Pyrroloquinoline quinone:a potential neuroprotective compound for neurodegenerative diseases targeting metabolism

Pyrroloquinoline quinone is a quinone described as a cofactor for many bacterial dehydrogenases and is reported to exert an effect on metabolism in mammalian cells/tissues.Pyrroloquinoline quinone is present in the diet being available in foodstuffs,conferring the potential of this compound to be supplemented by dietary administration.Pyrroloquinoline quinone’s nutritional role in mammalian health is supported by the extensive deficits in reproduction,growth,and immunity resulting from the dietary absence of pyrroloquinoline quinone,and as such,pyrroloquinoline quinone has been considered as a“new vitamin.”Although the classification of pyrroloquinoline quinone as a vitamin needs to be properly established,the wide range of benefits for health provided has been reported in many studies.In this respect,pyrroloquinoline quinone seems to be particularly involved in regulating cell signaling pathways that promote metabolic and mitochondrial processes in many experimental contexts,thus dictating the rationale to consider pyrroloquinoline quinone as a vital compound for mammalian life.Through the regulation of different metabolic mechanisms,pyrroloquinoline quinone may improve clinical deficits where dysfunctional metabolism and mitochondrial activity contribute to induce cell damage and death.Pyrroloquinoline quinone has been demonstrated to have neuroprotective properties in different experimental models of neurodegeneration,although the link between pyrroloquinoline quinone-promoted metabolism and improved neuronal viability in some of such contexts is still to be fully elucidated.Here,we review the general properties of pyrroloquinoline quinone and its capacity to modulate metabolic and mitochondrial mechanisms in physiological contexts.In addition,we analyze the neuroprotective properties of pyrroloquinoline quinone in different neurodegenerative conditions and consider future perspectives for pyrroloquinoline quinone’s potential in health and disease.

Transcriptome analysis of the effect of pyrroloquinoline quinone disodium（PQQ·Na2） on reproductive performance in sows during gestation and lactation

Background: Pyrroloquinoline quinone(PQQ), which is a water soluble, thermo-stable triglyceride-quinone, is widely distributed in nature and characterized as a mammalian vitamin-like redox cofactor. The objective of this study was to investigate the effects of pyrroloquinoline quinone disodium(PQQ·Na2) on reproductive performance in sows.Results: Dietary supplementation with PQQ·Na2 significantly increased the total number of piglets born, the number of piglets born alive and the born alive litter weight. It also increased the antioxidant status in the placenta, plasma and milk. The concentration of NO was significantly increased in the plasma and placenta. RNA-seq analysis showed that462 unigenes were differentially expressed between the control(Con) treatment and PQQ treatment groups.Among these unigenes, 199 were upregulated, while 263 unigenes were downregulated. The assigned functions of the unigenes covered a broad range of GO categories. Reproduction(27, 7.03%) and the reproduction process(27, 7.03%) were assigned to the biological process category. By matching DEGs to the KEGG database, we identified 29 pathways.Conclusions: In conclusion, dietary supplementation with PQQ·Na2 in gestating and lactating sows had positive effects on their reproductive performance.

Pyrroloquinoline quinone regulates the redox status in vitro and in vivo of weaned pigs via the Nrf2/HO-1 pathway

Background:Oxidative stress is a main cause of piglet gut damage and diarrhea.Pyrroloquinoline quinone(PQQ),is a novel redox cofactor with antioxidant properties.However,the effect and mechanism that PQQ supplementation decreases oxidative injury in weaned pigs is not understood.Therefore,the aim of this study is to confirm the effect of PQQ on regulating redox status in weaned pigs and the mechanism for antioxidant function by porcine intestinal epithelial cell line(IPEC-J2)challenged with H_(2)O_(2).Results:Experiment 1,144 Duroc×Landrace×Yorkshire pigs(weaned at 28 d)were allocated to four groups:received a basal diet(control)and diets supplemented with 0.15%,0.30%and 0.45%PQQ,respectively.On d 28,growth performance,diarrhea incidence and redox factors were measured.Experiment 2,IPEC-J2 were treated with or without PQQ in the presence or absence of H_(2)O_(2)for indicated time points.Experiment 3,IPEC-J2 were transfected with or without Nrf2 siRNA,then treated according to Experiment 2.The cell viability,redox factors,protein of tight junctions and Nrf2 pathway were determined.In vivo,PQQ supplementation demonstrated dose-related improvements in average daily gain,and gain to feed ratio(Linear P<0.05).During d 0–28,compared to controls,0.45%PQQ supplementation for pigs decreased diarrhea incidence and MDA content in liver and jejunum,and increased concentration of SOD in liver;0.3%PQQ supplementation decreased ileal and liver MDA concentration;and 0.15%PQQ supplementation decreased ileal MDA concentration(P<0.05).In vitro,compared to cells cultured with H_(2)O_(2),pre-treatment with PQQ increased cell viability,tight junction proteins expression including ZO-1,ZO-2,Occludin and Claudin-1;and decreased ROS concentration and level of Caspase-3(P<0.05);as well as upregulated the ratio of Bcl-2 to Bax and protein expression of nuclear Nrf2,HO-1.Notably,Nrf2 knockdown by transfection with Nrf2 siRNA largely abrogated the positive effects of PQQ pretreatment on H_(2)O_(2)-induced intracellular changes.Conclusions:PQQ administration attenuated oxidative stress in weaned pigs which is associated with activation of Nrf2/HO-1 pathway.

Protective Effect of Pyrroloquinoline Quinone on TNF-α-induced Mitochondrial Injury in Chondrocytes

Osteoarthritis(OA)is a degenerative disease characterized by matrix degradation and cell death leading to a gradual loss of articular cartilage integrity.As a bacterial synthesis of quinine,pyrroloquinoline quinone(PQQ)is a strong redox cofactor with a variety of biological benefits,including antioxidant,anti-inflammation-induced mitochondrial metabolism regulation.This study was designed to investigate the effect of PQQ on TNF-α-induced mitochondrial damage in chondrocytes.Chondrocytes isolated from C57BL/6 mice were exposed to TNF-α50 ng/mL,TNF-α50 ng/mL+PQQ 10µmol/L for 24 h.Then,morphological study,functional study and mechanism study were taken.The results revealed TNF-α-induced chondrocyte mitochondrion damage could be reduced by application of PQQ,evidenced by elevated number of mitochondria,well-kept mtDNA integrity,preserved ATP level,reestablished mitochondrial membrane potential,and prevented mitochondrial function.The present work strongly suggests that the mitochondrion is an important target for OA chondrocyte damage induced by TNF-αand the PQQ protection from this damage ameliorates mitochondrial dysfunction induced by TNF-α.PQQ might be a potential chemical for OA intervention.

Effect of dietary supplementation of pyrroloquinoline quinone disodium on growth performance, meat quality and antioxidative ability of broilers

This study was conducted to investigate the effect of dietary supplementation with pyrroloquinoline quinone(PQQ) in the form of PQQ disodium(PQQ·Na2) on the growth performance, carcass traits, meat quality and antioxidative ability of broilers. A total of 720 one-d-old Arbor Acres male broilers were randomly allocated to 1 of 6 treatments with 8 replicates of 15 birds per replicate in a completely randomized design. Birds were fed a PQQ·Na2-unsupplemented corn-soybean meal basal diet(control) or the basal diet supplemented with 0.1, 0.2, 0.3, 0.4 or 0.5 mg PQQ·Na2 kg-1 for 42 d. Compared with the control chicks, the chicks fed the diets supplemented with PQQ·Na2 had lower(P<0.05) feed:gain(F/G) during the grower phase and drip losses of breast muscles on day 42. As supplemental PQQ·Na2 level increased, plasma total antioxidant capacity(T-AOC) on d 42, liver T-AOC on d 21 and heart T-AOC on d 21 and 42 increased linearly(P<0.05), but malondialdehyde concentrations in plasma, liver and heart on d 21 or 42 decreased linearly(P<0.001) or quadratically(P<0.005). The results from the present study indicate that dietary supplemental PQQ·Na2 can improve antioxidant ability and meat quality of broilers, and in general, it is implied that the optimal supplemental PQQ·Na2 level is 0.1 mg kg-1 of diet for broilers from 1 to 42 d of age.

Dietary supplementation with pyrroloquinoline quinone promotes growth,relieves weaning stress,and regulates metabolism of piglets compared with adding zinc oxide

Hindered growth often occurs because of psychological and environmental stress during the weaning period of piglets.This study aimed to compare the effects of growth performance,diarrhea indices,digestibility of nutrients,antioxidant capacity,neurotransmitters levels and metabolism of weaned pigs fed diets supplemented with pyrroloquinoline quinone(PQQ)and zinc oxide(ZnO).Pigs weaned at d 28(n=108)were fed with three different diets including:the basal diet(CTRL group),the basal diet supplemented with 3.0 mg/kg PQQ(PQQ group)and the basal diet containing 1,600 mg/kg ZnO(ZNO group).During the first 14 d,weaned pigs fed the diet supplemented with PQQ and ZnO decreased feed to gain ratio and diarrhea rate(P<0.01).Compared with the CTRL group,average daily gain was increased in weaned pigs in the PQQ group from d 15 to 28(P=0.03).Compared with the CTRL group,pigs fed PQQ and ZnO supplemented diets showed improved apparent total tract digestibility(ATTD)of nutrients(P≤0.05).During the overall experimental period,the concentration of malondialdehyde was decreased in plasma of pigs in the PQQ and ZNO groups compared with the CTRL group(P<0.05).At d 28,the concentration of vasoactive intestinal peptide(VIP)and calcitonin gene-related peptide(CGRP)was lower in plasma of weaned pigs in the PQQ and ZNO groups compared with the CTRL group(P<0.05).There was no difference between the PQQ and ZNO group in growth performance,ATTD of nutrition,antioxidant capacity and neurotransmitters levels.PQQ increased 3-methoxy-4-hydroxymandelate(P<0.05)compared with the CTRL group.According to metabolomic analysis,erucamide,formononetin and 3-methyl-L-histidine were up-regulated in the PQQ group(P<0.05).Compared with the CTRL group,aloesin and dibutyl adipate were down-regulated in the PQQ group(P<0.05).In conclusion,similar to ZnO,PQQ improves growth performance,digestibility of nutrients,antioxidant capacity,neuromodulation and metabolism of weaned pigs.Thus,like ZnO,PQQ can be effectively applied in weaned pigs.

吡咯喹啉醌对运动性疲劳小鼠血清代谢组学的影响

目的:探讨吡咯喹啉醌(PQQ)对运动性疲劳小鼠血清代谢组学的影响,寻找关键标志物,揭示PQQ在缓解运动疲劳中的代谢途径及其潜在的调节机制。方法:采用反复力竭游泳构建运动性疲劳的小鼠模型,进行为期两周的PQQ补充干预,剂量为每日10 mg/kg,利用色谱与质谱联合技术对小鼠血清中的代谢产物进行检测,并对筛选出的关键代谢物及其相关的代谢路径进行详细分析。结果:(1)反复力竭后,运动性疲劳小鼠与正常安静小鼠相比,血清中有32种差异代谢物;(2)反复力竭后,补充PQQ小鼠,与没有补充PQQ的小鼠相比,血清中有10种潜在差异代谢物;(3)进一步的组间比较揭示了两组小鼠中共有的4种显著差异的代谢物,包含N-乙酰-L-苯丙氨酸、柠檬酸、木糖醇及L-脯氨酸;(4)代谢通路分析显示,主要的差异代谢路径包括由柠檬酸参与的三羧酸循环中的乙醛酸循环支路和木糖醇参与的糖醛酸途径。结论:PQQ在维持运动性疲劳小鼠的正常血清代谢水平上发挥着关键作用,其所具有的作用机制或许与调控柠檬酸、木糖醇、L-脯氨酸以及N-乙酰-L-苯丙氨酸等关键代谢物及其所属的代谢通路存在紧密关联。

新食品原料呲咯喹啉醌二钠盐固体饮料免疫功能作用的研究

目的:研究呲咯喹啉醌二钠盐固体饮料的免疫功能作用。方法:呲咯喹啉醌二钠盐低、中、高剂量组分别经口灌胃0.125 g·kg^(-1)、0.250 g·kg^(-1)、0.500 g·kg^(-1)受试物,对照组、模型组灌胃等量体积的生理盐水,连续30 d,考察各组小鼠免疫器官指数、碳廓清能力、巨噬细胞吞噬能力以及脾NK细胞活性。结果:与模型小鼠相比,经呲咯喹啉醌二钠盐灌胃30 d后,呲咯喹啉醌二钠盐各剂量组免疫器官指数上升,碳廓清能力、巨噬细胞吞噬能力均提升,脾NK细胞活性增强,其中呲咯喹啉醌二钠盐中、高剂量组变化明显(P<0.05,P<0.01),与模型组有显著差异。结论:呲咯喹啉醌二钠盐可通过调节非特异性免疫指标,达到调节免疫功能的作用。

PQQ和IAA促生因子对Rahnella aquatilis HX2菌株促生机理研究

【目的】Rahnella aquatilis HX2菌株能合成吡咯喹啉醌(PQQ)和吲哚乙酸(IAA),探明PQQ与IAA在HX2菌株促生作用中的作用与机理。【方法】通过试管苗试验、温室砂培试验,分别以纯品PQQ、纯品IAA、HX2菌株及PQQ合成缺失突变体及互补菌株等处理接种玉米,对各处理的玉米生长量、营养以及根形态方面的影响进行检测和分析。【结果】与空白对照相比,PQQ、IAA纯品处理均能在促进玉米生长方面均有好的效果,HX2处理在玉米生物量(株高、鲜重和干重)、玉米营养(全N、全P、全K)摄入有显著提高,处理效果更好;PQQ合成缺失突变体MH15处理,虽对玉米鲜重、干重、全N、全P与对照相比有促进作用,但与HX2和互补菌株CMH15(pqq)处理玉米的促生效果相比较低。纯品PQQ、IAA处理主要提高了其细根长、中根长、总根长的长度和根表面积增加,但其根平均直径降低;而HX2菌株处理增加了其细根长、中根长、粗根长的长度,使玉米根系不仅伸长,且根系变粗。【结论】PQQ可作为直接促生因子和IAA,共同参与了HX2菌株对增加玉米生物量,提高玉米营养的摄入,促进其根形态等方面起到关键调控作用,明确了HX2菌株-PQQ-玉米、HX2菌株-IAA-玉米之间的相互作用。

吡咯喹啉醌二钠盐加工环境的稳定性研究

为研究吡咯喹啉醌二钠盐(PQQ·Na2)在2种常见饮料剂型(固体饮料、近水饮品)中的稳定性。以PQQ·Na2含量为核心指标,通过影响因素试验(压力、pH值、杀菌强度)、加速试验、光照试验和长期试验系统性地考察PQQ·Na2在饮料开发、生产、储存过程中的稳定性。结果表明,PQQ·Na2在固体饮料中受压片压力影响较小,且具有良好的光稳定性;加速试验中,最大衰减率为17.93%;长期试验中,平均衰减率为9.32%。PQQ·Na2在近水饮品中具有光敏性,光照4周衰减率高达92.29%;长期试验中,平均衰减率为21.50%。此外,pH值对近水饮品中PQQ·Na2的稳定性有显著影响,当pH<4.0时,饮品色泽变化显著。3种杀菌条件(90℃/30 min,121℃/15 min,130℃/15 s)对PQQ·Na2稳定性无显著影响。研究为PQQ·Na2在饮料剂型中的应用提供参考。

低温胁迫下PQQ对黄瓜幼苗子叶防御系统的影响

报道了低温胁迫下吡咯喹啉醌（ＰｙｒｒｏｌｏｑｕｉｎｏｌｉｎｅＱｕｉｎｏｎｅ，ＰＱＱ）对黄瓜幼苗子叶超氧化物岐化酶（ＳＯＤ），抗坏血酸过氧化物酶（ＡｓＡＰＯＤ）和谷胱甘肽（ＧＳＨ）含量的影响，并与常规的外源活性氧清除剂８－羟基喹啉（８－ＨＱ），抗坏血酸（ＡｓＡ）进行了比较．结果表明，ＰＱＱ能提高ＳＯＤ，ＡｓＡＰＯＤ活性，增加ＧＳＨ含量．缓解电解质泄漏，减缓质脂过氧化作用．ＰＱＱ可作为活性氧清除剂，调节生物体内自由基代谢平衡，提高植物的抗逆性．

PQQ对四氯化碳和乙醇引起大鼠肝损伤的保护作用

将大鼠分成 5组 ,采用灌胃方式 ,连续 14d分别灌入 PQQ-水溶液、PQQ -乙醇溶液、乙醇溶液和生理盐水溶液 (阴性和阳性对照两组 ) ,尔后 ,除阴性对照组外 ,均灌入 CCL4.检测结果表明 :PQQ可明显降低大鼠血清中 GPT、GOT以及肝组织中 MDA的含量 ,可减轻肝细胞水变性、脂肪变性和肝细胞坏死的程度 ,由此说明 :PQQ对 CCl4和乙醇引起的肝损伤有一定的保护作用 .

两种甲醇脱氢酶在食甲基杆菌甲醇代谢中的作用

本研究以食葡糖食甲基杆菌MP688(Methylobacterium glucophilum MP688)的吡咯喹啉醌(pyrroloquino-line quinone,PQQ)高产突变株J1-1为研究对象,通过生物信息学分析从基因组上找到两个甲醇脱氢酶(methanol dehydrogenase,MDH)基因mpq0771和mpq2496。考察了Ca^(2+)及La^(3+)对菌体生长、PQQ合成、MDH表达及酶活力的影响,并研究两种酶在甲醇代谢中的作用。结果显示:Ca^(2+)和La^(3+)均能促进J1-1菌体生长,且在菌体快速生长的情况下导致PQQ合成下降;Ca^(2+)存在时,菌株J1-1中mpq0771表达量较高,添加La^(3+)后mpq0771表达受到阻遏,但增强了mpq2496表达,菌体MDH总活力也有所提高;敲除菌J1-1Δmpq0771不能利用甲醇生长,添加La^(3+)后可利用甲醇生长并能合成PQQ,且能检测到MDH活性。mpq0771编码产物是Ca^(2+)依赖的MDH,mpq2496编码产物是严格依赖La^(3+)的MDH,且La^(3+)能够诱导mpq2496表达并替代mpq0771发挥甲醇脱氢酶的作用。

吡咯喹啉醌菌株复合诱变及其高通量筛选

以一株能产生吡咯喹啉醌(pyrroloquinoline quinone,PQQ)的细菌为原始菌株,首先通过紫外、微波和氯化锂单一诱变,然后再进行紫外⁃微波⁃氯化锂三者复合诱变处理。研究结果表明,紫外照射50 s、微波(350 W)照射60 s和氯化锂浓度为0.4%处理效果最佳,获得突变株C5Y⁃6⁃4,该菌株摇瓶产量达134.9 mg/L,是原始菌株的1.32倍。通过96孔板高通量筛选和高效液相色谱法检测,结果表明,采用复合诱变在一定程度上提高了吡咯喹啉醌的产量,且突变株C5Y⁃6⁃4遗传稳定性好。

磁性纳米分子印迹聚合物的制备及其对生物体内PQQ-DA痕量产物的研究

以磁性Fe_3O_4为内核,对磁性纳米粒子表面进行包裹和修饰,制备了对吡咯并喹啉醌-多巴胺(PQQ-DA)具有高识别性、高选择性的磁性纳米分子印迹材料,并结合超高效液相色谱-质谱(UPLC-MS)测定了生物体内PQQ-DA的含量。结果显示,PQQ-DA在0.02～0.1 mg/mL范围内呈良好的线性关系,相关系数(r^2)为0.996 6,检出限为0.2×10^(-11) mg/mL,加标回收率为88.7%～95.5%,相对标准偏差为2.6%～3.2%。该方法灵敏度高、重复性好,可用于生物体内PQQ-DA痕量产物的检测。

HPLC法测定吡咯喹啉醌(PQQ)中咪唑并吡咯喹啉(IPQ)的含量

目的:建立吡咯喹啉醌(PQQ)中IPQ的含量测定方法。方法:采用TCI Kaseisorb LC ODS 2000色谱柱(4.6mm×150mm,5μm);流动相为乙腈-缓冲溶液(配制10mmol的磷酸氢二钾和15mmol的四丁基溴化铵水溶液,用磷酸调节pH至7.4)[28∶72];紫外检测器,检测波长为259nm;流速为1.0mL/min;进样量为20μL。结果:IPQ在0.05μg/mL^0.2μg/mL范围内线性关系良好,相关系数大于0.999。IPQ的回收率在104%~113%之间,RSD最大为3%。结论:该方法具有良好的专属性、检测灵敏度、精密度、线性和准确度,适用于PQQ中IPQ的质量控制。

依赖新辅基PQQ甲醇脱氢酶的研究

生长在以甲醇作唯一碳源的甲基营养菌（Ｍｅｔｈｙｌｏｔｒｏｐｈｉｃｂａｃｔｅｒｉａ）Ｎｏ．２细胞，经超声波破碎，缓冲液抽提，ＤＥＡＥ－和ＣＭ－纤维素柱层析等纯化步骤，可得到纯化的甲醇脱氢酶（ＭＤＨ），其比活力为５．７ｕ／ｍｇ．该酶进行不连续聚丙烯酰胺凝胶电泳后，用相应的试剂分别染色，其蛋白质，酶活性和醌蛋白谱带均呈现一条迁移距离相同的主带．该酶由两个β亚基（６０ｋｂ）和两个α亚基（１０ｋｂ）构成，每个α亚基束缚一个新辅基ＰＱＱ（吡咯喹啉醌）．光谱分析显示，２９０ｎｍ有一肩峰，３４５ｎｍ有一特征峰，４００ｎｍ有一平台．这些数据表明。

1985—2022年吡咯喹啉醌研究的文献计量学和可视化分析

目的探讨吡咯喹啉醌(PQQ)的研究热点与发展趋势,挖掘PQQ的研究及应用价值。方法本研究以Web of Science为检索的数据库,检索1985年至2022年发表的关于PQQ的文献,采用VOSviewer纳入文献的关键词、国家及地区、期刊等,对这些文献进行文献计量学分析。结果共纳入1512篇文献,年发文量整体呈现上升的趋势。发文量排名最高的期刊类别为Biochemistry Molecular Biology;引文期刊Journal of Biological Chemistry总链接强度最大;高频关键词主要包括膳食营养补充剂、线粒体、抗氧化等;国家及地区可视化结果显示中国虽然研究开始的时间较晚,但是与其他国家链接强度较大。结论近年来,对于PQQ的研究热度逐渐上升,其抗氧化作用、改善线粒体功能以及作用靶点可能是未来研究的热点。PQQ仍然具有广阔的发展前景,为医药健康产业注入新的活力。

依赖PQQ的甲醇脱氢酶与甘氨酸作用后的进程曲线

从革蓝氏阴性甲基营养菌Ｎｏ．２细胞提取的甲醇脱氢酶（ＭＤＨ）是一种氧化还原酶，已证明其辅基是新辅基ＰＱＱ（吡咯喹啉醌），笔者在研究ＭＤＨ及其辅基的理化性质过程中，发现甘氨酸（ｇｌｙ）对ＭＤＨ影响极为特殊，随后，以此为出发点得到的试验数据，对解释目前国...