International Journal of Current Research and Review
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IJCRR - 11(2), January, 2019

Pages: 07-10

Date of Publication: 22-Jan-2019


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An Innovative Quinone (Pyrroloquinoline Quinone) and its Antiproliferative Effects

Author: Flores-Encarnacion, M., Cabrera-Aguilar I., Aguilar-Gutierrez G.R., Cabrera-Maldonado, C.

Category: Healthcare

Abstract:The pyrroloquinoline quinine is a cofactor discovered in bacteria. It is associated with various bacterial soluble and membrane enzymes that directly oxidize sugars, alcohols, aldehydes. In higher organisms, it has been reported that pyrroloquinoline quinine acts as a potent free radical scavenger and it seems to intervene in different processes causing remarkable benefits. One of the most important effects is that pyrroloquinoline quinine induced apoptosis in different cancer cell lines. It is interesting to observe the role of pyrroloquinoline quinine as pro-apoptotic agent. This review shows the most relevant aspects of this cofactor and its antiproliferative effects.

Keywords: Pyrroloquinoline quinone, PQQ, Cofactor, Effect, Antiproliferative

Full Text:

INTRODUCTION

PQQ is a substance of quinoid nature discovered as a cofactor in different bacterial genera (Amador-Bravo, 2016; Ameyama et al., 1991; Choi et al., 2008; Misra et al., 2012). As a cofactor, it catalyzes the oxidation of organic compounds such as monosaccharides, alcohols and short chain aldehydes. It has been reported that PQQ is linked covalently and non-covalently to enzymes (Attwood et al., 1991; Flores-Encarnación et al., 2004; Goodwin and Anthony, 1998; Matsushita et al., 2002; Naveed et al., 2016). Due to its quinoid nature, PQQ has very active carbonyl groups, being a powerful antioxidant agent. It has been observed that the presence of PQQ in certain bacterial genera facilitates the activation of alternative metabolic pathways for the utilization of sugars; it also favors the production of high quantities of acidic substances in the external environment of bacteria by direct oxidation of sugars or alcohols (Choi et al., 2008). PQQ is a novel quinone of bacterial origin that has changed the vision regarding diseases such as cancer because PQQ has been proposed as a possible alternative for the treatment of this disease, according to results obtained in different cell lines.

In recent years, the benefits of PQQ have been demonstrated when this substance is administered in plants or diet of different experimental animals(Amador-Bravo et al., 2016; Bauerly et al., 2011; Choi et al., 2008; Flores-Encarnación et al., 2014; Harris et al., 2013; Misra et al., 2012; Oteino et al., 2015). For example, it has a been attributed to PQQ the promotion of growth factors in tomato plantations, increasing amount of macronutrients and number of fruits. In rats, the use of a diet supplemented with PQQ showed a significant change in the learning (Amador-Bravo et al., 2016; Fukui et al., 2001; Harris et al., 2013; Ohwada et al., 2008). It has been reported that PQQ acts as a potent free radical scavenger; it suppresses the production of superoxide radicals(Hamagishi et al., 1988; Matsumoto et al., 1988; Zhang et al., 2013). PQQ has been described as a new vitamin and it seems to intervene in different processes in higher organisms causing remarkable benefits(McIntire, 1998). In recent years, the effect of PQQ on different cancer cell lines has been studied and it has been observed that PQQ induces apoptosis (Min et al., 2014). This review shows the most relevant aspects of PQQ and its antiproliferative effects.

PQQ

PQQ is a soluble anionic compound of low molecular weight, which has been classified as a new vitamin and as an essential nutrient, since it has been proven that it plays important roles: in cell proliferation, it is an antioxidant of lipid peroxidation and its beneficial effects have also been observed in cellular lesions (Shui et al., 2015; Azizi et al., 2014). PQQ is a nutrient that is well distributed in nature and serves as a non-covalent cofactor of redox reactions in certain bacterial dehydrogenase (named quinoproteins) (Flores-Encarnación et al., 2004; Matsushita et al., 2002; Tao et al., 2007). PQQ is not synthesized in mammals, however it has been found in several levels of concentration in plants, in certain foods, such as kiwi, egg, wine, even in human breast milk (Noji et al., 2007). It has been found that PQQ develops many important functions in humans and animals, including roles in nutrition, protection of the heart by ischemia, preventing damage to the liver by alcohol, sequestering free radicals from the body, increasing the level of nerve growth factor (in astrocytes) and inhibiting melanin production in melanoma cells (Fukui et al., 2001; Wang et al., 2014).

PQQ as a vitamin

PQQ has been proposed as a new vitamin because it had beneficial effects on healthy cells at low concentrations (nanomolar to micromolar order) (Chowanadisai et al., 2010; Steinberg et al., 2003). It is known that glutamate is the free amino acid more abundant in the central nervous system but excess glutamate can affect progenitor cells and induces apoptosis in neural trunkand other cells(Pavlovic et al., 2006). However, in vitro studies have shown that when the cells were cultured at different PQQ concentrations (3 nM to 30 mM), it was observed that PQQ favored cell proliferation and significantly attenuated cell damage induced by glutamate (Shui et al., 2015). On the other hand, it is known that vitamins perform their function in team and in certain specific places of the body. Some authors have studied the effect of PQQ and vitamin E in peripheral nerves such as sciatica. They discovered that PQQ together with vitamin E favored the fastest recovery from nerve damage (increasing the regeneration of axons). Therefore, those two agents were been proposed for an effective regeneration in peripheral nerve lesions (Azizi et al., 2014; Naveedet al., 2016).Tao et al., (2007) proposed to PQQ as a cardioprotective agent after observing a remarkable reduction of peroxides treating adult rat myocardium cells with H2O2 and PQQ.

PQQ as growth promoter

This novel quinone was proposed as a potent growth factor in mice and as a promoter of DNA synthesis in human fibroblasts(Amador-Bravo et al., 2016;Chowanadisai et al., 2010;Harris et al., 2013; Misra et al., 2012). Kumazawa et al., (2007) observed in NIH3T3mouse fibroblasts that PQQ increased cell proliferation through of signals related to Rats and it was observed that effect of PQQ derived from regulation of nitric oxide (NO) levels. Those studies contributed to expand understanding of cellular mechanisms, cell signaling and gene expression relevant to PQQ in mammals (Kumazawa et al., 2007).

On the other hand, it has been reported that coenzymes such as PQQ showed a stimulating effect on the synthesis of nerve growth factor in mouse fibroblasts and BALBc/3T3 cell line, concluding that PQQ plays a important role in neuronal survival (Azizi et al., 2014; Misra et al., 2012; Murase et al., 1993). The effect of PQQ has also been studied in fibroblasts, myocytes and mouse brainmicrovascular endothelial cells, where it was observed that PQQ in nanomolar concentrations protected these cells from high glucose-induced damage, thus reducing apoptosis and increasing the number of mitochondria in the cells. Apparently the protective effect was due to intracellular expression of hypoxia-inducible factor 1 alpha subunit (HIF-1α) (Wang et al., 2014). It is known that liver fibrosis develops when there is chronic inflammation and destruction of liver cells, however it has been observed that PQQ has a suppressive, anti-oxidant and anti-fibrogenic effect. It has been reported that PQQ exerted a potent anti-fibrotic activity and reactive oxygen species (ROS) scavenging activity in Balb/C mouse models of liver fibrosis (Jia et al., 2015). In the majority of the studies that have been carried out, the effect of PQQ in nanomolar concentration has been tested, however in the last years other studies have been developed in different cell lines of malignant cells, showing that in micromolar quantities PQQ has apoptotic effects (Min et al., 2014).

The antiproliferative effects of PQQ

It has been reported that the murine melanoma cell line B16F1is characterized because melanocytes produce a large amount of tyrosinase enzyme. Tyrosinase is a key enzyme in melanin synthesis and that in high amounts produces hyperpigmentation of the skin and even cancer (melanoma) (Sato et al., 2008).Sato and Toriyama (2009) reported that PQQ between 12.5 to 25 μM inhibited the synthesis of mRNA that codes for tyrosinase involved in the production of melanin. These authors observed a decrease in cell proliferation and melanin production. Although the mechanism of action is still unknown, it has been proposed PQQ as a possible treatment against melanogenesis and hyperpigmentation disorders. In cell lines A-549 (adenocarcinoma of human lung), Neuro-2A (mouse neuroblastoma) and HCC-LM3 (human hepatocellular carcinoma), it has been observed that PQQ at concentrations 30 to 75 μM suppressed cell proliferation by inducing apoptosis. In addition, it was observed that PQQ increased the activity of caspase-3, produced cell cycle arrest in G0/G1 phase and produced the intracellular accumulation of reactive oxygen species (ROS) and the decline of ATP levels (Min et al., 2014). In the cell line A431 (human squamous cell carcinoma), it has been observed that PQQ at concentrations in the nanomolar order, promoted cell proliferation increasing growth up to 180%, however at concentrations in the micromolar order PQQ induced apoptosis (Kimura et al., 2012). In the cell line U937 (human promonocitic leukemia), it was reported that PQQ at concentrations of 50-100 μM induced a depletion of glutathione and, consequently, an increase in reactive oxygen species (ROS). The decrease in glutathione led to the cells suffering necrosis, indicating that PQQ increased cytotoxicity due to the change in the cellular redox state. Thus, glutathione depletion can change the mode of cell death to necrosis in the presence of PQQ. The modulation of intracellular glutathione could be a strategy to enhance the cytotoxicity of PQQ (Nunone et al., 2008; Shankar et al., 2013). As a scavenger of reactive oxygen species, PQQ appears to be a potent neuroprotector (Scanlon et al., 1997). Zhang et al. (2009 ) reported that the addition of 1 to 20 μM of PQQ in the human neuroblastoma cell line SH-SY5Y, together with the beta-amyloid protein (Aβ), prevents the damage caused by the latter, thus avoiding apotosis. Beta-amyloid proteins have been proposed as one of the causes of Alzheimer's disease that produces neurotoxicity (increasing the production of reactive oxygen species) and induces apoptosis of neurons (Zhang et al. (2013). The alpha-synuclein (α-syn) is a small soluble protein expressed primarily at presynaptic terminals in the central nervous system and it is related to several neurodegenerative diseases, including Parkinson’s disease (Amador-Bravo et al., 2016). The recent data suggest that α-syn has a role in regulating membrane stability and neuronal plasticity (Overk et al., 2014). When the α-syn is mutated the function is lostcausing the formation of bodies of Lewis, cytotoxicity, apoptosis in neurons of the substantia nigra and therefore Parkinson’s disease (Kim et al., 2010; Kobayashi et al., 2010;Overk et al., 2014; Recchia et al., 2004). On the other hand, the rotenone is a substance that has been used as a natural pesticide. Its use has increased in recent years. However, rotenone can cross the brain barrier by penetrating the cell membrane and acting as a potent inhibitor of mitochondrial complex I leading to cell death. It has been tested in several cellular models that PQQ added to different concentrations in the presence of rotenone, protects the cells from damage and delays their harmful effects (Qin et al., 2015).

CONCLUSION

PQQ is a novel cofactor that can act as a vitamin in nanomolar concentrations; at higher concentrations PQQ could be used for the treatment of certain diseases. PQQ can induce apoptosis in cancer cells, it is also protective of neurons, of myocardium and stimulates the cognitive system, among other things. However, PQQ can also have pro-oxidant characteristics and by binding to certain compounds can exacerbate cell toxicity.

ACKNOWLEDGEMENTS

Thank to PRODEP and Facultad de Medicina-BUAP for the facilities provided for the development of this work.

CONFLICT OF INTEREST

Authors have no conflict of interest.

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A Study by Bhat Asifa et al. entitled "Efficacy of Modified Carbapenem Inactivation Method for Carbapenemase Detection and Comparative Evaluation with Polymerase Chain Reaction for the Identification of Carbapenemase Producing Klebsiella pneumonia Isolates" is awarded Best Article for Vol 13 issue 17
A Study by Gupta R. et al. entitled "A Clinical Study of Paediatric Tracheostomy: Our Experience in a Tertiary Care Hospital in North India" is awarded Best Article for Vol 13 issue 16
A Study by Chandran Anand et al. entitled "A Prospective Study on Assessment of Quality of Life of Patients Receiving Sorafenib for Hepatocellular Carcinoma" is awarded Best article for Vol 13 issue 15
A Study by Rosa PS et al. entitled "Emotional State Due to the Covid – 19 Pandemic in People Residing in a Vulnerable Area in North Lima" is awarded Best Article for Vol 13 issue 14
A Study by Suvarna Sunder J et al. entitled "Endodontic Revascularization of Necrotic Permanent Anterior Tooth with Platelet Rich Fibrin, Platelet Rich Plasma, and Blood Clot - A Comparative Study" is awarded Best Article for Vol 13 issue 13
A Study by Mona Isam Eldin Osman et al. entitled "Psychological Impact and Risk Factors of Sexual Abuse on Sudanese Children in Khartoum State" is awarded Best Article for Vol 13 issue 12
A Study by Khaw Ming Sheng & Sathiapriya Ramiah entitled "Web Based Suicide Prevention Application for Patients Suffering from Depression" is awarded Best Article for Vol 13 issue 11
A Study by Purushottam S. G. et al. entitled "Development of Fenofibrate Solid Dispersions for the Plausible Aqueous Solubility Augmentation of this BCS Class-II Drug" is awarded Best article for Vol 13 issue 10
A Study by Kumar S. et al. entitled "A Study on Clinical Spectrum, Laboratory Profile, Complications and Outcome of Pediatric Scrub Typhus Patients Admitted to an Intensive Care Unit from a Tertiary Care Hospital from Eastern India" is awarded Best Article for Vol 13 issue 09
A Study by Mardhiah Kamaruddin et al. entitled "The Pattern of Creatinine Clearance in Gestational and Chronic Hypertension Women from the Third Trimester to 12 Weeks Postpartum" is awarded Best Article for Vol 13 issue 08
A Study by Sarmila G. B. et al. entitled "Study to Compare the Efficacy of Orally Administered Melatonin and Clonidine for Attenuation of Hemodynamic Response During Laryngoscopy and Endotracheal Intubation in Gastrointestinal Surgeries" is awarded Best Article for Vol 13 issue 07
A Study by M. Muthu Uma Maheswari et al. entitled "A Study on C-reactive Protein and Liver Function Tests in Laboratory RT-PCR Positive Covid-19 Patients in a Tertiary Care Centre – A Retrospective Study" is awarded Best Article of Vol 13 issue 06 Special issue Modern approaches for diagnosis of COVID-19 and current status of awareness
A Study by Gainneos PD et al. entitled "A Comparative Evaluation of the Levels of Salivary IgA in HIV Affected Children and the Children of the General Population within the Age Group of 9 – 12 Years – A Cross-Sectional Study" is awarded Best Article of Vol 13 issue 05 Special issue on Recent Advances in Dentistry for better Oral Health
A Study by Alkhansa Mahmoud et al. entitled "mRNA Expression of Somatostatin Receptors (1-5) in MCF7 and MDA-MB231 Breast Cancer Cells" is awarded Best Article of Vol 13 issue 06
A Study by Chen YY and Ghazali SRB entitled "Lifetime Trauma, posttraumatic stress disorder Symptoms and Early Adolescence Risk Factors for Poor Physical Health Outcome Among Malaysian Adolescents" is awarded Best Article of Vol 13 issue 04 Special issue on Current Updates in Plant Biology to Medicine to Healthcare Awareness in Malaysia
A Study by Kumari PM et al. entitled "Study to Evaluate the Adverse Drug Reactions in a Tertiary Care Teaching Hospital in Tamilnadu - A Cross-Sectional Study" is awarded Best Article for Vol 13 issue 05
A Study by Anu et al. entitled "Effectiveness of Cytological Scoring Systems for Evaluation of Breast Lesion Cytology with its Histopathological Correlation" is awarded Best Article of Vol 13 issue 04
A Study by Sharipov R. Kh. et al. entitled "Interaction of Correction of Lipid Peroxidation Disorders with Oxibral" is awarded Best Article of Vol 13 issue 03
A Study by Tarek Elwakil et al. entitled "Led Light Photobiomodulation Effect on Wound Healing Combined with Phenytoin in Mice Model" is awarded Best Article of Vol 13 issue 02
A Study by Mohita Ray et al. entitled "Accuracy of Intra-Operative Frozen Section Consultation of Gastrointestinal Biopsy Samples in Correlation with the Final Histopathological Diagnosis" is awarded Best Article for Vol 13 issue 01
A Study by Badritdinova MN et al. entitled "Peculiarities of a Pain in Patients with Ischemic Heart Disease in the Presence of Individual Combines of the Metabolic Syndrome" is awarded Best Article for Vol 12 issue 24
A Study by Sindhu Priya E S et al. entitled "Neuroprotective activity of Pyrazolone Derivatives Against Paraquat-induced Oxidative Stress and Locomotor Impairment in Drosophila melanogaster" is awarded Best Article for Vol 12 issue 23
A Study by Habiba Suhail et al. entitled "Effect of Majoon Murmakki in Dysmenorrhoea (Usre Tams): A Standard Controlled Clinical Study" is awarded Best Article for Vol 12 issue 22
A Study by Ghaffar UB et al. entitled "Correlation between Height and Foot Length in Saudi Population in Majmaah, Saudi Arabia" is awarded Best Article for Vol 12 issue 21
A Study by Siti Sarah Binti Maidin entitled "Sleep Well: Mobile Application to Address Sleeping Problems" is awarded Best Article for Vol 12 issue 20
A Study by Avijit Singh"Comparison of Post Operative Clinical Outcomes Between “Made in India” TTK Chitra Mechanical Heart Valve Versus St Jude Mechanical Heart Valve in Valve Replacement Surgery" is awarded Best Article for Vol 12 issue 19
A Study by Sonali Banerjee and Mary Mathews N. entitled "Exploring Quality of Life and Perceived Experiences Among Couples Undergoing Fertility Treatment in Western India: A Mixed Methodology" is awarded Best Article for Vol 12 issue 18
A Study by Jabbar Desai et al. entitled "Prevalence of Obstructive Airway Disease in Patients with Ischemic Heart Disease and Hypertension" is awarded Best Article for Vol 12 issue 17
A Study by Juna Byun et al. entitled "Study on Difference in Coronavirus-19 Related Anxiety between Face-to-face and Non-face-to-face Classes among University Students in South Korea" is awarded Best Article for Vol 12 issue 16
A Study by Sudha Ramachandra & Vinay Chavan entitled "Enhanced-Hybrid-Age Layered Population Structure (E-Hybrid-ALPS): A Genetic Algorithm with Adaptive Crossover for Molecular Docking Studies of Drug Discovery Process" is awarded Best article for Vol 12 issue 15
A Study by Varsha M. Shindhe et al. entitled "A Study on Effect of Smokeless Tobacco on Pulmonary Function Tests in Class IV Workers of USM-KLE (Universiti Sains Malaysia-Karnataka Lingayat Education Society) International Medical Programme, Belagavi" is awarded Best article of Vol 12 issue 14, July 2020
A study by Amruta Choudhary et al. entitled "Family Planning Knowledge, Attitude and Practice Among Women of Reproductive Age from Rural Area of Central India" is awarded Best Article for special issue "Modern Therapeutics Applications"
A study by Raunak Das entitled "Study of Cardiovascular Dysfunctions in Interstitial Lung Diseas epatients by Correlating the Levels of Serum NT PRO BNP and Microalbuminuria (Biomarkers of Cardiovascular Dysfunction) with Echocardiographic, Bronchoscopic and HighResolution Computed Tomography Findings of These ILD Patients" is awarded Best Article of Vol 12 issue 13 
A Study by Kannamani Ramasamy et al. entitled "COVID-19 Situation at Chennai City – Forecasting for the Better Pandemic Management" is awarded best article for  Vol 12 issue 12
A Study by Muhammet Lutfi SELCUK and Fatma entitled "Distinction of Gray and White Matter for Some Histological Staining Methods in New Zealand Rabbit's Brain" is awarded best article for  Vol 12 issue 11
A Study by Anamul Haq et al. entitled "Etiology of Abnormal Uterine Bleeding in Adolescents – Emphasis Upon Polycystic Ovarian Syndrome" is awarded best article for  Vol 12 issue 10
A Study by entitled "Estimation of Reference Interval of Serum Progesterone During Three Trimesters of Normal Pregnancy in a Tertiary Care Hospital of Kolkata" is awarded best article for  Vol 12 issue 09
A Study by Ilona Gracie De Souza & Pavan Kumar G. entitled "Effect of Releasing Myofascial Chain in Patients with Patellofemoral Pain Syndrome - A Randomized Clinical Trial" is awarded best article for  Vol 12 issue 08
A Study by Virendra Atam et. al. entitled "Clinical Profile and Short - Term Mortality Predictors in Acute Stroke with Emphasis on Stress Hyperglycemia and THRIVE Score : An Observational Study" is awarded best article for  Vol 12 issue 07
A Study by K. Krupashree et. al. entitled "Protective Effects of Picrorhizakurroa Against Fumonisin B1 Induced Hepatotoxicity in Mice" is awarded best article for issue Vol 10 issue 20
A study by Mithun K.P. et al "Larvicidal Activity of Crude Solanum Nigrum Leaf and Berries Extract Against Dengue Vector-Aedesaegypti" is awarded Best Article for Vol 10 issue 14 of IJCRR
A study by Asha Menon "Women in Child Care and Early Education: Truly Nontraditional Work" is awarded Best Article for Vol 10 issue 13
A study by Deep J. M. "Prevalence of Molar-Incisor Hypomineralization in 7-13 Years Old Children of Biratnagar, Nepal: A Cross Sectional Study" is awarded Best Article for Vol 10 issue 11 of IJCRR
A review by Chitra et al to analyse relation between Obesity and Type 2 diabetes is awarded 'Best Article' for Vol 10 issue 10 by IJCRR. 
A study by Karanpreet et al "Pregnancy Induced Hypertension: A Study on Its Multisystem Involvement" is given Best Paper Award for Vol 10 issue 09

List of Awardees

A Study by Ese Anibor et al. "Evaluation of Temporomandibular Joint Disorders Among Delta State University Students in Abraka, Nigeria" from Vol 13 issue 16 received Emerging Researcher Award


A Study by Alkhansa Mahmoud et al. entitled "mRNA Expression of Somatostatin Receptors (1-5) in MCF7 and MDA-MB231 Breast Cancer Cells" from Vol 13 issue 06 received Emerging Researcher Award


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International Journal of Current Research and Review (IJCRR) provides platform for researchers to publish and discuss their original research and review work. IJCRR can not be held responsible for views, opinions and written statements of researchers published in this journal

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