 6050; 95% CI, from 1:8013 to 1:4859) than in Northeast China (one in 19 262; 95% CI, from 1:33 088 to 1:13 585) (P<0.01) with an increasing trend from the north to the south. The most common clinical manifestations were hypotension (91.1%) and tachycardia (65.3%). The majority of patients (83.4%) were given epinephrine. A total of 27 patients (6.0%) required cardiopulmonary resuscitation. Ultimately, nine patients died (2.0%). CONCLUSIONS: This nationwide survey showed an incidence of perioperative anaphylaxis of one in 11 360, but this varied significantly by region. The underlying reason for this pattern remains unknown and could be attributable to environmental or genetic influences, which requires further investigation. CLINICAL REGISTRY NUMBER: ChiCTR1900025956.

The exposure levels and health risk assessment of antibiotics in urine and its association with platelet mitochondrial DNA methylation in adults from Tianjin, China: A preliminary study.

There has been extensive research on antibiotics exposure in adults by biomonitoring, but the biological mechanisms and potential risks to human health remain limited. In this study, 102 adults aged 26-44 years in Tianjin were studied and 23 common antibiotics in urine were analyzed by Liquid chromatography-mass spectrometry (LC-MS). All antibiotics were detected in urine, with an overall detection frequency of 40.4% (the detection frequencies of phenothiazines, quinolones, sulfonamides, tetracyclines, and chloramphenicol were 77%, 54%, 24%, 28%, and 49%, respectively.). Ofloxacin and enrofloxacin had the highest detection frequencies (85% and 81%), with median concentrations of 0.26 (IQR: 0.05-1.36) and 0.09 (IQR: 0.03-0.14) ng/mL, respectively. Based on health risk assessment, the predicted estimated daily exposures (EDEs) ranged from 0 µg/kg/day to 13.98 µg/kg/day. The hazard quotient (HQ) values of all the antibiotics except ofloxacin and ciprofloxacin were bellow one, which are considered safe. For all blood samples, the mitochondrial DNA (mtDNA) methylation levels in the MT-ATP6 (ranging between 3.86% and 34.18%) were slightly higher than MT-ATP8 and MT-ND5 (ranging between 0.57% and 9.32%, 1.08% and 19.62%, respectively). Furthermore, mtDNA methylation from MT-ATP6, MT-ATP8 and MT-ND5 were measured by bisulfite-PCR pyrosequencing. The association (P < 0.05) was found between mtDNA methylation level (MT-ATP8 and MT-ND5) and individual antibiotics including chlorpromazine, ciprofloxacin, enrofloxacin, norfloxacin, pefloxacin, sulfaquinoxaline, sulfachloropyridazine, chloramphenicol, and thiamphenicol, indicating that persistent exposure to low-dose multiple antibiotics may affect the mtDNA methylation level and in turn pose health risks.

[Serum metabolomics of chronic obstructive pulmonary disease with lung-Qi deficiency syndrome].

The present study analyzed the potential biomarkers of chronic obstructive pulmonary disease(COPD) with lung-Qi deficiency syndrome by non-targeted metabolomics and explored the biological basis of this syndrome. Blood samples of 96 COPD patients with lung-Qi deficiency syndrome(COPD with lung-Qi deficiency syndrome group) and 106 healthy people(healthy control group) were collected, and the metabolic profiles of both groups were analyzed by ultra-high performance liquid chromatography-quadrupole-time-of-flight mass spectrometry(UPLC-Q-TOF-MS). Multivariate statistical analysis and differential metabolite screening were carried out by using Progenesis QI and Simca-P. Metabolic pathways were constructed through the MetaboAnalyst. Seven potential biomarkers, such as L-cystathionine, protoporphyrinogen Ⅸ, and citalopram aldehyde, were identified. Compared with the results in the healthy control group, the content of citalopram aldehyde, N1-methyl-2-pyridone-5-carboxamide, and 11ß,17ß-dihydroxy-4-androsten-3-one was significantly up-regulated, while that of the other four compounds such as L-cystathionine, dihydrotestosterone, protoporphyrinogen Ⅸ, and D-urobilinogen was down-regulated. These potential biomarkers involved six metabolic pathways, including cysteine and methionine metabolism, porphyrin and chlorophyll metabolism, drug metabolism of cytochrome P450, steroid hormone biosynthesis, glycine, serine, and threonine metabolism, and nicotinate and nicotinamide meta-bolism. This study is expected to provide a certain scientific basis for the research on traditional Chinese medicine syndrome of COPD with lung-Qi deficiency syndrome from the molecular biology level.

[Study on alleviating effect of Glycyrrhizae Radix et Rhizoma on Psoraleae Fructus-induced liver injury based on network pharmacology and cell experiments].

This study was designed to explore the alleviating effect and mechanism of Glycyrrhizae Radix et Rhizoma against Psora-leae Fructus-induced liver injury based on network pharmacology and cell experiments. The active components of Glycyrrhizae Radix et Rhizoma and Psoraleae Fructus were first retrieved from the Encyclopedia of Traditional Chinese Medicine(ETCM), Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP), Comparative Toxicogenomics Database(CTD), and literature and further screened by SwissADME. The obtained 25 potential toxic components of Psoraleae Fructus and 29 flavonoids in Glycyrrhizae Radix et Rhizoma were input into the SwissTargetPrediction for target predication. A total of 818 targets related to liver injury were screened out based on GeneCards and MalaCards, and 91 common targets of Psoraleae Fructus, Glycyrrhizae Radix et Rhizoma, and liver injury were obtained from Venny. STRING was applied for constructing the PPI network, and Metascape for analyzing the biological processes and signaling pathways that common targets participated in. Cytoscape was used to construct the component-target-disease network and component-target-pathway network for Glycyrrhizae Radix et Rhizoma against Psoraleae Fructus-induced liver injury. The predicted core targets were proto-oncogene tyrosine-protein kinase(SRC), phosphatidylinositol 4,5-bisphosphate 3-kinase subunit alpha(PIK3 CA), RAC-alpha serine/threonine-protein kinase(AKT1), etc, with PI3 K-AKT signaling pathway, MAPK signaling pathway, apoptosis, Toll-like receptor signaling pathway, and NF-κB signaling pathway mainly involved. Following the scree-ning of the main toxic and pharmacodynamic components, the pharmacodynamic effects were investigated by cell experiments. The results showed that licochalcone A was mainly responsible for alleviating coryfolin-induced liver injury, licochalcone B for coryfolin-and psoralidin-induced liver injury, and echinatin for corylifolinin-and bakuchiol-induced liver injury. The preliminary revealing of the alleviating effect of Glycyrrhizae Radix et Rhizoma on Psoraleae Fructus-induced liver injury and the prediction of related mechanisms will provide reference for further mechanism research and reasonable clinical compatibility.

[Comparison on distribution of 8 components from ethanol extract of Psoraleae Fructus between normal and lipopolysaccharide-induced model rats].

UPLC-TQ/MS was employed to determine the content of 8 main components(psoralen, isopsoralen, psoralenoside, isopsoralenoside, bavachin, psoralidin, corylin, and neobavaisoflavone) in tissues of normal and lipopolysaccharide(LPS)-induced model rats 0.5, 1, 2, 6, and 12 h after intragastric administration of 3.6 g·kg~(-1) ethanol extract of Psoraleae Fructus. The distribution characteristics of the 8 main components in the different tissues(liver, kidney, spleen, heart, and lung) were studied and compared. The results showed that the distribution behaviors of the components varied among different tissues. At different time points, the components presented wide and uneven distribution in the body. Liver and kidney had higher content of the components, followed by spleen, heart, and lung. In both normal and LPS-induced model rats, the content of the 8 main components was higher in liver and kidney and varied significantly among different tissues. The content of psoralen in the tissues of LPS-induced model rat was significantly higher than that of the normal group 12 h after administration. The reason may be that the modeling slowed down the absorption and distribution of psoralen. The LPS-induced model rats had higher content of psoralenoside and isopsoralenoside in the liver tissue than the normal rats, which indicated that the modeling increased the absorption and distribution of psoralenoside and isopsoralenoside in the liver tissue. Further, it is hypothesized that psoralenoside and isopsoralenoside may be toxic substances of Psoraleae Fructus-induced liver injury.

Discovery of a novel and selective cathepsin L inhibitor with anti-metastatic ability in vitro and in vivo against breast cancer cells.

Asperphenamate is a natural product that has attracted considerable interest from researchers worldwide. In the last decade, aiming to increase the biological activity and improve druggability, modifications of the A-ring moiety in asperphenamate have been performed. Our laboratory has also recently reported functional derivatizations of the A ring and studied its effect on the inhibition of cysteine cathepsin L. However, the functional significance of the B-ring fragment toward cathepsin L has not been evaluated thus far. In this paper, forty-four derivatives of the B-ring substituted with different N-phenylsulfonyl groups were designed and synthesized. Among them, the paratrifluromethyl analog B-2a and the 2, 4-difluoro-5-chloro derivative B-11b showed more potent inhibitory activity against cathepsin L than the control compound, ABR, which displayed the strongest inhibitory effect on cathepsin L and S among all reported asperphenamate derivatives. In particular, compound B-2a showed more pronounced selectivity against cathepsin L than the other derivatives. Molecular docking revealed that the N-phenylsulfonylamide moiety was vital for the interactions between B-2a and cathepsin L. Moreover, B-2a displayed no toxicity against normal cells. Therefore, compound B-2a was selected for further studies. Wound-healing assays, Transwell chamber assays and breast cancer lung metastasis mouse models demonstrated that B-2a exhibited antimetastatic ability in vitro and in vivo.

Intrahepatic manifestation and distant extrahepatic disease in alveolar echinococcosis: a multicenter cohort study.

BACKGROUND: The main endemic areas of alveolar echinococcosis (AE) are in central Europe and western China. The infiltration of intrahepatic vascular and bile ducts as well as extrahepatic disease can lead to complications and may increase morbidity in AE. PURPOSE: To evaluate the vascular/biliary involvement of hepatic alveolar echinococcosis (HAE) and distant extrahepatic disease at each of four locations in Germany, France, and China. MATERIAL AND METHODS: Contrast-enhanced abdominal magnetic resonance imaging (MRI) scans of patients with HAE, 200 in total, were evaluated by five examiners. AE liver lesions were classified according to Kodama's classification. Furthermore, distant extrahepatic manifestations were documented with additionally performed imaging modalities. Vascular/biliary involvement of hepatic manifestations as well as the presence of extrahepatic manifestations were correlated with the respective Kodama type of the liver lesion. RESULTS: Distant extrahepatic AE manifestations were significantly more frequent in China than in Europe (12/100 vs. 3/100; Fisher's exact test: P=0.0286). A significant relationship exists between presence of distant extrahepatic disease manifestation and size of the AE liver lesion (132.53 ± 48.65 vs. 92.49 ± 50.06; P = 0.0030). Vascular/biliary involvement is significantly more frequent in China than in Europe (86/100 vs. 65/100; χ2 = 11.92; P = 0.0006). Vascular/biliary involvement depends on lesion size (111.10 ± 47.44 vs. 47.36 ± 24.36; P<0.0001). Different types of AE liver lesions are associated with differences in vascular/biliary involvement and extrahepatic manifestations. CONCLUSION: Vascular/biliary involvement and presence of distant extrahepatic manifestations depend on size of the HAE lesions and are more frequently detected in China. Different MRI morphological patterns influence vascular/biliary involvement and the occurrence of distant extrahepatic manifestations.

Anesthesia Management and Perioperative Infection Control in Patients With the Novel Coronavirus.

Anesthesiologists have a high risk of infection with COVID-19 during perioperative care and as first responders to airway emergencies. The potential of becoming infected can be reduced by a systematic and integrated approach that assesses infection risk. The latter leads to an acceptable choice of materials and techniques for personal protection and prevention of cross-contamination to other patients and staff. The authors have presented a protocolized approach that uses diagnostic criteria to clearly define benchmarks from the medical history along with clinical symptoms and laboratory tests. Patients can then be rapidly assigned into 1 of 3 risk categories that direct the choice of protective materials and/or techniques. Each hospital can adapt this approach to develop a system that fits its individual resources. Educating medical staff about the proper use of high-risk areas for containment serves to protect staff and patients.

A simple algorithm helps early identification of SARS-CoV-2 infection patients with severe progression tendency.

OBJECTIVES: We aimed to develop a simple algorithm to help early identification of SARS-CoV-2 infection patients with severe progression tendency. METHODS: The univariable and multivariable analysis were computed to identify the independent predictors of COVID-19 progression. The prediction model was established in a retrospective training set of 322 COVID-19 patients and was re-evaluated in a prospective validation set of 317 COVID-19 patients. RESULTS: The multivariable analysis identified age (OR = 1.061, p = 0.028), lactate dehydrogenase (LDH) (OR = 1.006, p = 0.037), and CD4 count (OR = 0.993, p = 0.006) as the independent predictors of COVID-19 progression. Consequently, the age-LDH-CD4 algorithm was derived as (age × LDH)/CD4 count. In the training set, the area under the ROC curve (AUROC) of age-LDH-CD4 model was significantly higher than that of single CD4 count, LDH, or age (0.92, 0.85, 0.80, and 0.75, respectively). In the prospective validation set, the AUROC of age-LDH-CD4 model was also significantly higher than that of single CD4 count, LDH, or age (0.92, 0.75, 0.81, and 0.82, respectively). The age-LDH-CD4 ≥ 82 has high sensitive (81%) and specific (93%) for the early identification of COVID-19 patients with severe progression tendency. CONCLUSIONS: The age-LDH-CD4 model is a simple algorithm for early identifying patients with severe progression tendency following SARS-CoV-2 infection, and warrants further validation.

Extracellular Hepatitis B Virus RNAs Are Heterogeneous in Length and Circulate as Capsid-Antibody Complexes in Addition to Virions in Chronic Hepatitis B Patients.

Extracellular HBV RNA has been detected in both HBV-replicating cell culture media and sera from chronic hepatitis B (CHB) patients, but its exact origin and composition remain controversial. Here, we demonstrated that extracellular HBV RNA species were of heterogeneous lengths, ranging from the length of pregenomic RNA to a few hundred nucleotides. In cell models, these RNAs were predominantly associated with naked capsids, although virions also harbored a minority of them. Moreover, HBV RNAs in hepatitis B patients' blood circulation were localized in unenveloped capsids in the form of capsid-antibody complexes (CACs) and in virions. Furthermore, we showed that extracellular HBV RNAs could serve as the template for viral DNA synthesis. In conclusion, extracellular HBV RNAs mainly consist of pgRNA or the pgRNA species degraded by the RNase H domain of the polymerase in the process of viral DNA synthesis and circulate as CACs and virions. Their presence in blood circulation of CHB patients may be exploited to develop novel biomarkers for HBV persistence.IMPORTANCE Although increasing evidence suggests the presence of extracellular HBV RNA species, their origin and molecular forms are still under debate. In addition to the infectious virions, HBV is known to secrete several species of incomplete viral particles, including hepatitis B surface antigen (HBsAg) particles, naked capsids, and empty virions, during its replication cycle. Here, we demonstrated that extracellular HBV RNAs were associated with naked capsids and virions in HepAD38 cells. Interestingly, we found that unenveloped capsids circulate in the blood of hepatitis B patients in the form of CACs and, together with virions, serve as vehicles carrying these RNA molecules. Moreover, extracellular HBV RNAs are heterogeneous in length and represent either pregenomic RNA (pgRNA) or products of incomplete reverse transcription during viral replication. These findings provide a conceptual basis for further application of extracellular RNA species as novel biomarkers for HBV persistence.

Worldwide literature on epidemiology of human alveolar echinococcosis: a systematic review of research published in the twenty-first century.

PURPOSE: Human alveolar echinococcosis (AE) is a potentially lethal zoonosis caused by the cestode Echinococcus multilocularis. The aim of this systematic review is to establish a comprehensive global AE literature overview taking into account the epidemiologically relevant AE research of the twenty-first century. METHODS: We systematically searched the global literature published from 2001 through 2018 via MEDLINE, EMBASE, the Russian databases eLIBRARY.RU, CyberLeninka, the Chinese databases CNKI, VIP, Journals. RESEARCH: ac.ir (Farsi language-based), Jordan E-Library (Arab language-based) and supplementary Google Scholar, in accordance with the PRISMA guidelines. QGIS software was used for the mapping of the affected countries. RESULTS: We have listed 154 relevant publications in the final literature synopsis in consideration of our quality assessment. Including non-autochthonous cases, human AE was reported in 36 countries within the northern hemisphere from 2001 to 2018. The first publication of AE in Tajikistan, Pakistan, South Korea, Belgium, the Netherlands, Slovakia, Hungary, Lithuania, Latvia, Slovenia and Morocco occurred in this century; further first cases in Taiwan, Thailand, and Denmark were considered to be non-autochthonous by the authors. The highest total case numbers (n ≥ 100 in a single article) were reported in France, Germany, Switzerland, Poland, and Lithuania, including China and Kyrgyzstan with by far the highest prevalence figures. CONCLUSIONS: Our paper emphasises the increasing spread of reported cases and the rise in its numbers in the literature of the twenty-first century, especially in western, northern and eastern Europe, as well as in central Asia. Epidemiological studies on human infections are lacking in many parts of the world.

A nanocomposite consisting of an amorphous seed and a molecularly imprinted covalent organic framework shell for extraction and HPLC determination of nonsteroidal anti-inflammatory drugs.

A novel nanocomposite consisting of an amorphous seed and a molecularly imprinted covalent organic framework shell was prepared via a heterogeneous nucleation and growth method. By using ibuprofen as the dummy template, a molecularly imprinted covalent organic framework (MICOF) with a large surface area was prepared from 1,3,5-triformylbenzene and 4,4'-diaminobiphenyl. It was placed on the surface of monodisperse amorphous seeds. Owing to strong π-interaction, the MICOF@SiO2 nanocomposite displays fast binding kinetics, large adsorption capacities and selectivity for nonsteroidal anti-inflammatory drugs (NSAIDs). Following desorption from the MICOF@SiO2 with methanol containing 1% ammonium hydroxide, the NSAIDs ketoprofen, ibuprofen, diclofenac, indomethacin, flurbiprofen and naproxen were quantified by HPLC with UV detection. Under optimized conditions, the method exhibits good linearity within the range of 0.002-1.0 µg mL-1, low limits of detection (0.38-2.92 µg L-1), and acceptable repeatability. The recoveries of NSAIDs at three spiking levels range from 77 to 112%, and the RSDs are <9.4%. The method was successfully applied to the analysis of NSAIDs in spiked environmental water samples. Graphical abstract A molecular imprinted covalent organic framework nanocomposite (MICOF@SiO2) was prepared by heterogeneous nucleation and growth method. It was explored as a sorbent for the solid phase extraction of nonsteroidal anti-inflammatory drugs before determination by HPLC with UV detection.

[Study on mechanism of Cuscutae Semen flavonoids in improving reproductive damage of Tripterygium Glycosides Tablets in rats based on high-throughput transcriptome sequencing].

Tripterygium Glycosides Tablets has good anti-inflammatory and immunomodulatory activities,but its reproductive damage is significant. Previous studies of the research group have found that Cuscutae Semen flavonoids can improve spermatogenic cell damage caused by Tripterygium Glycosides Tablets by regulating spermatogenic cell cycle,apoptosis and related protein expression,but the mechanism of action at the gene level is still unclear. In this study,Illumina high-throughput sequencing platform was applied in transcriptional sequencing of spermatogenic cells of rats after the intervention of Cuscutae Semen flavonoids and Tripterygium Glycosides Tablets. Differentially expressed genes were screened out and the GO enrichment and KEGG pathway analysis of differentially expressed genes were conducted to explore the mechanism of Cuscutae Semen flavonoids in improving reproductive injury caused by Tripterygium Glycosides Tablets. The results showed that 794 up-regulated genes and 491 down-regulated genes were screened in Tripterygium Glycosides Tablets group compared with the blank group. Compared with Tripterygium Glycosides Tablets,440 up-regulated genes and 784 down-regulated genes were screened in the Cuscutae Semen flavonoids+Tripterygium Glycosides Tablets group. Among them,the gene closely related to reproductive function is DNMT3 L. Analysis of GO function and KEGG signaling pathway enrichment showed that the above differentially expressed genes were mainly enriched in cell,cell process,catalytic activity,binding,ovarian steroid synthesis,thyroid hormone and other functions and pathways. The thyroid hormone signaling pathway was the common enrichment pathway of the two control groups. In a word,Cuscutae Semen flavonoids has a good treatment effect on male reproductive damage caused by Tripterygium Glycosides Tablets. The mechanism may be closely related to up-regulation of DNMT3 L genes and intervention of thyroid hormone signaling pathway. At the same time,the discovery of many different genes provides valuable information for study on the mechanism of Cuscutae Semen flavonoids and Tripterygium Glycosides Tablets compatibility decreasing toxicity and increasing efficiency.

[Screening of serum susceptibility biomarkers in patients with mild liver function abnormalities based on non-targeted metabolomics].

In the present study,non-targeted metabolomics technique was used to screen potentially susceptibility biomarkers in patients with mild liver function abnormalities during long-term use of Chinese herbal compound. According to the inclusion and exclusion criteria,we collected 7 cases of patients with abnormal liver function during the period of complete taking Chinese herbal medicine( 60 days),and 18 cases of patients with normal liver function in re-examination from the reproductive medicine center in our hospital. Ultra performance liquid chromatography coupled with time-of-flight mass spectrometry( UPLC-Q-TOF/MS~E) technique combined with Progenesis QI software was used to analyze the differential biomarkers in serum of patients with wild liver function abnormalities and normal liver function. 11 potential biomarkers such as bilirubin,pantothenic acid,hippuric acid,sphingomyelin,palmitic acid,and oleic acid were tentatively identified. Metabolic disorders in patients with herbal-induced mild liver abnormality were mainly related to two pathways: pantothenic acid and coenzyme A biosynthesis and linoleic acid metabolism. It could provide a reference for the early warning of mild liver function abnormalities of patients that may be caused by long-term use of Chinese medicine compound in clinical application,and will lay a foundation for further understanding the endogenous substance changes in different levels of liver injury.