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Introduction
PQQ (Pyrroloquinoline quinone or 4,5-dihydro-4,5-dioxo-1H-pyrrolo [2,3-f] quinoline-2,7,9-tricarboxylic acid) as known as methoxatin is a heat stable [8] and water soluble aromatic quinone that acts as a redox cofactor for membrane-bound dehydrogenases enzymes that are present in the bacterial systems. Due to its orthocyclic antioxidant nature that protects from oxidative damage by scavenging free radicals.[18] It also shows plant growth promoting activities by the release of organic acids into the soil. It can be found in some fruits and vegetables such as parsley, fermented soybeans, kiwi, and green peppers as well as animal products such as milk, serum and synovial fluid. [5, 14] These foods contain 2-3 ug per 100g, with humans consuming an estimate of 0.1-1 mg PQQ and its derivatives per day. Due to its vitamin-like property it has been considered as a putative and essential supplement [8] and can be 100-1000 times more efficient redox cycler, relatively stable to other quinone biofacters and does not easily polymerize.[6]

History
It was discovered by J. G. Hauge was the third redox cofactor after nicotinamide and flavin in bacteria. Anthony and Zatman also found the unknown redox cofactor in alcohol dehydrogenase. In 1979, Salisbury and colleagues as well as Duine and colleagues extracted this prosthetic group from methanol dehydrogenase of methylotrophs and identified its molecular structure. PQQ was first identified as a coenzyme of methanol dehydrogenase enzyme for methylotrophic bacteria and named as methoxatin.[21]

In animals
PQQ has the role of regulating cellular growth and differentiation in the mammalian system, as a nutrient and vitamin in stress tolerance. With its exceptionally high redox recycling ability, it has potential as anti-neurodegenerative, anticancer, anti-melanogenic and pharmacological agents due to its high redox cycling ability.[18] Recent studies suggest of PQQ having role of mediated cytotoxicity by inducing apoptosis in U937 (pro-monocytic, human histiocytic lymphoma) cells.[21] It has been reported to act as a mammalian redox cofactor for 2-aminoadipic acid dehydrogenase. [8, 10]

PQQ functions as a ROS scavenger especially for superoxide for conventional growth proliferation. It has been observed that PQQ deficiency affects the expression patterns of 438 genes some of which play a central role in the regulation of cellular energy metabolism, which with proper PQQ supplementation can be reversed. Of these, some of the pathways that are affected are cellular stress, MAPk kinase pathway, and transportation of metabolites.[6]

PQQ promotes and improves neonatal development [26. 27] and reproduction involving mitochondrial biogenesis promoting spontaneous generation of new mitochondria within aging cells [22] and cell signalling pathways. It also plays a vital role in liver fibrogenesis, signal transduction via mitochondrial biogenesis.[3] PQQ can provide considerable benefits in conditions that revolve around low mitochondrial function including in aging, many brain and neurological diseases (e.g., Alzheimer’s and Parkinson’s disease), and other chronic degenerative disorders.[7]

PQQ has been reported to influence the activity of DJ-1. DJ-1 is involved in cellular oxidative stress responses, and autosomal-recessive mutations in DJ-1 lead to Parkinson’s disease. A possible role of an interaction between DJ-1 and PQQ may be to facilitate and fine-tune overall cellular regulation. [19]

Current research has primarily focused on its ability to protect memory and cognition in aging animals and humans. Some of which include:[2]

·       Reversal of cognitive impairment caused by chronic oxidative stress and improved performance on memory tests in animal models [25, 1, 23]

·       Stimulation of the production and release of nerve growth factor [25, 1, 28]

·       Protection against the self-oxidation of the DJ-1 gene, an early step in the onset of Parkinson’s disease [25, 20]

·       Protection of brain cells against oxidative damage in stroke models [25, 1, 31]

·       Blocking the formation of inducible nitric oxide synthase (iNOS), a major source of the reactive nitrogen species (RNS) that are so damaging to brain cells [25, 1, 14]

·       Protection against the likelihood of severe stroke in an experimental animal model of stroke [25, 1, 9]

·       Protection of the brain against neurotoxicity induced by powerful toxins, including mercury, glutamate and oxidopamine (a potent neurotoxin used by scientists to induce Parkinsonism in laboratory animals) [25, 1, 29, 30]

·       Prevention of the development of alpha-synuclein, a protein associated with Parkinson’s disease [25, 1, 11]

·       Protection of nerve cells from the damaging effects of the beta-amyloid protein linked with Alzheimer’s disease [25, 1, 20]

·       Reduction of LDL cholesterol, presumably by activating AMP-kinase (AMPk) [25, 12].

In plants
PQQ acidifies extracellular medium by direct release of organic acid dissolving mineral phosphate for phosphate solubilization acting as a coenzyme for the membrane bound dehydrogenases enzyme present in microorganisms. The pqqC gene which encodes for PQQ synthesis protein C has been recognized to have antifungal activities and characterized for advancement of fungicides and unparalleled antibiotics. In addition, independent roles have been proposed for PQQ related to plant growth via activation of cell signalling, antioxidant defense, and viral protection. [24]

In animals
Quantitative analysis of PQQ by LC/MS/MS has shown that the free PQQ is present in all food samples ranging between 0.19 to 7.02 ƞg/g or /ml (fresh weight of solid foods or liquids respectively).[21] At varying concentration PQQ can act as an antioxidant and pro-oxidant having a significant functional aspect with no genotoxic effect on cells and its activities. It has also been recognized as an essential nutrient protecting the neurological cells by the suppression of peroxynitrile formation, it has also shown its function as a neuroprotectant.

PQQ presence in pg/ml levels in culture medium has been shown to stimulate bacterial growth by the reduction of their lag time suggesting its importance in the cell division process. It’s concentrations of 3 mg/Kg (body weight) has shown protection of cardiac and neural tissue in rodent models (ischemic). [6] t has been seen that mice fed with a PQQ deficient diet grow slowly, having fragile skin and reduced immune response, also not being able to reproduce well. [5, 3]

With the oral administration of PQQ, positive association of IL-6 and CRP was observed indicating PQQ having capability of attenuating an inflammatory response. [2, 22] PQQ treatments enhances IgA level, restores mass of GALT and indices immunity against bacterial or viral invasion.[18]

PQQ can act as a strong candidate in pharmacogenomics of brain injuries and other complications. PQQ offers remarkable radiation protection for cancer patients receiving radiation treatment, acting as an inhibitor of a pathway called mTOR causing tumour development and cancer cell proliferation.[18]

It contributes to epidermal water dissipation, skin moisture and viscoelasticity. It has also been listed as anti-aging as it preserves mitochondria and slows hardening of arteries, in a book published by The American Academy of Anti-Aging Medicine.[18]

PQQ supplementation (20mg) considerably improves the span of sleep and the total duration of sleep as insomnia may be indirectly involved with oxidative stress and ROS. 6 weeks of PQQ supplementation produced a statistically significant decrease in total cholesterol and LDL-cholesterol with persistent results at 12 weeks as well. [16]

PQQ exposure also increases the levels of NRF-1 and NRF-2, resulting in upregulation of the mitochondrial transcription factor A and mitochondrial gene expression [4].

In another trial relating to cognitive function, 17 healthy middle-age and elderly subjects ingested 20 mg of PQQ daily for 8 weeks. The results of the Profile of Mood States– Short Form showed that all six measures of vigour, fatigue, tension-anxiety, depression, anger-hostility and confusion significantly improved following PQQ supplementation compared with baseline scores. Improvements were also noted for drowsiness at awaking, sleep onset and maintenance, and sleep duration. These improvements correlated with changes in the cortisol awakening response. [17]

In plants
PQQ dependent mineral solubilization has shown a decrease in IAA canalization. PQQ also has roles such as acting as a biofertilizer, playing a bioenergetics role and foraging superoxide.

Dosage and toxicity
While the nutritional requirement of PQQ is below 500 ug per day, higher amounts are required to get a measurable response in mitochondrial function in adult animals. The recommended dosage in humans is 10-20 mg per day.

To no known toxicity or side effects of PQQ at recommended levels, when human volunteers were given higher dosage of PQQ (20 or 60 mg/day), no adverse effects were observed. A sensitive biomarker known as NAG for renal tubular damage was also determined to have no changes. [1]

Toxicology studies of PQQ in animals have show excellent safety profile with an LD50 being 1000-2000 mg PQQ/Kg in males and 500-1000 mg PQQ/Kg in female rats (by body weight). There have been no known drug interactions with PQQ at recommended levels.

Available PQQ supplements
1.      Douglas Laboratories PQQ Plus

2.      Pure Encapsulations SR-CoQ10 with PQQ

3.      Pure Encapsulations Ultra B-Complex w/PQQ

4.      HTN Ubiquinol PQQ Bundle

5.      Wellness resources PQQ (20 mg) capsules

6.      Jarrow Formulas, Ubiquinol, Qh+ PQQ

7.      Life extension PQQ caps with BioPQQ

8.      Mito cell PQQ

9.      Source Naturals PQQ mind 30T

10.  Biocyte Longevity PQQ Forte