Development and identification of two novel wheat-rye 6R derivative lines with adult-plant resistance to powdery mildew and high-yielding potential

Powdery mildew,caused by Blumeria graminis f.sp.tritici(Bgt),is a devastating disease that seriously threatens wheat yield and quality.To control this disease,host resistance is the most effective measure.Compared with the resistance genes from common wheat,alien resistance genes can better withstand infection of this highly variable pathogen.Development of elite alien germplasm resources with powdery mildew resistance and other key breeding traits is an attractive strategy in wheat breeding.In this study,three wheat-rye germplasm lines YT4-1,YT4-2,and YT4-3 were developed through hybridization between octoploid triticale and common wheat,out of which the lines YT4-1 and YT4-2 conferred adult-plant resistance(APR)to powdery mildew while the line YT4-3 was susceptible to powdery mildew during all of its growth stages.Using genomic in situ hybridization,multi-color fluorescence in situ hybridization,multi-color GISH,and molecular marker analysis,YT4-1,YT4-2,and YT4-3 were shown to be cytogenetically stable wheat-rye 6R addition and T1RS.1BL translocation line,6RL ditelosomic addition and T1RS.1BL translocation line,and T1RS.1BL translocation line,respectively.Compared with previously reported wheat-rye derivative lines carrying chromosome 6R,YT4-1 and YT4-2 showed stable APR without undesirable pleiotropic effects on agronomic traits.Therefore,these novel wheat-rye 6R derivative lines are expected to be promising bridge resources in wheat disease breeding.

Optimizing 6-mercaptopurine and azathioprine therapy in the management of inflammatory bowel disease

The thiopurine drugs,6-mercaptopurine(6-MP) and azathioprine,are efficacious in the arsenal of inflammatory bowel disease(IBD) therapy.Previous reports indicate that 6-thioguanine nucleotide(6-TGN) levels correlate with therapeutic efficacy,whereas high 6-methylmercaptopurine(6-MMP) levels are associated with hepatotoxicity and myelotoxicity.Due to their complex metabolism,there is wide individual variation in patient response therein,both in achieving therapeutic drug levels as well as in developing adverse reactions.Several strategies to optimize 6-TGN while minimizing 6-MMP levels have been adopted to administer the thiopurine class of drugs to patients who otherwise would not tolerate these drugs due to side-effects.In this report,we will review different approaches to administer the thiopurine medications,including the administration of 6-mercaptopurine in those unsuccessfully treated with azathioprine;coadministration of thiopurine with allopurinol;co-administration of thiopurine with anti-tumor necrosis factor α;6-TGN administration;desensitization trials;and split dosing of 6-MP.

Preliminary in vitro biological evaluation of novel O^6-benzylguanine derivative-precursors of PET tracers for the DNA repair protein AGT

A series of O6-benzylguanine （O6-BG） derivatives was synthesized, and their in vitro AGT （O^6-Alkylguanine DNA alkyltransferase） inhibitory ability was evaluated by MTT method to investigate the possibility to be promising precursors of PET tracers. O^6--BG and its derivatives, HMBG, MOBG, MOMBG, BABP and PEG, were synthesized from guanine respectively. The AGT inhibitory ability of the compounds were tested by evaluating their effects on increasing sensitivity of HeLa cancer cells to 1,3-bis （2-chloroethyl）-l-nitrosourea （BCNU） with MTT method. Their order of AGT inhibitory activities follows HMBG ≥ O^6-BG ≥ MOBG ≥ MOMBG, whereas the BABP and PEG showed no AGT inhibition activity. HMBG, MOBG and MOMBG would be promising as precursor candidates of PET tracers for tumor imaging.

On tolerability and safety of a maintenance treatment with 6-thioguanine in azathioprineor 6-mercaptopurine intolerant IBD patients

AIM: To determine the tolerability and safety profile of a low-dose maintenance therapy with 6-TG in azathioprine (AZA) or 6-mercaptopurine (6-MP) intolerant inflammatory bowel disease (IBD) patients over a treatment period of at least 1 year.METHODS: Database analysis.RESULTS: Twenty out of ninety-five (21%) patients discontinued 6-TG (mean dose 24.6 mg; mean 6-TGN level 540 pmol/8×108 RBC) within 1 year. Reasons for discontinuation were GI complaints (31%), malaise (15%)and hepatotoxicity (15%). Hematological events occurred in three patients, one discontinued treatment. In the 6-TG-tolerant group, 9% (7/75) could be classified as hepatotoxicity. An abdominal ultrasound was performed in 54% of patients, one patient had splenomegaly.CONCLUSION: The majority of AZA or 6-MP-intolerant IBD patients (79%) is able to tolerate maintenance treatment with 6-TG (dosages between 0.3 and 0.4 mg/kg per d). 6-TG may still be considered as an escape maintenance immunosuppressant in this difficult to treat group of patients, taking into account potential toxicity and efficacy of other alternatives. The recently reported hepatotoxicity is worrisome and 6-TG should therefore be administered only in prospective trials.

Efficacy of 6-mercaptopurine treatment after azathioprine hypersensitivity in inflammatory bowel disease

AIM:To investigate the efficacy of 6-mercaptopurine (6-MP) in cases of azathioprine (AZA) hypersensitivity in patients with inflammatory bowel disease. METHODS: Twenty nine previously confirmed Crohn’s disease (CD) (n = 14) and ulcerative colitis (UC) (n = 15) patients with a known previous (AZA) hypersensitivity reaction were studied prospectively. The 6-MP doses were gradually increased from 0.5 up to 1.0-1.5 mg/kg per day. Clinical activity indicies (CDAI/CAI), laboratory variables and daily doses of oral 5-ASA, corticosteroids, and 6-MP were assessed before and in the first, sixth and twelfth months of treatment. RESULTS: In 9 patients, 6-MP was withdrawn in the first 2 wk due to an early hypersensitivity reaction. Medication was ineffective within 6 mo in 6 CD patients, and myelotoxic reaction was observed in two. Data were evaluated at the end of the sixth month in 12 (8 UC, 4 CD) patients, and after the first year in 9 (6 UC, 3 CD) patients. CDAI decreased transiently at the end of the sixth month, but no significant changes were observed in the CDAI or the CAI values at the end of the year. Leukocyte counts (P = 0.01), CRP (P = 0.02), and serum iron (P = 0.05) values indicated decreased inflammatory reactions, especially in the UC patients at the end of the year, making the possibility to taper oral steroid doses. CONCLUSION: About one-third of the previously AZA- intolerant patients showed adverse effects on taking 6MP. In our series, 20 patients tolerated 6MP, but it was ineffective in 8 CD cases, and valuable mainly in ulcerative colitis patients.

Synthesis and preliminary biological evaluation of the derivatives of O^6-benzylguanine as inactivators of O^6-alkylguanine-DNA alkyltransferase

A series of new O6-BG derivatives （14-21,23-30） were synthesized as inactivators of O6-Alkylguanine-DNA alkyltransferase （AGT）, and their ability to inhibit AGT was preliminary evaluated by MTT with O6-BG as the control. The result suggested compound 30 displayed a higher activity than O6-BG.

Expert opinion: Experience with 6-mercaptopurine in the treatment of inflammatory bowel disease

Arbitrarily, modern day treatment of inflammatory bowel disease begins with the introduction of immuno- suppressives for ulcerative colitis. Clinical improvement with sulfasalazine had been meaningful but modest. Treatment with adrenocorticotropic hormone and corti- costeroids led to clinical responses never before realized but it took much too long to recognize that they were not capable of maintaining remission, that adverse reactions were subtle but potentially devastating and that some other agent would be necessary to capitalize on their transient advantage. This of course was true in the treatment of Crohn's disease as well. Not much was ever made of the role of sulfasalazine for Crohn' s disease, but with the severing of the diazobond and the elimination of the sulphur component, the 5-ami- nosalacylic acid (5-ASA) products clearly led to clinical improvement, especially in cases of Crohn's colitis and those with ileitis where the 5-ASA product was released in the terminal ileum and more proximal in the small bowel as well as in ulcerative colitis. The induction of remission was first demonstrated by 6-mercaptopurine (6-MP) with case reports and uncontrolled trials in pa- tients with ulcerative colitis, but its placebo controlled trial for Crohn's disease firmly established its role in inducing remission. No subsequent trial has confirmed its similar role for ulcerative colitis, but nevertheless cli- nicians know well that 6-MP works at least as well and probably more effectively for ulcerative colitis than for Crohn's disease. What changes have taken place utiliz- ing 6-MP in the management of inflammatory bowel disease since its introduction in the 1960's and 1970's and its trial for Crohn's disease published in the New England Journal of Medicine in 1980?

Design,Synthesis,and Biological Evaluation of 5H-Thiazolo[3,2-a]pyrimidine-6-carboxylic Acid Ethyl Ester Derivatives as a Novel Series of Acetylcholinesterase Inhibitors

Acetylcholinesterase inhibitors are the most frequently prescribed anti-Alzheimer＇s drugs. A series of 5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester derivatives as the novel acetylcholinesterase inhibitors was designed based on virtual screening methods. The target compounds were synthesized with Biginelli reaction and Hantzsch-type condensation of dihydropyrimidines with substituted phenacyl chlorides, and were characterized with elemental analysis, IR, MS, ^1H NMR, and ^13C NMR. The biological evaluation against human acetylcholinesterase in vitro indicated all the target compounds show more than 50% inhibition at 10μmol/L by means of the Ellman method. The results provide a starting point for the development of novel drugs to treat Alzheimer＇s disease and lay the foundation of searching for improved acetylcholinesterase inhibitors with the novel scaffolds.

血管性痴呆患者血清HDAC6和BDNF表达与患者认知功能及预后的相关性分析

目的探究血管性痴呆(VD)患者血清组蛋白脱乙酰基酶6(HDAC6)和脑源性神经营养因子(BDNF)表达与患者认知功能及预后的相关性。方法选取2020年10月至2022年12月我院收治的126例VD患者为研究对象(VD组),另选取同期在我院治疗但未发生VD的缺血性脑卒中患者100例为对照组。ELISA法测定所有受试者血清BDNF、HDAC6水平;根据蒙特利尔认知功能量表(MoCA)评估患者认知功能;比较不同病情程度、不同预后患者血清BDNF、HDAC6水平;Pearson相关性分析VD患者血清BDNF、HDAC6水平与MoCA评分之间的关系;受试者工作特征(ROC)曲线分析血清BDNF、HDAC6水平对Ⅲ级预后功能障碍的预测价值。结果与对照组相比,VD组患者血清BDNF水平显著降低(P<0.05),HDAC6水平显著升高(P<0.05)。Pearson相关性分析结果显示,血清BDNF与MoCA评分呈显著正相关(r=0.488,P<0.05),血清HDAC6与MoCA评分呈显著负相关(r=-0.490,P<0.05)。与Ⅰ级组相比,Ⅱ级、Ⅲ级组患者血清BDNF水平显著降低(P<0.05),且Ⅲ级组显著低于Ⅱ级组(P<0.05),而HDAC6水平显著升高(P<0.05),且Ⅲ级组显著高于Ⅱ级组(P<0.05)。ROC曲线结果显示,BDNF、HDAC6预测Ⅲ级预后功能障碍的曲线下面积(AUC)分别为0.906(95%CI 0.848~0.965)、0.905(95%CI 0.847~0.964),敏感度分别为95.5%、95.5%,特异度分别为74.3%、70.5%,二者联合预测Ⅲ级预后功能障碍的AUC为0.977(95%CI 0.940~1.000),敏感度为90.9%,特异度为89.9%。结论VD患者血清BDNF水平显著降低,HDAC6水平显著升高,且二者均与患者认知功能障碍及预后密切相关,可为临床诊治提供一定参考。

SYNTHESIS OF 6-AMINO, 6-METHOXY AND 6-ETHOXY PURINENUCLEOSIDE DERIVATIVES

A convenient route for the conversion of inosine to the corresponding 6-amino, 6-methoxy and 6-ethoxy derivatives is reported. This conversion can be achieved by ammoniation or etherification of the 6-pyridinium intermediate(3) which can be readily produced under mild reaction conditions. The chemistry and characterization of these compounds are presented, A plausible mechanism of the reaction is proposed.

Synthesis and fluorescence properties of Tb(Ⅲ) complexes with pyridine-2,6-dicarboxylic acid derivatives

Two novel ligands named 4-styrylpyridine-2,6-dicarboxylic acid (4-SPDA) and 4-(4-(2-(2, 6-dicarboxypyridin-4-yl)- vinyl)styryl)pyridine-2,6-dicarboxylic acid(DSPDA) and their complexes with Tb(Ⅲ) were synthesized and characterized by infrared spectrometry, 1H nuclear magnetic resonance, elemental analysis and gas chromatograph-mass spectrometry. The ligand synthetic route was optimized. The fluorescence properties of the complex in solid state, in different kind of solvents and in solutions with different pH values were investigated in detail. The results show that the yields of DSPDA and 4-SPDA reach over 78% by Wittig-Horner reaction and other eight pyridine-2, 6-dicarboxylic acid derivatives with different substituents on pyridine ring, and their complexes with Tb(Ⅲ) are also obtained. The fluorescence intensities of the complexes with electron-donating groups are more intense than those of the complexes with electron-withdrawing groups on pyridine ring; fluorescence intensities of the complexes are the strongest in neutral solution (pH=7), and the less the dipole moment of solvent molecule is, the stronger the fluorescence intensity is. It is found that the two ligands (4-APDA and DSPDA) are the good sensitizers for Tb(Ⅲ) ion.

RNA m^(6)A修饰对髓源性抑制细胞的调控作用

RNA N^(6)-甲基腺苷(N^(6)-methyladenosine,m^(6)A)修饰主要受m^(6)A甲基转移酶、m^(6)A去甲基化酶和m^(6)A结合蛋白的调控,可以改变基因转录,从而调节生理和病理过程。近年来,越来越多的证据表明,m^(6)A甲基化在调节肿瘤微环境(tumor microenvironment,TME)中发挥至关重要作用,影响各种癌症的发生、发展和转移过程。髓源性抑制细胞(myeloid-derived suppressor cell,MDSC)为一群病理激活的未成熟髓系细胞,是TME中的重要免疫细胞。其主要通过抑制T细胞的活性发挥作用,从而促进恶性肿瘤的免疫逃逸。研究表明,靶向MDSC能够重塑免疫抑制微环境,提高癌症免疫治疗的疗效,是一种新的、有希望的免疫治疗靶点。m^(6)A修饰在一些免疫细胞的激活、分化和效应功能等方面的作用已受到广泛关注,但是m^(6)A修饰如何影响MDSC的研究仍非常有限,因此,进一步探讨二者之间的关系显得尤为重要。本综述在介绍MDSC及RNA m^(6)A修饰的基础上,总结了RNA m^(6)A修饰调控TME中MDSC的机制及研究进展,以期从表观调控的角度为靶向MDSC提供治疗肿瘤的新策略。

Ratiometric Fluorescence Detection of 6-Mercaptopurine Based on the Nanohybrid of Fluorescence Carbon Dots and Gold Nanoclusters

The development of a simple and accurate quantitative method for the determination of 6-mercaptopurine (6-MP) is of great importance because of its serious side effects. Ratiometric fluorescence (RF) sensors are not subject to interference from environmental factors, and exhibit enhanced precision and accuracy. Therefore, a novel RF sensor for the selective detection of 6-MP was developed. The present work reports a sensitive and selective RF sensor for the detection of 6-mercaptopurine, by hybridizing carbon nanodots (CDots) and gold nanoclusters (AuNCs) capped with bovine serum albumin (BSA). The CDots serve as the reference signal and the AuNCs as the reporter. On addition of the 6-MP, AuNCs formed aggregates, because the existing cross-links within the AuNCs and BSA structure were broken in favour of the Au-S bonds, which can enhance the fluorescence of AuNCs, while the fluorescence of CDots is stable against 6-MP, leading to distinct ratiometric fluorescence changes when exposed to 6-MP. 6-MP could be detected in the range of 0 - 30.22 μM with a detection limit of 54 nM. The developed sensor was applied for the determination of 6-MP in human serum samples and satisfactory results were obtained.

First experience with intracytoplasmic sperm injection for extreme oligozoospermia associated with Crohn's disease and 6-mercaptopurine chemotherapy

<abstract>Aim: To describe the reproductive outcome following intracytoplasmic sperm injection (ICSI) for male factor infertility associated with Crohn's disease and 6-mercap-topurine (6-MP) chemotherapy. Methods: The male partner of a couple suffered from severe Crohn's disease and received a 3-month course of 6-MP for this condition. Two spontaneous conceptions were established before 6-MP, although post-chemotherapy semen analysis found the sperm concentration to be 8,000/mL. In vitro fertilization (IVF) with ICSI and embryo transfer was performed. Results: The woman underwent an uncomplicated controlled ovarian hyperstimulation sequence using a combined rec-FSH+hMG protocol, following late luteal phase pituitary downregulation. This culminated in the retrieval of 18 oocytes, 11 of which were fertilized with ICSI. She later delivered a normal male infant without urogenital anomaly. Four nontransferred blastocysts were cryopreserved. Conclusion: This report describes the first successful birth after ICSI for severe oligozoospermia associated with Crohn's disease and 6-MP therapy. We outline salient features of Crohn's disease, 6-MP pharmacology, and their relevance to human fertility.

Synthesis and Anti-influenza Virus Activity of Ethyl 6-Bromo-5-hydroxyindole-3-carboxylate Derivatives

A series of ethyl 6-bromo-5-hydroxyindole-3-carboxylate derivatives were synthesized and their in vitro anti-influenza virus activity was evaluated. All the compounds were characterized by 1H NMR and MS.

6E-UDCA通过FABP7信号通路对MAFLD小鼠脂质代谢的影响研究

目的探讨6位乙基取代的熊去氧胆酸(6E-UDCA)通过重组人脂肪酸结合蛋白7(FABP7)信号通路对代谢相关脂肪性肝病(MAFLD)小鼠脂质代谢的影响。方法选取野生型(WT)、WT-1小鼠、脑FABP7特异性敲除(B-FABP7^(-/-))小鼠各6只作为3组,均采用高脂肪饲料喂养16周法构建MAFLD小鼠模型,其中WT-1组、B-FABP7^(-/-)组的饲料中加6E-UDCA(23.50 mg/kg),记录各组小鼠体重和摄食情况。第16周末小鼠在麻醉下剖腹并采集腹主动脉血,检测血清TC、TG、ALT、血糖、尿酸、游离长链脂肪酸(LCFA)水平;小鼠麻醉下失血死亡后取肝脏组织,采用HE染色观察肝脏组织病理学变化,分离小鼠肝脏并称取质量,计算肝脏系数。结果WT组小鼠肝脏组织中存在明显炎性细胞浸润情况,且有大量脂肪堆积,肝细胞排列紊乱;WT-1组、B-FABP7^(-/-)组小鼠肝脏组织中炎性细胞浸润减轻,轻微脂肪堆积,且肝细胞排列紊乱明显减轻。WT-1组和B-FABP7^(-/-)组小鼠体重、摄食量、肝脏质量、肝脏系数以及TC、TG、ALT、血糖、尿酸水平均明显低于WT组(均P<0.05),游离LCFA水平高于WT组(P<0.05);B-FABP7^(-/-)组小鼠体重、摄食量、肝脏质量、肝脏系数以及TC、TG、ALT、血糖、尿酸水平均明显低于WT-1组(均P<0.05),游离LCFA水平高于WT-1组(P<0.05)。结论6E-UDCA可通过调控FABP7信号通路,进而改善MAFLD小鼠脂质代谢,提高游离LCFA水平。

Design, Synthesis and Antifungal Activity of 6-Fluoro-3,3a,4,5-tetrahydro-2H-pyrazolo[4,3-c]-quinoline-2-carboxamide Derivatives

A series of 6-fluoro-3,3a,4,5-tetrahydro-2H-pyrazolo[4,3-c]quinoline-2-carboxamide derivatives was designed based on the bioisosterism and combination principle in drug design. The target compounds were synthesized from substituted aniline through Michael addition, cyclization, Mannich reaction and condensation with 4-substituted semicarbazides, and the structures were confirmed by mass spectrometry（MS） and 1H NMR. The antifungal assay was carried out in vitro by two-fold dilution. The result shows that all the compounds are of antifungal activities against the tested fungi at different levels.

Chemiluminescence Determination of 6-Mercaptopurine in Pharmaceuticals

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Theoretical Investigation of Structures,Bonding and Electronic Properties for the Complexes of 6-Mercaptopurine and Ag8 Clusters

The Ag clusters have been investigated widely theoretically and experimentally. In particular, it has recently shown that the neutral Ag8 clusters embedded in an argon matrix have a strong fluorescence signal. As we can know, the metal clusters may have important effects on the structures and properties of biomolecules. More and more attention is paid to the interaction between nanomaterials and biomolecules. In this work, the B3LYP method in density functional theory was used on the complexes between the 6-mercaptopurine（6MP） and Ag8 clusters combined with 6-311＋＋G＊＊ as well as LANL2DZ base sets. The geometries of all the complexes were optimized with full degree of freedom and the structures, chemical bonds, orbital properties as well as Mulliken charges for ten possible complexes were analyzed based on the same theory level. In addition, the influence of temperature and pressure on the stabilities of the four complexes was further explored using standard statistical thermodynamic methods ranging from 50 to 500 K and at 100 kPa or 100 bar. The results show that the complex Ag8-6 MP-7-5 can be the most stable one among the investigated complexes, in which the Ag（11） atom interacts with the S（10） atom forming the strong chemical bond. The Mulliken charges also show that the Ag–S chemical bond is formed and the related charge has transferred. Additionally, the temperature and pressure can significantly influence the stability of the four stable complexes.

Theoretical Study on Two C_(16)H_(12)O_4 Isomers of Derivatives of Pagodane

Two C16H12O4 isomers of derivatives of pagodane were firstly reported and studied by using DFT method. Geometries, energies, and vibrational frequencies have been calculated for the two C16H12O4 isomers with pagodane-like structures at the B3LYP/6-31G^＊＊ level of theory. Symmetries of isomer 1 and 2 are D2h and D2d, respectively. Heats of formation for the two C16H12O4 isomers have been estimated in this paper. According to the heats of formation, the two C16H12O4 isomers are more stable than pagodane. Heats of formation as well as the vibrational analysis indicate that the two C16H12O4 isomers enjoy sufficient stability to allow for the experimental preparation.