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1.
Huan Jing Ke Xue ; 43(1): 472-480, 2022 Jan 08.
Artigo em Chinês | MEDLINE | ID: mdl-34989532

RESUMO

The bioavailability of heavy metals in soil and the physiological activities of rice determine the accumulation of heavy metals in brown rice. In this study, a field experiment was conducted in a rice paddy in which the total amount of Cd in the soil did not exceed the national standard, whereas the Cd in rice grains was at risk of overreaching in the suburbs of Guangzhou city. The bioavailability of heavy metals in the soil and the physiological barrier of rice were taken as the starting point. The early and late rice yield, brown rice heavy metal content, Cd and Pb enrichment coefficient, total soil heavy metals, soil physical and chemical properties, and soil Cd and Pb species distribution were investigated under the Si-rich amendment (JD), Ca-Mg amendment (YY), Si-rich amendment+flooding irrigation (JD+YS), and Ca-Mg amendment+flooding irrigation (YY+YS) treatments. The results showed that:① the total ω(Cd) in the soil was only 0.13 mg·kg-1 in the CK treatment. However, the average ω(Cd) in the grain of early rice reached up to 0.19 mg·kg-1. The early rice varieties (hybrid rice) had a more vital ability to accumulate Cd and total As in brown rice than that in late rice varieties (conventional rice) but a lower capacity for Pb accumulation. ② JD and YY application alone had no noticeable inhibitory effect on the accumulation of Cd and Pb in brown rice; however, JD+YS and YY+YS treatments significantly inhibited the accumulation of Cd and Pb in brown rice in both early and late rice, especially in the JD+YS treatment, which decreased the Cd and Pb accumulation by 65.8% and 68% for early rice and by 71.43% and 49.15% for late rice, respectively. The primary mechanism of JD+YS was to increase soil pH and maintain a low redox potential to promote soil Cd and Pb to be transformed from acid-soluble to a reduced state and residue state, thus decreasing Cd and Pb to migrate from the soil to the rice. At the same time, it effectively suppressed the absorption and transportation of Cd and Pb by early and late rice via the physiological barrier effect of Si nutrition and the competition for transportation channels between calcium and magnesium ions and cadmium and inhibited the accumulation of Cd and Pb in the brown rice of early and late rice. These results provide a theoretical basis for the exploration and application of the control technologies in the brown rice Cd and Pb resistance and have important practical significance for guiding the safe production in the rice-growing area in South China.


Assuntos
Oryza , Poluentes do Solo , Cádmio/análise , Chumbo , Solo , Poluentes do Solo/análise , Água , Abastecimento de Água
2.
Carbohydr Polym ; 275: 118694, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34742421

RESUMO

The elucidation of precise structure of fucoidan is essential for understanding their structure-function relationship and promoting the development of marine drugs. In this work, we firstly reported the oligosaccharide mapping of fucoidan from Holothuria floridana using a combination of hydrothermal depolymerization, hydrophilic interaction liquid chromatography (HILIC) coupled with electrospray mass spectrometry (ESI-FTMS) and high energy collision-induced dissociation (HCD-MS/MS) and 2D NMR analysis. With careful selection of fully deprotonated molecular ions of fucoidan oligosaccharides and their NaBD4 reduced alditols, HILIC-ESI-HCD-MS/MS provided structurally relevant glycosidic product ions with no sulfate loss for definitive assignment of sequence and sulfation pattern of all the oligosaccharides and their isomers from dp2 to dp7 from hydrothermal depolymerization. The oligosaccharide mapping clarified the structure of fucoidan with various oligosaccharide domains with 2,4-di-O-sulfated and 2-O sulfated fucose residues.

3.
Sci Total Environ ; 804: 150020, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34508932

RESUMO

The assessment of the exposure of aquatic wildlife to complex environmental mixtures of chemicals originating from both point and diffuse sources and evaluating the potential impact thereof constitutes a significant step towards mitigating toxic pressure and the improvement of ecological status. In the current proof-of-concept study, we demonstrate the potential of a novel Aggregated Biomarker Response (ABR) approach involving a comprehensive set of biomarkers to identify complex exposure and impacts on wild brown trout (Salmo trutta fario). Our scenario used a small lowland river in Germany (Holtemme river in the Elbe river catchment) impacted by two wastewater treatment plants (WWTP) and diffuse agricultural runoff as a case study. The trout were collected along a pollution gradient (characterised in a parallel study) in the river. Compared to fish from the reference site upstream of the first WWTP, the trout collected downstream of the WWTPs showed a significant increase in micronucleus formation, phase I and II enzyme activities, and oxidative stress parameters in agreement with increasing exposure to various chemicals. By integrating single biomarker responses into an aggregated biomarker response, the two WWTPs' contribution to the observed toxicity could be clearly differentiated. The ABR results were supported by chemical analyses and whole transcriptome data, which revealed alterations of steroid biosynthesis and associated pathways, including an anti-androgenic effect, as some of the key drivers of the observed toxicity. Overall, this combined approach of in situ biomarker responses complemented with molecular pathway analysis allowed for a comprehensive ecotoxicological assessment of fish along the river. This study provides evidence for specific hazard potentials caused by mixtures of agricultural and WWTP derived chemicals at sublethal concentrations. Using aggregated biomarker responses combined with chemical analyses enabled an evidence-based ranking of sites with different degrees of pollution according to toxic stress and observed effects.


Assuntos
Poluentes Químicos da Água , Purificação da Água , Animais , Biomarcadores , Rios , Truta , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/toxicidade
4.
Org Lett ; 24(1): 374-378, 2022 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-34928616

RESUMO

N-N axially chiral skeletons are significant structural motifs in natural products, pharmaceuticals, and functional materials. Herein we disclose a method for the asymmetric synthesis of N-N axially chiral compounds by phase-transfer catalysis. A wide range of N-N axially chiral quinazolinone derivatives were prepared in high yields with excellent stereoselectivities. Furthermore, the synthetic utility of the protocol was proved by large-scale reaction and transformation of the product. Density functional theory calculations provide insight into the mechanism.

5.
Front Endocrinol (Lausanne) ; 12: 759597, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34867801

RESUMO

Mutations in CD40 have been widely reported to be risk factors for Graves' disease (GD). The gene, along with its cognate ligand CD40L, may regulate pro-inflammatory and immune responses. Rs1883832, located at the -1 position of the Kozak sequence, is the most well-studied single nucleotide polymorphism (SNP) of CD40, and has been confirmed to predispose those with the alteration to GD, regardless of ethnicity. Our genome-wide association study (GWAS) indicated that several SNPs, including rs1883832 located within the vicinity of CD40 were associated with GD in the Han Chinese population. Aiming at identifying the most consequential SNP and its underlying pathogenic mechanism, we performed a two-stage refined study on 8,171 patients with GD and 7,906 controls, and found rs1883832 was the most significantly GD-associated SNP in the CD40 gene region (P Combined = 9.17×10-11, OR = 1.18). Through searching the cis-expression quantitative trait locus database and using quantitative RT-PCR, we further discovered that the rs1883832 genotype can influence CD40 gene transcription. Furthermore, we demonstrated that rs1883832 is a susceptibility locus for pTRAb+ GD patients. In conclusion, the current study provides robust evidence that rs1883832 can regulate CD40 gene expression and affect serum TRAb levels, which ultimately contributes to the development of GD.

6.
J Food Prot ; 2021 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-34882199

RESUMO

This study investigated the concentration of the pesticide residues found in Fragaria and Myrica rubra sold in the city of Hangzhou. From an analysis of 151 (77 Fragaria and 74 Myrica rubra ) samples using gas chromatography-tandem mass spectrometry (GC-MS/MS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS), a total of 41 different pesticide residues were found to be present. Of the 41 residues, 14 were found using GC-MS/MS and 27 using LC-MS/MS. Of the 151 samples, 10 (13.0%) of the 77 Fragaria and 5 (6.8%) of the 74 Myrica rubra samples were found to contain a specific pesticide residue, and only 4 Fragaria samples and 2 Myrica rubra samples were found to be without any pesticide residue. Eighteen of the 41 pesticides were not detected in either Fragaria or Myrica rubra samples. Of the 41 different residues, 10 were detected in Fragaria samples and 20 in Myrica rubra samples. In Fragaria , procymidone was the most commonly detected residue, with a detection rate of 88.3%, followed by prochloraz, with a detection rate of 53.2%. In Myrica rubra , prochloraz was the most commonly detected residue, with a detection rate of 71.6%, followed by carbendazim, with a detection rate of 68.9%. The pesticide residues in some of the samples exceeded the maximum residue limit (MRL) set in People's Republic of China. The MRL of dimethomorph was exceeded in 3 of the Fragaria samples and that of dichlorvos was exceeded in 2 of the Myrica rubra samples.

8.
J Immunol Res ; 2021: 3928323, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34859106

RESUMO

We performed a panoramic analysis on both human nonalcoholic steatohepatitis (NASH) microarray data and microarray/RNA-seq data from various mouse models of nonalcoholic fatty liver disease NASH/NAFLD with total 4249 genes examined and made the following findings: (i) human NASH and NAFLD mouse models upregulate both cytokines and chemokines; (ii) pathway analysis indicated that human NASH can be classified into metabolic and immune NASH; methionine- and choline-deficient (MCD)+high-fat diet (HFD), glycine N-methyltransferase deficient (GNMT-KO), methionine adenosyltransferase 1A deficient (MAT1A-KO), and HFCD (high-fat-cholesterol diet) can be classified into inflammatory, SAM accumulation, cholesterol/mevalonate, and LXR/RXR-fatty acid ß-oxidation NAFLD, respectively; (iii) canonical and noncanonical inflammasomes play differential roles in the pathogenesis of NASH/NAFLD; (iv) trained immunity (TI) enzymes are significantly upregulated in NASH/NAFLD; HFCD upregulates TI enzymes more than cytokines, chemokines, and inflammasome regulators; (v) the MCD+HFD is a model with the upregulation of proinflammatory cytokines and canonical and noncanonical inflammasomes; however, the HFCD is a model with upregulation of TI enzymes and lipid peroxidation enzymes; and (vi) caspase-11 and caspase-1 act as upstream master regulators, which partially upregulate the expressions of cytokines, chemokines, canonical and noncanonical inflammasome pathway regulators, TI enzymes, and lipid peroxidation enzymes. Our findings provide novel insights on the synergies between hyperlipidemia and hypomethylation in establishing TI and promoting inflammation in NASH and NAFLD progression and novel targets for future therapeutic interventions for NASH and NAFLD, metabolic diseases, transplantation, and cancers.

9.
Annu Int Conf IEEE Eng Med Biol Soc ; 2021: 6504-6510, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34892600

RESUMO

Transcutaneous Electrical Nerve Stimulation (TENS) suppresses chronic pain by stimulating deep nerves near the fascia from electrodes on the skin's surface. TENS has different effects on patients of different ages due to the variation of the thickness of skin layers when one becomes older.In this paper, we aim to optimize the stimulation effectiveness of TENS for patients of different ages through investigation of TENS stimulations of three different skin types categorized by age, Young, Old, and Older. In this investigation, the skin layer (stratum corneum, epidermis layer, dermis layer) in each model was created, and the thickness was varied. The effect of sin wave stimulation at 1 Hz, 100 Hz, and 10 kHz on the nerve stimulation effect near the fascia was examined.It is found that besides the well-known effect of stratum corneum, the thickness of the dermis layer significantly affects the stimulating effect. In addition, by using a lumped circuit model, it is showed that the change in the current path causes a mitigation in the stimulation effect in the dermis layer.

10.
Zhonghua Nan Ke Xue ; 27(8): 733-737, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34914247

RESUMO

Objective: To evaluate the efficacy and safety of Lingze Tablets in the treatment of BPH with kidney deficiency, blood stasis and dampness resistance. METHODS: Totally 235 eligible BPH patients, aged 50-80 years and meeting the inclusion criteria, were enrolled and treated with Lingze Tablets orally, 4 tablets per time, tid. Before and after an 8-week course of medication, IPSS, quality of life (QOL) and TCM syndromes scores were obtained from the patients. RESULTS: Of the total number of patients, 211 completed the whole course of treatment. Compared with the baseline, the IPSS was dramatically reduced after 4 and 8 weeks of medication (18.28 ± 5.29 vs 12.82 ± 4.66 and 9.23 ± 4.21, P < 0.01), and so were the QOL scores (6.44 ± 1.99 vs 4.95 ± 1.64 and 3.16 ± 1.53, P < 0.01) and TCM syndromes scores (17.49 ± 5.30 vs 12.45 ± 3.74 and 9.17 ± 3.24, P < 0.01). The incidence rates of adverse events and drug-related adverse reactions were 15.2% and 1.9%, respectively, and no organ function impairment was observed. CONCLUSIONS: Lingze Tablets are definitely effective and safe for the treatment of BPH with kidney deficiency, blood stasis and dampness resistance.


Assuntos
Hiperplasia Prostática , Qualidade de Vida , Humanos , Rim , Comprimidos
11.
Front Cardiovasc Med ; 8: 773473, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34912867

RESUMO

To determine whether pro-inflammatory lipid lysophosphatidylinositols (LPIs) upregulate the expressions of membrane proteins for adhesion/signaling and secretory proteins in human aortic endothelial cell (HAEC) activation, we developed an EC biology knowledge-based transcriptomic formula to profile RNA-Seq data panoramically. We made the following primary findings: first, G protein-coupled receptor 55 (GPR55), the LPI receptor, is expressed in the endothelium of both human and mouse aortas, and is significantly upregulated in hyperlipidemia; second, LPIs upregulate 43 clusters of differentiation (CD) in HAECs, promoting EC activation, innate immune trans-differentiation, and immune/inflammatory responses; 72.1% of LPI-upregulated CDs are not induced in influenza virus-, MERS-CoV virus- and herpes virus-infected human endothelial cells, which hinted the specificity of LPIs in HAEC activation; third, LPIs upregulate six types of 640 secretomic genes (SGs), namely, 216 canonical SGs, 60 caspase-1-gasdermin D (GSDMD) SGs, 117 caspase-4/11-GSDMD SGs, 40 exosome SGs, 179 Human Protein Atlas (HPA)-cytokines, and 28 HPA-chemokines, which make HAECs a large secretory organ for inflammation/immune responses and other functions; fourth, LPIs activate transcriptomic remodeling by upregulating 172 transcription factors (TFs), namely, pro-inflammatory factors NR4A3, FOS, KLF3, and HIF1A; fifth, LPIs upregulate 152 nuclear DNA-encoded mitochondrial (mitoCarta) genes, which alter mitochondrial mechanisms and functions, such as mitochondrial organization, respiration, translation, and transport; sixth, LPIs activate reactive oxygen species (ROS) mechanism by upregulating 18 ROS regulators; finally, utilizing the Cytoscape software, we found that three mechanisms, namely, LPI-upregulated TFs, mitoCarta genes, and ROS regulators, are integrated to promote HAEC activation. Our results provide novel insights into aortic EC activation, formulate an EC biology knowledge-based transcriptomic profile strategy, and identify new targets for the development of therapeutics for cardiovascular diseases, inflammatory conditions, immune diseases, organ transplantation, aging, and cancers.

12.
Zhonghua Nan Ke Xue ; 27(7): 635-640, 2021 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-34914232

RESUMO

Objective: To investigate the effect of Danhong Tongjing Prescription (DTP) on sperm quality in patients with bilateral varicocele (VC) after microsurgical varicocelectomy. METHODS: We randomly assigned 68 patients with bilateral VC to receive microsurgical varicocelectomy (the control group, n = 34) or microsurgical varicocelectomy followed by oral administration of DTP for a course of 90 days (the DTP group, n = 34). Before and after treatment, we obtained the sperm concentration, total sperm count, total sperm motility, the percentage of progressively motile sperm (PMS), sperm acrosomal enzyme activity, inhibin B (Inh-B) level, and sperm DNA fragmentation index (DFI) from the patients and compared the parameters between the two groups. RESULTS: There were no statistically significant differences in sperm concentration, PMS, acrosomal enzyme activity or sperm DFI among the patients with different degrees of VC preoperatively. After 3 months of medication, sperm concentration, total sperm count, total sperm motility, PMS and acrosomal enzyme activity were all increased while DFI decreased in both the control and DTP groups, even more significantly in the DTP group than in the control, and the Inh-B level was also markedly elevated in the DTP group in comparison with the baseline. CONCLUSIONS: The severity of bilateral VC is not correlated with the reduction of semen quality. DTP can improve sperm quality by improving total sperm count, PMS and acrosomal enzyme activity and reducing DFI in VC patients after varicocelectomy. The underlying mechanisms of the prescription may be related to its anti-oxidative stress action and abilities of improving reproductive hypoxia, spermatogenic environment and the function of Sertoli cells, but the specific signaling pathway involved is not yet clear.


Assuntos
Varicocele , Medicamentos de Ervas Chinesas , Humanos , Masculino , Prescrições , Análise do Sêmen , Motilidade Espermática , Espermatozoides , Varicocele/cirurgia
13.
Animals (Basel) ; 11(11)2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34827751

RESUMO

Avian pathogenic Escherichia coli (APEC) is the responsible pathogen for colibacillosis in poultry, and is a potential gene source for human extraintestinal pathogenic Escherichia coli. Escherichia coli type III secretion system 2 (ETT2) is widely distributed in human and animal ExPEC isolates, and is crucial for the virulence of ExPEC. Transcriptional regulator YgeK, located in the ETT2 gene cluster, was identified as an important regulator of gene expression in enterohemorrhagic E. coli (EHEC). However, the role of YgeK in APEC has not been reported. In this study, we performed amino acid alignment analysis of YgeK among different E. coli strains and generated ygeK mutant strain AE81ΔygeK from clinical APEC strain AE81. Flagellar formation, bacterial motility, serum sensitivity, adhesion, and virulence were all significantly reduced following the inactivation of YgeK in APEC. Then, we performed transcriptome sequencing to analyze the functional pathways involved in the biological processes. Results suggested that ETT2 transcriptional regulator YgeK plays a crucial role in APEC virulence. These findings thus contribute to our understanding of the function of the ETT2 cluster, and clarify the pathogenic mechanism of APEC.

14.
Viruses ; 13(11)2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34835090

RESUMO

Porcine circovirus-like virus (PCLV) is a type of circular Rep-encoding single-stranded DNA virus and may be associated with the development of diarrheal symptoms in pigs. In this study, we retrospectively analyzed three years of past cases in Anhui, China, and reported a case of hemorrhagic enteritis and death in a pregnant sow possibly caused by PCLV. In addition, we analyzed the evolutionary characteristics of PCLV and found that mutation, recombination and selective pressure all played an important role in the evolution of PCLV. We identified N15D and T17S as well as L56T, T58R, K59Q, M62R, L75I and R190K mutations in two different branches, and we noted recombination events in the Rep of a group of Chinese strains. Analysis of selection pressure revealed that PCLV gained more positive selection, indicating that the virus is in a continuous evolutionary state. The PR2 plot, ENC-plot and neutrality analysis showed a greater role of natural selection than that of mutational pressure in the formation of codon usage patterns. This study is the first to identify PCLV in sows with hemorrhagic dysentery and death, and it provides new epidemiological information on PCLV infection in pigs in China.

15.
Vet Microbiol ; 263: 109276, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34785478

RESUMO

Fowl adenovirus serotype 4 (FAdV-4) has caused substantial economic losses to the poultry industry and it has become a serious pathogen of poultry in China since 2015. MicroRNAs (miRNAs) play vital roles in regulating viral infection. However, how miRNAs regulate FAdV-4 replication in Leghorn male hepatocellular (LMH) cells remains unclear. This study aimed to elucidate the role of gga-miR-181a-5p in regulating FAdV-4 replication. The findings indicated that the expression of gga-miR-181a-5p was significantly upregulated in LMH cells during FAdV-4 infection. Also, the transfection of gga-miR-181a-5p mimics promoted FAdV-4 replication, while the opposite result was observed when gga-miR-181a-5p inhibitor was transfected in LMH cells. Moreover, the stimulator of interferon genes (STING) was found to be the target gene of gga-miR-181a-5p using software analysis, further confirming that STING was the target of gga-miR-181a-5p and gga-miR-181a-5p could negatively regulate the expression of STING at the mRNA and protein levels. Finally, the results showed that the overexpression of STING inhibited FAdV-4 replication and the knockout of STING promoted FAdV-4 replication. The collective findings revealed a novel host evasion mechanism adopted by FAdV-4 via gga-miR-181a-5p, suggesting novel strategies for designing miRNA-based vaccines and therapies.

16.
BMC Cancer ; 21(1): 1233, 2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-34789196

RESUMO

BACKGROUND: RNA editing leads to post-transcriptional variation in protein sequences and has important biological implications. We sought to elucidate the landscape of RNA editing events across pediatric cancers. METHODS: Using RNA-Seq data mapped by a pipeline designed to minimize mapping ambiguity, we investigated RNA editing in 711 pediatric cancers from the St. Jude/Washington University Pediatric Cancer Genome Project focusing on coding variants which can potentially increase protein sequence diversity. We combined de novo detection using paired tumor DNA-RNA data with analysis of known RNA editing sites. RESULTS: We identified 722 unique RNA editing sites in coding regions across pediatric cancers, 70% of which were nonsynonymous recoding variants. Nearly all editing sites represented the canonical A-to-I (n = 706) or C-to-U sites (n = 14). RNA editing was enriched in brain tumors compared to other cancers, including editing of glutamate receptors and ion channels involved in neurotransmitter signaling. RNA editing profiles of each pediatric cancer subtype resembled those of the corresponding normal tissue profiled by the Genotype-Tissue Expression (GTEx) project. CONCLUSIONS: In this first comprehensive analysis of RNA editing events in pediatric cancer, we found that the RNA editing profile of each cancer subtype is similar to its normal tissue of origin. Tumor-specific RNA editing events were not identified indicating that successful immunotherapeutic targeting of RNA-edited peptides in pediatric cancer should rely on increased antigen presentation on tumor cells compared to normal but not on tumor-specific RNA editing per se.

17.
Comp Immunol Microbiol Infect Dis ; 79: 101722, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34823134

RESUMO

The Escherichia coli type III secretion system 2 (ETT2) is found in most pathogenic E. coli strains. Although many ETT2 gene clusters carry multiple genetic mutations or deletions, ETT2 is known to be involved in bacterial virulence. To date, no studies have been conducted on the role of ETT2 in the virulence of avian pathogenic Escherichia coli (APEC), which harbours ETT2. Thus, we deleted the ETT2 of APEC strain and evaluated the phenotypes and pathogenicities of the mutant. The results showed that deletion of ETT2 had no effect on APEC growth, but significantly promoted biofilm formation. In addition, as compared to the wild-type (WT) strain, the ETT2 deletion significantly promoted adherence to and invasion of DF-1 chicken fibroblasts and facilitated survival in the sera of specific-pathogen-free chickens. Analysis of the role of ETT2 in animal infection models demonstrated that the distribution of viable bacteria in the blood and organs of chicks infected with the ΔETT2 was significantly higher than those infected with WT. The results of RNA sequencing indicated that multiple genes involved in biofilm formation, lipopolysaccharide components, fimbrial genes and virulence effector proteins are regulated by ETT2. Collectively, these results implicated ETT2 is involved in the biofilm formation and pathogenicity of APEC.

19.
Cancer Discov ; 2021 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-34772733

RESUMO

Gene expression is regulated by promoters and enhancers marked by histone H3-lysine-27 acetylation (H3K27ac), which is established by the paralogous histone acetyltransferases (HATs), EP300 and CBP. These enzymes display overlapping regulatory roles in untransformed cells, but less characterized roles in cancer cells. We demonstrate that the majority of high-risk pediatric neuroblastoma (NB) depend on EP300, whereas CBP has a limited role. EP300 controls enhancer acetylation by interacting with TFAP2ß, a transcription factor member of the lineage-defining transcriptional core regulatory circuitry (CRC) in NB. To disrupt EP300, we developed a proteolysis-targeted-chimaera (PROTAC) compound termed "JQAD1" that selectively targets EP300 for degradation. JQAD1 treatment causes loss of H3K27ac at CRC enhancers and rapid neuroblastoma apoptosis, with limited toxicity to untransformed cells where CBP may compensate. Further, JQAD1 activity is critically determined by cereblon (CRBN) expression across neuroblastoma cells.

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