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.

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.

Pyrroloquinoline quinone enhances regeneration of transected sciatic nerve in rats

Objective: To investigate the effect of pyrroloquinoline quinone (PQQ) on nerve regeneration of transected sciatic nerve in animal models.Methods: Forty SD rats weighing 220-240 g were randomized into a PQQ group (n=20) and a control group (n=20). Each animal underwent sciatic nerve transection operation. After the operation, PQQ 0.5 ml ( 250 μg/Kg) was injected at the operation site in the PQQ group, while the same volume of normal saline was delivered in the control group. Nerve functional evaluation, electrophysiological index recording were carried out according to the experimental design. Newly generated nerve specimens were harvested 12 weeks postoperatively for morphological studies. Results: In the PQQ group there was a good nerve regeneration and the sciatic nerve function, sciatic nerve function index, electrophysiological index and morphological appearance were superior to the control group (P< 0.05).Conclusions: PQQ has a remarkable effect in enhancing nerve regeneration of transected peripheral nerve.

Identification of transporter proteins for PQQ-secretion pathways by transcriptomics and proteomics analysis in Gluconobacter oxydans WSH-003

Pyrroloquinoline quinone （PQQ） plays a sig- nificant role as a redox cofactor in combination with dehydrogenases in bacteria. These dehydrogenases play key roles in the oxidation of important substrates for the biotechnology industry, such as vitamin C production. While biosynthesis of PQQ genes has been widely studied, PQQ-transport mechanisms used both two-dimensional remain unclear. Herein, we fluorescence-difference gel electrophoresis tandem mass spectrometry and RNA sequencing to investigate the effects ofpqqB overexpres- sion in an industrial strain of Gluconobacter oxydans WSH-003. We have identified 73 differentially expressed proteins and 99 differentially expressed genes, a majority of which are related to oxidation-reduction and transport processes by gene ontology analysis. We also described several putative candidate effectors that responded to increased PQQ levels resulting from pqqB overexpression. Furthermore, quantitative PCR was used to verify five putative PQQ-transport genes among different PQQ producing strains, and the results showed that ompW, B932 1930 and B932_2186 were upregulated in all conditions. Then the three genes were over-expressed in G. oxydans WSH-003 and PQQ production were detected. The results showed that extracellular PQQ of B932_1930 （a transporter） and B932_2186 （an ABC transporter perrnease） overexpression strains were enhanced by 1.77- fold and 1.67-fold, respectively. The results suggest that the proteins encoded by PqqB, B932_1930 and B932 2186 might enhance the PQQ secretion process.