Design, synthesis and biological evaluation of the positional isomers of the galactose conjugates able to target hepatocellular carcinoma cells via ASGPR-mediated cellular uptake and cytotoxicity.

Galactose as a recognizing motif for asialoglycoprotein receptor (ASGPR) is a widely accepted vector to deliver cytotoxic agents in the therapy of hepatocellular carcinoma (HCC), however, the individual hydroxyl group of galactose (Gal) contributed to recognizing ASGPR is obscure and remains largely unanswered in the design of glycoconjugates. Herein, we designed and synthesized five positional isomers of Gal-anthocyanin Cy5.0 conjugates and three Gal-doxorubicin (Dox) isomers, respectively. The fluorescence intensity of Gal-Cy5.0 conjugates accumulated in cancer cells hinted the optimal modification sites of positions C2 and C6. Comparing to the cytotoxicity of other conjugates, C2-Gal-Dox (11) was the most potent. Moreover, Gal-Dox conjugates significantly the toxicity of Dox. A progressively lower internalization capacity and siRNA technology implied the cellular uptake and cytotoxicity directly related to the ASGPR expression level. Accordingly, position C2 of galactose may be the best substitution site via ASGPR mediation in the design of anti-HCC glycoconjugates.

Antibacterial activities of anthraquinones: structure-activity relationships and action mechanisms.

With the increasing prevalence of untreatable infections caused by antibiotic-resistant bacteria, the discovery of new drugs from natural products has become a hot research topic. The antibacterial activity of anthraquinones widely distributed in traditional Chinese medicine has attracted much attention. Herein, the structure and activity relationships (SARs) of anthraquinones as bacteriostatic agents are reviewed and elucidated. The substituents of anthraquinone and its derivatives are closely related to their antibacterial activities. The stronger the polarity of anthraquinone substituents is, the more potent the antibacterial effects appear. The presence of hydroxyl groups is not necessary for the antibacterial activity of hydroxyanthraquinone derivatives. Substitution of di-isopentenyl groups can improve the antibacterial activity of anthraquinone derivatives. The rigid plane structure of anthraquinone lowers its water solubility and results in the reduced activity. Meanwhile, the antibacterial mechanisms of anthraquinone and its analogs are explored, mainly including biofilm formation inhibition, destruction of the cell wall, endotoxin inhibition, inhibition of nucleic acid and protein synthesis, and blockage of energy metabolism and other substances.

Preparation of Structure Vacancy Defect Modified Diatomic-Layered g-C3 N4 Nanosheet with Enhanced Photocatalytic Performance.

Structure self-modification of graphitic carbon nitride (g-C3 N4 ) without the assistance of other species has attracted considerable attention. In this study, the structure vacancy defect modified diatomic-layered g-C3 N4 nanosheet (VCN) is synthesized by thermal treatment of bulk g-C3 N4 in a quartz tube with vacuum atmosphere that will generate a pressure-thermal dual driving force to boost the exfoliation and formation of structure vacancy for g-C3 N4 . The as-prepared VCN possesses a large specific surface area with a rich pore structure to provide more active centers for catalytic reactions. Furthermore, the as-formed special defect level in VCN sample can generate a higher exciton density at photoexcitation stage. Meanwhile, the photogenerated charges will rapidly transfer to VCN surface due to the greatly shortened transfer path resulting from the ultrathin structure (≈1.5 nm), which corresponds to two graphite carbon nitride atomic layers. In addition, the defect level alleviates the drawback of enlarged bandgap caused by the quantum size effect of nano-scaled g-C3 N4 , resulting in a well visible-light utilization. As a result, the VCN sample exhibits an excellent photocatalytic performance both in hydrogen production and photodegradation of typical antibiotics.

Novel xanthone antibacterials: Semi-synthesis, biological evaluation, and the action mechanisms.

α-Mangostin (α-MG) has demonstrated to display potent activities against Gram-positive bacterial. However, the contribution of phenolic hydroxyl groups of α-MG to the antibacterial activity remains obscure, severely hampering selection of structure modification to develop more potential α-MG-based anti-bacterial derivatives. Herein, twenty-one α-MG derivatives are designed, synthesized and evaluated for the antibacterial activities. The structure activity relationships (SARs) reveal that the contribution of the phenolic groups ranks as C3 > C6 > C1, and the phenolic hydroxyl group at C3 is essential to the antibacterial activity. Of note, compared to the parent compound α-MG, 10a with one acetyl at C1 exhibits the higher safety profiles due to its higher selectivity and no hemolysis, and the more potent antibacterial efficacy in an animal skin abscess model. Our evidences further present that, in comparison with α-MG, 10a has a stronger ability in depolarizing membrane potentials and leads to more leakage of bacterial proteins, consistent with the results observed by transmission electron microscopy (TEM). Transcriptomics analysis demonstrates those observations possibly relate to disturbed synthesis of proteins participating in the biological process of membrane permeability and integrity. Collectively, our findings provide a valuable insight for developing α-MG-based antibacterial agents with little hemolysis and new action mechanism via structural modifications at C1.

Achieving ultrastability and efficient lithium storage capacity with high-energy iron(II) oxalate anode materials by compositing Ge nano-conductive sites.

Transition metal oxalates (TMOxs, represented by iron oxalate) have attracted considerable interest in anode materials due to their excellent lithium storage properties and consistent cyclic performance. Although investigations into their electrochemical capabilities and lithium storage mechanisms are gradually deepening, the complex and varied electrochemical reactions in the initial cycle, poor inherent conductivity, and high irreversible capacity constrain their further development. Herein, to solve the above-mentioned problems, we controlled the hydrothermal synthesis conditions of iron oxalate with the assistance of organic solvents, which induced the growth of iron oxalate crystals with nano Ge metal as the core. The metal Ge space sites compounded to the stacked iron oxalate particles act as conductive nodes and metal frames, which enhances both the strength of iron oxalate samples and electronic conductivity and lithium-ion diffusion inside the electrode materials. This special structure enhances the electrochemical activity of iron oxalates and improves their lithium storage capability. The iron oxalate @ nano Ge metal composite (FCO@Ge-1) exhibits an excellent cycling performance and an appreciable reversible specific capacity (1090 mA h g-1 after 200 cycles at 1 A g-1). The obvious polarization and variation of the electrochemical reaction in the initial cycle of iron oxalate are reduced by compositing nano Ge metal. It is demonstrated that nano Ge metal can promote reversible capacity retention from 67.72% to 80.69% in the early cycles. The distinctive structure of iron oxalate @ nano Ge metal composite provides a fresh pathway to enhance oxalate electrochemical reversible lithium storage activity and develop high-energy electrode material by constructing composite space conductive sites.

Haplotype-phased and chromosome-level genome assembly of Puccinia polysora, a giga-scale fungal pathogen causing southern corn rust.

Rust fungi are characterized by large genomes with high repeat content and have two haploid nuclei in most life stages, which makes achieving high-quality genome assemblies challenging. Here, we described a pipeline using HiFi reads and Hi-C data to assemble a gigabase-sized fungal pathogen, Puccinia polysora f.sp. zeae, to haplotype-phased and chromosome-scale. The final assembled genome is 1.71 Gbp, with ~850 Mbp and 18 chromosomes in each haplotype, being currently one of the two giga-scale fungi assembled to chromosome level. Transcript-based annotation identified 47,512 genes for the dikaryotic genome with a similar number for each haplotype. A high level of interhaplotype variation was found with 10% haplotype-specific BUSCO genes, 5.8 SNPs/kbp, and structural variation accounting for 3% of the genome size. The P. polysora genome displayed over 85% repeat contents, with genome-size expansion and copy number increasing of species-specific orthogroups. Interestingly, these features did not affect overall synteny with other Puccinia species having smaller genomes. Fine-time-point transcriptomics revealed seven clusters of coexpressed secreted proteins that are conserved between two haplotypes. The fact that candidate effectors interspersed with all genes indicated the absence of a "two-speed genome" evolution in P. polysora. Genome resequencing of 79 additional isolates revealed a clonal population structure of P. polysora in China with low geographic differentiation. Nevertheless, a minor population differentiated from the major population by having mutations on secreted proteins including AvrRppC, indicating the ongoing virulence to evade recognition by RppC, a major resistance gene in Chinese corn cultivars. The high-quality assembly provides valuable genomic resources for future studies on disease management and the evolution of P. polysora.

Effects of ethanamizuril, sulfachlorpyridazine or their combination on cecum microbial community and metabolomics in chickens infected with Eimeria tenella.

Coccidiostat and antibiotics are widely used in poultry industry, but their effects on cecum microbial community and metabolomics in chickens infected with coccidia have been rarely studied. In this study, we analyzed the changes of microbiota and metabolomic which associated with Eimeria tenella infection in 8 days of age chickens in the presence or absence of ethanamizuril, sulfachlorpyridazine or their combinations treatment for 3 consecutive days. 16S rRNA gene sequencing and LC-MS/MS analyses were used to profile the cecal microbiome and metabolome in each group of chickens on 7 days post-infection. The results showed that coccidial infection induced significant perturbations in the distribution of microbial taxonomy and the metabolism of physiological functional molecules in cecal contents. Ethanamizuril treatment seemed to transform microbiota into a steady state conducive to animal health, and sulfachlorpyridazine treatment alleviated the growth of potentially harmful bacteria such as Escherichia-Shigella. The change trends of metabolites such as n-carbamoylglutamic acid were consistent with the anticoccidial effect of ethanamizuril. The combinations of ethanamizuril and sulfachlorpyridazine at low-dose had little effect on gut microbiota, metabolism and anticoccidial effect. These data indicate that the cecal microbiota and metabolic status of chickens infected with E. tenella following ethanamizuril treatment could be used to monitor the response to drug efficacy. This study provides a new system approach to elucidate the microbiota, metabolic and therapeutic effects of the combination of coccidiostat and antibiotics in the context of avian coccidiosis.

Label-free quantitative proteomic analysis of ethanamizuril-resistant versus -sensitive strains of Eimeria tenella.

BACKGROUND: Avian coccidiosis is an important parasitic disease that has serious adverse effects on the global poultry industry. The extensive use of anticoccidial drugs has resulted in an increase in drug resistance. Ethanamizuril (EZL) is a novel triazine with high anticoccidial activity. METHODS: We compared oocyst production and sporulation between EZL-sensitive (S) and EZL-resistant Eimeria tenella strains (R10 and R200) and used label-free quantitative proteomics to identify differentially expressed proteins (DEPs) between these strains. RESULTS: We generated two EZL-resistant E. tenella strains: strain R10, which was induced using a constant dose of 10 mg EZL/kg poultry feed, and strain R200, which was generated by gradually increasing the EZL dosage to 200 mg EZL/kg poultry feed. With an increase in resistance, the total oocyst output decreased, but the percentage of sporulation did not change significantly. We identified a total of 7511 peptides and 1282 proteins, and found 152 DEPs in the R10 strain versus the S strain, 426 DEPs in the R200 strain versus the S strain and 494 DEPs in the R200 strain versus the R10 strain. When compared with the S strain, 86 DEPs were found to have consistent trends in both resistant strains. The DEPs were primarily involved in ATP and GTP binding, invasion, and membrane components. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses of the DEPs suggested that they are involved in transcription and translation processes. Protein-protein interaction network analysis of the 86 DEPs showed that 10 proteins were hubs in the functional interaction network (≥ 8 edges) and five of them were ribosomal proteins. CONCLUSIONS: The results of the present study indicate that the resistance mechanisms of E. tenella against EZL might be related to the transcriptional and translational processes, especially in the factors that inhibit the growth of parasites. The DEPs found in this study provide new insights into the resistance mechanisms of E. tenella against EZL. Further research on these potential targets holds promise for new chemotherapeutic approaches for controlling E. tenella infections.

Effects of salinomycin and ethanamizuril on the three microbial communities in vivo and in vitro.

The fate of a drug is not only the process of drug metabolism in vivo and in vitro but also the homeostasis of drug-exposed microbial communities may be disturbed. Anticoccidial drugs are widely used to combat the detrimental effects of protozoan parasites in the poultry industry. Salinomycin and ethanamizuril belong to two different classes of anticoccidial drugs. The effect of salinomycin and ethanamizuril on the microbiota of cecal content, manure compost, and soil remains unknown. Our results showed that although both salinomycin and ethanamizuril treatments suppressed some opportunistic pathogens, they failed to repair the great changes in chicken cecal microbial compositions caused by coccidia infection. Subsequently, the metabolite5 profiling of cecal content by LC-MS/MS analyses confirmed the great impact of coccidia infection on chicken cecum and showed that histidine metabolism may be the main action pathway of salinomycin, and aminoacyl tRNA biosynthesis may be the major regulatory mechanism of ethanamizuril. The microbial community of manure compost showed a mild response to ethanamizuril treatment, but ethanamizuril in soil could promote Actinobacteria reproduction, which may inhibit other taxonomic bacteria. When the soil and manure were exposed to salinomycin, the Proteobacteria abundance of microbial communities showed a significant increase, which suggested that salinomycin may improve the ability of the microbiota to utilize carbon sources. This hypothesis was confirmed by a BIOLOG ECO microplate analysis. In the animal model of coccidia infection, the treatment of salinomycin and ethanamizuril may reconstruct a new equilibrium of the intestinal microbiota. In an in vitro environment, the effect of ethanamizuril on composting and soil microbiota seems to be slight. However, salinomycin has a great impact on the microbial communities of manure composting and soil. In particular, the promoting effect of salinomycin on Proteobacteria phylum should be further concerned. In general, salinomycin and ethanamizuril have diverse effects on various microbial communities.

Facile Dissolution-Crystallization Strategy to Achieve Rapid and Uniform Distribution of Sulfur on Porous Carbon for Lithium-Sulfur Batteries.

In this work, we proposed a facile dissolution-crystallization strategy based on density functional theory calculations to achieve rapid as well as uniform distribution of sulfur on porous carbon. Sulfur-containing solution can completely penetrate porous material and in preference remove into the pores under the influence of capillary force, and sulfur tends to crystallize on the defective even non-defective carbon matrix rather than agglomerate. The S/PC composites prepared by this method can still achieve uniform distribution of sulfur when the sulfur content is as high as 85%. All operations can be completed within a few minutes without any heating. Compared with common melt-diffusion and vapor-phase infusion, this approach has lower energy consumption and is simple, safe, continuous, and rapid.

Casticin and chrysosplenol D from Artemisia annua L. induce apoptosis by inhibiting topoisomerase IIα in human non-small-cell lung cancer cells.

BACKGROUND: Artemisia annua L. (A. annua) and its active components exhibit antitumour effects in many cancer cells. However, the biological processes and mechanisms involved are not well understood, especially for the treatment of non-small-cell lung cancer (NSCLC). PURPOSE: This study aimed to comprehensively explore the biological processes of A. annua and its active components in NSCLC cells and to identify the mechanism by which these compounds induce apoptosis. STUDY DESIGNS/METHODS: Cell viability and flow cytometry assays were used to evaluate the cytotoxicity of A. annua active components casticin (CAS) and chrysosplenol D (CHD) in A. annua in NSCLC cells. After treatment with CAS and CHD, A549 cells were subjected to RNA sequencing (RNA-seq) analysis, differentially expressed genes (DEGs) were screened and subjected to functional enrichment analysis (KEGG and GO analysis) as well as protein interaction network analysis. The key targets associated with apoptosis induction in A549 cells were screened by Cytoscape, and the screened DEGs were validated by qRT-PCR. Immunoblotting, immunofluorescence, and molecular docking assays were used to determine whether CAS and/or CHD could induce apoptosis in NSCLC cells by inducing DNA damage through down-regulation of topoisomerase IIα (topo IIα) expression. The same experiments were verified again in the H1299 lung cancer cell line. RESULTS: CAS and CHD inhibited NSCLC cells proliferation in a time- and dose-dependent manner, and significantly induced apoptosis. A total of 115 co-upregulated DEGs and 277 co-downregulated DEGs were identified in A549 cells following treatment with CAS and CHD. Comprehensive and systematic data about biological processes and mechanisms were obtained. DNA damage pathways and topo IIα targets were screened to study the apoptosis effects of CAS and CHD on NSCLC cells. CAS and CHD may be able to induce DNA damage by binding to topo IIα-DNA and reducing topo IIα activity. CONCLUSION: This study suggested that CAS and CHD may reduce topo IIα activity by binding to topo IIα-DNA, affecting the replication of DNA, triggering DNA damage, and inducing apoptosis. It described a novel mechanism associated with topo IIα inhibition to reveal a novel role for CAS and CHD in A. annua as potential anticancer agents and/or adjuvants in NSCLC cells.

Epigenetic modifications in thymic epithelial cells: an evolutionary perspective for thymus atrophy.

BACKGROUND: The thymic microenvironment is mainly comprised of thymic epithelial cells, the cytokines, exosomes, surface molecules, and hormones from the cells, and plays a vital role in the development, differentiation, maturation and homeostasis of T lymphocytes. However, the thymus begins to degenerate as early as the second year of life and continues through aging in human beings, leading to a decreased output of naïve T cells, the limited TCR diversity and an expansion of monoclonal memory T cells in the periphery organs. These alternations will reduce the adaptive immune response to tumors and emerging infectious diseases, such as COVID-19, also it is easier to suffer from autoimmune diseases in older people. In the context of global aging, it is important to investigate and clarify the causes and mechanisms of thymus involution. MAIN BODY: Epigenetics include histone modification, DNA methylation, non-coding RNA effects, and chromatin remodeling. In this review, we discuss how senescent thymic epithelial cells determine and control age-related thymic atrophy, how this process is altered by epigenetic modification. How the thymus adipose influences the dysfunctions of the thymic epithelial cells, and the prospects of targeting thymic epithelial cells for the treatment of thymus atrophy. CONCLUSION: Epigenetic modifications are emerging as key regulators in governing the development and senescence of thymic epithelial cells. It is beneficial to re-establish effective thymopoiesis, identify the potential therapeutic strategy and rejuvenate the immune function in the elderly.

De novo transcriptome assembly, polymorphic SSR markers development and population genetics analyses for southern corn rust (Puccinia polysora).

Southern corn rust is a destructive maize disease caused by Puccinia polysora Underw that can lead to severe yield losses. However, genomic information and microsatellite markers are currently unavailable for this disease. In this study, we generated a total of 27,295,216 high-quality cDNA sequence reads using Illumina sequencing technology. These reads were assembled into 17,496 unigenes with an average length of 1015 bp. The functional annotation indicated that 8113 (46.37%), 1933 (11.04%) and 5516 (31.52%) unigenes showed significant similarity to known proteins in the NCBI Nr, Nt and Swiss-Prot databases, respectively. In addition, 2921 (16.70%) unigenes were assigned to KEGG database categories; 4218 (24.11%), to KOG database categories; and 6,603 (37.74%), to GO database categories. Furthermore, we identified 8,798 potential SSRs among 6653 unigenes. A total of 9 polymorphic SSR markers were developed to evaluate the genetic diversity and population structure of 96 isolates collected from Guangdong Province in China. Clonal reproduction of P. polysora in Guangdong was dominant. The YJ (Yangjiang) population had the highest genotypic diversity and the greatest number of the multilocus genotypes, followed by the HY (Heyuan), HZ (Huizhou) and XY (Xinyi) populations. These results provide valuable information for the molecular genetic analysis of P. polysora and related species.

α-naphthoflavone-derived cytochrome P450 (CYP)1B1 degraders specific for sensitizing CYP1B1-mediated drug resistance to prostate cancer DU145: Structure activity relationship.

We previously discovered extrahepatic cytochrome P450 1B1 (CYP1B1) degraders able to overcome drug resistance toward docetaxel using a PROTACs technology, however, the underexplored structure activity relationships and poor water solubility posed a major hurdle in the development of CYP1B1 degraders. Herein, continuous efforts are made to develop more promising α-naphthoflavone (ANF)-derived chimeras for degrading CYP1B1. Guided by the strongest ANF-derived CYP1B1 degrader 3a we ever reported, 17 ANF analogues are designed and synthesized to evaluate the CYP1B1 degradation and resultant resistance reversal. In degrading CYP1B1 and sensitizing drug resistance, 4d with a 1, 5-cis triazole coupling mode at (C3') of B ring of ANF exhibited the similar potency as 3a carrying a 1, 4-trans triazole fragment at (C4') of B ring, but more obvious selectivity of 4d toward CYP1B1 over CYP1A2 is observed. When an oxygen was inserted into the linker of 4d, 4f demonstrated better water solubility, a more potent ability in degrading CYP1B1 and reversing drug resistance, and a promising selectivity. Collectively, a substitution position, an alkyne-azide cyclization and a liker type significantly affect the ability of ANF-thalidomide conjugates in eliminating drug resistance of CYP1B1-expressing DU145 (DU145/CY) cells to docetaxel via targeted CYP1B1 degradation.

Occurrence and distribution characteristics of antibiotic resistance genes in sediments between urban and rural of the Liaohe River Basin, China.

Antibiotic resistance genes (ARGs) are considered to be emerging pollutants related to human activities. The rapid development of global urbanization has expanded human activities, thereby exacerbating the global human health risks caused by antibiotic resistance genes. The effects of urban and rural environments are multifarious, which makes the source and distribution of ARGs in the environment diversification. Understanding the distribution and spread of ARGs is essential for studying the environmental behavior of ARGs. In this study, the occurrence 296 genes were detected by the high-throughput qPCR technology, and FC value was used to analyze the diversity of ARGs and mobile genetic elements (MGEs) in sediments between urban and rural areas of the Liaohe River Basin, China. The co-occurrence of MGEs and ARGs was analyzed using network to decipher core genes. A total of 187 ARGs and 10 MGEs were detected in all sediment samples. The average number of genes detected in urban sites is 89 higher than that in rural sites. The high abundance and various types of ARGs and MGEs detected in urban river sediments indicate that the occurrence of urban ARGs is more complex. MGEs were detected high levels and were significantly correlated with the abundance and diversity of ARGs in river sediments providing evidence that MGEs were related to the occurrence and distribution of ARGs and tnpA (tnpA-07, tnpA-01, and tnpA-03) gene were at the key position of co-occurrence of various types of ARGs.

[Research advances of biosynthesis, in vivo analysis and pharmacokinetics of chemical constituents in Artemisiae Annuae Herba].

Artemisiae Annuae Herba is a traditional Chinese medicine for clearing deficiency and heat. It is the only natural source of artemisinin, which is a specific antimalarial drug, and has been widely concerned all over the world. In addition to artemisinin, Artemisiae Annuae Herba also contains many sesquiterpenes, coumarins, flavonoids, volatile oils, polysaccharides and other chemical components, which show antipyretic, anti-inflammatory, antiviral microorganisms, anti-asthma, anti-oxidation, anti-tumor and other pharmacological activities. In addition to their own pharmacological activities, some components could enhance the antimalarial activity of artemisinin through different mechanisms at absorption and metabolism in vivo. In order to understand the pharmacokinetic characte-ristics of the chemical constituents contained in Artemisiae Annuae Herba and provide reference for the full development and clinical utilization of Artemisiae Annuae Herba resources in China, this present paper systematically collated the modern research literatures, and summarized the biosynthesis, in vivo analysis and pharmacokinetics of the chemical constituents in Artemisiae Annuae Herba.

Oral Bioavailability Comparison of Artemisinin, Deoxyartemisinin, and 10-Deoxoartemisinin Based on Computer Simulations and Pharmacokinetics in Rats.

Deoxyartemisinin, a compound separated from Artemisinin annua L., shows anti-inflammatory and antiulcer activities. 10-Deoxoartemisinin is a novel compound with a strong antimalarial effect derivatized from artemisinin. Compared to the famous antimalarial natural compound artemisinin, deoxyartemisinin lacks the peroxide bridge structure, while 10-deoxoartemisinin remains this special peroxide bridge group but loses the 10-position keto group. To clarify their pharmacological differences, the absorption, distribution, metabolism, excretion (ADME) properties of artemisinin, deoxyartemisinin, and 10-deoxoartemisinin were first predicted using QikProp software. Also, their pharmacokinetic behaviors in rats were further evaluated by a rapid, sensitive, and specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method after oral and intravenous administration of each compound, in which deoxyartemisinin and 10-deoxoartemisinin were first evaluated for their pharmacokinetics. All parameters about ADME properties calculated by software met the criteria and the ADME performance order was 10-deoxoartemisinin > deoxyartemisinin > artemisinin. The oral bioavailability of artemisinin was calculated to be 12.2 ± 0.832%, which was about 7 times higher than that of deoxyartemisinin (1.60 ± 0.317%). For 10-deoxoartemisinin, its bioavailability (26.1 ± 7.04%) was superior to artemisinin at a degree of more than twice. Considering their chemical structures, losing the peroxide bridge might decrease the absorption rate of deoxyartemisinin in the gastrointestinal tract, while retaining the peroxide bridge but losing the 10-position ketone might improve the bioavailability of 10-deoxoartemisinin.

Stem cell-like memory T cells: A perspective from the dark side.

Much attention has been paid to a newly discovered subset of memory T (TM) cells-stem cell-like memory T (TSCM) cells for their high self-renewal ability, multi-differentiation potential and long-term effector function in adoptive therapy against tumors. Despite their application in cancer therapy, an excess of TSCM cells also contributes to the persistence of autoimmune diseases for their immune memory and HIV infection as a long-lived HIV reservoir. Signaling pathways Wnt, AMPK/mTOR and NF-κB are key determinants for TM cell generation, maintenance and proinflammatory effect. In this review, we focus on the phenotypic and functional characteristics of TSCM cells and discuss their role in autoimmune diseases and HIV-1 chronic infection. Also, we explore the potential mechanism and signaling pathways involved in immune memory and look into the future therapy strategies of targeting long-lived TM cells to suppress pathogenic immune memory.

Pharmacokinetics and anticoccidial activity of ethanamizuril in broiler chickens.

The treatment effect of ethanamizuril (EZL) to broiler chickens experimentally infected with 8 × 104Eimeria tenella was evaluated. On the third day after infection, the broiler chickens were treated with EZL by gavage at doses of 2, 4, and 8 mg/kg body weight (bw) for once. For double administration, the challenged broiler chickens were administered EZL at doses of 1, 2, 4, and 8 mg/kg bw by gavage continually on the third day and fourth day and once a day. Throughout the experimental period, performance parameters including body weight gain, mortality, cecal lesion score, bloody diarrhoea and oocyst output were recorded. The anticoccidial efficacy was evaluated using the anticoccidial index (ACI). Meanwhile, the concentrations of EZL in chicken cecal contents were measured, and the data were analyzed with a non-compartmental model. The results indicated that EZL showed good anticoccidial activity at single dose of 4 mg/kgbw, with the corresponding ACI of 175.73. When the challenged chickens were treated with EZL under double administration, the EZL showed a medium level of anticoccidial activity at a dose of 2 mg/kg bw, with the corresponding ACI of 162.48. The maximum concentrations (Cmax) of EZL in content were 2.43 ±â€¯1.16, 4.28 ±â€¯1.56, and 8.57 ±â€¯1.33 mg/kg after the chickens were administrated at doses of 2, 4, and 8 mg/kg bw, respectively. The respective areas under the curve were 36.93 ±â€¯8.91, 96 ±â€¯16.31, and 262.76 ±â€¯51.52 mg/kg h. The respective half-lives (T1/2) were 10.82 ±â€¯2.02, 10.53 ±â€¯2.23, and 10.60 ±â€¯1.50 h. The results show that when the concentrations of EZL in chicken cecal contents reached 4.28 ±â€¯1.56 mg/kg, there is a significant therapeutic effect on chicken coccidiosis.

Simultaneous quantification and pharmacokinetic evaluation of roflumilast and its N-oxide in cynomolgus monkey plasma by LC-MS/MS method.

Roflumilast (ROF), a nonsteroidal anti-inflammatory drug, has successfully been used to treat systemic and pulmonary inflammation associated with chronic obstructive pulmonary disease. To evaluate its pharmacokinetics in monkeys, a sensitive, rapid and reliable liquid chromatography with tandem mass spectrometry (LC-MS/MS) method was developed for the simultaneous determination of ROF and its N-oxide metabolite (RNO). The mobile phase contained 0.1% formic acid aqueous solution (A) and 0.1% formic acid acetonitrile solution (B). All monkey plasma samples were pretreated using protein precipitation with methanol-acetonitrile (50:50, v/v) in 50 µl plasma samples. Chromatographic separation was performed with mass spectral acquisition performed in positive electrospray ionization, utilizing multiple reaction monitoring. This method was successfully applied to a pharmacokinetic study in cynomolgus monkeys. Following administration of a single oral dose of 1 mg/kg ROF in monkeys, pharmacokinetic data for ROF and RNO was reported for the first time. After oral administration, ROF was rapidly absorbed and metabolized to its metabolite RNO. The mean area under the curve value of RNO was ~13 times larger than that of ROF, suggesting that most ROF was metabolized to RNO in cynomolgus monkeys.