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It has been a long‐standing goal for chemists to develop selective catalytic oxidation systems with molecular oxygen as a green terminal oxidant from the inspiration of active sites in natural metalloenzymes. Lanthanide‐centered methanol dehydrogenase (Ln‐MDH), which contains the same pyrroloquinoline quinone (PQQ) redox cofactor as the analogous calcium‐based MDH (Ca‐MDH) and exhibits good reactivity in alcohol oxidation, was discovered in 2011 and aroused extensive research interest during the past decade. In this review, we present the progress in the bioinorganic and biomimetic chemistry of the metal‐PQQ‐MDH that includes (1) an introduction of the structure, synthesis, and property of the coenzyme PQQ, the metal‐PQQ active sites, the two commonly believed mechanisms of alcohol oxidation, and the insights from computation chemistry; (2) representative structures and the alcohol oxidation mechanism of Ca‐MDH inspired transition‐metal models from an earlier time to around 2000; (3) the developments in the ligand modifications, coordination chemistry, and catalytic alcohol oxidation of the model systems of Ln‐MDH from 2011 to June 2024; and (4) other biological or chemical metal‐PQQ‐like systems and the applications in broader fields. Finally, the challenge and opportunity in the bioinspired catalytic oxidation systems, as well as the clarification of the enzymatic mechanism, were mentioned. [ABSTRACT FROM AUTHOR]

This study investigates the underlying mechanism through which dietary supplementation of pyrroloquinoline quinone disodium (PQQ) alleviates intestinal inflammation and cell apoptosis in piglets challenged with lipopolysaccharide (LPS). Seventy-two barrows were divided into three groups: control (CTRL), LPS challenged (LPS), and LPS challenged with PQQ supplementation (PQQ + LPS). On d 7, 11, and 14, piglets received intraperitoneal injections of LPS or 0.9% of NaCl (80 μg/kg). After a 4 h interval following the final LPS injection on d 14, blood samples were obtained, and all piglets were euthanized for harvesting jejunal samples. The results showed that dietary supplementation of PQQ improved the damage of intestinal morphology, increased the down-regulated tight junction proteins, and reduced the increase of serum diamine oxidase activity, the intestinal fatty acid binding protein, and TNF-α levels in piglets challenged with LPS (p < 0.05). The proteomics analysis revealed a total of 141 differentially expressed proteins (DEPs), consisting of 64 up-regulated DEPs and 77 down-regulated DEPs in the PQQ + LPS group compared to the LPS group. The KEGG pathway analysis indicated enrichment of the tight junction pathway and the apoptosis pathway (p < 0.05). Compared to the LPS group, the piglets in the PQQ + LPS group had increased levels of Bcl-2 protein, reduced positive apoptosis signals, and a decrease in the abundance of MKK 3/6 and p-p38 proteins (p < 0.05). In conclusion, dietary supplementation of PQQ could alleviate jejunal inflammatory damage and cell apoptosis in piglets challenged with LPS through the MKK3/6-p38 signaling pathway. [ABSTRACT FROM AUTHOR]

Rhodopseudomonas palustris is a purple non-sulfide bacterium (PNSB), and some strains have been proven to promote plant growth. However, the mechanism underlying the effect of these PNSBs remains limited. Based on genetic information, R. palustris possesses the ability to produce pyrroloquinoline quinone (PQQ). PQQ is known to play a crucial role in stimulating plant growth, facilitating phosphorous solubilization, and acting as a reactive oxygen species scavenger. However, it is still uncertain whether growth conditions influence R. palustriss production of PQQ and other characteristics. In the present study, it was found that R. palustris exhibited a higher expression of genes related to PQQ synthesis under autotrophic culture conditions as compared to acetate culture conditions. Moreover, similar patterns were observed for phosphorous solubilization and siderophore activity, both of which are recognized to contribute to plant-growth benefits. However, these PNSB culture conditions did not show differences in Arabidopsis growth experiments, indicating that there may be other factors influencing plant growth in addition to PQQ content. Furthermore, the endophytic bacterial strains isolated from Arabidopsis exhibited differences according to the PNSB culture conditions. These findings imply that, depending on the PNSBs growing conditions, it may interact with various soil bacteria and facilitate their infiltration into plants.

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.

Abstract Background Folates are a family of B9 vitamins essential for normal growth and development in the central nervous system (CNS). Transport of folates is mediated by three major transport proteins: folate receptor alpha (FRα), proton-coupled folate transporter (PCFT), and reduced folate carrier (RFC). Brain folate uptake occurs at the choroid plexus (CP) epithelium through coordinated actions of FRα and PCFT, or directly into brain parenchyma at the vascular blood–brain barrier (BBB), mediated by RFC. Impaired folate transport can occur due to loss of function mutations in FRα or PCFT, resulting in suboptimal CSF folate levels. Our previous reports have demonstrated RFC upregulation by nuclear respiratory factor-1 (NRF-1) once activated by the natural compound pyrroloquinoline quinone (PQQ). More recently, we have identified folate transporter localization at the arachnoid barrier (AB). The purpose of the present study was to further characterize folate transporters localization and function in AB cells, as well as their regulation by NRF-1/PGC-1α signaling and folate deficiency. Methods In immortalized mouse AB cells, polarized localization of RFC and PCFT was assessed by immunocytochemical analysis, with RFC and PCFT functionality examined with transport assays. The effects of PQQ treatment on changes in RFC functional expression were also investigated. Mouse AB cells grown in folate-deficient conditions were assessed for changes in gene expression of the folate transporters, and other key transporters and tight junction proteins. Results Immunocytochemical analysis revealed apical localization of RFC at the mouse AB epithelium, with PCFT localized on the basolateral side and within intracellular compartments. PQQ led to significant increases in RFC functional expression, mediated by activation of the NRF-1/PGC-1α signalling cascade. Folate deficiency led to significant increases in expression of RFC, MRP3, P-gp, GLUT1 and the tight junction protein claudin-5. Conclusion These results uncover the polarized expression of RFC and PCFT at the AB, with induction of RFC functional expression by activation of the NRF-1/PGC-1α signalling pathway and folate deficiency. These results suggest that the AB may contribute to the flow of folates into the CSF, representing an additional pathway when folate transport at the CP is impaired.

Background: Folates are a family of B9 vitamins essential for normal growth and development in the central nervous system (CNS). Transport of folates is mediated by three major transport proteins: folate receptor alpha (FRα), proton-coupled folate transporter (PCFT), and reduced folate carrier (RFC). Brain folate uptake occurs at the choroid plexus (CP) epithelium through coordinated actions of FRα and PCFT, or directly into brain parenchyma at the vascular blood–brain barrier (BBB), mediated by RFC. Impaired folate transport can occur due to loss of function mutations in FRα or PCFT, resulting in suboptimal CSF folate levels. Our previous reports have demonstrated RFC upregulation by nuclear respiratory factor-1 (NRF-1) once activated by the natural compound pyrroloquinoline quinone (PQQ). More recently, we have identified folate transporter localization at the arachnoid barrier (AB). The purpose of the present study was to further characterize folate transporters localization and function in AB cells, as well as their regulation by NRF-1/PGC-1α signaling and folate deficiency. Methods: In immortalized mouse AB cells, polarized localization of RFC and PCFT was assessed by immunocytochemical analysis, with RFC and PCFT functionality examined with transport assays. The effects of PQQ treatment on changes in RFC functional expression were also investigated. Mouse AB cells grown in folate-deficient conditions were assessed for changes in gene expression of the folate transporters, and other key transporters and tight junction proteins. Results: Immunocytochemical analysis revealed apical localization of RFC at the mouse AB epithelium, with PCFT localized on the basolateral side and within intracellular compartments. PQQ led to significant increases in RFC functional expression, mediated by activation of the NRF-1/PGC-1α signalling cascade. Folate deficiency led to significant increases in expression of RFC, MRP3, P-gp, GLUT1 and the tight junction protein claudin-5. Conclusion: These results uncover the polarized expression of RFC and PCFT at the AB, with induction of RFC functional expression by activation of the NRF-1/PGC-1α signalling pathway and folate deficiency. These results suggest that the AB may contribute to the flow of folates into the CSF, representing an additional pathway when folate transport at the CP is impaired. [ABSTRACT FROM AUTHOR]

The 2011 discovery of the first rare earth-dependent enzyme in methylotrophic Methylobacterium extorquens AM1 prompted intensive research toward understanding the unique chemistry at play in these systems. This enzyme, an alcohol dehydrogenase (ADH), features a La3+ ion closely associated with redox-active coenzyme pyrroloquinoline quinone (PQQ) and is structurally homologous to the Ca2+-dependent ADH from the same organism. AM1 also produces a periplasmic PQQ-binding protein, PqqT, which we have now structurally characterized to 1.46-Å resolution by X-ray diffraction. This crystal structure reveals a Lys residue hydrogen-bonded to PQQ at the site analogously occupied by a Lewis acidic cation in ADH. Accordingly, we prepared K142A-and K142D-PqqT variants to assess the relevance of this site toward metal binding. Isothermal titration calorimetry experiments and titrations monitored by UV-Vis absorption and emission spectroscopies support that K142D-PqqT binds tightly (Kd = 0.6 ± 0.2 μM) to La3+ in the presence of bound PQQ and produces spectral signatures consistent with those of ADH enzymes. These spectral signatures are not observed for WT-or K142A-variants or upon addition of Ca2+ to PQQ ⊏ K142D-PqqT. Addition of benzyl alcohol to La3+-bound PQQ ⊏ K142D-PqqT (but not Ca2+-bound PQQ ⊏ K142D-PqqT, or La3+-bound PQQ ⊏ WT-PqqT) produces spectroscopic changes associated with PQQ reduction, and chemical trapping experiments reveal the production of benzaldehyde, supporting ADH activity. By creating a metal binding site that mimics native ADH enzymes, we present a rare earth-dependent artificial metalloenzyme primed for future mechanistic, biocatalytic, and biosensing applications. [ABSTRACT FROM AUTHOR]

Microbial infections pose a significant global health threat, affecting millions of individuals and leading to substantial mortality rates. The increasing resistance of microorganisms to conventional treatments requires the development of novel antimicrobial agents. Pyrroloquinoline quinone (PQQ), a natural medicinal drug involved in various cellular processes, holds promise as a potential antimicrobial agent. In the present study, our aim was, for the first time, to explore the antimicrobial activity of PQQ against 29 pathogenic microbes, including 13 fungal strains, 8 Gram-positive bacteria, and 8 Gram-negative bacteria. Our findings revealed potent antifungal properties of PQQ, particularly against Syncephalastrum racemosum, Talaromyces marneffei, Candida lipolytica, and Trichophyton rubrum. The MIC values varied between fungal strains, and T. marneffei exhibited a lower MIC, indicating a greater susceptibility to PQQ. In addition, PQQ exhibited notable antibacterial activity against Gram-positive and -negative bacteria, with a prominent inhibition observed against Staphylococcus epidermidis, Proteus vulgaris, and MRSA strains. Remarkably, PQQ demonstrated considerable biofilm inhibition against the MRSA, S. epidermidis, and P. vulgaris strains. Transmission electron microscopy (TEM) studies revealed that PQQ caused structural damage and disrupted cell metabolism in bacterial cells, leading to aberrant morphology, compromised cell membrane integrity, and leakage of cytoplasmic contents. These findings were further affirmed by shotgun proteomic analysis, which revealed that PQQ targets several important cellular processes in bacteria, including membrane proteins, ATP metabolic processes, DNA repair processes, metal-binding proteins, and stress response. Finally, detailed molecular modeling investigations indicated that PQQ exhibits a substantial binding affinity score for key microbial targets, including the mannoprotein Mp1P, the transcriptional regulator TcaR, and the endonuclease PvuRTs1I. Taken together, our study underscores the effectiveness of PQQ as a broad-spectrum antimicrobial agent capable of combating pathogenic fungi and bacteria, while also inhibiting biofilm formation and targeting several critical biological processes, making it a promising therapeutic option for biofilm-related infections. [ABSTRACT FROM AUTHOR]

Age‐related intervertebral disk degeneration (IVDD) involves increased oxidative damage, cellular senescence, and matrix degradation. Pyrroloquinoline quinone (PQQ) is a water‐soluble vitamin‐like compound with strong anti‐oxidant capacity. The goal of this study was to determine whether PQQ can prevent aging‐related IVDD, and the underlying mechanism. Here, we found that dietary PQQ supplementation for 12 months alleviated IVDD phenotypes in aged mice, including increased disk height index and reduced histological scores and cell loss, without toxicity. Mechanistically, PQQ inhibited oxidative stress, cellular senescence, and senescence‐associated secretory phenotype (SASP) in the nucleus pulposus and annulus fibrosus of aged mice. Similarly, PQQ protected against interleukin‐1β‐induced matrix degradation, reactive oxygen species accumulation, and senescence in human nucleus pulposus cells (NPCs) in vitro. Molecular docking predicted and biochemical assays validated that PQQ interacts with specific residues to dissociate the Keap1–Nrf2 complex, thereby increasing nuclear Nrf2 translocation and activation of Nrf2‐ARE signaling. RNA sequencing and luciferase assays revealed Nrf2 can transcriptionally upregulate Wnt5a by binding to its promoter, while Wnt5a knockdown prevented PQQ inhibition of matrix metalloproteinase‐13 in NPCs. Notably, PQQ supplementation failed to alleviate aging‐associated IVDD phenotypes and oxidative stress in aged Nrf2 knockout mice, indicating Nrf2 is indispensable for PQQ bioactivities. Collectively, this study demonstrates Nrf2 activation by PQQ inhibits aging‐induced IVDD by attenuating cellular senescence and matrix degradation. This study clarifies Keap1–Nrf2–Wnt5a axis as the novel signaling underlying the protective effects of PQQ against aging‐related IVDD, and provides evidence for PQQ as a potential agent for clinical prevention and treatment of natural aging‐induced IVDD. [ABSTRACT FROM AUTHOR]

Fulminant hepatitis (FH) is a life-threatening clinical liver syndrome characterized by substantial hepatocyte necrosis and severe liver damage. FH is typically associated with severe oxidative stress, inflammation, and mitochondrial dysfunction. Pyrroloquinoline quinone (PQQ), a naturally occurring redox cofactor, functions as an essential nutrient and antioxidant and reportedly inhibits oxidative stress and exerts potent anti-inflammatory effects. In the present study, we aimed to evaluate the therapeutic efficacy of PQQ in murine hepatitis virus strain 3 (MHV-3)-induced FH and examined the underlying mechanism. An MHV-3-induced FH mouse model was established for in vivo examination. Liver sinusoidal endothelial cells (LSECs) were used for in vitro experiments. Herein, we observed that PQQ supplementation significantly attenuated MHV-3-induced hepatic injury by suppressing inflammatory responses and reducing oxidative stress. Mechanistically, PQQ supplementation ameliorated MHV-3-induced hepatic damage by down-regulating the Keap1/Nrf2 signaling pathway in vivo and in vitro. Furthermore, Nrf2 small interfering RNA targeting LSECs abrogated the PQQ-mediated protective effects against MHV-3-related liver injury. Our results deepen our understanding of the hepatoprotective function of PQQ against MHV-3-induced liver injury and provide evidence that alleviating oxidative stress might afford a novel therapeutic strategy for treating FH. [ABSTRACT FROM AUTHOR]

The Clearfield® technology is an useful tool for controlling weedy rice due to the effectiveness of imazamox and the cultivation of rice varieties resistant to imidazolines. However, residual imazamox in the soil probably causes phytotoxicity to subsequent non-resistant rice crops. We previously found that pyrroloquinoline quinone (PQQ), a bioactive elicitor, can enhance rice tolerance to imazamox. In this study, we explored the molecular mechanism of PQQ-mediated rice tolerance to imazamox by RNA-seq analysis, real-time quantitative PCR (RT-qPCR) assay, and enzyme activity assay. The results indicated that compared to imazamox at 66.7 mg a.i./L (IMA) alone, rice plants treated with imazamox at 66.7 mg a.i./L and PQQ at 0.66 mg a.i./L (IMA + PQQ) exhibited significantly reduced sensitivity to imazamox. Seven days post-treatment, IMA + PQQ-treated rice plants showed partial chlorosis and leaf curling, but IMA-treated rice plants had severe wilting and died. The fresh weight inhibition rate was 29.3% in the IMA + PQQ group, significantly lower than that of 56.6% in the IMA group alone. RNA-seq analysis showed differentially expressed genes were mainly involved in phenylpropanoid biosynthesis, diterpenoid biosynthesis, and MAPK signaling pathways in response to IMA + PQQ treatment. Both RNA-seq analysis and RT-qPCR assay showed that the expression of OsCATB gene in the catalase (CAT) gene family was upregulated at 12 h, the expression of OsGSTU1 gene was upregulated at 12, 24, and 48 h, while the expressions of OsABCB2, OsABCB11, and OsABCG11 genes were upregulated at 24 and 48 h. Enzyme activity assays revealed that the activity of superoxide dismutase in the IMA + PQQ group was increased by 47.45~120.31% during 12~72 h, compared to that in the IMA group. CAT activity in the IMA + PQQ group was increased by 123.72 and 59.04% at 12 and 48 h, respectively. Moreover, malondialdehyde levels indicative of oxidative damage were consistently lower in IMA + PQQ-treated plants, with a reduction of 46.29, 11.37, and 14.50% at 12, 36, and 72 h, respectively. Overall, these findings discover that PQQ has potential in reducing imazamox phytotoxicity in rice by enhancing antioxidant enzyme activities and regulating oxidative stress responses. They will provide valuable strategies for improving imazamox tolerance in crops. [ABSTRACT FROM AUTHOR]

In this study, the pyrroloquinoline quinone (PQQ) high-yield mutant J1-1 of Methylobacterium glucophilum MP688 was used to do bioinformatics analysis to extract the two methanol dehydrogenase (MDH) genes from the genome, mpq0771 and mpq2496. The effects of Ca2+ and La3+ on bacterial growth, PQQ synthesis, MDH expression, and enzyme activity were explored, as well as the roles of the two enzymes in methanol metabolism. The results showed that Ca2+ and La3+ both increased J1-1 bacteriophage growth and decreased PQQ synthesis in the context of fast viral development. In the presence of Ca2+, mpq0771 expression increased in strain J1-1. La3+ inhibited mpq0771 expression while promoting mpq2496 expression and increasing total bacterial MDH viability. The knockout bacteria J1-1Δmpq0771 could not grow in methanol, but with the addition of La3+, it could grow in methanol and synthesize PQQ, and MDH activity was identified. The product encoded by mpq0771 was a Ca2+-dependent MDH, and the product encoded by mpq2496 was a La3+-dependent MDH, and La3+ could increase the production of mpq2496 and replace mpq0771 as a methanol dehydrogenase.

Abstract Background DNA damage and oxidative stress induced by chemotherapy are important factors in the onset of premature ovarian insufficiency (POI). Studies have shown that mitochondria derived from mesenchymal stem cells (MSC-Mito) are beneficial for age-related diseases, but their efficacy alone is limited. Pyrroloquinoline quinone (PQQ) is a potent antioxidant with significant antiaging and fertility enhancement effects. This study aimed to investigate the therapeutic effect of MSC-Mito in combination with PQQ on POI and the underlying mechanisms involved. Methods A POI animal model was established in C57BL/6J mice by cyclophosphamide and busulfan. The effects of MSC-Mito and PQQ administration on the estrous cycle, ovarian pathological damage, sex hormone secretion, and oxidative stress in mice were evaluated using methods such as vaginal smears and ELISAs. Western blotting and immunohistochemistry were used to assess the expression of SIRT1, PGC-1α, and ATM/p53 pathway proteins in ovarian tissues. A cell model was constructed using KGN cells treated with phosphoramide mustard to investigate DNA damage and apoptosis through comet assays and flow cytometry. SIRT1 siRNA was transfected into KGN cells to further explore the role of the SIRT1/ATM/p53 pathway in combination therapy with MSC-Mito and PQQ for POI. Results The combined treatment of MSC-Mito and PQQ significantly restored ovarian function and antioxidant capacity in mice with POI. This treatment also reduced the loss of follicles at various stages, improving the disrupted estrous cycle. In vitro experiments demonstrated that PQQ facilitated the proliferation of MitoTracker-labelled MSC-Mito, synergistically restoring mitochondrial function and inhibiting oxidative stress in combination with MSC-Mito. Both in vivo and in vitro, the combination of MSC-Mito and PQQ increased mitochondrial biogenesis mediated by SIRT1 and PGC-1α while inhibiting the activation of ATM and p53, consequently reducing DNA damage-mediated cell apoptosis. Furthermore, pretreatment of KGN cells with SIRT1 siRNA reversed nearly all the aforementioned changes induced by the combined treatment. Conclusions Our research findings indicate that PQQ facilitates MSC-Mito proliferation and, in combination with MSC-Mito, ameliorates chemotherapy-induced POI through the SIRT1/ATM/p53 signaling pathway.

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Background: DNA damage and oxidative stress induced by chemotherapy are important factors in the onset of premature ovarian insufficiency (POI). Studies have shown that mitochondria derived from mesenchymal stem cells (MSC-Mito) are beneficial for age-related diseases, but their efficacy alone is limited. Pyrroloquinoline quinone (PQQ) is a potent antioxidant with significant antiaging and fertility enhancement effects. This study aimed to investigate the therapeutic effect of MSC-Mito in combination with PQQ on POI and the underlying mechanisms involved. Methods: A POI animal model was established in C57BL/6J mice by cyclophosphamide and busulfan. The effects of MSC-Mito and PQQ administration on the estrous cycle, ovarian pathological damage, sex hormone secretion, and oxidative stress in mice were evaluated using methods such as vaginal smears and ELISAs. Western blotting and immunohistochemistry were used to assess the expression of SIRT1, PGC-1α, and ATM/p53 pathway proteins in ovarian tissues. A cell model was constructed using KGN cells treated with phosphoramide mustard to investigate DNA damage and apoptosis through comet assays and flow cytometry. SIRT1 siRNA was transfected into KGN cells to further explore the role of the SIRT1/ATM/p53 pathway in combination therapy with MSC-Mito and PQQ for POI. Results: The combined treatment of MSC-Mito and PQQ significantly restored ovarian function and antioxidant capacity in mice with POI. This treatment also reduced the loss of follicles at various stages, improving the disrupted estrous cycle. In vitro experiments demonstrated that PQQ facilitated the proliferation of MitoTracker-labelled MSC-Mito, synergistically restoring mitochondrial function and inhibiting oxidative stress in combination with MSC-Mito. Both in vivo and in vitro, the combination of MSC-Mito and PQQ increased mitochondrial biogenesis mediated by SIRT1 and PGC-1α while inhibiting the activation of ATM and p53, consequently reducing DNA damage-mediated cell apoptosis. Furthermore, pretreatment of KGN cells with SIRT1 siRNA reversed nearly all the aforementioned changes induced by the combined treatment. Conclusions: Our research findings indicate that PQQ facilitates MSC-Mito proliferation and, in combination with MSC-Mito, ameliorates chemotherapy-induced POI through the SIRT1/ATM/p53 signaling pathway. [ABSTRACT FROM AUTHOR]

Objectives: To assess the impact of medium-term supplementation with dihydrogen and pyrroloquinoline quinone (PQQ) on mitochondrial biomarkers, brain metabolism, and cognition in elderly individuals diagnosed with mild cognitive impairment. Design: A parallel-group, randomized, placebo-controlled, double-blind experimental design, maintaining a 1:1 allocation ratio between the experimental group (receiving the dihydrogen-producing minerals and PQQ) and the control group (receiving the placebo) throughout the trial. Setting and participants: Thirty-four elderly individuals with mild cognitive impairment (mean age 71.9 ± 3.8 years; 28 females) voluntarily provided written consent to participate in this trial. Participants were assigned in a double-blind parallel-group design to receive either a dihydrogen-PQQ mixture (Alpha Hope®, CalerieLife, Irvine, CA) or placebo twice daily for a 6-week intervention period. Methods: The primary endpoint was the change in serum brain-derived neurotrophic factor (BDNF) from baseline to the 6-week follow-up; secondary outcomes included cognitive function indices, specific metabolites in brain tissue, brain oxygenation, and the prevalence and severity of side effects. Interaction effects (time vs. intervention) were evaluated using two-way ANOVA with repeated measures and Friedman’s 2-way ANOVA by ranks, for normally distributed data with homogeneous variances and non-homogeneous variances, respectively. Results: Dihydrogen-PQQ resulted in a significant elevation in serum BDNF levels at the six-week follow-up (P = 0.01); conversely, no changes in BDNF levels were observed in the placebo group throughout the study duration (P = 0.27). A non-significant trend in the impact of interventions on BDNF levels was observed (treatment vs. time interaction, P = 0.14), suggesting a tendency for dihydrogen-PQQ to upregulate BDNF levels compared to the placebo. A significant interaction effect was observed for the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) scores in the orientation domain (P = 0.03), indicating the superiority of dihydrogen-PQQ over placebo in enhancing this cognitive aspect. Cerebral oxygenation saturation exhibited a significant increase following the administration of the dihydrogen-PQQ mixture, from 48.4 ± 7.2% at baseline to 52.8 ± 6.6% at 6-week post-administration (P = 0.005). In addition, brain N-acetyl aspartate levels significantly increased at seven out of thirteen locations post-intervention in participants receiving the mixture (P ≤ 0.05). Conclusions: Despite the limited number of participants included in the study for interpreting clinical parameters, the dihydrogen-PQQ mixture blend shows promise as a potential dietary intervention for enhancing mental orientation and brain metabolism in individuals with age-related mild cognitive decline.

Graves’ disease (GD) is an autoimmune disorder disease, and its prevalence continues to increase worldwide. Pyrroloquinoline quinone (PQQ) is a naturally antioxidant compound in milk, vegetables, and meat. We aim to identify the treatment efficacy of PQQ on GD and its regulatory effect on intestinal microbiota. The GD mice model was built by an adenovirus expressing autoantigen thyroid-stimulating hormone receptor (Ad-TSHR289). Fecal samples were collected for 16S rDNA sequencing after PQQ pretreatments (20, 40, or 60 mg/kg BW/day) for 4 weeks. Thyroid and intestine functions were measured. The levels of serum TSHR and T4 were significantly raised, and the thyroid gland size was typically enlarged in the GD group than in controls, reversed by PQQ therapy. After PQQ replenishment, IL6 and TNFα levels in small intestine tissues were lower than those in the GD group, with Nrf2 and HO1 levels improved. Also, the PQQ supplement could maintain the mucosal epithelial barrier impaired by GD. In microbial analyses, PQQ treatment could prompt the diversity recovery of gut microbiota and reconstruct the microbiota composition injured by GD. Lactobacillus served as the most abundant genus in all groups, and the abundance of Lactobacillus was increased in the GD group than in control and PQQ groups. Besides, Lactobacillus was highly correlative with all samples and the top 50 genera. PQQ supplementation regulates thyroid function and relieves intestine injury. PQQ changes the primary composition and abundance of GD’s intestine microbiota by moderating Lactobacillus, which may exert in the pathogenesis and progression of GD.

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

This study investigates the underlying mechanism through which dietary supplementation of pyrroloquinoline quinone disodium (PQQ) alleviates intestinal inflammation and cell apoptosis in piglets challenged with lipopolysaccharide (LPS). Seventy-two barrows were divided into three groups: control (CTRL), LPS challenged (LPS), and LPS challenged with PQQ supplementation (PQQ + LPS). On d 7, 11, and 14, piglets received intraperitoneal injections of LPS or 0.9% of NaCl (80 μg/kg). After a 4 h interval following the final LPS injection on d 14, blood samples were obtained, and all piglets were euthanized for harvesting jejunal samples. The results showed that dietary supplementation of PQQ improved the damage of intestinal morphology, increased the down-regulated tight junction proteins, and reduced the increase of serum diamine oxidase activity, the intestinal fatty acid binding protein, and TNF-α levels in piglets challenged with LPS (p < 0.05). The proteomics analysis revealed a total of 141 differentially expressed proteins (DEPs), consisting of 64 up-regulated DEPs and 77 down-regulated DEPs in the PQQ + LPS group compared to the LPS group. The KEGG pathway analysis indicated enrichment of the tight junction pathway and the apoptosis pathway (p < 0.05). Compared to the LPS group, the piglets in the PQQ + LPS group had increased levels of Bcl-2 protein, reduced positive apoptosis signals, and a decrease in the abundance of MKK 3/6 and p-p38 proteins (p < 0.05). In conclusion, dietary supplementation of PQQ could alleviate jejunal inflammatory damage and cell apoptosis in piglets challenged with LPS through the MKK3/6-p38 signaling pathway.

Pyrroloquinoline quinone (PQQ) is a natural antioxidant with diverse applications in food and pharmaceutical industries. A lot of effort has been devoted toward the discovery of PQQ high-producing microbial species and characterization of biosynthesis, but it is still challenging to achieve a high PQQ yield. In this study, a combined strategy of random mutagenesis and adaptive laboratory evolution (ALE) with fermentation optimization was applied to improve PQQ production in Hyphomicrobium denitrificans H4-45. A mutant strain AE-9 was obtained after nearly 400 generations of UV-LiCl mutagenesis, followed by an ALE process, which was conducted with a consecutive increase of oxidative stress generated by kanamycin, sodium sulfide, and potassium tellurite. In the flask culture condition, the PQQ production in mutant strain AE-9 had an 80.4% increase, and the cell density increased by 14.9% when compared with that of the initial strain H4-45. Moreover, batch and fed-batch fermentation processes were optimized to further improve PQQ production by pH control strategy, methanol and H2O2 feed flow, and segmented fermentation process. Finally, the highest PQQ production and productivity of the mutant strain AE-9 reached 307 mg/L and 4.26 mg/L/h in a 3.7-L bioreactor, respectively. Whole genome sequencing analysis showed that genetic mutations in the ftfL gene and thiC gene might contribute to improving PQQ production by enhancing methanol consumption and cell growth in the AE-9 strain. Our study provided a systematic strategy to obtain a PQQ high-producing mutant strain and achieve high production of PQQ in fermentation. These practical methods could be applicable to improve the production of other antioxidant compounds with uncleared regulation mechanisms. Key points: • Improvement of PQQ production by UV-LiCl mutagenesis combined with adaptive laboratory evolution (ALE) and fermentation optimization. • A consecutive increase of oxidative stress could be used as the antagonistic factor for ALE to enhance PQQ production. • Mutations in the ftfL gene and thiC gene indicated that PQQ production might be increased by enhancing methanol consumption and cell growth. [ABSTRACT FROM AUTHOR]

Copyright of Acta Materiae Compositae Sinica is the property of Acta Materiea Compositae Sinica Editorial Department and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Gentamicin (GM) is one of the commonly used antibiotics in the aminoglycoside class but is ototoxic, which constantly impacts the quality of human life. Pyrroloquinoline quinone (PQQ) as a redox cofactor produced by bacteria was found in soil and foods that exert an antioxidant and redox modulator. It is well documented that the PQQ can alleviate inflammatory responses and cytotoxicity. However, our understanding of PQQ in ototoxicity remains unclear. We reported that PQQ could protect against GM‐induced ototoxicity in House Ear Institute‐Organ of Corti 1 (HEI‐OC1) cells in vitro. To evaluate reactive oxygen species (ROS) production and mitochondrial function, ROS and JC‐1 staining, oxygen consumption rate (OCR), and extracellular acidification rate (ECAR) measurements in living cells, mitochondrial dynamics analysis was performed. GM‐mediated damage was performed by reducing the production of ROS and inhibiting mitochondria biogenesis and dynamics. PQQ ameliorated the cellular oxidative stress and recovered mitochondrial membrane potential, facilitating the recovery of mitochondrial biogenesis and dynamics. Our in vitro findings improve our understanding of the GM‐induced ototoxicity with therapeutic implications for PQQ. Gentamicin (GM), a commonly used antibiotic, is often associated with ototoxicity. PQQ exhibits neuroprotective, cardiovascular, and anti‐tumor effects as potent antioxidants. We found that PQQ protected HEI‐OC1 cells in vitro from gentamicin‐induced ototoxicity. Additionally, PQQ enhanced mitochondrial depolarization and reduced ROS levels while preventing the decline of mitochondrial basal respiration and respiratory capacity, thereby improving mitochondrial dynamic impairments. Our in vitro findings enhance our understanding of the ototoxicity caused by genetically modified organisms and have potential therapeutic implications for PQQ. [ABSTRACT FROM AUTHOR]

Pyrroloquinoline quinone (PQQ) is a peptide-modified natural product. PQQ has important physiological functions such as anti-oxidation, anti-aging, and immunity enhancement. However, due to the lack of in-depth understanding of PQQ biosynthesis and regulation, inefficient PQQ production level limits its wide application. Accordingly, there is still an urgent need to develop high-yielding strains for synthesis of PQQ. This paper reviewed the research and development trends on the PQQ biosynthetic pathways, catalytic reaction mechanism of key enzymes, and the selection of high-yielding strains, which also prospects for the future construction of PQQ biosynthetic microbial cell factories. [ABSTRACT FROM AUTHOR]

Sleep is essential to animals with circadian rhythms. Sleep deprivation causes serious pathophysiological consequences, such as DNA damage and oxidative stress. Pyrroloquinoline quinone (PQQ) is a bioactive food ingredient with antioxidant properties. Here, we used zebrafish continuous swimming paradigm sleep deprivation model to investigate the effect of PQQ on DNA damage. We found that DNA damage and neuronal activity increase following sleep deprivation. PQQ pretreatment reduced DNA damage in the zebrafish dorsal pallium. As an antioxidant, PQQ effectively inhibited reactive oxygen species (ROS) production induced by 2,2′-azobis-2-methyl-propanimidamide dihydrochloride (AAPH) and sleep deprivation, and upregulated the expression of antioxidant genes sod1 and gpx4b. Also, PQQ ameliorated the decreased silent information regulator 1 (SIRT1) expression level, suggesting that PQQ may remove excessive ROS by activating SIRT1, thereby reducing DNA damage within neurons. This study indicates that PQQ has strong antioxidant function, provides ideas for further development of ingredients for sleep recovery.

Abstract Background Folates (Vitamin B9) are critical for normal neurodevelopment and function, with transport mediated by three major pathways: folate receptor alpha (FRα), proton-coupled folate transporter (PCFT), and reduced folate carrier (RFC). Cerebral folate uptake primarily occurs at the blood-cerebrospinal fluid barrier (BCSFB) through concerted actions of FRα and PCFT, with impaired folate transport resulting in the neurological disorder cerebral folate deficiency (CFD). Increasing evidence suggests that disorders associated with CFD also present with neuroinflammation, oxidative stress, and mitochondrial dysfunction, however the role of brain folate deficiency in inducing these abnormalities is not well-understood. Our laboratory has identified the upregulation of RFC by nuclear respiratory factor 1 (NRF-1) at the blood–brain barrier (BBB) once indirectly activated by the natural compound pyrroloquinoline quinone (PQQ). PQQ is also of interest due to its anti-inflammatory, antioxidant, and mitochondrial biogenesis effects. In this study, we examined the effects of folate deficiency and PQQ treatment on inflammatory and oxidative stress responses, and changes in mitochondrial function. Methods Primary cultures of mouse mixed glial cells exposed to folate-deficient (FD) conditions and treated with PQQ were analyzed for changes in gene expression of the folate transporters, inflammatory markers, oxidative stress markers, and mitochondrial DNA (mtDNA) content through qPCR analysis. Changes in cellular reactive oxygen species (ROS) levels were analyzed in vitro through a DCFDA assay. Wildtype (C57BL6/N) mice exposed to FD (0 mg/kg folate), or control (2 mg/kg folate) diets underwent a 10-day (20 mg/kg/day) PQQ treatment regimen and brain tissues were collected and analyzed. Results Folate deficiency resulted in increased expression of inflammatory and oxidative stress markers in vitro and in vivo, with increased cellular ROS levels observed in mixed glial cells as well as a reduction of mitochondrial DNA (mtDNA) content observed in FD mixed glial cells. PQQ treatment was able to reverse these changes, while increasing RFC expression through activation of the PGC-1α/NRF-1 signaling pathway. Conclusion These results demonstrate the effects of brain folate deficiency, which may contribute to the neurological deficits commonly seen in disorders of CFD. PQQ may represent a novel treatment strategy for disorders associated with CFD, as it can increase folate uptake, while in parallel reversing many abnormalities that arise with brain folate deficiency.

Ischemia/reperfusion can cause tissue damage and affect organ function. Ischemia-reperfusion injury (IRI) occurs in a variety of clinical manifestations such as stroke, trauma, and surgery. The present study investigated the role of pyrroloquinoline quinone (PQQ) on the renal damage after IRI. Rats were assigned to four groups randomly (n = 8): Control group, Sham group, Renal IRI (45 minutes ischemia and subsequently 24 hours reperfusion) and renal IRI + PQQ (10 mg/kg /IP). Serum level of urea, creatinine, TNF-α and IL-6 were measured by a biochemical analyzer using commercial kits. In kidney tissue samples total antioxidant capacity (TAC), malondialdehyde (MDA), and myeloperoxidase (MPO) were measured using commercial kits. The results showed that IRI injury increased serum urea, creatinine levels, TNF-α and IL-6 along with MDA, MPO levels in the renal tissue, and decreased renal TAC levels. A decrease in serum urea, creatinine levels as well as MDA, MPO levels of the IR + PQQ group were observed in renal tissues. In addition, TAC levels in the kidney tissues of PQQ-treated animals were improved in comparison with the IRI group. In conclusion, pyrroloquinoline quinone treatment ameliorated renal IR injury by anti-oxidative stress and anti-inflammatory properties. Consequently, it could be promising as a potential therapeutic agent for renal ischemia-reperfusion injury.

Maternal obesity and consumption of a high-fat diet significantly elevate risk for pediatric nonalcoholic fatty liver disease (NAFLD), affecting 10% of children in the US. Almost half of these children are diagnosed with nonalcoholic steatohepatitis (NASH), a leading etiology for liver transplant. Animal models show that signs of liver injury and perturbed lipid metabolism associated with NAFLD begin in utero; however, safe dietary therapeutics to blunt developmental programming of NAFLD are unavailable. Using a mouse model of maternal Western-style diet (WD), we previously showed that pyrroloquinoline quinone (PQQ), a potent dietary antioxidant, protected offspring of WD-fed dams from development of NAFLD and NASH. Here, we used untargeted mass spectrometry-based lipidomics to delineate lipotoxic effects of WD on offspring liver and identify lipid targets of PQQ. PQQ exposure during pregnancy altered hepatic lipid profiles of WD-exposed offspring, upregulating peroxisome proliferator-activated receptor (PPAR) α signaling and mitochondrial fatty acid oxidation to markedly attenuate triglyceride accumulation beginning in utero. Surprisingly, the abundance of very long-chain ceramides, important in promoting gut barrier and hepatic function, was significantly elevated in PQQ-treated offspring. PQQ exposure reduced the hepatic phosphatidylcholine/phosphatidylethanolamine (PC/PE) ratio in WD-fed offspring and improved glucose tolerance. Notably, levels of protective n - 3 polyunsaturated fatty acids (PUFAs) were elevated in offspring exposed to PQQ, beginning in utero, and the increase in n - 3 PUFAs persisted into adulthood. Our findings suggest that PQQ supplementation during gestation and lactation augments pathways involved in the biosynthesis of long-chain fatty acids and plays a unique role in modifying specific bioactive lipid species critical for protection against NAFLD risk in later life.

Microbial infections pose a significant global health threat, affecting millions of individuals and leading to substantial mortality rates. The increasing resistance of microorganisms to conventional treatments requires the development of novel antimicrobial agents. Pyrroloquinoline quinone (PQQ), a natural medicinal drug involved in various cellular processes, holds promise as a potential antimicrobial agent. In the present study, our aim was, for the first time, to explore the antimicrobial activity of PQQ against 29 pathogenic microbes, including 13 fungal strains, 8 Gram-positive bacteria, and 8 Gram-negative bacteria. Our findings revealed potent antifungal properties of PQQ, particularly against Syncephalastrum racemosum, Talaromyces marneffei, Candida lipolytica, and Trichophyton rubrum. The MIC values varied between fungal strains, and T. marneffei exhibited a lower MIC, indicating a greater susceptibility to PQQ. In addition, PQQ exhibited notable antibacterial activity against Gram-positive and -negative bacteria, with a prominent inhibition observed against Staphylococcus epidermidis, Proteus vulgaris, and MRSA strains. Remarkably, PQQ demonstrated considerable biofilm inhibition against the MRSA, S. epidermidis, and P. vulgaris strains. Transmission electron microscopy (TEM) studies revealed that PQQ caused structural damage and disrupted cell metabolism in bacterial cells, leading to aberrant morphology, compromised cell membrane integrity, and leakage of cytoplasmic contents. These findings were further affirmed by shotgun proteomic analysis, which revealed that PQQ targets several important cellular processes in bacteria, including membrane proteins, ATP metabolic processes, DNA repair processes, metal-binding proteins, and stress response. Finally, detailed molecular modeling investigations indicated that PQQ exhibits a substantial binding affinity score for key microbial targets, including the mannoprotein Mp1P, the transcriptional regulator TcaR, and the endonuclease PvuRTs1I. Taken together, our study underscores the effectiveness of PQQ as a broad-spectrum antimicrobial agent capable of combating pathogenic fungi and bacteria, while also inhibiting biofilm formation and targeting several critical biological processes, making it a promising therapeutic option for biofilm-related infections.

The Clearfield® technology is an useful tool for controlling weedy rice due to the effectiveness of imazamox and the cultivation of rice varieties resistant to imidazolines. However, residual imazamox in the soil probably causes phytotoxicity to subsequent non-resistant rice crops. We previously found that pyrroloquinoline quinone (PQQ), a bioactive elicitor, can enhance rice tolerance to imazamox. In this study, we explored the molecular mechanism of PQQ-mediated rice tolerance to imazamox by RNA-seq analysis, real-time quantitative PCR (RT-qPCR) assay, and enzyme activity assay. The results indicated that compared to imazamox at 66.7 mg a.i./L (IMA) alone, rice plants treated with imazamox at 66.7 mg a.i./L and PQQ at 0.66 mg a.i./L (IMA + PQQ) exhibited significantly reduced sensitivity to imazamox. Seven days post-treatment, IMA + PQQ-treated rice plants showed partial chlorosis and leaf curling, but IMA-treated rice plants had severe wilting and died. The fresh weight inhibition rate was 29.3% in the IMA + PQQ group, significantly lower than that of 56.6% in the IMA group alone. RNA-seq analysis showed differentially expressed genes were mainly involved in phenylpropanoid biosynthesis, diterpenoid biosynthesis, and MAPK signaling pathways in response to IMA + PQQ treatment. Both RNA-seq analysis and RT-qPCR assay showed that the expression of OsCATB gene in the catalase (CAT) gene family was upregulated at 12 h, the expression of OsGSTU1 gene was upregulated at 12, 24, and 48 h, while the expressions of OsABCB2, OsABCB11, and OsABCG11 genes were upregulated at 24 and 48 h. Enzyme activity assays revealed that the activity of superoxide dismutase in the IMA + PQQ group was increased by 47.45~120.31% during 12~72 h, compared to that in the IMA group. CAT activity in the IMA + PQQ group was increased by 123.72 and 59.04% at 12 and 48 h, respectively. Moreover, malondialdehyde levels indicative of oxidative damage were consistently lower in IMA + PQQ-treated plants, with a reduction of 46.29, 11.37, and 14.50% at 12, 36, and 72 h, respectively. Overall, these findings discover that PQQ has potential in reducing imazamox phytotoxicity in rice by enhancing antioxidant enzyme activities and regulating oxidative stress responses. They will provide valuable strategies for improving imazamox tolerance in crops.

In this study, three kinds of nanomaterials with silanized or ion pair silanized surface modifications were synthesized, and the extraction and adsorption properties of these three materials for pyrroloquinoline quinone were studied. Results showed that the adsorption capacity of surface modified magnetic nanomaterials for pyrroloquinoline quinone was positively correlated with the intermolecular interaction force between surface active groups and adsorption targets, and the intermolecular interaction force between surface active groups of ion pair silanized Fe3O4 materials and adsorption targets was the strongest. Its adsorption capacity to pyrroloquinoline quinone was the strongest. The maximum adsorption capacity can reach 160.81 mg·g−1. The adsorption kinetics of the nanomaterial was explored. The adsorption of pyrroloquinoline quinone on the nanomaterial was divided into two processes. The first adsorption process occurred at 0~30 min, which was a fast adsorption process. With the decrease of adsorption sites, the adsorption came into the second stage, and pyrroloquinoline quinone molecules diffused inside the surface layer of the nanomaterial. The adsorption of pyrroloquinoline quinone on magnetic nanomaterials was more suitable for the Lgangmuir model, indicating that the adsorption of pyrroloquinoline quinone on magnetic nanomaterials was suitable for single-layer adsorption, and the adsorption binding sites on the adsorbent surface were uniform. The desorption agent was 0.05% sodium hydroxide, and the desorption time was 3 h, and the resolution rate was 87.00%. The material had a good reusability for solid phase extraction, and the adsorption capacity decreases by only 9.23% after continuous use for more than 5 times. These results showed that the ion pair silylated nanomaterial with good adsorption and release properties for pyrroloquinoline quinone could be used as a candidate magnetic solid phase extraction material.

Background: Folates (Vitamin B9) are critical for normal neurodevelopment and function, with transport mediated by three major pathways: folate receptor alpha (FRα), proton-coupled folate transporter (PCFT), and reduced folate carrier (RFC). Cerebral folate uptake primarily occurs at the blood-cerebrospinal fluid barrier (BCSFB) through concerted actions of FRα and PCFT, with impaired folate transport resulting in the neurological disorder cerebral folate deficiency (CFD). Increasing evidence suggests that disorders associated with CFD also present with neuroinflammation, oxidative stress, and mitochondrial dysfunction, however the role of brain folate deficiency in inducing these abnormalities is not well-understood. Our laboratory has identified the upregulation of RFC by nuclear respiratory factor 1 (NRF-1) at the blood–brain barrier (BBB) once indirectly activated by the natural compound pyrroloquinoline quinone (PQQ). PQQ is also of interest due to its anti-inflammatory, antioxidant, and mitochondrial biogenesis effects. In this study, we examined the effects of folate deficiency and PQQ treatment on inflammatory and oxidative stress responses, and changes in mitochondrial function. Methods: Primary cultures of mouse mixed glial cells exposed to folate-deficient (FD) conditions and treated with PQQ were analyzed for changes in gene expression of the folate transporters, inflammatory markers, oxidative stress markers, and mitochondrial DNA (mtDNA) content through qPCR analysis. Changes in cellular reactive oxygen species (ROS) levels were analyzed in vitro through a DCFDA assay. Wildtype (C57BL6/N) mice exposed to FD (0 mg/kg folate), or control (2 mg/kg folate) diets underwent a 10-day (20 mg/kg/day) PQQ treatment regimen and brain tissues were collected and analyzed. Results: Folate deficiency resulted in increased expression of inflammatory and oxidative stress markers in vitro and in vivo, with increased cellular ROS levels observed in mixed glial cells as well as a reduction of mitochondrial DNA (mtDNA) content observed in FD mixed glial cells. PQQ treatment was able to reverse these changes, while increasing RFC expression through activation of the PGC-1α/NRF-1 signaling pathway. Conclusion: These results demonstrate the effects of brain folate deficiency, which may contribute to the neurological deficits commonly seen in disorders of CFD. PQQ may represent a novel treatment strategy for disorders associated with CFD, as it can increase folate uptake, while in parallel reversing many abnormalities that arise with brain folate deficiency. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Food Safety & Quality is the property of Journal of Food Safety & Quality Editorial Department and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Age‐related osteoporosis is associated with increased oxidative stress and cellular senescence. Pyrroloquinoline quinone (PQQ) is a water‐soluble vitamin‐like compound that has strong antioxidant capacity; however, the effect and underlying mechanism of PQQ on aging‐related osteoporosis remain unclear. The purpose of this study was to investigate whether dietary PQQ supplementation can prevent osteoporosis caused by natural aging, and the potential mechanism underlying PQQ antioxidant activity. Here, we found that when 6‐month‐old or 12‐month‐old wild‐type mice were supplemented with PQQ for 12 months or 6 months, respectively, PQQ could prevent age‐related osteoporosis in mice by inhibiting osteoclastic bone resorption and stimulating osteoblastic bone formation. Mechanistically, pharmmapper screening and molecular docking studies revealed that PQQ appears to bind to MCM3 and reduces its ubiquitination‐mediated degradation; stabilized MCM3 then competes with Nrf2 for binding to Keap1, thus activating Nrf2‐antioxidant response element (ARE) signaling. PQQ‐induced Nrf2 activation inhibited bone resorption through increasing stress response capacity and transcriptionally upregulating fibrillin‐1 (Fbn1), thus reducing Rankl production in osteoblast‐lineage cells and decreasing osteoclast activation; as well, bone formation was stimulated by inhibiting osteoblastic DNA damage and osteocyte senescence. Furthermore, Nrf2 knockout significantly blunted the inhibitory effects of PQQ on oxidative stress, on increased osteoclast activity and on the development of aging‐related osteoporosis. This study reveals the underlying mechanism of PQQ's strong antioxidant capacity and provides evidence for PQQ as a potential agent for clinical prevention and treatment of natural aging‐induced osteoporosis. [ABSTRACT FROM AUTHOR]

As an important metabolic enzyme in methylotrophs, pyrroloquinoline quinone (PQQ)-dependent alcohol dehydrogenases play significant roles in the global carbon and nitrogen cycles. In this article, a calcium (Ca2+)-dependent alcohol dehydrogenase PedE_M.s., derived from the methylotroph Methylopila sp. M107 was inserted into the modified vector pCM80 and heterologously expressed in the host Methylorubrum extorquens AM1. Based on sequence analysis, PedE_M.s., a PQQ-dependent dehydrogenase belonging to a methanol/ethanol family, was successfully extracted and purified. Showing by biochemical results, its enzymatic activity was detected as 0.72 U/mg while the Km value was 0.028 mM while employing ethanol as optimal substrate. The activity of PedE_M.s. could be enhanced by the presence of potassium (K+) and calcium (Ca2+), while acetonitrile and certain common detergents have been found to decrease the activity of PedE_M.s. In addition, its optimum temperature and pH were 30°C and pH 9.0, respectively. Chiefly, as a type of Ca2+-dependent alcohol dehydrogenase, PedE_M.s. maintained 60-80% activity in the presence of 10 mM lanthanides and displayed high affinity for ethanol compared to other PedEtype enzymes. The 3D structure of PedE_M.s. was predicted by AlphaFold, and it had an 8-bladed propeller-like super-barrel. Meanwhile, we could speculate that PedE_M.s. contained the conserved residues Glu213, Asn300, and Asp350 through multiple sequence alignment by Clustal and ESpript. The analysis of enzymatic properties of PedE_M.s. enriches our knowledge of the methanol/ethanol family PQQ-dependent dehydrogenase. This study provides new ideas to broaden the application of alcohol dehydrogenase in alcohol concentration calculation, biosensor preparation, and other industries. [ABSTRACT FROM AUTHOR]

Ischemia/reperfusion can cause tissue damage and affect organ function. Ischemiareperfusion injury (IRI) occurs in a variety of clinical manifestations such as stroke, trauma, and surgery. The present study investigated the role of pyrroloquinoline quinone (PQQ) on the renal damage after IRI. Rats were assigned to four groups randomly (n = 8): Control group, Sham group, Renal IRI (45 minutes ischemia and subsequently 24 hours reperfusion) and renal IRI + PQQ (10 mg/kg/IP). Serum level of urea, creatinine, TNF-α and IL-6 were measured by a biochemical analyzer using commercial kits. In kidney tissue samples total antioxidant capacity (TAC), malondialdehyde (MDA), and myeloperoxidase (MPO) were measured using commercial kits. The results showed that IRI injury increased serum urea, creatinine levels, TNF-α and IL-6 along with MDA, MPO levels in the renal tissue, and decreased renal TAC levels. A decrease in serum urea, creatinine levels as well as MDA, MPO levels of the IR + PQQ group were observed in renal tissues. In addition, TAC levels in the kidney tissues of PQQ-treated animals were improved in comparison with the IRI group. In conclusion, pyrroloquinoline quinone treatment ameliorated renal IR injury by anti-oxidative stress and anti-inflammatory properties. Consequently, it could be promising as a potential therapeutic agent for renal ischemia-reperfusion injury. [ABSTRACT FROM AUTHOR]

Abstract Background Pyrroloquinoline quinone (PQQ), a cofactor for bacterial dehydrogenases, is associated with biological processes such as mitochondriogenesis, reproduction, growth, and aging. Due to the extremely high cost of chemical synthesis and low yield of microbial synthesis, the election of effective strains and the development of dynamic fermentation strategies for enhancing PQQ production are meaningful movements to meet the large-scale industrial requirements. Results A high-titer PQQ-producing mutant strain, Hyphomicrobium denitrificans FJNU-A26, was obtained by integrating ARTP (atmospheric and room‑temperature plasma) mutagenesis, adaptive laboratory evolution and high-throughput screening strategies. Afterward, the systematic optimization of the fermentation medium was conducted using a one-factor-at-a-time strategy and response surface methodology to increase the PQQ concentration from 1.02 to 1.37 g/L. The transcriptional analysis using qRT-PCR revealed that the expression of genes involved in PQQ biosynthesis were significantly upregulated when the ARTP-ALE-derived mutant was applied. Furthermore, a novel two-stage pH control strategy was introduced to address the inconsistent effects of the pH value on cell growth and PQQ production. These combined strategies led to a 148% increase in the PQQ concentration compared with that of the initial strain FJNU-6, reaching 1.52 g/L with a yield of 40.3 mg/g DCW after 144 h of fed-batch fermentation in a 5-L fermenter. Conclusion The characteristics above suggest that FJNU-A26 represents an effective candidate as an industrial PQQ producer, and the integrated strategies can be readily extended to other microorganisms for the large-scale production of PQQ.

Pyrroloquinoline quinone (PQQ) is an important cofactor of methanol dehydrogenases and glycose dehydrogenases. In addition, isolated PQQ is used as a central component in sensors and biomimetic complexes. The synthesis of PQQ derivatives is of interest for developing new alcohol oxidation catalysts and redox sensors. This work describes a modular synthesis for derivatives of PQQ bearing methyl and ketone groups instead of carboxylic acid moieties. These modifications reduce the possible coordination sites of PQQ for metal ions outside the protein environment. [ABSTRACT FROM AUTHOR]

Direct electron transfer (DET)-enabled oxidoreductase has been utilized to develop mediator-free bioelectronic devices. Fungal pyrroloquinoline quinone-dependent dehydrogenase from Coprinopsis cinerea is an attractive quinohemoprotein in which the catalytic PQQ domain and cytochrome domain perform DET. Here, we examined the difference in the distance from the active center to the protein surface between PQQ and heme. Then, we studied the direct bioelectrocatalysis of the full-length enzyme by regulating the distance between the enzyme and electrode with various alkyl chains of self-assembled monolayers (SAMs). The catalytic currents by the full-length enzyme were obtained on SAM of chain alkyl lengths of C6 or more, while no catalytic currents have been obtained by the isolated PQQ domain. After approximately 15 Å from PQQ in the active site to the electrode surface, the onset potential of the current shifted from the redox potential of PQQred/PQQsemi to Hemered/Hemeox. The results indicated that the chain length-dependent electron transfer pathway from the PQQ domain directly to the electrode changed via the cytochrome domain. The amount of electroactive cytochrome domain that had immobilized decreased with increasing pH (pH 6.0 to pH 9.5). In direct bioelectrocatalysis through interdomain electron transfer of the cytochrome domain, kcat was found to be pH dependent with an optimal pH of 8.5; therefore, the rate-limiting step that governs pH dependence is likely the IET process.

Obesity is a major health concern worldwide, and its prevalence continues to increase in several countries. Pyrroloquinoline quinone (PQQ) is naturally found in some foods and is available as a dietary supplement in its disodium crystal form. The potential health benefits of PQQ have been studied, considering its antioxidant and anti-inflammatory properties. Furthermore, PQQ has been demonstrated to significantly influence the functions of mitochondria, the organelles responsible for energy production within cells, and their dysfunction is associated with various health conditions, including obesity complications. Here, we explore PQQ properties that can be exploited in obesity treatment and highlight the underlying molecular mechanisms. We review animal and cell culture studies demonstrating that PQQ is beneficial for reducing the accumulation of visceral and hepatic fat. In addition to inhibiting lipogenesis, PQQ can increase mitochondria number and function, leading to improved lipid metabolism. Besides diet-induced obesity, PQQ ameliorates programing obesity of the offspring through maternal supplementation and alters gut microbiota, which reduces obesity risk. In obesity progression, PQQ mitigates mitochondrial dysfunction and obesity-associated inflammation, resulting in the amelioration of the progression of obesity co-morbidities, including non-alcoholic fatty liver disease, chronic kidney disease, and Type 2 diabetes. Overall, PQQ has great potential as an anti-obesity and preventive agent for obesity-related complications. Although human studies are still lacking, further investigations to address obesity and associated disorders are still warranted.

Background: Pyrroloquinoline quinone (PQQ), a cofactor for bacterial dehydrogenases, is associated with biological processes such as mitochondriogenesis, reproduction, growth, and aging. Due to the extremely high cost of chemical synthesis and low yield of microbial synthesis, the election of effective strains and the development of dynamic fermentation strategies for enhancing PQQ production are meaningful movements to meet the large-scale industrial requirements. Results: A high-titer PQQ-producing mutant strain, Hyphomicrobium denitrificans FJNU-A26, was obtained by integrating ARTP (atmospheric and room‑temperature plasma) mutagenesis, adaptive laboratory evolution and high-throughput screening strategies. Afterward, the systematic optimization of the fermentation medium was conducted using a one-factor-at-a-time strategy and response surface methodology to increase the PQQ concentration from 1.02 to 1.37 g/L. The transcriptional analysis using qRT-PCR revealed that the expression of genes involved in PQQ biosynthesis were significantly upregulated when the ARTP-ALE-derived mutant was applied. Furthermore, a novel two-stage pH control strategy was introduced to address the inconsistent effects of the pH value on cell growth and PQQ production. These combined strategies led to a 148% increase in the PQQ concentration compared with that of the initial strain FJNU-6, reaching 1.52 g/L with a yield of 40.3 mg/g DCW after 144 h of fed-batch fermentation in a 5-L fermenter. Conclusion: The characteristics above suggest that FJNU-A26 represents an effective candidate as an industrial PQQ producer, and the integrated strategies can be readily extended to other microorganisms for the large-scale production of PQQ. [ABSTRACT FROM AUTHOR]

Following a growing interest in the physiological effects of pyrroloquinoline quinone (PQQ), more cell culture experiments have begun to elucidate its mechanism of action. However, to our knowledge, no reports have used instrumental analysis, such as liquid chromatography-tandem mass spectrometry (LCMS/MS), to study cellular uptake of PQQ. In addition, despite the propensity of PQQ to react with amino acids and other compounds, only a handful of cell culture experiments have been conducted on PQQ derivatives. In the present study, we prepared PQQ derivatives by reacting PQQ with various amino acids and used them as reference standards for optimizing the LC-MS/MS analysis conditions to detect PQQ and its derivatives. Using this method, we evaluated the uptake of PQQ into mouse 3T3-L1 cells and found that most PQQ added to the medium was taken up by the cells in its unchanged form, while some PQQ reacted with amino acids in the medium and was taken up by the cells as PQQ derivatives. These results suggest that PQQ derivatives may contribute to the physiological effects of PQQ. To further elucidate the function of PQQ, it is necessary for future studies to clarify the activity of PQQ derivatives and to evaluate the types of PQQ present in food, animal, and cell samples in more detail. [ABSTRACT FROM AUTHOR]

Peptidyl arginine deiminase 4 (PAD4) plays a critical role in many autoimmune diseases including rheumatoid arthritis. Herein, a trypsin assisted highly immunoassay method was established to determine PAD4 activity and screen potent inhibitors from herbal plants extracts and purified natural products. The method was applied to determine endogenous PAD4 activity in both cell and tissue lysates, as well as the inhibitory effects of 20 herbal plants and 50 purified natural products. The Cinnamomi ramulus extract showed strongest inhibitory potency with IC 50 value lower than 5 μg/mL. Meanwhile, pyrroloquinoline quinone (PQQ), widely used as a dietary supplement, was discovered as a promising PAD4 inhibitor with an IC 50 value lower than 4 μM. The inhibition kinetic analysis, drug affinity response target stability (DARTS) and molecular docking were performed to confirm the interaction between PQQ and PAD4. This method has great potential for researchers to monitor activities and discover potential inhibitors of PAD4. [Display omitted] • A trypsin assisted highly sensitive immunoassay method was developed for PAD4 activity assay. • The method was used to screen PAD4 inhibitors from herbal plant extracts and natural products. • Cinnamomi ramulus extracts were found to hold high inhibitory activity against PAD4. • PQQ was discovered as a promising PAD4 inhibitor with an IC 50 value lower than 4 μM. • PQQ had good interaction with PAD4 by both DARTS and molecular docking verification analysis. [ABSTRACT FROM AUTHOR]

Rhodopseudomonas palustris is a purple non-sulfide bacterium (PNSB), and some strains have been proven to promote plant growth. However, the mechanism underlying the effect of these PNSBs remains limited. Based on genetic information, R. palustris possesses the ability to produce pyrroloquinoline quinone (PQQ). PQQ is known to play a crucial role in stimulating plant growth, facilitating phosphorous solubilization, and acting as a reactive oxygen species scavenger. However, it is still uncertain whether growth conditions influence R. palustris’s production of PQQ and other characteristics. In the present study, it was found that R. palustris exhibited a higher expression of genes related to PQQ synthesis under autotrophic culture conditions as compared to acetate culture conditions. Moreover, similar patterns were observed for phosphorous solubilization and siderophore activity, both of which are recognized to contribute to plant-growth benefits. However, these PNSB culture conditions did not show differences in Arabidopsis growth experiments, indicating that there may be other factors influencing plant growth in addition to PQQ content. Furthermore, the endophytic bacterial strains isolated from Arabidopsis exhibited differences according to the PNSB culture conditions. These findings imply that, depending on the PNSB’s growing conditions, it may interact with various soil bacteria and facilitate their infiltration into plants.

Parkinson’s disease (PD) is an irreversible neurodegenerative disorder clinically manifesting in uncontrolled motor symptoms. There are two primary hallmark features of Parkinson’s disease—an irreversible loss of dopaminergic neurons of the substantia nigra pars compacta and formation of intracellular insoluble aggregates called Lewy bodies mostly composed of alpha-synuclein. Using a clinical improvements-first approach, we identified several clinical trials involving consumption of a specific diet or nutritional supplementation that improved motor and nonmotor functions. Here, we aimed to investigate if and how pyrroloquinoline quinone (PQQ) compound disrupts preformed alpha-synuclein deposits using SH-SY5Y cells, widely used Parkinson’s disease cellular model. SH-SY5Y neuroblastoma cells, incubated in presence of potassium chloride (KCl) to induce alpha-synuclein protein aggregation, were treated with PQQ for up to 48 hr. Resulting aggregates were examined and quantified using confocal microscopy. Overall, nutritional compound PQQ reduced the average number and overall size of intracellular cytoplasmic alpha-synuclein aggregates in a PD cellular model.

Using bioactive inducers to enhance rice resistance is an effective means of green prevention and control of diseases during rice production. In a previous study, we found that foliar sprays of pyrroloquinoline quinone (PQQ) as the bioactive inducer could remarkably reduce the occurrence index of rice sheath blight (ShB) Rhizoctonia solani and increase the grain yield of rice under field conditions. However, little information is available on the mechanism of PQQ-induced rice resistance to ShB. In this study, the phenotype and mechanism of foliar sprayed PQQ-induced rice resistance to ShB were investigated by artificial inoculation method, RNA-seq technology, and quantitative real-time PCR (qRT-PCR) assay in the laboratory. The results showed that at 144 h after inoculation (hai) with the ShB C30 strain, many disease spots occurred obviously in a susceptible variety, Lemont (L), treated by 1.0 μmol/L PQQ (P+) with the disease score (DS) of 4.36, and almost all plants were withered and died under the ddH2O (P−) treatment alone, with the DS of 8.39. By comparison, the DS of a resistant variety, Gaopin 6 (G), was only 0.88 in the P+ treatment and 3.82 in the P− treatment. The results of hormone determination showed that jasmonic acid (JA) contents in the G and L varieties treated by P+ were increased significantly, by 78% and 197% respectively, at 48 hai. There was no significant difference in salicylic acid (SA) contents in these varieties between P+ and ddH2O (P−) treatments during the period of 48 hai. These results suggest that JA may play a key role in PQQ-induced rice resistance to ShB. The transcriptome analysis of the leaf sheath of the G and L varieties indicated that 165 and 250 differentially expressed genes (DEGs) were found in the intersection of LP− vs. LP+ and GP− vs. GP+ at 24 and 48 hai, respectively. Kyoto encyclopedia of genes and genomes analysis showed that these DEGs were related to plant–pathogen interaction, ribosome, plant hormone signaling transduction, mitogen-activated protein kinas signaling pathway, and phenylpropanoid biosynthesis. For ten highly expressed genes related to disease resistance, the results of qRT-PCR assay showed that eight genes, especially OsAOS2 and OsOSM1, were regulated positively, and two genes, OsGF14e and OsWRKY72, were regulated negatively. Among these, four up-regulated genes, OsOSM1, OsAOS2, OsHI-LOX, and OsLOX1, and one down-regulated gene, OsWRKY72, belonging to the JA signaling pathway, may be involved in PQQ-induced rice resistance to ShB. These results provide valuable information for green prevention and control of ShB by PQQ foliar spraying in the field. [ABSTRACT FROM AUTHOR]

Background: Pyrroloquinoline quinone (PQQ) has been reported to exhibit cardioprotective and antioxidant activities. Accordingly, this study was developed to explore the effects of PQQ treatment on myocardial hypertrophy and the underlyingmechanism of action governing any observed beneficial effects. Methods: A transverse aortic constriction (TAC) model of myocardial hypertrophy was established in vivo using C57BL/6 mice, while neonatal murine cardiomyocytes were stimulated with phenylephrine (PE) as an in vitro validation model system. Results: Treatment of TAC model mice with PQQ significantly suppressed myocardial hypertrophy and fibrosis, in addition to inhibiting the ferroptotic death of hypertrophic myocardial cells in vivo. Subsequent in vitro analyses revealed that treatment with PQQwas sufficient to significantly alleviate PE-induced hypertrophic activity and to prevent ferroptotic induction in these primarymurine cardiomyocytes. At the mechanistic level, PQQ was found to promote the upregulation of Yesassociated Protein (YAP), to suppress YAP phosphorylation, and to drive the nuclear translocation of YAPwithin hypertrophic cardiomyocytes. The use of a specificsiRNA construct to knock down YAP expression in vitro further confirmed the ability of PQQ to protect against myocardial hypertrophy at least in part through antiferroptotic mechanisms. Conclusion: PQQ can regulate the pathogenesis of myocardial hypertrophy through the induction of YAP-related anti-ferroptotic activity, highlighting the potential value of PQQ as a novel therapeutic agent capable of slowing or preventing the progression of myocardial hypertrophy and thus delaying the onset of heart failure. [ABSTRACT FROM AUTHOR]

Radiation-induced lung injury (RILI) is a prevalent complication of thoracic tumor radiotherapy and accidental radiation exposure. Pyrroloquinoline quinone (PQQ), a novel vitamin B, plays a crucial role in delaying aging, antioxidation, anti-inflammation, and antiapoptosis. This study aims to investigate the protective effect and mechanisms of PQQ against RILI. C57BL/6 mice were exposed to a 20 Gy dose of X-ray radiation on the entire thorax with or without daily oral administration of PQQ for 2 weeks. PQQ effectively mitigated radiation-induced lung tissue damage, inflammation, oxidative stress, and epithelial cell apoptosis. Additionally, PQQ significantly inhibited oxidative stress and mitochondrial damage in MLE-12 cells. Mechanistically, PQQ upregulated the mRNA and protein levels of MOTS-c in irradiated lung tissue and MLE-12 cells. Knockdown of MOTS-c by siRNA substantially attenuated the protective effects of PQQ on oxidative stress, inflammation, and apoptosis. In conclusion, PQQ alleviates RILI by preserving mitochondrial function through a MOTS-c-dependent mechanism, suggesting that PQQ may serve as a promising nutraceutical intervention against RILI.

This study aimed to evaluate the impacts of dietary pyrroloquinoline quinone (PQQ) supplement on growth performance, serum biochemical parameters, antioxidant status, and growth-related genes expressions in juvenile yellow catfish, Pelteobagrus fulvidraco. Triplicate groups of fish (n = 40) with an average weight of 5 g were fed with five gradient levels PQQ-incorporated diets (0 (basal), 1.5 mg/kg; 3.0 mg/kg; 4.5 mg/kg, 6.0 mg/kg) for 56 days. Our findings revealed that fish fed with the diets containing PQQ at the level of 3.0-6.0 mg/kg showed significantly higher final body weight, weight gain rate, and specific growth rate than those of that in the control group (P < 0.05). The activities of protease were observed significantly increased in fish fed with diets containing 4.5 mg/kg and 6 mg/kg PQQ (P < 0.05). Meanwhile, fish in 4.5 mg/kg PQQ group showed significantly lower levels of serum total cholesterol, triglycerides, and low-density lipoprotein cholesterol, and significantly higher level of the high-density lipoprotein cholesterol (P < 0.05). The antioxidant-related parameters of superoxide dismutase and total antioxidant capacity were markedly elevated (P < 0.05), while malondialdehyde content was significantly reduced in 3.0-6.0 mg/kg PQQ group (P < 0.05). Meanwhile, the mRNA expression levels of growth-related genes (growth hormone, insulin-like growth factor 1, and insulin-like growth factor 2) were dramatically up-regulated in the liver of fish fed with the diets containing 3-6 mg/kg PQQ in comparison with the control group (P < 0.05). In conclusion, dietary PQQ could improve the growth performance, serum biochemical parameters, antioxidant status, and growth-related genes expressions in juvenile yellow catfish, and the optimal dietary PQQ level was evaluated to be 4.92 mg/kg of dry diet for juvenile yellow catfish.