NADPH oxidase 4(NOX4)as a biomarker and therapeutic target in neurodegenerative diseases

Diseases like Alzheimer’s and Parkinson’s diseases are defined by inflammation and the damage neurons undergo due to oxidative stress. A primary reactive oxygen species contributor in the central nervous system, NADPH oxidase 4, is viewed as a potential therapeutic touchstone and indicative marker for these ailments. This in-depth review brings to light distinct features of NADPH oxidase 4, responsible for generating superoxide and hydrogen peroxide, emphasizing its pivotal role in activating glial cells, inciting inflammation, and disturbing neuronal functions. Significantly, malfunctioning astrocytes, forming the majority in the central nervous system, play a part in advancing neurodegenerative diseases, due to their reactive oxygen species and inflammatory factor secretion. Our study reveals that aiming at NADPH oxidase 4 within astrocytes could be a viable treatment pathway to reduce oxidative damage and halt neurodegenerative processes. Adjusting NADPH oxidase 4 activity might influence the neuroinflammatory cytokine levels, including myeloperoxidase and osteopontin, offering better prospects for conditions like Alzheimer’s disease and Parkinson’s disease. This review sheds light on the role of NADPH oxidase 4 in neural degeneration, emphasizing its drug target potential, and paving the path for novel treatment approaches to combat these severe conditions.

Type-B monoamine oxidase inhibitors in neurological diseases:clinical applications based on preclinical findings

Type-B monoamine oxidase inhibitors,encompassing selegiline,rasagiline,and safinamide,are available to treat Parkinson's disease.These drugs ameliorate motor symptoms and improve motor fluctuation in the advanced stages of the disease.There is also evidence suppo rting the benefit of type-B monoamine oxidase inhibitors on non-motor symptoms of Parkinson's disease,such as mood deflection,cognitive impairment,sleep disturbances,and fatigue.Preclinical studies indicate that type-B monoamine oxidase inhibitors hold a strong neuroprotective potential in Parkinson's disease and other neurodegenerative diseases for reducing oxidative stress and stimulating the production and release of neurotrophic factors,particularly glial cell line-derived neurotrophic factor,which suppo rt dopaminergic neurons.Besides,safinamide may interfere with neurodegenerative mechanisms,countera cting excessive glutamate overdrive in basal ganglia motor circuit and reducing death from excitotoxicity.Due to the dual mechanism of action,the new generation of type-B monoamine oxidase inhibitors,including safinamide,is gaining interest in other neurological pathologies,and many supporting preclinical studies are now available.The potential fields of application concern epilepsy,Duchenne muscular dystrophy,multiple scle rosis,and above all,ischemic brain injury.The purpose of this review is to investigate the preclinical and clinical pharmacology of selegiline,rasagiline,and safinamide in Parkinson's disease and beyond,focusing on possible future therapeutic applications.

Natural variation in the cytochrome c oxidase subunit 5B OsCOX5B regulates seed vigor by altering energy production in rice

Seed vigor is a crucial trait for the direct seeding of rice.Here we examined the genetic regulation of seed vigor traits in rice,including germination index(GI)and germination potential(GP),using a genome-wide association study approach.One major quantitative trait locus,qGI6/qGP6,was identified simultaneously for both GI and GP.The candidate gene encoding the cytochrome c oxidase subunit 5B(OsCOX5B)was validated for qGI6/qGP6.The disruption of OsCOX5B caused the vigor traits to be significantly lower in Oscox5b mutants than in the japonica Nipponbare wild type(WT).Gene co-expression analysis revealed that OsCOX5B influences seed vigor mainly by modulating the tricarboxylic acid cycle process.The glucose levels were significantly higher while the pyruvic acid and adenosine triphosphate levels were significantly lower in Oscox5b mutants than in WT during seed germination.The elite haplotype of OsCOX5B facilitates seed vigor by increasing its expression during seed germination.Thus,we propose that OsCOX5B is a potential target for the breeding of rice varieties with enhanced seed vigor for direct seeding.

Enhancing metformin-induced tumor metabolism destruction by glucose oxidase for triple-combination therapy

Despite decades of laboratory and clinical trials,breast cancer remains the main cause of cancer-related disease burden in women.Considering the metabolism destruction effect of metformin(Met)and cancer cell starvation induced by glucose oxidase(GOx),after their efficient delivery to tumor sites,GOx and Met may consume a large amount of glucose and produce sufficient hydrogen peroxide in situ.Herein,a pH-responsive epigallocatechin gallate(EGCG)-conjugated low-molecular-weight chitosan(LC-EGCG,LE)nanoparticle(Met–GOx/Fe@LE NPs)was constructed.The coordination between iron ions(Fe3+)and EGCG in this nanoplatform can enhance the efficacy of chemodynamic therapy via the Fenton reaction.Met–GOx/Fe@LE NPs allow GOx to retain its enzymatic activity while simultaneously improving its stability.Moreover,this pH-responsive nanoplatform presents controllable drug release behavior.An in vivo biodistribution study showed that the intracranial accumulation of GOx delivered by this nanoplatform was 3.6-fold higher than that of the free drug.The in vivo anticancer results indicated that this metabolism destruction/starvation/chemodynamic triple-combination therapy could induce increased apoptosis/death of tumor cells and reduce their proliferation.This triple-combination therapy approach is promising for efficient and targeted cancer treatment.

The Implantation and Transmission of Plague Culture by the Five Plague Gods in Shuilu Murals

The Five Plague Gods(五瘟神) in the Shuilu(水陆) murals from the Ming and Qing dynasties exemplify a distinctive manifestation of plague gods image developed under the pedigree of Taoist gods.As a significant system for expelling disasters in Shuilu,the depiction of the Five Plague Gods prominently merges human beings and livestock.This shape form to a large extent,draws on the image of Nuo(傩),a figure reflecting an imagination of the host of plague pathogens.In terms of the numbers of gods,it aligns with the conceptual framework of Wu Xing(五行 the five elements),a foundational principle in traditional Chinese medicine.The internal cultural connection highlights the means of plague prevention and control in China,as well as the external reflection of plague culture.Through multi-dimensional interpretations with the double proof method,this article dissects the formation,core elements,and cultural characteristics of the beliefs in the Five Plague Gods reflected in the Shuilu murals,and transcends mere visual semantics,offering a deeper understanding of these complex cultural symbols.

Petrographic and Geochemical Characteristics of the Granitoids in the South of Godé (North of the Square Degree of Léo-Burkina Faso, West Africa)

South of Godé, in the central-western region of Burkina Faso, granitoids of Paleoproterozoic age are similar to those of the Man/Leo shield. This study focused on the petrographic and geochemical characteristics of these granitoids, with the following results: 1) The tonalite that outcrops in the south-west of the study area belongs to the TTG group or first generation granitoids. They are most often ribboned at outcrop and have a geochemical signature close to that of Archean TTGs. Tonalite has a metaluminous character and the REE spectrum indicates that it may be derived from partial melting of basic magmatic rocks. 2) Biotite granites have no outcrop structure. They are weakly metaluminous to peraluminous and potassic to highly potassic. Their rare earth spectra indicate that they may be derived from the partial melting of TTG granitoids. 3) Geotectonic diagrams show that the granitoids studied to the south of Godé were emplaced in an active tectonic context similar to that of present-day subduction zones.

Monoamine Oxidase-B Inhibitor Rasagiline Effects on Motor and Non-Motor Symptoms in Individuals with Parkinson’s Disease: A Systematic Review and Meta-Analysis

Objective: In the manuscript titled Monoamine Oxidase-B Inhibitor Rasagiline Effects on Motor and Non-Motor Symptoms in Individuals with Parkinsons Disease: A Systematic Review and Meta-Analysis, the objective was to conduct a systematic review with meta-analysis to investigate the effects that Rasagiline has on motor and non-motor symptoms in individuals with PD. Introduction: Rasagiline is a second-generation monoamine oxidase-B (MAO-B) inhibitor used both as monotherapy and adjunctive therapy for Parkinsons Disease (PD). Methods: A systematic literature search and meta-analysis were performed with randomized control trials that investigated the effects of Rasagiline on motor and non-motor symptoms in individuals with PD. The systematic search was conducted in PubMed, Cochrane, and EBSCO databases. Methodological quality was assessed using the Cochrane Grading Recommendations Assessment, Development and Evaluation approach. Results: Fourteen studies were included in our review. There were trivial to small and statistically significant improvements in motor symptoms for individuals with PD treated with Rasagiline compared to placebo. Non-motor symptoms showed no significant improvement with Rasagiline compared to placebo in five of six meta-analyses. Results were based on very low to moderate certainty of evidence. Conclusion: 1 mg/day Rasagiline significantly improved Parkinsonian motor symptoms in individuals with PD compared with placebo. For all outcomes, the 1 mg/day Rasagiline group was favored over the placebo group.

项目的PPP模式适用性GOD分析——以智慧城市建设项目为例

政府和社会资本合作模式的应用越来越广。然而,并不是所有的项目都适合采用PPP模式,出现了PPP模式的滥用。为了判断项目的 PPP模式适用性,本文提出GOD(Goods-Operation-Delivery)分析方法,把PPP模式适用性问题简化为三个步骤及三项判断准则:首先,以公共产品理论为基础,根据项目产出的属性识别出无需采用PPP模式的项目;其次,以公共权力理论为基础,根据项目运行的属性识别出不能采用PPP模式的项目;最后,基于比较优势理念,根据项目交付模式的效率确定是否优先采用PPP模式。为了演示GOD分析的应用,本文对智慧城市建设项目的 PPP模式适用性进行了演示性分析,结果表明GOD分析可以较好地分析项目的 PPP适用性。

Application Progresses of Glucose Oxidase(GOD)in Feed

Glucose oxidase （GOD） is a new pollution-free enzyme preparation which can improve morphological structure and micro ecological balance of intestine in livestock and poultry, perfect intestinal environment, and increase feed digestibility, growth performance and disease resistance. This paper summarizes the physical and chemical properties and biological function of GOD and its application status in feed.

Knockdown of NADPH oxidase 4 reduces mitochondrial oxidative stress and neuronal pyroptosis following intracerebral hemorrhage

Intracerebral hemorrhage is often accompanied by oxidative stress induced by reactive oxygen species,which causes abnormal mitochondrial function and secondary reactive oxygen species generation.This creates a vicious cycle leading to reactive oxygen species accumulation,resulting in progression of the pathological process.Therefore,breaking the cycle to inhibit reactive oxygen species accumulation is critical for reducing neuronal death after intracerebral hemorrhage.Our previous study found that increased expression of nicotinamide adenine dinucleotide phosphate oxidase 4(NADPH oxidase 4,NOX4)led to neuronal apoptosis and damage to the blood-brain barrier after intracerebral hemorrhage.The purpose of this study was to investigate the role of NOX4 in the circle involving the neuronal tolerance to oxidative stress,mitochondrial reactive oxygen species and modes of neuronal death other than apoptosis after intracerebral hemorrhage.We found that NOX4 knockdown by adeno-associated virus(AAV-NOX4)in rats enhanced neuronal tolerance to oxidative stress,enabling them to better resist the oxidative stress caused by intracerebral hemorrhage.Knockdown of NOX4 also reduced the production of reactive oxygen species in the mitochondria,relieved mitochondrial damage,prevented secondary reactive oxygen species accumulation,reduced neuronal pyroptosis and contributed to relieving secondary brain injury after intracerebral hemorrhage in rats.Finally,we used a mitochondria-targeted superoxide dismutase mimetic to explore the relationship between reactive oxygen species and NOX4.The mitochondria-targeted superoxide dismutase mimetic inhibited the expression of NOX4 and neuronal pyroptosis,which is similar to the effect of AAV-NOX4.This indicates that NOX4 is likely to be an important target for inhibiting mitochondrial reactive oxygen species production,and NOX4 inhibitors can be used to alleviate oxidative stress response induced by intracerebral hemorrhage.

采前氨基乙氧基乙烯甘氨酸处理对‘黄冠’梨长期冷藏后果实品质和果心褐变的影响

为延长‘黄冠’梨贮藏期,减轻长期贮藏后货架期间果实品质劣变,采用不同浓度氨基乙氧基乙烯甘氨酸(aminoethoxyvinylglycine,AVG)在采前喷施‘黄冠’梨果实,在冷藏180 d及货架7 d((180+7)d)后检测相关指标。结果显示,采前喷施AVG可延缓‘黄冠’梨果实硬度下降,维持可溶性固形物含量以及可滴定酸含量,有效抑制果面褐斑和果心褐变的发生,其中以200 mg/L AVG效果最好。‘黄冠’梨果实在长期冷藏时果心发生褐变,同时熊果苷、绿原酸以及总酚含量增加,多酚氧化酶活性升高;PbPAL1、PbPAL2、PbPPO1、PbPPO5、PbLOX1以及PbLOX5在冷藏期间表达量升高,货架期表达量随之下降。采前200 mg/L AVG处理‘黄冠’梨,可显著促进熊果苷、绿原酸以及总酚在整个贮藏过程中含量的增加,抑制多酚氧化酶活性升高,抑制PbPAL1、PbPAL2、PbPPO1、PbPPO5以及PbLOX5的表达,进而有效减少果心褐变的发生。

The Comic Image of City God in Contemporary China

Three short performances from three regional operas present an eccentric comic image of Chenghuang城隍(City God).This serious and formidable god is performed by the role of chou丑(clown),and the role’s physical art shatters the audience’s perception of this god’s traditional image.The role’s exaggerated and awkward body also results in a performance-centered structure in which negative aspects of human nature are vividly portrayed.The eccentric representation brings laughter,but the laughter is also fully charged with Confucian concepts of goodness,righteousness,justice,and tianli天理(the way of heaven).Turning a divine image into a hilarious one is an unconventional manner and also a peculiar tactic of these performers.Through this tactic,these performers not only hide their subtle criticism of the reality and the authority to survive censorship but also disseminate successfully traditional values and folk religious beliefs.This tactic indicates the cultural function of the theater and demonstrates how traditions can remain valid and functional through a force that arises from the interaction between Confucianism,folk religious beliefs,and performance.

On Multimodal Criticism of The Kitchen God’s Wife

Studying the covers of the three editions of The Kitchen God’s Wife by Amy Tan,a famous female Chinese American writer,the author finds Chinese cultural elements stood out in publishers’earliest recommendations,but later were replaced by immigrant mother-daughter relationship,and then were overwhelmed by the concern for human beings.It is interesting that this change fits the changing focuses of Chinese American writers in the 21st century.

Value of combining the serum D-lactate, diamine oxidase, and endotoxin levels to predict gut-derived infections in cancer patients

Objective:This is a retrospective observational cohort study.The objective of this retrospective observational cohort study was to evaluate the value of the combined serum D-lactic acid,diamine oxidase(DAO),and endotoxin levels to predict intestinal barrier impairment and gut-derived infection(GDI)in cancer patients.Methods:Cancer patients receiving chemotherapy or palliative care treatment at our hospital were enrolled in the study.The serum concentrations of DAO,D-lactic acid,and endotoxin were determined using the intestinal barrier function biochemical index analysis system.The patients'infection information came from the hospital's Medicom Prescription Automatic Screening System and themedical records.Three hundred fifty-three cancer patients were included in the study(53.8%female,73.7%cancer stage IV,27.8%had bowel obstruction).Results:The total incidence of GDI was 33.4%(118/353).The median length of hospital stay was 16 days for patients with GDI,compared with 7 days for patients without GDI(P<0.001).The media hospitalization costs were¥27,362.35 for patients with GDI compared with¥11,614.08 for patients without GDI(P<0.001).The serum concentrations of DAO,D-lactic acid,and endotoxin were significantly higher in patients with GDI.As malignant bowel obstruction(MBO)worsened,the concentrations of DAO,D-lactic acid,and endotoxin increased.Multivariate logistic regression models revealed that the DAO,endotoxin,IL-6,and C-reactive protein levels were significantly associated with an increased risk of GDI.In addition,we also found a fivefold increased risk of infection in patients withMBO compared with those without bowel obstruction(OR=6.210,P<0.001).All of the areas under the receiver operating characteristic curve(AUCs)for DAO,D-lactate,and endotoxin to predict GDI were<0.7(AUC=0.648,P<0.001;AUC=0.624,P<0.01;AUC=0.620,P<0.01,respectively).However,when the parameters were combined(DAO+D-lactate+endotoxin),the predictive power increased significantly(AUC=0.797,P<0.001).Moreover,combining these intestinal barrier indicators and the presence of MBO had better power to predict GDI than either alone(AUC=0.837,P<0.001).Conclusions:Combining the serum DAO,D-lactic acid,and endotoxin levels was a better predictor of GDI than any of the indicators alone,and combining these with the diagnosis of MBO could further improve the efficacy for predicting GDI.

柴胡皂苷D对高尿酸血症大鼠尿酸及相关酶活性的影响

目的:探讨柴胡皂苷D对高尿酸血症大鼠体内尿酸水平及相关酶活性的影响。方法:柴胡皂苷D用0.9%氯化钠溶液溶解,配制成5、10、20 mg/mL药液。将50只SD大鼠随机分为对照组、模型组及柴胡皂苷D大、中、小剂量组。除对照组外,其余大鼠每天上午灌胃腺嘌呤0.2 g/kg+乙胺丁醇0.25 g/kg,建立高尿酸血症模型。柴胡皂苷D各剂量组大鼠均以10 mL/kg的剂量灌胃给药,对照组大鼠与模型组大鼠灌胃同等剂量0.9%氯化钠溶液。检测给药前、给药后14、21、28 d大鼠血尿酸、尿尿酸以及黄嘌呤氧化酶(XOD)、腺苷脱氨酶(ADA)、肌酐和尿素氮的水平。结果:给药后21 d,与对照组比较,模型组大鼠血尿酸水平明显升高;与模型组相比,柴胡皂苷D中剂量组血尿酸水平显著下降,差异均具有统计学意义(P<0.05);给药后28 d,与模型组相比,柴胡皂苷D大剂量组、中剂量组血尿酸水平显著下降,中剂量组及小剂量组大鼠尿尿酸水平显著降低;柴胡皂苷D各剂量组大鼠的ADA、XOD、肌酐及尿素氮水平均显著下降,差异均具有统计学意义(P<0.05)。结论:柴胡皂苷D可以通过降低ADA以及XOD水平,抑制尿酸生成,起到降尿酸的作用,具有显著的肾脏保护功能。

酶制剂对大米面包品质的改良作用研究

该试验以小麦粉和大米粉为主要原料制备大米面包,研究由葡萄糖氧化酶(glucose oxidase, GOD)、α-淀粉酶(α-amylase, AM)和脂肪酶(lipase, LIP)制备的复配酶制剂对大米面包品质的改良作用。以面包的质构特性、比容、高度、感官评分为评价指标,最终得到3种酶以GOD 25 mg/kg、AM 15 mg/kg、LIP 50 mg/kg复配时,大米面包的硬度和咀嚼性分别为88.71 g和93.12 g,与空白组比较分别减少了51.3%和55.2%;大米面包的弹性、比容、高度、感官评分分别为0.92、4.57 (mL/g)、6.02 cm和80分,与空白组比较分别增加了17.9%、27.3%、32.8%和11.1%。复配酶制剂对大米面包具有良好的改良效果。

葡萄糖氧化酶和植物乳杆菌抑菌性能的研究

采用牛津杯法研究葡萄糖氧化酶(GOD)和植物乳杆菌(Lactobacillus plantarum)对鸡源、猪源大肠杆菌(Escherichia coli)和沙门氏菌(Salmonella)的抑菌作用。结果表明,牛津杯法检测到GOD对不同来源致病菌均具有抑菌性,且在一定浓度范围内随浓度增加抑菌性能增强,在GOD酶活10 U/mL时仍具有抑菌作用,抑菌圈直径均≥9.25 mm。GOD酶在37~75℃干热处理10 min后仍具有较好的抑菌活性,65℃时对猪源大肠杆菌K88和37℃时对沙门氏菌0533抑菌作用最强,抑菌圈直径分别为10.75 mm和12.25 mm。植物乳杆菌BLCC2-0126对被试病原菌抑菌圈直径最大,对猪源大肠杆菌K99和沙门氏菌0533抑菌圈直径为13.75 mm。总之,GOD和BLCC2-0126均具有抑菌作用,且可共用于实际生产中。

大肠杆菌多酚氧化酶的分子克隆及异源高效表达

菜籽粕、棉籽粕等非粮饲料资源存在的酚类化合物芥子碱、棉酚等抗营养因子,严重影响了其饲喂价值。本课题组筛选出的一株大肠杆菌属芥子碱降解菌SDB2已被证实能通过分泌多酚氧化酶来降解芥子碱和棉酚,本试验旨在运用基因工程技术克隆SDB2多酚氧化酶基因,实现其高效表达,为SDB2多酚氧化酶在饲料工业上的规模化应用奠定基础。从大肠杆菌SDB2中克隆出多酚氧化酶基因,将其与质粒pET28a连接后转化至大肠杆菌BL21感受态细胞中培养,通过PCR鉴定及质粒酶切验证方法构建重组菌株,同时对重组克隆基因进行生物信息学分析。采用“2×2”交叉试验设计,以温度和诱导剂IPTG浓度两个影响因素诱导SDB2多酚氧化酶基因在重组菌株中高效表达,经SDS-PAGE和WB双重验证后,确立最佳诱导条件,最终纯化出目标酶蛋白。结果表明:(1)成功克隆SDB2多酚氧化酶基因,构建出异源表达重组菌株。(2)克隆出的SDB2重组多酚氧化酶基因含目标核苷酸741个,总编码氨基酸263个(含标签氨基酸20个),氨基酸组成的蛋白相对分子质量为28499.0,理论等电点为6.94,据此预测出SDB2重组多酚氧化酶三维结构模型。(3)确立SDB2多酚氧化酶异源高效表达的最佳诱导条件为温度37℃,IPTG浓度1 mmol,该条件下表达出大量可溶性酶蛋白,有利于工业化生产。本试验条件下,大肠杆菌SDB2多酚氧化酶成功实现了分子克隆及异源高效表达,为我国非粮饲料资源实现高效利用提供了技术参考。

基于生物信息学探讨赖氨酸氧化酶在食管癌原发灶中的表达及对骨转移患者预后的影响

目的基于生物信息学探讨赖氨酸氧化酶(Lox)在食管癌(ESCA)原发灶及骨转移灶中的表达及临床意义。方法通过癌症基因组图谱(TCGA)及基因表达谱分析互动平台(GEPIA)数据库筛选ESCA与正常食管组织中差异表达的基因。筛选2016年1月—2020年12月河北医科大学第四医院收治的食管癌手术患者的随访信息,收集在随访过程中确诊骨转移患者的临床资料。应用蛋白免疫印迹(Western blot)验证Lox在ESCA及正常食管组织中的表达;通过免疫组化染色检测人ESCA组织、正常组织中Lox的表达;应用Kaplan-Meier曲线及Cox回归探索Lox的表达对于生存期的影响。结果对GEPIA及TCGA数据库有关ESCA数据分析发现,Lox在ESCA病灶中的表达高于正常组织,差异有统计学意义(P<0.05);应用京都基因与基因组百科全书(KEGG)及基因富集分析(GO)发现,Lox可能参与多种信号通路的信息传导;Western blot结果显示,癌组织中Lox表达高于癌旁正常组织,差异有统计学意义(P<0.05);对随访资料的分析发现,Lox高表达患者更倾向于发生多发骨转移;生存分析发现Lox高表达患者无骨转移生存期和总生存期短于Lox低表达的患者,差异有统计学意义(P<0.05);Cox回归发现Lox是食管癌骨转移患者预后的独立危险因素。结论Lox在ESCA中呈高表达,并与临床预后相关,其可作为ESCA诊断及治疗的有效靶点。

新型大黄酸-牛磺酸化合物的合成、表征及其抑制黄嘌呤氧化酶的活性研究

大黄酸(Rhein,RH)可以促进尿酸肠道排泄,改善肾脏损伤,降低血清尿酸水平。牛磺酸(Taurine,T)可以修复肾脏损伤,降低黄嘌呤氧化酶(Xanthine oxidase,XOD)活力,还可降低血清尿酸水平。因此两种化合物在降尿酸、改善肾损伤方面具有相似的药理活性。通过拼合原理,将RH和T通过酰胺键连接,合成大黄酸-牛磺酸化合物(T-RH),以期发挥协同增效作用。采用^(1)H NMR、^(13)C NMR、IR和MS(ESI)对T-RH化学结构进行表征,并考察了T-RH对体外XOD的抑制作用。结果表明:T-RH被成功合成,产率为65.73%。T-RH对体外XOD的抑制作用均显著优于大黄酸(^(**)P<0.01)和牛磺酸(^(##)P<0.01),且抑制活性与T-RH的浓度呈正相关。