Selective eradication of venetoclax-resistant monocytic acute myeloid leukemia with iron oxide nanozymes.

The clinical treatment of human acute myeloid leukemia (AML) is rapidly progressing from chemotherapy to targeted therapies led by the BCL-2 inhibitor venetoclax (VEN). Despite its unprecedented success, VEN still encounters clinical resistance. Thus, uncovering the biological vulnerability of VEN-resistant AML disease and identifying effective therapies to treat them are urgently needed. We have previously demonstrated that iron oxide nanozymes (IONE) are capable of overcoming chemoresistance in AML. The current study reports a new activity of IONE in overcoming VEN resistance. Specifically, we revealed an aberrant redox balance with excessive intracellular reactive oxygen species (ROS) in VEN-resistant monocytic AML. Treatment with IONE potently induced ROS-dependent cell death in monocytic AML in both cell lines and primary AML models. In primary AML with developmental heterogeneity containing primitive and monocytic subpopulations, IONE selectively eradicated the VEN-resistant ROS-high monocytic subpopulation, successfully resolving the challenge of developmental heterogeneity faced by VEN. Overall, our study revealed an aberrant redox balance as a therapeutic target for monocytic AML and identified a candidate IONE that could selectively and potently eradicate VEN-resistant monocytic disease.

First Genomic Prediction of Single-Step Models in Large Yellow Croaker.

Genome selection is mainly used in disease-resistant traits of aquatic species; however, its implementation is hindered by a high cost of genotype and phenotype data collection. Single-step genomic best linear unbiased prediction (SSGBLUP) can integrate phenotypes, genetic markers, and pedigree records into simultaneous prediction without increasing genotyping costs. The objective of this study is to investigate the performance of SSGBLUP in large yellow croaker and to evaluate the effects of the number of phenotypic records and genotyping per family on the predictive ability of SSGBLUP. A large yellow croaker population consists of 6898 individuals from 14 families with survival time resistant against Cryptocaryon irritans (C. irritans), body weight (BW), and body length (BL) traits were collected, of which 669 individuals were genotyped. Results showed that the mean predictive ability of all traits in the individuals randomly sampling for SSGBLUP, GBLUP, and BLUP was 0.738, 0.738, and 0.736, respectively. Moreover, the predictive ability of SSGBLUP and BLUP models did not increase with the extra phenotypic records per family, in which the predictive ability of SSGBLUP and BLUP in survival time was 0.853 and 0.851 for only genotyped data (N = 0) used, and 0.852, 0.845 for all phenotypic records (N = 600) used, respectively. However, with the increase in the genotype number of training set, the prediction ability of SSGBLUP and GBLUP model was increased and the highest predictive ability was gained when the genotype number per family was 40 or 45. In addition, the prediction ability of SSGBLUP model was higher than that of GBLUP. Our study showed that the SSGBLUP model still has great potential and advantages in genomic breeding of large yellow croakers. It is recommended that each family provide 100 phenotypic individuals, of which 40 individuals with genotyping data for SSGBLUP model prediction and family resistance evaluation.

Incidence and risk factors of tuberculosis in systemic lupus erythematosus patients: a multi-center prospective cohort study.

Objectives: Both burdens of tuberculosis (TB) and systemic lupus erythematosus (SLE) in China are ranked as top three in the world. SLE patients are at high risk for TB, but so far, there are no guidelines for TB prevention and management targeting this population in China. This study aims to investigate the incidence of active tuberculosis (ATB) and to explore the risk factors for developing ATB in SLE patients, and to provide evidence for TB prevention and management for SLE patients in China. Methods: A multi-center prospective cohort study was conducted. SLE patients were enrolled from clinics and wards of 13 tertiary hospitals in Eastern, Middle, and Western China from September 2014 to March 2016. Baseline demographic features, TB infection status, clinical information, and laboratory data were collected. ATB development was examined during follow-up visits. Kaplan-Meier method was applied to plot survival curves, and Log-rank test was used to evaluate differences. Cox proportional-hazards model was used to explore the risk factors for ATB development. Results: With a median follow-up time of 58 months [interquartile range (IQR): 55-62], 16 out of 1361 SLE patients developed ATB. The 1-year incidence of ATB was 368 [95% confidence interval (CI): 46-691] per 100,000. Over a 5-year period, the cumulative incidence of ATB was 1141 [95% CI: 564-1718] per 100,000, and the incidence density was 245 per 100,000 person-years. Cox regression models were constructed with maximum daily dose of glucocorticoids (GCs) as a continuous variable and a categorical variable, respectively. In model 1, maximum daily dose of GCs (pills per day) [adjusted hazard ratio (aHR)=1.16, 95%CI: 1.04-1.30, p=0.010] and TB infection (aHR=8.52, 95%CI: 3.17-22.92, p<0.001) were independent risk factors for ATB development. In model 2, maximum daily dose of GCs≥30 mg/d (aHR =4.81, 95%CI: 1.09-22.21, P=0.038) and TB infection (aHR=8.55, 95%CI: 3.18-23.00, p<0.001] were independent risk factors for ATB development. Conclusions: SLE patients had a higher incidence of ATB compared to the general population. The risk of developing ATB was even higher with increased daily dose of GCs or in a status of TB infection, in which case TB preventive treatment should be considered.

Latent Tuberculosis Infection and Associated Factors in Patients with Systemic Lupus Erythematosus: a Multicenter, Cross-Sectional Study.

The objectives of this study were to screen for latent tuberculosis infection (LTBI) among patients with systemic lupus erythematosus (SLE) using the T-SPOT.TB assay and to identify factors affecting the assay results. SLE patients were enrolled from 13 tertiary hospitals in eastern, central, and western China from September 2014 to March 2016 and were screened using the T-SPOT.TB assay to detect LTBI. Basic information about the subjects was collected, including gender, age, body mass index (BMI), course of disease, evidence of previous tuberculosis, Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score, and the use of glucocorticoids and immunosuppressants. Univariate analysis and multivariable logistic regression were performed to identify factors affecting the results of the T-SPOT.TB assay. In all, 2,229 SLE patients were screened using the T-SPOT.TB assay, of whom 334 patients tested positive, yielding a positivity rate of 15% (95% confidence interval [CI], 13.5% to 16.5%). The positivity rate was higher in male than female patients and had an increasing trend with age. Multivariable logistic regression analysis showed that patients over 40 (odds ratio [OR], 1.65; 95% CI, 1.29 to 2.10) and with evidence of previous tuberculosis (OR, 4.43; 95% CI, 2.81 to 6.99) were more likely to have positive T-SPOT.TB results, while patients with a SLEDAI-2K score of ≥10 (OR, 0.61; 95% CI, 0.43 to 0.88), a glucocorticoid dose of ≥60 mg/d (OR, 0.62; 95% CI, 0.39 to 0.98), leflunomide (LEF) treatment (OR, 0.51; 95% CI, 0.29 to 0.88), or tacrolimus (FK506) treatment (OR, 0.40; 95% CI, 0.16 to 1.00) were more likely to have negative T-SPOT.TB results. The frequencies of CFP-10-specific gamma interferon (IFN-γ)-secreting T cells were significantly lower in SLE patients with severe disease activity or high-dose glucocorticoids (P < 0.05). The positivity rate of the T-SPOT.TB assay was 15% among SLE patients. Severe, active SLE disease and the use of high-dose glucocorticoids and some types of immunosuppressants are likely to result in negative T-SPOT.TB results. For SLE patients with the above conditions, diagnosing LTBI based on a positive T-SPOT.TB result may lead to underestimation of the prevalence. IMPORTANCE The burden of tuberculosis and systemic lupus erythematosus in China ranks among the top three in the world. Therefore, active screening for LTBI and preventive intervention in SLE patients are of great significance in China. In view of the lack of relevant data in a large sample, we conducted a multicenter, cross-sectional study using T-SPOT.TB as a screening method for LTBI, to investigate the prevalence of LTBI and analyze the factors affecting the results of the T-SPOT.TB assay in SLE patients. Our study showed that the overall positivity rate of the T-SPOT.TB assay in SLE patients was 15.0%, which was lower than the estimated LTBI prevalence in the general population in China (~20%). For SLE patients with severe, active disease, high-dose glucocorticoids, and some types of immunosuppressants, a diagnosis of LTBI based on only positive T-SPOT.TB results may lead to underestimation of the prevalence.

Intercross population study reveals that co-mutation of mitfa genes in two subgenomes induces red skin color in common carp ( Cyprinus carpio wuyuanensis).

Common carp are among the oldest domesticated fish in the world. As such, there are many food and ornamental carp strains with abundant phenotypic variations due to natural and artificial selection. Hebao red carp (HB, Cyprinus carpio wuyuanensis), an indigenous strain in China, is renowned for its unique body morphology and reddish skin. To reveal the genetic basis underlying the distinct skin color of HB, we constructed an improved high-fidelity (HiFi) HB genome with good contiguity, completeness, and correctness. Genome structure comparison was conducted between HB and a representative wild strain, Yellow River carp (YR, C. carpio haematopterus), to identify structural variants and genes under positive selection. Signatures of artificial selection during domestication were identified in HB and YR populations, while phenotype mapping was performed in a segregating population generated by HB×YR crosses. Body color in HB was associated with regions with fixed mutations. The simultaneous mutation and superposition of a pair of homologous genes ( mitfa) in chromosomes A06 and B06 conferred the reddish color in domesticated HB. Transcriptome analysis of common carp with different alleles of the mitfa mutation confirmed that gene duplication can buffer the deleterious effects of mutation in allotetraploids. This study provides new insights into genotype-phenotype associations in allotetraploid species and lays a foundation for future breeding of common carp.

The neuropeptide Y receptor gene repository, phylogeny and comparative expression in allotetraploid common carp.

NPY-family receptors belong to G protein-coupled receptors (GPCR), which lays a physiological foundation for the transmembrane transport of an endogenous appetite-stimulating factor neuropeptide Y and related peptides. In this study, we investigated the npyr genes in ten representative species, and twelve npyr genes were identified from allotetraploid C. carpio, the npyr gene number of C. carpio was twice the number of its subgenome B progenitor-like diploid Poropuntius huangchuchieni. Phylogenetic analysis showed that all npyr genes were divided into three subgroups, and they underwent strong purifying selection according to selection pressure analysis. Subsequently, synteny analysis showed that most npyr genes were evenly distributed on the homologous chromosomes of two subgenomes in allotetraploid C. carpio, in which npy1r and npy2r were tandem duplicated, respectively. In addition, the global expression of npyr genes during embryonic development in allotetraploid C. carpio suggested the potential function of npyr genes in immunity and reproduction. In adult tissues, npyr genes were mainly distributed in the brain, gonad, and skin, which displayed a similar expression pattern between the C. carpio B subgenome and P. huangchuchieni. In general, our research could provide reference information for future exploration of the NPY receptors and neuroendocrine system of allotetraploid C. carpio and vertebrates.

Chromosome-Level Assembly of the Southern Rock Bream (Oplegnathus fasciatus) Genome Using PacBio and Hi-C Technologies.

The Rock Bream (Oplegnathus fasciatus) is an economically important rocky reef fish of the Northwest Pacific Ocean. In recent years, it has been cultivated as an important edible fish in coastal areas of China. Despite its economic importance, genome-wide adaptions of domesticated O. fasciatus are largely unknown. Here we report a chromosome-level reference genome of female O. fasciatus (from the southern population in the subtropical region) using the PacBio single molecule sequencing technique (SMRT) and High-through chromosome conformation capture (Hi-C) technologies. The genome was assembled into 120 contigs with a total length of 732.95 Mb and a contig N50 length of 27.33 Mb. After chromosome-level scaffolding, 24 chromosomes with a total length of 723.22 Mb were constructed. Moreover, a total of 27,015 protein-coding genes and 5,880 ncRNAs were annotated in the reference genome. This reference genome of O. fasciatus will provide an important resource not only for basic ecological and population genetic studies but also for dissect artificial selection mechanisms in marine aquaculture.

A comparative study of toxicity of TiO2, ZnO, and Ag nanoparticles to human aortic smooth-muscle cells.

PURPOSE: To evaluate the adverse vascular effects of nanoparticles (NPs) in vitro, extensive studies have investigated the toxicity of NPs on endothelial cells, but the knowledge of potential toxicity on human smooth-muscle cells (SMCs) is currently limited. METHODS: This study compared the toxicity of TiO2, ZnO, and Ag NPs to human aortic SMCs. RESULTS: Only ZnO NPs significantly induced cytotoxicity, accompanied by increased intracellular reactive oxygen species, Zn ions, and endoplasmic reticulum stress biomarkers (DDIT3 expression and p-Chop proteins). All the NPs significantly promoted the release of soluble VCAM1 and soluble sICAM1, but not IL6, which suggested that metal-based NPs might promote inflammatory responses. Furthermore, KLF4 expression (a transcription factor for SMC-phenotype switch) was significantly induced by TiO2 NPs and modestly by ZnO NPs, but the expression of CD68 remained unaltered. CONCLUSION: Our data indicated that ZnO NPs were more cytotoxic to human aortic SMCs than TiO2 and Ag NPs at the same mass concentrations, which might have been associated with intracellular reactive oxygen species, Zn ions, and endoplasmic reticulum stress.

Vasculoprotective Effects of Water Extracts of Black, Green and Dark Tea in Vitro.

To investigate the preventive effects of tea on hyperglycemia and vascular complications of diabetes, we report the extraction and composition as well as the vasculoprotective effects of black tea extract (BTE), green tea extract (GTE), and dark tea extract (DTE). High Performance Liquid Chromatography (HPLC) and colorimetric methods were conducted to analyze for tea catechins, caffeine, polyphenols, amino acids and polysaccharides of BTE, GTE and DTE. The inhibitory effects of α-glucosidase, aldose reductase (AR), advanced glycation end-products (AGEs) and glucose uptake promotion effect in BTE, GTE and DTE were explored in vitro. Contents of six major catechin forms and total catechin as well as polyphenols are higher in GTE and DTE than BTE. BTE, GTE, and DTE showed the inhibitory effects of a-glucosidase, AR, and AGEs, but only DTE exhibited the glucose uptake promotion effect in HepG2 cells. The results suggest that regular consumption of tea can help prevent the progression of hyperglycemia and the vascular complications of diabetes.

[Growth and decline of Oncomelania hupensis status in Duchang County at North shore of Poyang Lake, 2005-2012].

OBJECTIVE: To understand the dynamic of Oncomelania hupensis snail status in Duchang County at north shore of Poyang Lake, so as to provide the evidence for formulating the strategy of schistosomiasis control. METHODS: The data about the snail status in Duchang County from 2005 to 2012 were collected, and the change trend of the snail status was analyzed. Results From 2005 to 2012, all the average density of living snails, the occurrence rate of frames with living snails, the density of infected snails and the area with infected snails showed a trend of sharp decline, and stayed at a low level. Compared to 2005, the above 4 indexes in 2008 decreased by 70.06%, 90.33%, 79.48%, and 37.88%, respectively, and those in 2012 decreased by 99.35%, 98.98%, 99.33%, and 93.84%, respectively. The infection rates of snails fluctuated between 0.06% and 0.53%, which showed a trend of first decrease and then increase. The snail area maintained at the level of 2052.5 hm2 since 2007. CONCLUSIONS: Most of the indexes of the snail status in Duchang County have decreased to the lowest level in history since 2012, but the snail area is stable and the infection rate of snails shows a fluctuation trend, which suggests that the risks of schistosomiasis transmission still exist, and the snail control still should be strengthened.

Synthesis, nitric oxide release, and α-glucosidase inhibition of nitric oxide donating apigenin and chrysin derivatives.

α-Glucosidase (AG) play crucial roles in the digestion of carbohydrates. Inhibitors of α-glucosidase (AGIs) are promising candidates for the development of anti-diabetic drugs. Here, five series of apigenin and chrysin nitric oxide (NO)-donating derivatives were synthesised and evaluated for their AG inhibitory activity and NO releasing capacity in vitro. Except for 9a-c, twelve compounds showed remarkable inhibitory activity against α-glucosidase, with potency being better than that of acarbose and 1-deoxynojirimycin. All organic nitrate derivatives released low concentrations of NO in the presence of l-cysteine. Structure activity relationship studies indicated that 5-OH, hydrophobic coupling chain, and carbonyl groups of the coupling chain could enhance the inhibitory activity. Apigenin and chrysin derivatives therefore represents a new class of promising compounds that can inhibit α-glucosidase activity and supply moderate NO for preventing the development of diabetic complications.

Synthesis of organic nitrates of luteolin as a novel class of potent aldose reductase inhibitors.

Aldose reductase (AR) plays an important role in the design of drugs that prevent and treat diabetic complications. Aldose reductase inhibitors (ARIs) have received significant attentions as potent therapeutic drugs. Based on combination principles, three series of luteolin derivatives were synthesised and evaluated for their AR inhibitory activity and nitric oxide (NO)-releasing capacity in vitro. Eighteen compounds were found to be potent ARIs with IC50 values ranging from (0.099±0.008) µM to (2.833±0.102) µM. O(7)-Nitrooxyethyl-O(3'),O(4')-ethylidene luteolin (La1) showed the most potent AR inhibitory activity [IC50=(0.099±0.008) µM]. All organic nitrate derivatives released low concentrations of NO in the presence of l-cysteine. Structure-activity relationship studies suggested that introduction of an NO donor, protection of the catechol structure, and the ether chain of a 2-carbon spacer as a coupling chain on the luteolin scaffold all help increase the AR inhibitory activity of the resulting compound. This class of NO-donor luteolin derivatives as efficient ARIs offer a new concept for the development and design of new drug for preventive and therapeutic drugs for diabetic complications.

Hypoglycemic effect of the water extract of Pu-erh tea.

The water extraction and composition of pu-erh tea, as well as the hypoglycemic effect of the water extract of pu-erh tea (WEPT) in vivo and in vitro, are reported to investigate its hypoglycemic effect on diabetes. High-performance liquid chromatography and colorimetric methods are used to analyze the tea catechins, caffeine, polyphenols, amino acids, and polysaccharides of the WEPT. The effect of the WEPT on glucose uptake by cultured HepG2 cells and the inhibition effect of rat intestinal sucrase, maltase, and porcine pancreatic amylase are determined in vitro. Then, the blood glucose and insulin levels of intragastrically administered WEPT on fasting and oral glucose tolerance test (OGTT) using type 2 diabetic db/db (BKS.Cg-m +/+ Lepr(db)/J) mice are determined in vivo. The results showed that the WEPT dose-dependently and significantly increased glucose uptake by HepG2 cells and inhibited rat intestinal sucrase, maltase, and porcine pancreatic amylase activity. The WEPT intragastrically given for 4 weeks suppressed the increase in blood insulin and glucose levels of db/db mice fasted overnight. In OGTT, the WEPT improved impaired glucose tolerance and ameliorated retarded insulin response at 60 and 120 min in db/db mice. These results suggest that the WEPT has beneficial effects on glucose homeostasis in type 2 diabetes and in amendment of insulin resistance.

Furoxan nitric oxide donor coupled chrysin derivatives: synthesis and vasculoprotection.

A series of furoxan-based nitric oxide-releasing chrysin derivatives were synthesized. Pharmacological assays indicated that all chrysin derivatives exhibited in vitro inhibitory activities against aldose reductase and advanced glycation end-product formation. Some chrysin derivatives were also found to increase the glucose consumption of HepG2 cells. Furthermore, the compounds released a low amount of NO in the presence of L-cysteine (range from 0.20% to 1.89%). These hybrid furoxan-based NO donor chrysin derivatives offer a mutual prodrug design concept for the development of therapeutic or preventive agents for vascular complications due to diabetes.

Study on nucleic acid (CT-DNA and yeast tRNA) binding behaviors and cytotoxic properties of a heterodinuclear Ru(II)-Co(III) polypyridyl complex.

A heterodinuclear (Ru(II), Co(III)) metal polypyridyl complex [(phen)(2)Ru(bpibH(2))Co(phen)(2)](5+) {phen = 1,10-phenanthroline, bpibH(2) = 1,4-bis([1,10]phebanthroline-[5,6-d]imidazol-2-yl)-benzene} has been designed and synthesized. The comparative study on the interactions of the Ru(II)-Co(III) complex with calf thymus DNA (CT-DNA) and yeast tRNA has been investigated by UV-visible spectroscopy, fluorescence spectroscopy, viscosity, as well as equilibrium dialysis and circular dichroism (CD). The antitumor activities of the complex have been evaluated by MTT {3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide} method and Giemsa staining experiment. These results indicate that the structures of nucleic acids have significant effects on the binding behaviors of metal complexes. Furthermore, the complex demonstrates different antitumor activity against selected tumor cell lines in vitro, and can make the cell apoptosis.

Synthesis, characterization and vasculoprotective effects of nitric oxide-donating derivatives of chrysin.

Vascular complications are major causes of disability and death in patients with diabetes mellitus. It is often characterized by endothelial dysfunction. Studies have shown that either the loss of nitric oxide bioactivity or the decreased biosynthesis of NO is a central mechanism in endothelial dysfunction. As such, the delivery of exogenous NO is an attractive therapeutic option that has been used to slow the progress of diabetic vascular complications. In this paper, a novel group of hybrid nitric oxide-releasing chrysin derivatives was synthesized. The results indicated that all these chrysin derivatives exhibited in vitro inhibitory activities against aldose reductase and advanced glycation end-products formation. And some of them were even found to increase the glucose consumption of HepG2 cells. Furthermore, all compounds released NO upon incubation with phosphate buffer at pH 7.4. These hybrid ester NO donor prodrugs offer a potential drug design concept for the development of therapeutic or preventive agents for vascular complications due to diabetes.

Asymmetric dimethylarginine impairs glucose utilization via ROS/TLR4 pathway in adipocytes: an effect prevented by vitamin E.

BACKGROUND: Asymmetric dimethylarginine (ADMA), the inhibitor of nitric oxide synthase (NOS), has been reported to be associated with glucose metabolism, but its mechanisms remain unknown. METHODS: In 3T3-L1 adipocytes, we measured the effects of ADMA on glucose transport process under basal or insulin-induced condition, and examined the production of nitric oxide (NO), reactive oxygen species (ROS) and tumor necrosis factor alpha (TNF-alpha), and the expression of toll-like receptor 4 (TLR4). RESULTS: ADMA significantly impaired basal or insulin-stimulated 2-deoxy- [3H] glucose uptake, and decreased the expression of insulin receptor substrate-1 (IRS-1) and glucose transporter-4 (GLUT4). Phosphorylated protein of IRS-1 and translocation of GLUT4 with insulin-stimulation were also inhibited by ADMA. NO decreased, while production of ROS and TNF-alpha, and expression of TLR4 increased after ADMA treatment. Vitamin E reduced the effects of ADMA on glucose transport system, and on NO, ROS and TLR4. Moreover, vitamin E decreased ADMA contents by up-regulating dimethylarginine dimethylaminohydrolase (DDAH) activity in adipocytes. Though L-arginine also increased NO level, but failed to reduce the effects of ADMA. CONCLUSION: ADMA significantly impairs both basal and insulin-stimulated glucose transport in adipocytes, which may relate to activation of the ROS/TLR4 pathway.

Synthesis and promotion angiogenesis effect of chrysin derivatives coupled to NO donors.

Two types of new chrysin derivatives were prepared by coupling NO donors of alkyl nitrate and furazan derivatives and were fully characterized by (1)H NMR and other techniques. These compounds were tested in human umbilical vein endothelial cells (HUVECs-12) and all the compounds exhibited cell proliferation. Notable effects of promoting angiogenesis were observed for all the modified compounds using chick chorioallantoic membrane (CAM) assay.