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Review

Combined Supplementation of Coenzyme Q10 and Other Nutrients in Specific Medical Conditions

by
Torsak Tippairote
1,
Geir Bjørklund
2,*,
Amin Gasmi
3,
Yuliya Semenova
4,
Massimiliano Peana
5,
Salvatore Chirumbolo
6,7 and
Tony Hangan
8
1
Department of Nutritional and Environmental Medicine, HP Medical Center, Bangkok 10540, Thailand
2
Council for Nutritional and Environmental Medicine, Toften 24, 8610 Mo i Rana, Norway
3
Société Francophone de Nutrithérapie et de Nutrigénétique Appliquée, 69100 Villeurbanne, France
4
School of Medicine, Nazarbayev University, Astana 020000, Kazakhstan
5
Department of Chemical, Physical, Mathematical and Natural Sciences, University of Sassari, via Vienna 2, 07100 Sassari, Italy
6
Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37134 Verona, Italy
7
CONEM Scientific Secretary, Strada Le Grazie 9, 37134 Verona, Italy
8
Faculty of Medicine, Ovidius University of Constanta, 900470 Constanta, Romania
*
Author to whom correspondence should be addressed.
Nutrients 2022, 14(20), 4383; https://doi.org/10.3390/nu14204383
Submission received: 2 September 2022 / Revised: 7 October 2022 / Accepted: 15 October 2022 / Published: 19 October 2022
(This article belongs to the Special Issue Nutrition and Aging - Featured Perspectives on Health and Metabolism)
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Abstract

:
Coenzyme Q10 (CoQ10) is a compound with a crucial role in mitochondrial bioenergetics and membrane antioxidant protection. Despite the ubiquitous endogenous biosynthesis, specific medical conditions are associated with low circulating CoQ10 levels. However, previous studies of oral CoQ10 supplementation yielded inconsistent outcomes. In this article, we reviewed previous CoQ10 trials, either single or in combination with other nutrients, and stratified the study participants according to their metabolic statuses and medical conditions. The CoQ10 supplementation trials in elders reported many favorable outcomes. However, the single intervention was less promising when the host metabolic statuses were worsening with the likelihood of multiple nutrient insufficiencies, as in patients with an established diagnosis of metabolic or immune-related disorders. On the contrary, the mixed CoQ10 supplementation with other interacting nutrients created more promising impacts in hosts with compromised nutrient reserves. Furthermore, the results of either single or combined intervention will be less promising in far-advanced conditions with established damage, such as neurodegenerative disorders or cancers. With the limited high-level evidence studies on each host metabolic category, we could only conclude that the considerations of whether to take supplementation varied by the individuals’ metabolic status and their nutrient reserves. Further studies are warranted.

1. Introduction

In 1957, Crane et al. isolated a new quinone compound, initially referred to as Q-275, from beef heart mitochondria and described its ability to undergo reversible oxidation and reduction [1]. With its functional quinone moiety and its ubiquitous presence in living cells, this compound was later officially named ‘ubiquinone’ by the IUPAC-IUB Commission on Biochemical Nomenclature [2,3]. However, there were other common names for ubiquinone, including Coenzyme Q10 (CoQ10), CoQ, ubiquinone-Q10, vitamin Q10, and ubidecarenone [4].
CoQ10 consists of two functional groups, i.e., the five-carbon isoprene ‘tail’ and the benzoquinone ‘head’. The lipid-soluble tail consists of ten isoprenes, with a total of 50 carbon atoms, hence the name ‘CoQ10’ [5,6]. Humans can internally synthesize CoQ10. The synthesis of the benzoquinone head requires amino acids, either tyrosine or phenylalanine, while the mevalonate pathway provides the acetyl coenzyme A for the polyisoprenoid tail synthesis [5,7,8]. The CoQ10 head and tail are synthesized in the cytosol but the joining of both functional groups occurs in the mitochondria [5,9]. The CoQ10 biosynthesis requires support from various macro- and micronutrients, such as pantothenic acid for the CoA precursor, pyridoxine for the benzoquinone production, and s-adenosyl methionine for methylation support and isoprene production [10].
Humans can internally synthesize CoQ10, while the dietary CoQ10 sources additionally contribute to its total tissue pool. The main dietary sources of CoQ10 include fish and meat, while vegetables generally contain low CoQ10 quantity. Dietary CoQ10 sparsely absorbs in the hydrophilic intestinal environment due to its lipophilic and high molecular weight properties. Following the gut uptake, CoQ10 circulates in the lymphatic system and ultimately drains into the blood circulation [11]. Consequently, the CoQ10 level in the liver and plasma lipoproteins appears shortly after absorption, but the elevation of plasma CoQ10 level varies by the blood cholesterol and lipoprotein concentrations [6,12]. The CoQ10 turnover in the body is relatively fast, with a 49 to 125 h half-life, depending on the tissue type [13].
The combination of endogenous biosynthesis and dietary intake is largely sufficient to prevent the CoQ10 deficiency state in a healthy individual [14,15]. However, cumulative studies reported the association of low CoQ10 levels in specific conditions such as following strenuous exercise, during aging, after taking some prescribed medications, in patients with various metabolic disorders, and in individuals with cancers [6,8,16,17,18,19,20,21,22]. Despite the documented low CoQ10 levels, the clinical outcomes of CoQ10 interventions, either single or in combination with other nutrients, were generally inconsistent. In this review, we explored the previous CoQ10 clinical trials, both single and combined supplementations, in specific medical conditions and deduced whether the differences in host metabolic status influence the CoQ10 interventional outcomes.

2. Materials and Methods

2.1. Search Strategy

From the available public databases up to the date 10 January 2021, we initially acquired 256 publications by using the Medical Subject Heading (MeSH) Ubiquinone, Dietary Supplements, and randomized controlled trials, together with the truncated keywords Coenzyme Q* and supplement*. In the PubMed database, we used the following search query: (((“Ubiquinone”(MeSH)) OR (Coenzyme Q*(tw))) AND ((“Dietary Supplements” (MeSH)) OR (supplement*(tw)))) AND (“randomized controlled trials as topic”(MeSH)). We also retrieved additional articles from Cochrane Library, Scopus, Google Scholar, ResearchGate, and relevant citation searches.

2.2. Study Screening, Selection, and Inclusion

We initially identified the studies by their titles and abstracts for their compliance with the following inclusion criteria: (i) controlled clinical trials on the effects of CoQ10 and its analogs with or without the addition of other nutrients; (ii) controlled clinical trials that addressed the effects of CoQ10 and its analogs in a range of medical conditions; (iii) studies for which the full texts were available to enable a comprehensive review.
With all retrieved full texts of articles, we screened and grouped them according to participants’ status or medical conditions. We then evaluated their suitability for inclusion in the present review. We also acquired additional studies from the relevant citation searches.
After excluding the duplicated, irrelevant, and no full-text-available articles, we included 156 studies in this narrative review. We generated a PRISMA diagram to describe the flow of information through the processes of identification, screening, and including records in this literature review, as shown in Figure 1 [23,24].

3. Physiological Roles of CoQ10 in Humans

3.1. CoQ10 Roles in Mitochondrial Bioenergetics

CoQ10 roles are crucial to the mitochondrial respiratory chain as the electron acceptor. It modulates the electron transferring from the bioenergetic-derived reducing equivalents, i.e., nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2), through the complex I, II, and III in the electron transport chain (ETC). The concurrent proton flow, from the mitochondrial matrix to the intermembrane space, generates the intermembrane proton gradients, which are essential for oxidative phosphorylation and subsequent adenosine triphosphate (ATP) synthesis [5]. Accordingly, CoQ10 intervention could have potential bioenergetic benefits in clinical conditions with mitochondrial dysfunction.
While mitochondria are the bioenergetic hub of the cells, they are also the predominant source of reactive oxygen species (ROS) production, oxidative stress, and immunologic and apoptotic regulation. The imbalances of these physiological processes underly diverse metabolic conditions [25]. As the critical supporter of mitochondrial functions, the importance of CoQ10 might extend beyond bioenergetics.

3.2. CoQ10 Role as an Antioxidant

With its reversible redox potential and membrane-associated locations, CoQ10 renders antioxidant protection to the organelles and cell lipid membranes [13,26,27,28]. Inside the cells, the benzoquinone head of CoQ10 exists in three interchangeable oxidation states, i.e., the fully reduced ubiquinol (CoQ10H2), the ubisemiquinone intermediate (CoQ10H•), and the fully oxidized ubiquinone (CoQ10). These redox states are culpable for the scavenging of ROS as well as the mediation of electrons transferring in the mitochondrial ETC.
Nevertheless, the integrated redox modulation of CoQ10 requires support from other nutrients, specifically α-tocopherol, vitamin C, and other micronutrients. Figure 2 depicts this integrated antioxidant network of CoQ10 against lipid peroxidation [29,30]. While the ROS induces unsaturated lipid peroxidation, it yields the highly reactive lipid peroxyl radicals, which are quickly neutralized by α-tocopherol through the donation of its hydrogen to the peroxyl radicals, thus holding their propagations within membranes and circulating lipoproteins. The reduced ubiquinol then helps regenerate the α-tocopherol antioxidant capacity through their redox interactions. Thereafter, the ubisemiquinone intermediate can either react with the oxygen molecule and produce the superoxide anion radicals or oxidize further to the fully oxidized ubiquinone that does not react with oxygen. Reduced NADP (NADPH), glutathione, and other antioxidants such as vitamin C then help to regenerate the oxidized ubiquinone and α-tocopherol back and maintain their reduction states [13,31,32,33]. In this integrated manner, CoQ10 limits the production of lipid peroxyl radicals and protects the circulating lipoproteins, the cellular membrane proteins, the mitochondrial DNA, and the ETC membranes [26,34,35,36].
For oral CoQ10 supplementation, a 2020 meta-analysis of 17 randomized clinical trials (RCT) documented its antioxidant potentials, comprising the reduction of membrane oxidative damage level, the enhancement of total antioxidant capacity, and the activation of antioxidant defense system enzymes [30]. As a dietary supplement, the antioxidant capability of CoQ10 might provide benefits to clinical conditions with underlying oxidative stress pathophysiology.

3.3. Other Physiological Roles of CoQ10

CoQ10 also serves as the structural component of the ETC membrane supercomplexes that ascertains the efficient ETC functions and prevents the leakage of the electron from the respiratory chain [28,37,38,39]. The combined result of its structural contribution, lipid peroxidation protection, ROS scavenging, and uncoupling protein activations contribute to the pivotal role of CoQ10 in mitochondrial membrane integrity [13,40]. Besides this, the conservation of mitochondrial membrane permeability is also crucial for cellular survival and functions [13,41,42].
Apart from the mitochondria, the containment of highly acidic enzymes within the lipid-membrane boundary of lysosomes requires the CoQ10-induced intermembrane proton gradient [8,43]. Furthermore, CoQ10–redox interaction maintains the balance of cytosolic redox intermediates such as NADH, NADPH, and FADH2. The CoQ10-mediated reaction also supplies orotate for the de novo pyrimidine synthesis through the oxidative activity of dihydroorotate dehydrogenase [44]. These intracellular redox balances influence several cellular signalings and gene transcriptions. Such homeostasis modulates apoptosis, bioenergetics, cell growth, and inflammatory responses [28,45].
Interestingly, the oral CoQ10 supplementation showed different 115 gene expressions in the muscle tissue samples from aged individuals compared to their placebo controls [46]. These findings supported the diverse physiologic roles of CoQ10 and the potential benefit of its intervention. Several clinical studies also reported that oral CoQ10 supplementation showed anti-inflammatory effects, including the reduction of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and C-reactive protein (CRP) [47,48,49,50]. This immunomodulatory potential of CoQ10 supplementation also suggests its potential benefit to various immune-mediated clinical conditions.

4. CoQ10 Supplementation in Specific Medical Conditions

Cumulative evidence supports the association of low plasma CoQ10 levels in several medical conditions such as diabetes mellitus, cancers, and congestive heart failure [2,51,52,53]. Several studies have also explored the role of oral CoQ10 supplementation in various conditions. Despite the concerns that oral CoQ10 supplementation may excessively raise the tissue CoQ10 concentrations in humans [43,54,55], the tissue CoQ10 uptake in a healthy individual is relatively low due to its ongoing endogenous biosynthesis [56]. Following the oral supplementation, the plasma CoQ10 level appeared to reach the plateau at the dosage of 2400 mg/day while the tissue CoQ10 uptakes appeared at a relatively higher plasma concentration than this level [57,58,59]. The tissue uptakes probably increase under the pathological CoQ10 deficit [60]. To support this notion, CoQ10 supplementation in elders who underwent cardiac interventions showed increased CoQ10 uptake in their cardiac tissue samples [61,62]. As for the potential adverse effects of oral CoQ10 supplementation, previous studies reported no major side effects after eight months for the dosage of 3000 mg/day, sixteen months for 1200 mg/day, and thirty months for 600 mg/day [58,59,63,64]. Nevertheless, the documented minor gastrointestinal symptoms included nausea, diarrhea, low appetite, heartburn, and discomfort, notably when the daily dosage exceeded 200 mg/day. The two or three daily divided doses minimized most of these side effects [65]. The concurrent intake of high-fat meals also facilitates CoQ10 absorption and reduces gut-related symptoms.
Many clinical studies explored the role of CoQ10 supplementation, either as a single intervention or as a combination with other nutrients, in several medical conditions. In general, the outcomes of single CoQ10 supplementation from these trials were largely inconsistent. We herein explored previous CoQ10 supplementation studies and deduced the potential contributing factors to the interventional outcomes.

4.1. Single CoQ10 Supplementation

4.1.1. Single CoQ10 Supplementation in the Primary CoQ10 Deficiencies

The primary CoQ10 deficiencies are genetic conditions with mutations in one of the nine CoQ10 biosynthetic genes [5]. These mutations lead to the disruption in the mitochondria respiratory chain functions with the clinical phenotypes of multisystem involvement [66,67]. Despite the incurability of the primary CoQ10 deficiencies, studies reported a partial improvement of muscular and neurological symptoms in some patients with oral CoQ10 supplementation [68]. A systematic review of the intervention in patients with primary CoQ10 deficiencies, a total of 89 cases, reported symptom improvements in 27% of patients. Five cases even deteriorated after discontinuing CoQ10 supplementation [69]. The intervention on this genetic condition generally required a high dosage, ranging from 5 to 50 mg/kg/day, of oral CoQ10 supplementation to achieve favorable responses [70].

4.1.2. Single CoQ10 Supplementation in Healthy Adults and Athletes

A single bout of vigorous exercise in young athletes induces a rapid decrease in plasma CoQ10 level and one month of supplementation minimized that effect [16]. Two weeks of CoQ10 supplementation, 200 mg/day, before performing strenuous exercise sessions showed antioxidant benefits in a group of 100 healthy and trained adults in a 2016 RCT. These oxidative stress protections included the reduction of oxidative damage markers and enhanced antioxidant enzyme activities [71]. A systematic review of 13 clinical studies also supported these findings [72]. A recent 2022 RCT also supported the improved endothelial reactivity from CoQ10 supplementation in 20 healthy adults [73]. Apart from the antioxidant protections, a trial on oral supplementation during the periods of high-intensity exercises also showed benefits in the modulation of inflammatory signaling, the pro- and anti-inflammatory cytokines released, together with a potential pro-angiogenic effect on hematologic parameters such as hemoglobin, red blood cell number, vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF) [74].
On the contrary, a cross-over, double-blind, and placebo-controlled trial did not show significant changes in the aerobic capacity and lipid peroxidation markers in 19 trained adults, 11 young and 8 older, after six weeks of ubiquinone supplementation at 120 mg/day [75]. Despite the recovery of exercise-induced depleted plasma CoQ10 level, the athletes’ biomarkers of muscular damage and physical performance remained unchanged [16]. Several RCTs also failed to support the benefits to the anaerobic performance during high-intensity training from oral supplementation [76,77,78]. During the intensive Kendo training, CoQ10 supplementation did not ameliorate exercise-induced muscle damage in a study of a four-day training period but showed a protective effect in another study of a six-day training period [79,80]. The high-altitude trekkers did not obtain a protective effect for cardiac alterations after their 17-day trek to Everest Base Camp [81]. An 8-week supplementation in ten trained cyclists did not show measurable effects on their performance, VO2max, or lipid peroxidation [82]. Another study on endurance athletes also showed no significant changes in their cardiorespiratory fitness parameters and blood metabolic markers [83].
Nonetheless, 25 Finnish top-level cross-country skiers achieved significant improvement in all physical performance indices with supplementation [84]. Short-term CoQ10 supplementation in elite swimmers modulated their energy metabolism, enhanced antioxidant capacity, and prevented the elevation of lipid peroxidation and cardiac damage markers [85,86,87,88]. Another study on a six-day Kendo training period reported the downregulation of toll-like receptor 4 (TLR-4) in monocytes in the athletes who took the supplementation for 20 days [89].
Several RCTs on oral CoQ10 supplementation in healthy adults and athletes yielded inconsistent outcomes for their exercise performance, muscle damage prevention, antioxidant protection, and immunologic modulations. Up to now, only one systematic review of supplementation in healthy adults has been published, with no relevant meta-analysis. The outcome discrepancies might depend on contributing factors such as individual host metabolic status, type and intensity of exercises, timing and dosing of supplementation, or other interacting nutrients.

4.1.3. Single CoQ10 Supplementation in Elders

Human CoQ10 biosynthesis decreases with advancing age [17,34]. At the age of 80, the myocardial CoQ10 production is only half compared to levels in a 20-year-old person [8,17]. The elderly also extensively use many prescribed medications, including statin, bisphosphonates, and β-blockers, which interfere with endogenous CoQ10 biosynthesis [20,21,90,91,92,93]. In addition to their eating pattern alteration and presumably compromised metabolic status, the likelihood of low blood levels of CoQ10 in elders is not uncommon [5].
In addition to the Mediterranean diet, healthy elders with oral CoQ10 supplementation showed significant benefits in their redox-state parameters, postprandial metabolism of advanced glycation end products (AGEs), metabolomic profiles, and the modulation of gene expressions that involved anti-inflammatory, endoplasmic reticulum stress, DNA repair, and antioxidant functions [94,95,96,97,98,99].
Even though there was no available meta-analysis, we found no study not supporting the benefits of oral CoQ10 supplementation in elders as compared to the trials in healthy adults and athletes. These different outcomes could partly be due to the temporary nature of depleted CoQ10 levels in healthy adults and athletes after their physical exertions, while the depleted CoQ10 levels in elders are a result of their ages, illnesses, and metabolic statuses.

4.1.4. Single CoQ10 Supplementation in Metabolic and Immune-Related Disorders

The early two systematic reviews in 2003 and 2009 failed to conclude whether the oral CoQ10 supplementation had any effect on blood pressure [100,101]. Contrarily, the following four meta-analysis studies, in 2012, 2016, and two in 2018, of 5, 14, 17, and 21 RCTs, respectively, reported that CoQ10 supplementation improved endothelial function, reduced systolic blood pressure, fasting blood glucose, and serum triglycerides, and improved lipid profiles [102,103,104,105]. While the 2015 RCT suggested that daily supplementation could help decrease the pro-inflammatory cytokines [106], a 2011 RCT in 51 obese subjects did not find an association between the supplementation and lipid profile, oxidative and inflammatory markers, arterial stiffness, and fatigue indices [107].
Contrarily, another 2019 meta-analysis of 17 RCTs did not support the benefits of CoQ10 supplementation on the body weight and BMI of patients [108]. In dyslipidemic individuals, the 2016 and 2018 RCTs on CoQ10 supplementation showed benefits in the improvements of lipid and glycemic profiles, antioxidant capacity, endothelial reactivity, and blood pressure [109,110]. A 2000 RCT in 12 hypercholesterolemic young adults did not show a significant effect on endothelial dysfunction [111]. Conflictingly, another 2020 RCT in 51 dyslipidemic subjects had benefits of endothelial dysfunction amelioration from CoQ10 supplementation [112]. We did not find a meta-analysis on the supplementation impacts on dyslipidemic subjects.
In diabetes patients, the clinical impacts of CoQ10 supplementation were also inconsistent despite the significant association of low CoQ10 levels in these patients [113,114,115]. A 2015 meta-analysis of 7 RCTs concluded no benefit on glycemic and lipid profiles in diabetes subjects [19]. Nevertheless, three RCTs, one in 2017 and two in 2018, on overweight or obese diabetic patients showed reduced glycosylated hemoglobin levels, reduced insulin levels, and increased antioxidant enzyme activities [116,117,118]. A 2018 meta-analysis of 13 RCTs suggested the benefits of CoQ10 supplementation on glycemic and lipid profiles in type 2 diabetic patients [119]. The single CoQ10 supplementation, 400 mg, also improved the visual acuity, intraocular pressure, and oxidative stress biomarkers in a 2016 RCT of patients with diabetic retinopathy [120]. A cell line study also demonstrated the CoQ10 protective effects on retinal ganglion cells from intraocular-pressure-induced hypoxia and subsequent oxidative stress, which are part of glaucoma pathogenesis [121,122].
In patients with coronary artery disease, a 2018 meta-analysis of eight RCTs reported the effects of supplementation on lowering total cholesterol and increasing high-density lipoprotein-cholesterol levels, but no changes in low-density lipoprotein-cholesterol and lipoprotein(a) levels [123]. Another 2019 meta-analysis of 13 RCTs documented the increased antioxidant enzyme activities and decreased oxidative damage markers despite the nonsignificant changes in pro-inflammatory cytokines and CRP [124].
The benefits of oral CoQ10 supplementation were likely evident in advancing clinical stages such as congestive heart failure. A 1997 meta-analysis of 14 RCTs concluded the benefits of improved hemodynamic cardiac parameters such as stroke volume, cardiac output, ejection fraction, cardiac index, and end-diastolic volume index [125]. While a 2014 pooled analysis of seven RCTs concluded neither benefits nor harms of the supplementation in patients with heart failure [126], the 1993 and 2020 RCTs supported the supplementation’s benefit on improved endothelial function, reduced hospitalization, and reduced serious complications in patients with heart failure [127,128].
The CoQ10 supplementation in patients with chronic kidney disease could improve some of their metabolic profiles, such as creatinine, lipid parameters, and oxidative damage markers, as reported in a 2018 meta-analysis of seven RCTs [129]. In diabetic nephropathy, CoQ10 supplementation modulated gene expression of peroxisome proliferator-activated receptor-γ, interleukin-1, and TNF-α, together with the favorable impacts on glucose metabolism [130,131]. The supplementation in diabetic hemodialysis patients also provided benefits to insulin metabolism, with increased antioxidant capacity and decreased CRP, although there were no changes in exercise performance, diastolic heart function, fasting glucose, glycosylated hemoglobin, lipid profile, and oxidative damage markers [132,133,134,135].
For nonalcoholic fatty liver disease patients, CoQ10 supplementation also provided benefits in several anthropometric and biochemical parameters, including waist circumference, liver aminotransferases, CRP, TNF-α, adiponectin, leptin, vaspin, chemerin, and pentraxin 3 [136,137].
In chronic inflammatory conditions, the 2019 meta-analysis of nine RCTs supported the significant impacts of CoQ10 supplementation on the modulation of pro-inflammatory signals, including TNF-α and IL-6 [50]. Several RCTs on other immune-related conditions, including fibromyalgia, rheumatoid arthritis, and multiple sclerosis, supported the immunomodulatory effects of supplementation [138,139,140,141,142]. For instance, a 2015 RCT of 500 mg CoQ10 supplementation documented the amelioration of pro-inflammatory biomarkers such as TNF-α, IL-6, and MMP-9 in patients with relapsing-remitting multiple sclerosis [143].
Despite the inconsistent results on single CoQ10 supplementation clinical trials in various metabolic disorders, the following meta-analysis tended to show more positive metabolic benefits in patients with advanced clinical stages, such as cardiovascular diseases, heart failure, or kidney failure, than the ones in early clinical phases, such as hypertension or dyslipidemia.

4.1.5. Single CoQ10 Supplementation in Those Who Take Prescribed Medications

CoQ10 biosynthesis requires an enzyme in the mevalonate pathway, 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase, which is the common enzyme for cholesterol biosynthesis [144,145]. Statin is a commonly prescribed lipid-lowering medication that inhibits HMG-CoA reductase. Statin is used in combination with other prescribed medications to treat various conditions that particularly co-exist in aging adults, therefore contributing to the decreased plasma CoQ10 levels [20,21]. Nitrogen-bisphosphonates (N-BPs) is another prescribed medication in elders, commonly used for the treatment of age-related osteoporosis [92]. N-BPs inhibit farnesyl pyrophosphate synthase, another enzyme in the CoQ10 biosynthesis, therefore affecting the circulating CoQ10 level as well [146]. Moreover, women with osteoporosis who were treated with N-BPs showed a concurrent reduction of the γ-tocopherol level, a crucial nutrient in integrated antioxidant defenses [92]. These combined effects of prescribed medications could potentiate the adverse consequences of depleted CoQ10 levels.
Despite the established correlation of statin-induced myopathy, a 2015 meta-analysis of six RCTs did not support the post-interventional benefits of CoQ10 supplementation [147]. Contrarily, another 2018 meta-analysis of 12 RCTs supported the amelioration of statin-associated myopathy [148]. Derosa et al. also reported the significant mitigation of statin-related side effects with liquid CoQ10 supplementation for three months in the 2019 RCT of 60 Caucasian patients [149]. On the contrary, a recent 2022 retrospective multicenter study did not find any benefits of the supplementation to statin-associated muscle symptoms [150].
Despite the likelihood of low CoQ10 levels in subjects who take medications, the benefits from the supplementation studies were also inconsistent, even though the available meta-analysis seemed to support the intervention. Other contributing factors, such as the concurrent depletion of multiple interacting nutrients within the integrated antioxidant network, might hinder the outcome of single CoQ10 supplementations in these subjects. Unfortunately, these potential confounders were not controlled in the participants of previous clinical trials.

4.1.6. Single CoQ10 Supplementation in Neurological Disorders

Neurogenerative disorders such as Parkinson’s disease (PD) and Alzheimer’s disease (AD) share some pathophysiologies, including mitochondrial dysfunction and oxidative stress [151]. Increased oxidative stress was shown as the significant elevation of the serum oxidized CoQ10 levels in patients with amyotrophic lateral sclerosis, compared to their age-matched healthy controls [152]. Nevertheless, many RCTs on these neurodegenerative subjects showed conflicting results similar to other single CoQ10 supplementation trials. Despite the assurance of its safety and tolerance in these conditions, a 2017 meta-analysis failed to suggest the intervention’s benefits [153].
In AD patients, early 1994 and 1998 RCTs demonstrated the clinical benefits of single CoQ10 supplementations for memory, attention, orientation, and disease progression [154,155]. However, the 2003 RCT did not find significant differences between the study groups [156]. A dose of 360 mg CoQ10 for 4 weeks in patients with PD provided moderate benefits on scored PD symptoms and visual function [157]. In neuromuscular disorders such as Huntington’s disease (HD), a 2017 large multicenter RCT on high doses of CoQ10, at 2400 mg a day, did not significantly slow the progressive functional declination in these patients compared to their controls [158,159].
For neurological conditions, the effectiveness of CoQ10 supplementation was rather promising in small-scale clinical studies. However, larger-scale RCTs failed to provide consistent effects. The advanced nature of these neurological conditions, with established neuronal losses at the time of diagnosis, could partly contribute to these disparities in the results of a single CoQ10 intervention. Unlike the previously mentioned trends in metabolic diseases, a nutrient intervention is less likely to be effective in advanced neurological conditions.

4.1.7. Single CoQ10 Supplementation in Cancers

Low circulating CoQ10 levels are associated with increased breast cancer risk [160]. In vivo CoQ10 supplementation appeared to enhance the DNA repair enzyme activities and protect the DNA from oxidative damage [22]. A CoQ10 intervention, at 300 mg/day for 12 weeks, significantly improved the antioxidant capacity and reduced oxidative damage and inflammatory levels in post-surgical patients with hepatocellular carcinoma [161]. However, a 24-week-supplementation RCT did not show improvements in fatigue and other quality of life parameters in women with breast cancer [162]. A 2004 systematic review of six studies, could not conclude whether CoQ10 supplementation could improve the tolerability of cancer treatments [163]. The benefits of single CoQ10 supplementation in cancers are either preventive or protective rather than curative.

4.2. Combined CoQ10 Supplementation with Other Nutrients

Human metabolism fundamentally requires support from an integrated nutrient network. Abided by this fact, CoQ10 contributes its essential role by coordinating with other macro- and micronutrients in the bioenergetic and antioxidant circuits [5]. Genetic predisposing conditions are the only exception to this integrated function, where the prone individuals are subjected to a specific nutrient inadequacy, which may require high-dose single nutrient intervention to alleviate the situation, as previously mentioned in primary CoQ10 deficiencies. Patients with chronic illnesses largely endure concurrent multiple nutrient insufficiencies [164]. Hence, it is understandable why single CoQ10 supplementation yielded inconsistent outcomes, particularly in hosts with severely compromised nutrient reserves. For this reason, combining CoQ10 supplementations with other nutrients could potentially augment the clinical benefits in these situations [6,165,166,167].
Accordingly, studies in rat models and cell lineages reaffirmed that the combination of CoQ10, multivitamins, and minerals protected organ damage through the reduction of oxidative damage and inflammation [168,169,170,171]. Several human trials also reported oral combined supplementation of CoQ10 and other nutrients with beneficial responses [166,172,173,174]. Among the previous trials, the familiar combined supplementation was CoQ10 and selenium, an important cofactor of glutathione peroxidase—a key antioxidant enzyme. However, numerous studies use different nutrient combinations, which generally comprised those that supported mitochondrial bioenergetic and antioxidant networks, including vitamin Bs, vitamin C, vitamin E, selenium, zinc, lipoic acid, L-carnitine, and taurine [175].

4.2.1. The Combined Supplementation of CoQ10 in Healthy Adults and Athletes

In a 2016 RCT of healthy volunteers, the 6-month combined supplementation of CoQ10, multivitamins, and minerals reduced nitrosative stress and improved mitochondrial bioenergetics [176]. A total of 83 infertile males taking a combined supplementation of CoQ10, l-carnitine/acetyl-l-carnitine, l-arginine, glutathione, zinc, vitamin B9, vitamin B12, and selenium improved their sperm quality and increased the pregnancy rate in a 2020 RCT [177]. Two meta-analyses, in 2018 and 2019, of 15 and 18 RCTs, respectively, suggested the favorable effects on sperm quality parameters of infertile males from CoQ10 and other nutrients such as selenium, zinc, l-carnitine, and omega-3 fatty acids [178,179].
However, triathletes with the combined supplementation of CoQ10, vitamin C, and alpha-tocopherol did not gain benefits in their exercise performance [180]. In a 2005 RCT, the combined supplementation of CoQ10, alpha-lipoic acid, N-acetyl cysteine, vitamin C, alpha-tocopherol, manganese, and selenium did not protect against exercise-induced DNA damage [181]. Prior supplementation of combined CoQ10 and alpha-tocopherol also did not attenuate either lipoprotein oxidation or muscle damage during exhaustive exercise in marathon runners [182]. Contrarily, a mixture of CoQ10, multivitamins, and minerals helped lower the oxidative damage markers following a 60-min soccer match after 3-month supplementation in pre-professional footballers [183]. The cocktail of CoQ10, vitamin C, and alpha-tocopherol also raised the LDL antioxidant potential in endurance athletes [184].
The combined supplementation likely improved the favorable outcomes in healthy adults, while the outcomes from clinical trials in athletes were still inconsistent. The differences in types and intensities of exercise could partly account for these discrepancies. However, a systematic review or meta-analysis on athletic intervention is not yet available.

4.2.2. The Combined Supplementation of CoQ10 in Elders

The 6-month oral supplementation of combined CoQ10, multivitamins, and selenium significantly elevated the blood CoQ10 level in healthy elderly women [185]. A 2015 RCT on active 48-month supplementation of CoQ10 and selenium in Swedish elders showed the reduction of CRP and P-selectin levels, together with the increased levels of insulin-like growth factor 1 and insulin-like growth factor binding protein 1 [165,186]. The metabolomic profiles of these elders suggested changes in the pentose phosphate, the mevalonate, the beta-oxidation, and the xanthine oxidase pathways, together with the changes in the urea cycle and the increased neurotransmitter precursors after 18 months of intervention [187]. Elders in the supplementation group also had an increased number of days out of the hospital and a slowed deterioration of health-related quality of life scores [188]. The 12-year follow-up of these 443 elders, who continued the combined supplementation for four years, still had significantly reduced cardiovascular mortality [174]. Apart from the combination with selenium, the 12-week mixed supplementation of CoQ10, essential amino acids, creatine, and vitamin D also showed positive effects on the muscle mass, strength, power, and visceral adipose tissue of 38 healthy elders in a 2019 RCT [189]. While CoQ10 decreased by 40% in elders, the combined supplementation of CoQ10, acetyl-L-carnitine, and omega-3 fatty acids in 106 patients with early age-related macular degeneration improved visual functions and stabilized fundus alterations in an RCT [190,191].
Although without available meta-analysis, the results from these RCTs on elders provided consistent trends of benefits from combined supplementation of CoQ10.

4.2.3. The Combined Supplementation of CoQ10 in Metabolic and Immune-Related Disorders

A 2016 meta-analysis of 14 RCTs of the formulated supplementation of CoQ10, red yeast rice, berberine, policosanol, astaxanthin, and folic acid suggested its benefits on lipid and glucose profiles [192]. Two RCTs, in 2017 and 2019, in patients with dyslipidemia and pre-hypertension. respectively, also documented the positive impacts on lipid and glucose profiles, CRP, and liver transaminase with the combination of CoQ10, red yeast rice, and other nutrients [193,194]. For patients with metabolic syndrome, the combination of CoQ10 and red yeast rice provided benefits to their blood pressure, lipid, and glycemic biomarkers in another 2018 RCT [195]. A recent 2021 meta-analysis of 12 RCTs also supported the beneficial impacts on serum lipids, glucose, and CRP with the combination of CoQ10, red yeast extract, policosanols, berberine, folic acid, and astaxanthin [196].
In patients with nonproliferative diabetic retinopathy, their plasma CoQ10 levels were decreased as compared with the healthy controls [18]. The supplementation of CoQ10, pycnogenol, and vitamin E led to decreased circulating free oxygen radical levels, although there was no significant change in central macular thickness at six months, compared to the controls [197]. The local application of visudrop, the combination of CoQ10 and vitamin E, during cataract surgery significantly reduced postoperative corneal edema and pain, with enhanced vision outcomes [198]. The application of an ophthalmic solution containing CoQ10 and vitamin E in patients with open-angle glaucoma showed benefits on the inner retinal function, with subsequent enhanced visual cortical responses [199].
For patients with cardiovascular disease, a 2006 narrative review suggested CoQ10 as one of the first-line conditionally essential nutrients, along with l-arginine, l-carnitine, and propionyl-l-carnitine, while the supplementation of these nutrients could provide favorable clinical impacts [200]. A pilot study on combined supplementation of CoQ10, magnesium, potassium, vitamin B12, folic acid, and niacin reported improved left ventricular diastolic function parameters and fasting insulin levels in patients with cardiac arrhythmia [201]. The elders with chronic heart failure improved their left ventricular functions and quality-of-life parameters with the combined supplementation of CoQ10, multivitamins, and minerals [202]. Two RCTs, in 2007 and 2011, in chronic heart failure patients, also supported the favorable effects on their physical performance parameters and inflammatory signal modulation, from the combined supplementations of either CoQ10 and creatine or CoQ10 and l-carnitine [203,204].
The supplementation of CoQ10, together with multivitamins and minerals modulated the biomarkers of immunologic and autonomic dysfunctions in patients with end-stage renal disease [205]. Two months with the combined CoQ10 and creatine supplementation also helped to improve functional performance, body composition, and dyspnea symptoms in patients with the chronic obstructive pulmonary disease [206]. On the contrary, the combination of CoQ10 and omega-3 fatty acids did not provide a significant change in plasma myeloperoxidase level, a mediator of chronic inflammation, in patients with chronic kidney disease, in a 2018 RCT [207].
For immune-related disorders, psoriatic patients showed increased activities of antioxidant defenses in the circulating granulocytes and the affected epidermis with the combined supplementation of CoQ10, vitamin E, and selenium [208]. Patients with chronic fatigue syndrome improved their bioenergetic biomarkers and age-predicted maximum heart rate during a cycle ergometer test with CoQ10 and NADH supplementation [209,210]. A total of 130 adults with migraine also significantly reduced the pain intensity with the supplementation with CoQ10, riboflavin, and magnesium in an RCT from Gaul et al. [211]. The benefits of migraine prophylaxis were also supported either with CoQ10 and l-carnitine or CoQ10 and curcumin interventions in 2019 and 2021 RCTs [212,213].
Even though a recent meta-analysis was still not available, the trends of previous studies were encouraging for clinical benefits in various metabolic and immune-related disorders with combined CoQ10 supplementation.

4.2.4. The Combined Supplementation of CoQ10 in Those Who Take Prescribed Medications

The combined CoQ10 and selenium supplementation substantially elevated the relevant serum levels in patients taking statins but did not significantly mitigate their myopathy symptoms in two 2013 RCTs [214,215]. However, three months on CoQ10 and carnitine supplementation showed a significant reduction of serum lipoprotein(a) in hemodialysis patients with statin therapy [216]. With the context of a limited study number, the conclusion for the impacts of combined supplementation on these patients warrants future trials.

4.2.5. The Combined Supplementation of CoQ10 in Neurological Disorders

There were also few studies on mixed CoQ10 intervention in various neurological conditions. According to the Alzheimer’s Disease Cooperative Study, the combined CoQ10 and vitamin E, vitamin C, and α-lipoic acid did not influence the levels of amyloid or tau proteins in cerebrospinal fluid. Interestingly, the intervention group had a more rapid cognitive declination than their controls, which raised the safety concerns of this mixed supplementation [217]. Thus far, the impacts of combined CoQ10 supplementation were still inconclusive in these complex clinical conditions.

4.2.6. The Combined Supplementation of CoQ10 in Cancers

Patients with end-stage cancers significantly increased their life expectancy, from an average of 12 to 17 months, with a combined supplementation of CoQ10 and antioxidant mixture [218]. In breast cancer patients under tamoxifen treatment, the daily supplementation of CoQ10, riboflavin, and niacin decreased their pro-inflammatory cytokine levels, increased the DNA repair enzyme levels, and suppressed the DNA methylation pattern, which might lead to tumor burden reduction [219,220]. In a multicenter RCT, 57 women with breast cancer women, who took combined supplementation of CoQ10 and L-carnitine, reported relieved cancer-associated fatigue symptoms [162,221]. However, several RCTs in high-risk people or patients with prostate cancers did not support the benefit of combined supplementation of CoQ10, vitamin E, selenium, and vitamin C, along with several phytochemicals [222,223].

5. Discussion

The inconsistent results of CoQ10 interventions implied the presence of unaccounted factors that contributed to clinical outcomes. After reviewing the participants’ status in previous CoQ10 clinical trials, we herein proposed two potentially confounding aspects, i.e., differences in host metabolic status and the need for CoQ10 interacting nutrients.
Human metabolism fundamentally relies on host macro- and micronutrient reserves. Depleted host nutrient reserve leads to metabolic triage of nutrients toward the preservation of short-term metabolic survival, usually at the cost of compromised long-term health [224,225]. The protein deformations, with altered enzyme binding constants for various coenzymes, underly these nutrient triage processes [226]. Compromised host nutrients induce metabolic triage and accelerate the pathophysiologies of degenerative and metabolic diseases [227]. Therefore, nutrient interventions could hinder mitochondrial decay and delay age-associated illnesses [225].
Even the so-called healthy subjects were still prone to conditional micronutrient inadequacies following intense physical activities, despite their good metabolic statuses and no established clinical diagnosis at baseline. The combined nutrient interventions hold better chances to address the conditional nutritional insufficiencies than a single nutrient. To support this notion, previous studies showed the favorable trends of combined CoQ10 intervention in healthy adults and athletes performing exercise sessions, as compared to single supplementation.
Elders and patients with diagnosed metabolic and immune-related disorders likely had compromised metabolic status, along with multiple nutrient insufficiency. The depleted nutrient reserves increased with the advancement of these chronic situations. Hosts with specific nutrient depletion, such as primary CoQ10 deficiencies, benefited from single CoQ10 supplementation, even though the outcomes were mostly palliative, not curative. The single intervention was also beneficial in hosts with early stages of declined metabolic status, such as the elderly. The benefits decreased with the advancement of metabolic conditions, as seen in patients with diabetes, cardiovascular diseases, or kidney failure. Despite the improvement of some surrogate biomarkers such as proinflammatory cytokines, antioxidative capacities, and lipid or glycemic profiles, the positive trends in clinical outcomes were less promising with single supplementation. Contrarily, combined CoQ10 interventions provided more encouraging results in hosts with impaired metabolic status due to the readily available interacting nutrients in the formulations.
However, both CoQ10 interventions would be less beneficial in far-advanced conditions with established damage such as neurodegenerative conditions or cancers. The results of both single and combined supplementation, at best, affected some surrogate biomarkers but not the overall clinical outcomes. Therefore, nutrient interventions are preventive or protective rather than curative measures.

6. Conclusions and Future Perspectives

CoQ10 is a compound with crucial roles in mitochondrial bioenergetics, membrane antioxidant protection, and many cellular signaling regulations. However, no single nutrient could magically drive whole physiological processes. Single CoQ10 supplementation will be beneficial only for hosts that specifically require it, such as hereditary CoQ10 deficiencies. The single intervention will be less promising when the host metabolic status worsens with the likelihood of multiple nutrient insufficiencies. On the contrary, the mixed CoQ10 supplementation with other interacting nutrients will create more promising impacts in hosts with compromised nutrient reserves. However, the results of either single or combined intervention will be less promising in far-advanced conditions with established damage.
With the limited amount of high-level evidence, such as provided by systematic reviews and meta-analyses, we could only conclude that the considerations of whether to take supplementation varied by the individuals’ metabolic status and their nutrient reserves, which span across the continuum of metabolic triage processes that lead to chronic health issues. Future studies are warranted, particularly for the RCT with the design to control the host metabolic and nutrient status of participants and the meta-analysis of upcoming CoQ10 studies on each subject’s metabolic status.

Author Contributions

Conceptualization, T.T., G.B., A.G.,Y.S., M.P., S.C. and T.H.; writing—original draft preparation, T.T., G.B., A.G., Y.S., S.C. and T.H.; writing—review and editing, G.B. and M.P.; revision T.T., G.B. and M.P.; supervision, G.B. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Crane, F.L.; Hatefi, Y.; Lester, R.L.; Widmer, C. Isolation of a quinone from beef heart mitochondria. Biochim. Biophys. Acta 1957, 25, 220–221. [Google Scholar] [CrossRef]
  2. Garrido-Maraver, J.; Cordero, M.D.; Oropesa-Avila, M.; Fernandez Vega, A.; de la Mata, M.; Delgado Pavon, A.; de Miguel, M.; Perez Calero, C.; Villanueva Paz, M.; Cotan, D.; et al. Coenzyme q10 therapy. Mol Syndr. 2014, 5, 187–197. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Nomenclature of Quinones with Isoprenoid Side-Chains. Eur. J. Biochem. 1975, 53, 15–18. [CrossRef]
  4. Saini, R. Coenzyme Q10: The essential nutrient. J. Pharm. Bioallied Sci. 2011, 3, 466–467. [Google Scholar] [CrossRef] [PubMed]
  5. Acosta, M.J.; Vazquez Fonseca, L.; Desbats, M.A.; Cerqua, C.; Zordan, R.; Trevisson, E.; Salviati, L. Coenzyme Q biosynthesis in health and disease. Biochim. Biophys. Acta 2016, 1857, 1079–1085. [Google Scholar] [CrossRef]
  6. Clement, A.M. The Antioxidant Defense Network: Synergistic Combinations to Prevent Oxidative Damage; Brigham Young University: Provo, UT, USA, 2008. [Google Scholar]
  7. Trevisson, E.; DiMauro, S.; Navas, P.; Salviati, L. Coenzyme Q deficiency in muscle. Curr. Opin. Neurol. 2011, 24, 449–456. [Google Scholar] [CrossRef]
  8. Quinzii, C.M.; Tadesse, S.; Naini, A.; Hirano, M. Effects of inhibiting CoQ10 biosynthesis with 4-nitrobenzoate in human fibroblasts. PLoS ONE 2012, 7, e30606. [Google Scholar] [CrossRef] [Green Version]
  9. Laredj, L.N.; Licitra, F.; Puccio, H.M. The molecular genetics of coenzyme Q biosynthesis in health and disease. Biochimie 2014, 100, 78–87. [Google Scholar] [CrossRef]
  10. Rodick, T.C.; Seibels, D.R.; Babu, J.R.; Huggins, K.W.; Ren, G.; Mathews, S.T. Potential role of coenzyme Q 10 in health and disease conditions. Nutr. Diet. Suppl. 2018, 10, 1–11. [Google Scholar] [CrossRef] [Green Version]
  11. Palamakula, A.; Soliman, M.; Khan, M.M. Regional permeability of coenzyme Q10 in isolated rat gastrointestinal tracts. Pharmazie 2005, 60, 212–214. [Google Scholar]
  12. Bhagavan, H.N.; Chopra, R.K. Coenzyme Q10: Absorption, tissue uptake, metabolism and pharmacokinetics. Free Radic. Res. 2006, 40, 445–453. [Google Scholar] [CrossRef] [PubMed]
  13. Turunen, M.; Olsson, J.; Dallner, G. Metabolism and function of coenzyme Q. Biochim. Biophys. Acta 2004, 1660, 171–199. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Cirilli, I.; Damiani, E.; Dludla, P.V.; Hargreaves, I.; Marcheggiani, F.; Millichap, L.E.; Orlando, P.; Silvestri, S.; Tiano, L. Role of Coenzyme Q10 in Health and Disease: An Update on the Last 10 Years (2010–2020). Antioxidants 2021, 10, 1325. [Google Scholar] [CrossRef] [PubMed]
  15. Overvad, K.; Diamant, B.; Holm, L.; Holmer, G.; Mortensen, S.A.; Stender, S. Coenzyme Q10 in health and disease. Eur. J. Clin. Nutr. 1999, 53, 764–770. [Google Scholar] [CrossRef] [Green Version]
  16. Orlando, P.; Silvestri, S.; Galeazzi, R.; Antonicelli, R.; Marcheggiani, F.; Cirilli, I.; Bacchetti, T.; Tiano, L. Effect of ubiquinol supplementation on biochemical and oxidative stress indexes after intense exercise in young athletes. Redox Rep. Commun. Free Radic. Res. 2018, 23, 136–145. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  17. Kalen, A.; Appelkvist, E.L.; Dallner, G. Age-related changes in the lipid compositions of rat and human tissues. Lipids 1989, 24, 579–584. [Google Scholar] [CrossRef]
  18. Ates, O.; Bilen, H.; Keles, S.; Alp, H.H.; Keleş, M.S.; Yıldırım, K.; Ondaş, O.; Pınar, L.C.; Civelekler, M.; Baykal, O. Plasma coenzyme Q10 levels in type 2 diabetic patients with retinopathy. Int. J. Ophthalmol. 2013, 6, 675–679. [Google Scholar] [CrossRef]
  19. Suksomboon, N.; Poolsup, N.; Juanak, N. Effects of coenzyme Q10 supplementation on metabolic profile in diabetes: A systematic review and meta-analysis. J. Clin. Pharm. Ther. 2015, 40, 413–418. [Google Scholar] [CrossRef]
  20. Nawarskas, J.J. HMG-CoA reductase inhibitors and coenzyme Q10. Cardiol. Rev. 2005, 13, 76–79. [Google Scholar] [CrossRef]
  21. Littarru, G.P.; Langsjoen, P. Coenzyme Q10 and statins: Biochemical and clinical implications. Mitochondrion 2007, 7, S168–S174. [Google Scholar] [CrossRef]
  22. Tomasetti, M.; Alleva, R.; Borghi, B.; Collins, A.R. In vivo supplementation with coenzyme Q10 enhances the recovery of human lymphocytes from oxidative DNA damage. FASEB J. 2001, 15, 1425–1427. [Google Scholar] [CrossRef]
  23. Haddaway, N.R.; Page, M.J.; Pritchard, C.C.; McGuinness, L.A. PRISMA2020: An R package and Shiny app for producing PRISMA 2020-compliant flow diagrams, with interactivity for optimised digital transparency and Open Synthesis. Campbell Syst. Rev. 2022, 18, e1230. [Google Scholar] [CrossRef]
  24. Page, M.J.; McKenzie, J.E.; Bossuyt, P.M.; Boutron, I.; Hoffmann, T.C.; Mulrow, C.D.; Shamseer, L.; Tetzlaff, J.M.; Akl, E.A.; Brennan, S.E.; et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. Syst. Rev. 2021, 10, 89. [Google Scholar] [CrossRef] [PubMed]
  25. García-García, F.J.; Monistrol-Mula, A.; Cardellach, F.; Garrabou, G. Nutrition, Bioenergetics, and Metabolic Syndrome. Nutrients 2020, 12, 2785. [Google Scholar] [CrossRef] [PubMed]
  26. Navas, P.; Villalba, J.M.; de Cabo, R. The importance of plasma membrane coenzyme Q in aging and stress responses. Mitochondrion 2007, 7, S34–S40. [Google Scholar] [CrossRef]
  27. Zhang, Y.; Liu, J.; Chen, X.-Q.; Oliver Chen, C.Y. Ubiquinol is superior to ubiquinone to enhance Coenzyme Q10 status in older men. Food Funct. 2018, 9, 5653–5659. [Google Scholar] [CrossRef]
  28. Lopez-Lluch, G.; Del Pozo-Cruz, J.; Sanchez-Cuesta, A.; Cortes-Rodriguez, A.B.; Navas, P. Bioavailability of coenzyme Q10 supplements depends on carrier lipids and solubilization. Nutrition 2019, 57, 133–140. [Google Scholar] [CrossRef]
  29. Delkhosh, A.; Shoorei, H.; Niazi, V.; Delashoub, M.; Gharamaleki, M.N.; Ahani-Nahayati, M.; Dehaghi, Y.K.; Raza, S.; Taheri, M.H.; Mohaqiq, M.; et al. Coenzyme Q10 ameliorates inflammation, oxidative stress, and testicular histopathology in rats exposed to heat stress. Hum. Exp. Toxicol. 2021, 40, 3–15. [Google Scholar] [CrossRef]
  30. Akbari, A.; Mobini, G.R.; Agah, S.; Morvaridzadeh, M.; Omidi, A.; Potter, E.; Fazelian, S.; Ardehali, S.H.; Daneshzad, E.; Dehghani, S. Coenzyme Q10 supplementation and oxidative stress parameters: A systematic review and meta-analysis of clinical trials. Eur. J. Clin. Pharm. 2020, 76, 1483–1499. [Google Scholar] [CrossRef]
  31. Thomas, S.R.; Stocker, R. Mechanisms of antioxidant action of ubiquinol-10 for low-density lipoprotein. In COENZYME Q; Kagan, V.E., Quinn, P.J., Eds.; CRC Press: Boca Raton, FL, USA, 2001; p. 131. [Google Scholar]
  32. Uekaji, Y.; Nakata, D.; Shiga, H.; Jo, A.; Tachi, I.; Fukumi, H.; Urano, A.; Terao, K. Formation of CoQ10 reduced form by mixing CoQ10 oxidized form γCD complex and vitamin C in powder. J. Incl. Phenom. Macrocycl. Chem. 2011, 70, 447–451. [Google Scholar] [CrossRef]
  33. Zaki, N.M. Strategies for oral delivery and mitochondrial targeting of CoQ10. Drug Deliv. 2016, 23, 1868–1881. [Google Scholar] [CrossRef] [PubMed]
  34. Ernster, L.; Dallner, G. Biochemical, physiological and medical aspects of ubiquinone function. Biochim. Et Biophys. Acta 1995, 1271, 195–204. [Google Scholar] [CrossRef] [Green Version]
  35. Pacanowski, M.A.; Frye, R.F.; Enogieru, O.; Schofield, R.S.; Zineh, I. Plasma Coenzyme Q10 Predicts Lipid-lowering Response to High-Dose Atorvastatin. J. Clin. Lipidol. 2008, 2, 289–297. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  36. Kagan, V.E.; Quinn, P.J. Coenzyme Q: Molecular Mechanisms in Health and Disease; CRC Press: Boca Raton, FL, USA, 2000. [Google Scholar]
  37. Genova, M.L.; Lenaz, G. Functional role of mitochondrial respiratory supercomplexes. Biochim. Biophys. Acta 2014, 1837, 427–443. [Google Scholar] [CrossRef] [Green Version]
  38. Guo, R.; Zong, S.; Wu, M.; Gu, J.; Yang, M. Architecture of Human Mitochondrial Respiratory Megacomplex I2III2IV2. Cell 2017, 170, 1247–1257.e12. [Google Scholar] [CrossRef] [Green Version]
  39. Milenkovic, D.; Blaza, J.N.; Larsson, N.G.; Hirst, J. The Enigma of the Respiratory Chain Supercomplex. Cell Metab. 2017, 25, 765–776. [Google Scholar] [CrossRef] [Green Version]
  40. Hernandez-Camacho, J.D.; Bernier, M.; Lopez-Lluch, G.; Navas, P. Coenzyme Q10 Supplementation in Aging and Disease. Front. Physiol. 2018, 9, 44. [Google Scholar] [CrossRef] [Green Version]
  41. Choo, H.J.; Kholmukhamedov, A.; Zhou, C.; Jobe, S. Inner Mitochondrial Membrane Disruption Links Apoptotic and Agonist-Initiated Phosphatidylserine Externalization in Platelets. Arterioscler. Thromb. Vasc. Biol. 2017, 37, 1503–1512. [Google Scholar] [CrossRef] [Green Version]
  42. Schenkel, L.C.; Bakovic, M. Formation and regulation of mitochondrial membranes. Int. J. Cell Biol. 2014, 2014, 709828. [Google Scholar] [CrossRef] [Green Version]
  43. Crane, F.L. Biochemical functions of coenzyme Q10. J. Am. Coll. Nutr. 2001, 20, 591–598. [Google Scholar] [CrossRef]
  44. Alcazar-Fabra, M.; Navas, P.; Brea-Calvo, G. Coenzyme Q biosynthesis and its role in the respiratory chain structure. Biochim. Biophys. Acta 2016, 1857, 1073–1078. [Google Scholar] [CrossRef] [PubMed]
  45. Schmelzer, C.; Lindner, I.; Rimbach, G.; Niklowitz, P.; Menke, T.; Doring, F. Functions of coenzyme Q10 in inflammation and gene expression. BioFactors 2008, 32, 179–183. [Google Scholar] [CrossRef] [PubMed]
  46. Linnane, A.W.; Kopsidas, G.; Zhang, C.; Yarovaya, N.; Kovalenko, S.; Papakostopoulos, P.; Eastwood, H.; Graves, S.; Richardson, M. Cellular redox activity of coenzyme Q10: Effect of CoQ10 supplementation on human skeletal muscle. Free Radic. Res. 2002, 36, 445–453. [Google Scholar] [CrossRef] [PubMed]
  47. Zhai, J.; Bo, Y.; Lu, Y.; Liu, C.; Zhang, L. Effects of Coenzyme Q10 on Markers of Inflammation: A Systematic Review and Meta-Analysis. PLoS ONE 2017, 12, e0170172. [Google Scholar] [CrossRef] [Green Version]
  48. Fan, L.; Feng, Y.; Chen, G.C.; Qin, L.Q.; Fu, C.L.; Chen, L.H. Effects of coenzyme Q10 supplementation on inflammatory markers: A systematic review and meta-analysis of randomized controlled trials. Pharmacol. Res. Off. J. Ital. Pharmacol. Soc. 2017, 119, 128–136. [Google Scholar] [CrossRef]
  49. Mazidi, M.; Kengne, A.P.; Banach, M. Effects of coenzyme Q10 supplementation on plasma C-reactive protein concentrations: A systematic review and meta-analysis of randomized controlled trials. Pharmacol. Res. Off. J. Ital. Pharmacol. Soc. 2018, 128, 130–136. [Google Scholar] [CrossRef]
  50. Farsi, F.; Heshmati, J.; Keshtkar, A.; Irandoost, P.; Alamdari, N.M.; Akbari, A.; Janani, L.; Morshedzadeh, N.; Vafa, M. Can coenzyme Q10 supplementation effectively reduce human tumor necrosis factor-α and interleukin-6 levels in chronic inflammatory diseases? A systematic review and meta-analysis of randomized controlled trials. Pharmacol. Res. Off. J. Ital. Pharmacol. Soc. 2019, 148, 104290. [Google Scholar] [CrossRef]
  51. McMurray, J.J.; Dunselman, P.; Wedel, H.; Cleland, J.G.; Lindberg, M.; Hjalmarson, A.; Kjekshus, J.; Waagstein, F.; Apetrei, E.; Barrios, V.; et al. Coenzyme Q10, rosuvastatin, and clinical outcomes in heart failure: A pre-specified substudy of CORONA (controlled rosuvastatin multinational study in heart failure). J. Am. Coll. Cardiol. 2010, 56, 1196–1204. [Google Scholar] [CrossRef] [Green Version]
  52. Lim, S.C.; Tan, H.H.; Goh, S.K.; Subramaniam, T.; Sum, C.F.; Tan, I.K.; Lee, B.L.; Ong, C.N. Oxidative burden in prediabetic and diabetic individuals: Evidence from plasma coenzyme Q10. Diabet. Med. 2006, 23, 1344–1349. [Google Scholar] [CrossRef]
  53. McDonnell, M.G.; Archbold, G.P.R. Plasma ubiquinol/cholesterol ratios in patients with hyperlipidaemia, those with diabetes mellitus and in patients requiring dialysis. Clin. Chim. Acta 1996, 253, 117–126. [Google Scholar] [CrossRef]
  54. Singh, R.B.; Niaz, M.A.; Kumar, A.; Sindberg, C.D.; Moesgaard, S.; Littarru, G.P. Effect on absorption and oxidative stress of different oral Coenzyme Q10 dosages and intake strategy in healthy men. BioFactors 2005, 25, 219–224. [Google Scholar] [CrossRef] [PubMed]
  55. Mohr, D.; Bowry, V.W.; Stocker, R. Dietary supplementation with coenzyme Q10 results in increased levels of ubiquinol-10 within circulating lipoproteins and increased resistance of human low-density lipoprotein to the initiation of lipid peroxidation. Biochim. Et Biophys. Acta (BBA)—Lipids Lipid Metab. 1992, 1126, 247–254. [Google Scholar] [CrossRef]
  56. Svensson, M.; Malm, C.; Tonkonogi, M.; Ekblom, B.; Sjodin, B.; Sahlin, K. Effect of Q10 supplementation on tissue Q10 levels and adenine nucleotide catabolism during high-intensity exercise. Int. J. Sport Nutr. 1999, 9, 166–180. [Google Scholar] [CrossRef] [PubMed]
  57. Bhagavan, H.N.; Chopra, R.K.; Craft, N.E.; Chitchumroonchokchai, C.; Failla, M.L. Assessment of coenzyme Q10 absorption using an in vitro digestion-Caco-2 cell model. Int. J. Pharm. 2007, 333, 112–117. [Google Scholar] [CrossRef]
  58. Shults, C.W.; Flint Beal, M.; Song, D.; Fontaine, D. Pilot trial of high dosages of coenzyme Q10 in patients with Parkinson’s disease. Exp. Neurol. 2004, 188, 491–494. [Google Scholar] [CrossRef] [PubMed]
  59. Ferrante, K.L.; Shefner, J.; Zhang, H.; Betensky, R.; O’Brien, M.; Yu, H.; Fantasia, M.; Taft, J.; Beal, M.F.; Traynor, B.; et al. Tolerance of high-dose (3,000 mg/day) coenzyme Q10 in ALS. Neurology 2005, 65, 1834–1836. [Google Scholar] [CrossRef] [PubMed]
  60. Manzar, H.; Abdulhussein, D.; Yap, T.E.; Cordeiro, M.F. Cellular Consequences of Coenzyme Q10 Deficiency in Neurodegeneration of the Retina and Brain. Int. J. Mol. Sci. 2020, 21, 9299. [Google Scholar] [CrossRef]
  61. Rosenfeldt, F.L.; Pepe, S.; Linnane, A.; Nagley, P.; Rowland, M.; Ou, R.; Marasco, S.; Lyon, W. The effects of ageing on the response to cardiac surgery: Protective strategies for the ageing myocardium. Biogerontology 2002, 3, 37–40. [Google Scholar] [CrossRef]
  62. Keith, M.; Mazer, C.D.; Mikhail, P.; Jeejeebhoy, F.; Briet, F.; Errett, L. Coenzyme Q10 in patients undergoing CABG: Effect of statins and nutritional supplementation. Nutr. Metab. Cardiovasc. Dis. 2008, 18, 105–111. [Google Scholar] [CrossRef]
  63. Cornelius, N.; Wardman, J.H.; Hargreaves, I.P.; Neergheen, V.; Bie, A.S.; Tumer, Z.; Nielsen, J.E.; Nielsen, T.T. Evidence of oxidative stress and mitochondrial dysfunction in spinocerebellar ataxia type 2 (SCA2) patient fibroblasts: Effect of coenzyme Q10 supplementation on these parameters. Mitochondrion 2017, 34, 103–114. [Google Scholar] [CrossRef]
  64. The Huntington Study Group. A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington’s disease. Neurology 2001, 57, 397–404. [Google Scholar] [CrossRef]
  65. Hendler, S.S.; Rorvik, D.M. PDR for Nutritional Supplements; Thomson Reuters: Toronto, ON, Canada, 2008. [Google Scholar]
  66. Zhang, L.; Ashizawa, T.; Peng, D. Primary coenzyme Q10 deficiency due to COQ8A gene mutations. Mol. Genet. Genom. Med. 2020, 8, e1420. [Google Scholar] [CrossRef] [PubMed]
  67. Potgieter, M.; Pretorius, E.; Pepper, M.S. Primary and secondary coenzyme Q10 deficiency: The role of therapeutic supplementation. Nutr. Rev. 2013, 71, 180–188. [Google Scholar] [CrossRef]
  68. Garcia-Corzo, L.; Luna-Sanchez, M.; Doerrier, C.; Ortiz, F.; Escames, G.; Acuna-Castroviejo, D.; Lopez, L.C. Ubiquinol-10 ameliorates mitochondrial encephalopathy associated with CoQ deficiency. Biochim. Biophys. Acta 2014, 1842, 893–901. [Google Scholar] [CrossRef] [Green Version]
  69. Wang, Y.; Hekimi, S. The efficacy of coenzyme Q(10) treatment in alleviating the symptoms of primary coenzyme Q(10) deficiency: A systematic review. J. Cell. Mol. Med. 2022, 26, 4635–4644. [Google Scholar] [CrossRef]
  70. Desbats, M.A.; Lunardi, G.; Doimo, M.; Trevisson, E.; Salviati, L. Genetic bases and clinical manifestations of coenzyme Q10 (CoQ 10) deficiency. J. Inherit. Metab. Dis. 2015, 38, 145–156. [Google Scholar] [CrossRef] [PubMed]
  71. Sarmiento, A.; Diaz-Castro, J.; Pulido-Moran, M.; Moreno-Fernandez, J.; Kajarabille, N.; Chirosa, I.; Guisado, I.M.; Javier Chirosa, L.; Guisado, R.; Ochoa, J.J. Short-term ubiquinol supplementation reduces oxidative stress associated with strenuous exercise in healthy adults: A randomized trial. BioFactors 2016, 42, 612–622. [Google Scholar] [CrossRef] [PubMed]
  72. Sarmiento, A.; Diaz-Castro, J.; Pulido-Moran, M.; Kajarabille, N.; Guisado, R.; Ochoa, J.J. Coenzyme Q10 Supplementation and Exercise in Healthy Humans: A Systematic Review. Curr. Drug Metab. 2016, 17, 345–358. [Google Scholar] [CrossRef]
  73. Cicero, A.F.G.; Fogacci, F.; Di Micoli, A.; Veronesi, M.; Borghi, C. Noninvasive instrumental evaluation of coenzyme Q(10) phytosome on endothelial reactivity in healthy nonsmoking young volunteers: A double-blind, randomized, placebo-controlled crossover clinical trial. BioFactors 2022, 48, 1160–1165. [Google Scholar] [CrossRef]
  74. Diaz-Castro, J.; Moreno-Fernandez, J.; Chirosa, I.; Chirosa, L.J.; Guisado, R.; Ochoa, J.J. Beneficial Effect of Ubiquinol on Hematological and Inflammatory Signaling during Exercise. Nutrients 2020, 12, 424. [Google Scholar] [CrossRef] [Green Version]
  75. Laaksonen, R.; Fogelholm, M.; Himberg, J.J.; Laakso, J.; Salorinne, Y. Ubiquinone supplementation and exercise capacity in trained young and older men. Eur. J. Appl. Physiol. Occup. Physiol. 1995, 72, 95–100. [Google Scholar] [CrossRef] [PubMed]
  76. Malm, C.; Svensson, M.; Ekblom, B.; Sjödin, B. Effects of ubiquinone-10 supplementation and high intensity training on physical performance in humans. Acta Physiol. Scand. 1997, 161, 379–384. [Google Scholar] [CrossRef] [PubMed]
  77. Ho, C.C.; Tseng, C.Y.; Chen, H.W.; Chiu, Y.W.; Tsai, M.C.; Chang, P.S.; Lin, P.T. Coenzyme Q10 status, glucose parameters, and antioxidative capacity in college athletes. J. Int. Soc. Sports Nutr. 2020, 17, 5. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  78. Sanchez-Cuesta, A.; Cortes-Rodriguez, A.B.; Navas-Enamorado, I.; Lekue, J.A.; Viar, T.; Axpe, M.; Navas, P.; Lopez-Lluch, G. High coenzyme Q10 plasma levels improve stress and damage markers in professional soccer players during competition. Int. J. Vitam. Nutr. Res. 2022, 92, 192–203. [Google Scholar] [CrossRef] [PubMed]
  79. Kizaki, K.; Terada, T.; Arikawa, H.; Tajima, T.; Imai, H.; Takahashi, T.; Era, S. Effect of reduced coenzyme Q10 (ubiquinol) supplementation on blood pressure and muscle damage during kendo training camp: A double-blind, randomized controlled study. J. Sports Med. Phys. Fit. 2015, 55, 797–804. [Google Scholar]
  80. Kon, M.; Tanabe, K.; Akimoto, T.; Kimura, F.; Tanimura, Y.; Shimizu, K.; Okamoto, T.; Kono, I. Reducing exercise-induced muscular injury in kendo athletes with supplementation of coenzyme Q10. Br. J. Nutr. 2008, 100, 903–909. [Google Scholar] [CrossRef] [Green Version]
  81. Holloway, C.J.; Murray, A.J.; Mitchell, K.; Martin, D.S.; Johnson, A.W.; Cochlin, L.E.; Codreanu, I.; Dhillon, S.; Rodway, G.W.; Ashmore, T.; et al. Oral Coenzyme Q10 supplementation does not prevent cardiac alterations during a high altitude trek to everest base cAMP. High Alt. Med. Biol. 2014, 15, 459–467. [Google Scholar] [CrossRef] [Green Version]
  82. Braun, B.; Clarkson, P.M.; Freedson, P.S.; Kohl, R.L. Effects of coenzyme Q10 supplementation on exercise performance, VO2max, and lipid peroxidation in trained cyclists. Int. J. Sport Nutr. 1991, 1, 353–365. [Google Scholar] [CrossRef]
  83. Weston, S.B.; Zhou, S.; Weatherby, R.P.; Robson, S.J. Does exogenous coenzyme Q10 affect aerobic capacity in endurance athletes? Int. J. Sport Nutr. 1997, 7, 197–206. [Google Scholar] [CrossRef] [Green Version]
  84. Ylikoski, T.; Piirainen, J.; Hanninen, O.; Penttinen, J. The effect of coenzyme Q10 on the exercise performance of cross-country skiers. Mol. Asp. Med. 1997, 18, S283–S290. [Google Scholar] [CrossRef]
  85. Gül, I.; Gökbel, H.; Belviranli, M.; Okudan, N.; Büyükbaş, S.; Başarali, K. Oxidative stress and antioxidant defense in plasma after repeated bouts of supramaximal exercise: The effect of coenzyme Q10. J. Sports Med. Phys. Fit. 2011, 51, 305–312. [Google Scholar]
  86. Diaz-Castro, J.; Mira-Rufino, P.J.; Moreno-Fernandez, J.; Chirosa, I.; Chirosa, J.L.; Guisado, R.; Ochoa, J.J. Ubiquinol supplementation modulates energy metabolism and bone turnover during high intensity exercise. Food Funct. 2020, 11, 7523–7531. [Google Scholar] [CrossRef] [PubMed]
  87. Emami, A.; Tofighi, A.; Asri-Rezaei, S.; Bazargani-Gilani, B. Effect of Short-term Coenzyme Q10 Supplementation and Precooling on Serum Endogenous Antioxidant Enzymes of Elite Swimmers. J. Strength Cond. Res. 2018, 32, 1431–1439. [Google Scholar] [CrossRef]
  88. Emami, A.; Tofighi, A.; Asri-Rezaei, S.; Bazargani-Gilani, B. The effect of short-term coenzyme Q10 supplementation and pre-cooling strategy on cardiac damage markers in elite swimmers. Br. J. Nutr. 2018, 119, 381–390. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  89. Shimizu, K.; Kon, M.; Tanimura, Y.; Hanaoka, Y.; Kimura, F.; Akama, T.; Kono, I. Coenzyme Q10 supplementation downregulates the increase of monocytes expressing toll-like receptor 4 in response to 6-day intensive training in kendo athletes. Appl. Physiol. Nutr. Metab. Physiol. Appl. Nutr. Et Metab. 2015, 40, 575–581. [Google Scholar] [CrossRef] [PubMed]
  90. Rundek, T.; Naini, A.; Sacco, R.; Coates, K.; DiMauro, S. Atorvastatin decreases the coenzyme Q10 level in the blood of patients at risk for cardiovascular disease and stroke. Arch. Neurol. 2004, 61, 889–892. [Google Scholar] [CrossRef] [Green Version]
  91. Berthold, H.K.; Naini, A.; Di Mauro, S.; Hallikainen, M.; Gylling, H.; Krone, W.; Gouni-Berthold, I. Effect of ezetimibe and/or simvastatin on coenzyme Q10 levels in plasma: A randomised trial. Drug Saf. 2006, 29, 703–712. [Google Scholar] [CrossRef] [PubMed]
  92. Kalyan, S.; Huebbe, P.; Esatbeyoglu, T.; Niklowitz, P.; Cote, H.C.; Rimbach, G.; Kabelitz, D. Nitrogen-bisphosphonate therapy is linked to compromised coenzyme Q10 and vitamin E status in postmenopausal women. J. Clin. Endocrinol. Metab. 2014, 99, 1307–1313. [Google Scholar] [CrossRef] [Green Version]
  93. Kishi, T.; Watanabe, T.; Folkers, K. Bioenergetics in clinical medicine XV. Inhibition of coenzyme Q10-enzymes by clinically used adrenergic blockers of beta-receptors. Res. Commun. Chem. Pathol. Pharm. 1977, 17, 157–164. [Google Scholar]
  94. Lopez-Moreno, J.; Quintana-Navarro, G.M.; Delgado-Lista, J.; Garcia-Rios, A.; Alcala-Diaz, J.F.; Gomez-Delgado, F.; Camargo, A.; Perez-Martinez, P.; Tinahones, F.J.; Striker, G.E.; et al. Mediterranean Diet Supplemented With Coenzyme Q10 Modulates the Postprandial Metabolism of Advanced Glycation End Products in Elderly Men and Women. J. Gerontol. Ser. A Biol. Sci. Med. Sci. 2018, 73, 340–346. [Google Scholar] [CrossRef] [Green Version]
  95. Yubero-Serrano, E.M.; Gonzalez-Guardia, L.; Rangel-Zuñiga, O.; Delgado-Lista, J.; Gutierrez-Mariscal, F.M.; Perez-Martinez, P.; Delgado-Casado, N.; Cruz-Teno, C.; Tinahones, F.J.; Villalba, J.M.; et al. Mediterranean diet supplemented with coenzyme Q10 modifies the expression of proinflammatory and endoplasmic reticulum stress-related genes in elderly men and women. J. Gerontol. Ser. A Biol. Sci. Med. Sci. 2012, 67, 3–10. [Google Scholar] [CrossRef] [Green Version]
  96. Yubero-Serrano, E.M.; Gonzalez-Guardia, L.; Rangel-Zuñiga, O.; Delgado-Casado, N.; Delgado-Lista, J.; Perez-Martinez, P.; Garcia-Rios, A.; Caballero, J.; Marin, C.; Gutierrez-Mariscal, F.M.; et al. Postprandial antioxidant gene expression is modified by Mediterranean diet supplemented with coenzyme Q(10) in elderly men and women. Age 2013, 35, 159–170. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  97. González-Guardia, L.; Yubero-Serrano, E.M.; Delgado-Lista, J.; Perez-Martinez, P.; Garcia-Rios, A.; Marin, C.; Camargo, A.; Delgado-Casado, N.; Roche, H.M.; Perez-Jimenez, F.; et al. Effects of the Mediterranean diet supplemented with coenzyme q10 on metabolomic profiles in elderly men and women. J. Gerontol. Ser. A Biol. Sci. Med. Sci. 2015, 70, 78–84. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  98. Gutierrez-Mariscal, F.M.; Yubero-Serrano, E.M.; Rangel-Zúñiga, O.A.; Marín, C.; García-Rios, A.; Perez-Martinez, P.; Delgado-Lista, J.; Malagón, M.M.; Tinahones, F.J.; Pérez-Jimenez, F.; et al. Postprandial activation of p53-dependent DNA repair is modified by Mediterranean diet supplemented with coenzyme Q10 in elderly subjects. J. Gerontol. Ser. A Biol. Sci. Med. Sci. 2014, 69, 886–893. [Google Scholar] [CrossRef] [PubMed]
  99. Gutierrez-Mariscal, F.M.; Perez-Martinez, P.; Delgado-Lista, J.; Yubero-Serrano, E.M.; Camargo, A.; Delgado-Casado, N.; Cruz-Teno, C.; Santos-Gonzalez, M.; Rodriguez-Cantalejo, F.; Castaño, J.P.; et al. Mediterranean diet supplemented with coenzyme Q10 induces postprandial changes in p53 in response to oxidative DNA damage in elderly subjects. Age 2012, 34, 389–403. [Google Scholar] [CrossRef]
  100. Ho, M.J.; Bellusci, A.; Wright, J.M. Blood pressure lowering efficacy of coenzyme Q10 for primary hypertension. Cochrane Database Syst. Rev. 2009, 3, CD007435. [Google Scholar] [CrossRef]
  101. Rosenfeldt, F.; Hilton, D.; Pepe, S.; Krum, H. Systematic review of effect of coenzyme Q10 in physical exercise, hypertension and heart failure. BioFactors 2003, 18, 91–100. [Google Scholar] [CrossRef]
  102. Moradi, M.; Haghighatdoost, F.; Feizi, A.; Larijani, B.; Azadbakht, L. Effect of Coenzyme Q10 Supplementation on Diabetes Biomarkers: A Systematic Review and Meta-analysis of Randomized Controlled Clinical Trials. Arch. Iran. Med. 2016, 19, 588–596. [Google Scholar]
  103. Tabrizi, R.; Akbari, M.; Sharifi, N.; Lankarani, K.B.; Moosazadeh, M.; Kolahdooz, F.; Taghizadeh, M.; Asemi, Z. The Effects of Coenzyme Q10 Supplementation on Blood Pressures Among Patients with Metabolic Diseases: A Systematic Review and Meta-analysis of Randomized Controlled Trials. High Blood Press. Cardiovasc. Prev. Off. J. Ital. Soc. Hypertens. 2018, 25, 41–50. [Google Scholar] [CrossRef]
  104. Sharifi, N.; Tabrizi, R.; Moosazadeh, M.; Mirhosseini, N.; Lankarani, K.B.; Akbari, M.; Chamani, M.; Kolahdooz, F.; Asemi, Z. The Effects of Coenzyme Q10 Supplementation on Lipid Profiles Among Patients with Metabolic Diseases: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Curr. Pharm. Des. 2018, 24, 2729–2742. [Google Scholar] [CrossRef]
  105. Gao, L.; Mao, Q.; Cao, J.; Wang, Y.; Zhou, X.; Fan, L. Effects of coenzyme Q10 on vascular endothelial function in humans: A meta-analysis of randomized controlled trials. Atherosclerosis 2012, 221, 311–316. [Google Scholar] [CrossRef] [PubMed]
  106. Bagheri Nesami, N.; Mozaffari-Khosravi, H.; Najarzadeh, A.; Salehifar, E. The Effect of Coenzyme Q10 Supplementation on Pro-Inflammatory Factors and Adiponectin in Mildly Hypertensive Patients: A Randomized, Double-Blind, Placebo-Controlled Trial. Int. J. Vitam. Nutr. Res. 2015, 85, 156–164. [Google Scholar] [CrossRef] [PubMed]
  107. Lee, Y.J.; Cho, W.J.; Kim, J.K.; Lee, D.C. Effects of coenzyme Q10 on arterial stiffness, metabolic parameters, and fatigue in obese subjects: A double-blind randomized controlled study. J. Med. Food 2011, 14, 386–390. [Google Scholar] [CrossRef] [PubMed]
  108. Saboori, S.; Rad, E.Y.; Mardani, M.; Khosroshahi, M.Z.; Nouri, Y.; Falahi, E. Effect of Q10 supplementation on body weight and body mass index: A systematic review and meta-analysis of randomized controlled clinical trials. Diabetes Metab. Syndr. 2019, 13, 1179–1185. [Google Scholar] [CrossRef] [PubMed]
  109. Zhang, P.; Yang, C.; Guo, H.; Wang, J.; Lin, S.; Li, H.; Yang, Y.; Ling, W. Treatment of coenzyme Q10 for 24 weeks improves lipid and glycemic profile in dyslipidemic individuals. J. Clin. Lipidol. 2018, 12, 417–427.e5. [Google Scholar] [CrossRef]
  110. Cicero, A.F.; Morbini, M.; Rosticci, M.; D’’Addato, S.; Grandi, E.; Borghi, C. Middle-Term Dietary Supplementation with Red Yeast Rice Plus Coenzyme Q10 Improves Lipid Pattern, Endothelial Reactivity and Arterial Stiffness in Moderately Hypercholesterolemic Subjects. Ann. Nutr. Metab. 2016, 68, 213–219. [Google Scholar] [CrossRef]
  111. Raitakari, O.T.; McCredie, R.J.; Witting, P.; Griffiths, K.A.; Letters, J.; Sullivan, D.; Stocker, R.; Celermajer, D.S. Coenzyme Q improves LDL resistance to ex vivo oxidation but does not enhance endothelial function in hypercholesterolemic young adults. Free Radic. Biol. Med. 2000, 28, 1100–1105. [Google Scholar] [CrossRef]
  112. Sabbatinelli, J.; Orlando, P.; Galeazzi, R.; Silvestri, S.; Cirilli, I.; Marcheggiani, F.; Dludla, P.V.; Giuliani, A.; Bonfigli, A.R.; Mazzanti, L.; et al. Ubiquinol Ameliorates Endothelial Dysfunction in Subjects with Mild-to-Moderate Dyslipidemia: A Randomized Clinical Trial. Nutrients 2020, 12, 1098. [Google Scholar] [CrossRef] [Green Version]
  113. Hamilton, S.J.; Chew, G.T.; Watts, G.F. Coenzyme Q10 improves endothelial dysfunction in statin-treated type 2 diabetic patients. Diabetes Care 2009, 32, 810–812. [Google Scholar] [CrossRef] [Green Version]
  114. Playford, D.A.; Watts, G.F.; Croft, K.D.; Burke, V. Combined effect of coenzyme Q10 and fenofibrate on forearm microcirculatory function in type 2 diabetes. Atherosclerosis 2003, 168, 169–179. [Google Scholar] [CrossRef]
  115. Hernandez-Ojeda, J.; Cardona-Munoz, E.G.; Roman-Pintos, L.M.; Troyo-Sanroman, R.; Ortiz-Lazareno, P.C.; Cardenas-Meza, M.A.; Pascoe-Gonzalez, S.; Miranda-Diaz, A.G. The effect of ubiquinone in diabetic polyneuropathy: A randomized double-blind placebo-controlled study. J. Diabetes Complicat. 2012, 26, 352–358. [Google Scholar] [CrossRef] [PubMed]
  116. Mehrdadi, P.; Kolahdouz Mohammadi, R.; Alipoor, E.; Eshraghian, M.R.; Esteghamati, A.; Hosseinzadeh-Attar, M.J. The Effect of Coenzyme Q10 Supplementation on Circulating Levels of Novel Adipokine Adipolin/CTRP12 in Overweight and Obese Patients with Type 2 Diabetes. Exp. Clin. Endocrinol. Diabetes 2017, 125, 156–162. [Google Scholar] [CrossRef] [PubMed]
  117. Yen, C.H.; Chu, Y.J.; Lee, B.J.; Lin, Y.C.; Lin, P.T. Effect of liquid ubiquinol supplementation on glucose, lipids and antioxidant capacity in type 2 diabetes patients: A double-blind, randomised, placebo-controlled trial. Br. J. Nutr. 2018, 120, 57–63. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  118. Raygan, F.; Rezavandi, Z.; Dadkhah Tehrani, S.; Farrokhian, A.; Asemi, Z. The effects of coenzyme Q10 administration on glucose homeostasis parameters, lipid profiles, biomarkers of inflammation and oxidative stress in patients with metabolic syndrome. Eur. J. Nutr. 2016, 55, 2357–2364. [Google Scholar] [CrossRef] [PubMed]
  119. Zhang, S.Y.; Yang, K.L.; Zeng, L.T.; Wu, X.H.; Huang, H.Y. Effectiveness of Coenzyme Q10 Supplementation for Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis. Int. J. Endocrinol. 2018, 2018, 6484839. [Google Scholar] [CrossRef]
  120. Rodriguez-Carrizalez, A.D.; Castellanos-Gonzalez, J.A.; Martinez-Romero, E.C.; Miller-Arrevillaga, G.; Pacheco-Moises, F.P.; Roman-Pintos, L.M.; Miranda-Diaz, A.G. The effect of ubiquinone and combined antioxidant therapy on oxidative stress markers in non-proliferative diabetic retinopathy: A phase IIa, randomized, double-blind, and placebo-controlled study. Redox Rep. Commun. Free Radic. Res. 2016, 21, 155–163. [Google Scholar] [CrossRef]
  121. Tezel, G. Oxidative stress in glaucomatous neurodegeneration: Mechanisms and consequences. Prog. Retin. Eye Res. 2006, 25, 490–513. [Google Scholar] [CrossRef] [Green Version]
  122. Lee, D.; Kim, K.Y.; Shim, M.S.; Kim, S.Y.; Ellisman, M.H.; Weinreb, R.N.; Ju, W.K. Coenzyme Q10 ameliorates oxidative stress and prevents mitochondrial alteration in ischemic retinal injury. Apoptosis 2014, 19, 603–614. [Google Scholar] [CrossRef] [Green Version]
  123. Jorat, M.V.; Tabrizi, R.; Mirhosseini, N.; Lankarani, K.B.; Akbari, M.; Heydari, S.T.; Mottaghi, R.; Asemi, Z. The effects of coenzyme Q10 supplementation on lipid profiles among patients with coronary artery disease: A systematic review and meta-analysis of randomized controlled trials. Lipids Health Dis 2018, 17, 230. [Google Scholar] [CrossRef] [Green Version]
  124. Jorat, M.V.; Tabrizi, R.; Kolahdooz, F.; Akbari, M.; Salami, M.; Heydari, S.T.; Asemi, Z. The effects of coenzyme Q10 supplementation on biomarkers of inflammation and oxidative stress in among coronary artery disease: A systematic review and meta-analysis of randomized controlled trials. Inflammopharmacology 2019, 27, 233–248. [Google Scholar] [CrossRef]
  125. Soja, A.M.; Mortensen, S.A. Treatment of congestive heart failure with coenzyme Q10 illuminated by meta-analyses of clinical trials. Mol. Asp. Med. 1997, 18, S159–S168. [Google Scholar] [CrossRef]
  126. Madmani, M.E.; Yusuf Solaiman, A.; Tamr Agha, K.; Madmani, Y.; Shahrour, Y.; Essali, A.; Kadro, W. Coenzyme Q10 for heart failure. Cochrane Database Syst. Rev. 2014, 9, CD008684. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  127. Kawashima, C.; Matsuzawa, Y.; Konishi, M.; Akiyama, E.; Suzuki, H.; Sato, R.; Nakahashi, H.; Kikuchi, S.; Kimura, Y.; Maejima, N.; et al. Ubiquinol Improves Endothelial Function in Patients with Heart Failure with Reduced Ejection Fraction: A Single-Center, Randomized Double-Blind Placebo-Controlled Crossover Pilot Study. Am. J. Cardiovasc. Drugs Drugs Devices Other Interv. 2020, 20, 363–372. [Google Scholar] [CrossRef] [PubMed]
  128. Morisco, C.; Trimarco, B.; Condorelli, M. Effect of coenzyme Q10 therapy in patients with congestive heart failure: A long-term multicenter randomized study. Clin. Investig. 1993, 71, S134–S136. [Google Scholar] [CrossRef]
  129. Bakhshayeshkaram, M.; Lankarani, K.B.; Mirhosseini, N.; Tabrizi, R.; Akbari, M.; Dabbaghmanesh, M.H.; Asemi, Z. The Effects of Coenzyme Q10 Supplementation on Metabolic Profiles of Patients with Chronic Kidney Disease: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Curr. Pharm. Des. 2018, 24, 3710–3723. [Google Scholar] [CrossRef]
  130. Gholnari, T.; Aghadavod, E.; Soleimani, A.; Hamidi, G.A.; Sharifi, N.; Asemi, Z. The Effects of Coenzyme Q10 Supplementation on Glucose Metabolism, Lipid Profiles, Inflammation, and Oxidative Stress in Patients With Diabetic Nephropathy: A Randomized, Double-Blind, Placebo-Controlled Trial. J. Am. Coll. Nutr. 2018, 37, 188–193. [Google Scholar] [CrossRef]
  131. Heidari, A.; Hamidi, G.; Soleimani, A.; Aghadavod, E.; Asemi, Z. Effects of Coenzyme Q10 Supplementation on Gene Expressions Related to Insulin, Lipid, and Inflammation Pathways in Patients With Diabetic Nephropathy. Iran. J. Kidney Dis. 2018, 12, 14–21. [Google Scholar]
  132. Fallah, M.; Askari, G.; Soleimani, A.; Feizi, A.; Asemi, Z. Clinical trial of the effects of coenzyme Q10 supplementation on glycemic control and markers of lipid profiles in diabetic hemodialysis patients. Int. Urol. Nephrol. 2018, 50, 2073–2079. [Google Scholar] [CrossRef]
  133. Fallah, M.; Askari, G.; Soleimani, A.; Feizi, A.; Asemi, Z. Clinical Trial of the Effects of Coenzyme Q10 Supplementation on Biomarkers of Inflammation and Oxidative Stress in Diabetic Hemodialysis Patients. Int. J. Prev. Med. 2019, 10, 12. [Google Scholar] [CrossRef]
  134. Turk, S.; Baki, A.; Solak, Y.; Kayrak, M.; Atalay, H.; Gaipov, A.; Aribas, A.; Akilli, H.; Biyik, Z.; Okudan, N.; et al. Coenzyme Q10 supplementation and diastolic heart functions in hemodialysis patients: A randomized double-blind placebo-controlled trial. Hemodial. Int. 2013, 17, 374–381. [Google Scholar] [CrossRef]
  135. Gokbel, H.; Turk, S.; Okudan, N.; Atalay, H.; Belviranli, M.; Gaipov, A.; Solak, Y. Effects of Coenzyme Q10 Supplementation on Exercise Performance and Markers of Oxidative Stress in Hemodialysis Patients: A Double-Blind Placebo-Controlled Crossover Trial. Am. J. Ther. 2016, 23, e1736–e1743. [Google Scholar] [CrossRef] [PubMed]
  136. Farsi, F.; Mohammadshahi, M.; Alavinejad, P.; Rezazadeh, A.; Zarei, M.; Engali, K.A. Functions of Coenzyme Q10 Supplementation on Liver Enzymes, Markers of Systemic Inflammation, and Adipokines in Patients Affected by Nonalcoholic Fatty Liver Disease: A Double-Blind, Placebo-Controlled, Randomized Clinical Trial. J. Am. Coll. Nutr. 2016, 35, 346–353. [Google Scholar] [CrossRef] [PubMed]
  137. Farhangi, M.A.; Alipour, B.; Jafarvand, E.; Khoshbaten, M. Oral coenzyme Q10 supplementation in patients with nonalcoholic fatty liver disease: Effects on serum vaspin, chemerin, pentraxin 3, insulin resistance and oxidative stress. Arch. Med. Res. 2014, 45, 589–595. [Google Scholar] [CrossRef] [PubMed]
  138. Cordero, M.D.; Alcocer-Gómez, E.; de Miguel, M.; Culic, O.; Carrión, A.M.; Alvarez-Suarez, J.M.; Bullón, P.; Battino, M.; Fernández-Rodríguez, A.; Sánchez-Alcazar, J.A. Can coenzyme q10 improve clinical and molecular parameters in fibromyalgia? Antioxid. Redox Signal. 2013, 19, 1356–1361. [Google Scholar] [CrossRef]
  139. Di Pierro, F.; Rossi, A.; Consensi, A.; Giacomelli, C.; Bazzichi, L. Role for a water-soluble form of CoQ10 in female subjects affected by fibromyalgia. A preliminary study. Clin. Exp. Rheumatol. 2017, 35 (Suppl. 105), 20–27. [Google Scholar]
  140. Sawaddiruk, P.; Apaijai, N.; Paiboonworachat, S.; Kaewchur, T.; Kasitanon, N.; Jaiwongkam, T.; Kerdphoo, S.; Chattipakorn, N.; Chattipakorn, S.C. Coenzyme Q10 supplementation alleviates pain in pregabalin-treated fibromyalgia patients via reducing brain activity and mitochondrial dysfunction. Free Radic. Res. 2019, 53, 901–909. [Google Scholar] [CrossRef]
  141. Nachvak, S.M.; Alipour, B.; Mahdavi, A.M.; Aghdashi, M.A.; Abdollahzad, H.; Pasdar, Y.; Samadi, M.; Mostafai, R. Effects of coenzyme Q10 supplementation on matrix metalloproteinases and DAS-28 in patients with rheumatoid arthritis: A randomized, double-blind, placebo-controlled clinical trial. Clin. Rheumatol. 2019, 38, 3367–3374. [Google Scholar] [CrossRef]
  142. Lopez-Pedrera, C.; Villalba, J.M.; Patino-Trives, A.M.; Luque-Tevar, M.; Barbarroja, N.; Aguirre, M.A.; Escudero-Contreras, A.; Perez-Sanchez, C. Therapeutic Potential and Immunomodulatory Role of Coenzyme Q10 and Its Analogues in Systemic Autoimmune Diseases. Antioxidants 2021, 10, 600. [Google Scholar] [CrossRef]
  143. Sanoobar, M.; Eghtesadi, S.; Azimi, A.; Khalili, M.; Khodadadi, B.; Jazayeri, S.; Gohari, M.R.; Aryaeian, N. Coenzyme Q10 supplementation ameliorates inflammatory markers in patients with multiple sclerosis: A double blind, placebo, controlled randomized clinical trial. Nutr. Neurosci. 2015, 18, 169–176. [Google Scholar] [CrossRef]
  144. Villalba, J.M.; Navas, P. Regulation of coenzyme Q biosynthesis pathway in eukaryotes. Free Radic. Biol. Med. 2021, 165, 312–323. [Google Scholar] [CrossRef]
  145. Kawamukai, M. Biosynthesis of coenzyme Q in eukaryotes. Biosci. Biotechnol. Biochem. 2016, 80, 23–33. [Google Scholar] [CrossRef] [PubMed]
  146. Tricarico, P.M.; Crovella, S.; Celsi, F. Mevalonate Pathway Blockade, Mitochondrial Dysfunction and Autophagy: A Possible Link. Int. J. Mol. Sci. 2015, 16, 16067–16084. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  147. Banach, M.; Serban, C.; Sahebkar, A.; Ursoniu, S.; Rysz, J.; Muntner, P.; Toth, P.P.; Jones, S.R.; Rizzo, M.; Glasser, S.P.; et al. Effects of coenzyme Q10 on statin-induced myopathy: A meta-analysis of randomized controlled trials. Mayo Clin. Proc. 2015, 90, 24–34. [Google Scholar] [CrossRef]
  148. Qu, H.; Guo, M.; Chai, H.; Wang, W.T.; Gao, Z.Y.; Shi, D.Z. Effects of Coenzyme Q10 on Statin-Induced Myopathy: An Updated Meta-Analysis of Randomized Controlled Trials. J. Am. Heart Assoc 2018, 7, e009835. [Google Scholar] [CrossRef] [Green Version]
  149. Derosa, G.; D’Angelo, A.; Maffioli, P. Coenzyme q10 liquid supplementation in dyslipidemic subjects with statin-related clinical symptoms: A double-blind, randomized, placebo-controlled study. Drug Des. Dev. Ther. 2019, 13, 3647–3655. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  150. Chen, W.; Ochs-Balcom, H.M.; Ma, C.; Isackson, P.J.; Vladutiu, G.D.; Luzum, J.A. Coenzyme Q10 supplementation for the treatment of statin-associated muscle symptoms. Future Cardiol. 2022, 18, 461–470. [Google Scholar] [CrossRef] [PubMed]
  151. Erkkinen, M.G.; Kim, M.O.; Geschwind, M.D. Clinical Neurology and Epidemiology of the Major Neurodegenerative Diseases. Cold Spring Harb. Perspect. Biol. 2018, 10, a033118. [Google Scholar] [CrossRef]
  152. Nagase, M.; Yamamoto, Y.; Miyazaki, Y.; Yoshino, H. Increased oxidative stress in patients with amyotrophic lateral sclerosis and the effect of edaravone administration. Redox Rep. Commun. Free Radic. Res. 2016, 21, 104–112. [Google Scholar] [CrossRef]
  153. Zhu, Z.G.; Sun, M.X.; Zhang, W.L.; Wang, W.W.; Jin, Y.M.; Xie, C.L. The efficacy and safety of coenzyme Q10 in Parkinson’s disease: A meta-analysis of randomized controlled trials. Neurol. Sci. 2017, 38, 215–224. [Google Scholar] [CrossRef]
  154. Gutzmann, H.; Hadler, D. Sustained efficacy and safety of idebenone in the treatment of Alzheimer’s disease: Update on a 2-year double-blind multicentre study. J. Neural Transm. Suppl. 1998, 54, 301–310. [Google Scholar] [CrossRef]
  155. Bergamasco, B.; Scarzella, L.; La Commare, P. Idebenone, a new drug in the treatment of cognitive impairment in patients with dementia of the Alzheimer type. Funct. Neurol. 1994, 9, 161–168. [Google Scholar] [PubMed]
  156. Thal, L.J.; Grundman, M.; Berg, J.; Ernstrom, K.; Margolin, R.; Pfeiffer, E.; Weiner, M.F.; Zamrini, E.; Thomas, R.G. Idebenone treatment fails to slow cognitive decline in Alzheimer’s disease. Neurology 2003, 61, 1498–1502. [Google Scholar] [CrossRef] [PubMed]
  157. Müller, T.; Büttner, T.; Gholipour, A.F.; Kuhn, W. Coenzyme Q10 supplementation provides mild symptomatic benefit in patients with Parkinson’s disease. Neurosci. Lett. 2003, 341, 201–204. [Google Scholar] [CrossRef]
  158. Korinthenberg, R. Neuromuscular Disorders in Children and Adolescents. Neuropediatrics 2017, 48, 209–210. [Google Scholar] [CrossRef] [Green Version]
  159. McGarry, A.; McDermott, M.; Kieburtz, K.; de Blieck, E.A.; Beal, F.; Marder, K.; Ross, C.; Shoulson, I.; Gilbert, P.; Mallonee, W.M.; et al. A randomized, double-blind, placebo-controlled trial of coenzyme Q10 in Huntington disease. Neurology 2017, 88, 152–159. [Google Scholar] [CrossRef] [Green Version]
  160. Cooney, R.V.; Dai, Q.; Gao, Y.-T.; Chow, W.-H.; Franke, A.A.; Shu, X.-O.; Li, H.; Ji, B.; Cai, Q.; Chai, W.; et al. Low Plasma Coenzyme Q10 Levels and Breast Cancer Risk in Chinese Women. Cancer Epidemiol. Biomark. Prev. 2011, 20, 1124–1130. [Google Scholar] [CrossRef] [Green Version]
  161. Liu, H.T.; Huang, Y.C.; Cheng, S.B.; Huang, Y.T.; Lin, P.T. Effects of coenzyme Q10 supplementation on antioxidant capacity and inflammation in hepatocellular carcinoma patients after surgery: A randomized, placebo-controlled trial. Nutr. J. 2016, 15, 85. [Google Scholar] [CrossRef]
  162. Lesser, G.J.; Case, D.; Stark, N.; Williford, S.; Giguere, J.; Garino, L.A.; Naughton, M.J.; Vitolins, M.Z.; Lively, M.O.; Shaw, E.G. A randomized, double-blind, placebo-controlled study of oral coenzyme Q10 to relieve self-reported treatment-related fatigue in newly diagnosed patients with breast cancer. J. Support. Oncol. 2013, 11, 31–42. [Google Scholar] [CrossRef] [Green Version]
  163. Roffe, L.; Schmidt, K.; Ernst, E. Efficacy of coenzyme Q10 for improved tolerability of cancer treatments: A systematic review. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2004, 22, 4418–4424. [Google Scholar] [CrossRef] [Green Version]
  164. Fairfield, K.M.; Fletcher, R.H. Vitamins for chronic disease prevention in adults: Scientific review. JAMA 2002, 287, 3116–3126. [Google Scholar] [CrossRef]
  165. Alehagen, U.; Lindahl, T.L.; Aaseth, J.; Svensson, E.; Johansson, P. Levels of sP-selectin and hs-CRP Decrease with Dietary Intervention with Selenium and Coenzyme Q10 Combined: A Secondary Analysis of a Randomized Clinical Trial. PLoS ONE 2015, 10, e0137680. [Google Scholar] [CrossRef] [PubMed]
  166. Alehagen, U.; Aaseth, J.; Johansson, P. Less increase of copeptin and MR-proADM due to intervention with selenium and coenzyme Q10 combined: Results from a 4-year prospective randomized double-blind placebo-controlled trial among elderly Swedish citizens. BioFactors 2015, 41, 443–452. [Google Scholar] [CrossRef] [PubMed]
  167. Berbel-Garcia, A.; Barbera-Farre, J.R.; Etessam, J.P.; Salio, A.M.; Cabello, A.; Gutierrez-Rivas, E.; Campos, Y. Coenzyme Q 10 improves lactic acidosis, strokelike episodes, and epilepsy in a patient with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes). Clin. Neuropharmacol. 2004, 27, 187–191. [Google Scholar] [CrossRef]
  168. Ustuner, M.A.; Kaman, D.; Colakoglu, N. Effects of benfotiamine and coenzyme Q10 on kidney damage induced gentamicin. Tissue Cell 2017, 49, 691–696. [Google Scholar] [CrossRef]
  169. Balakumar, P.; Rohilla, A.; Krishan, P.; Solairaj, P.; Thangathirupathi, A. The multifaceted therapeutic potential of benfotiamine. Pharm. Res 2010, 61, 482–488. [Google Scholar] [CrossRef] [PubMed]
  170. Astolfi, L.; Simoni, E.; Valente, F.; Ghiselli, S.; Hatzopoulos, S.; Chicca, M.; Martini, A. Correction: Coenzyme Q10 plus Multivitamin Treatment Prevents Cisplatin Ototoxicity in Rats. PLoS ONE 2017, 12, e0185525. [Google Scholar] [CrossRef] [Green Version]
  171. Astolfi, L.; Simoni, E.; Valente, F.; Ghiselli, S.; Hatzopoulos, S.; Chicca, M.; Martini, A. Coenzyme Q10 plus Multivitamin Treatment Prevents Cisplatin Ototoxicity in Rats. PLoS ONE 2016, 11, e0162106. [Google Scholar] [CrossRef]
  172. Lo, R.Y.; Figueroa, K.P.; Pulst, S.M.; Lin, C.Y.; Perlman, S.; Wilmot, G.; Gomez, C.; Schmahmann, J.; Paulson, H.; Shakkottai, V.G.; et al. Coenzyme Q10 and spinocerebellar ataxias. Mov. Disord. Off. J. Mov. Disord. Soc. 2015, 30, 214–220. [Google Scholar] [CrossRef] [Green Version]
  173. Castro-Marrero, J.; Domingo, J.C.; Cordobilla, B.; Ferrer, R.; Giralt, M.; Sanmartin-Sentanes, R.; Alegre-Martin, J. Does Coenzyme Q10 Plus Selenium Supplementation Ameliorate Clinical Outcomes by Modulating Oxidative Stress and Inflammation in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome? Antioxid. Redox. Signal 2022, 36, 729–739. [Google Scholar] [CrossRef]
  174. Alehagen, U.; Aaseth, J.; Alexander, J.; Johansson, P. Still reduced cardiovascular mortality 12 years after supplementation with selenium and coenzyme Q10 for four years: A validation of previous 10-year follow-up results of a prospective randomized double-blind placebo-controlled trial in elderly. PLoS ONE 2018, 13, e0193120. [Google Scholar] [CrossRef] [Green Version]
  175. Wesselink, E.; Koekkoek, W.A.C.; Grefte, S.; Witkamp, R.F.; van Zanten, A.R.H. Feeding mitochondria: Potential role of nutritional components to improve critical illness convalescence. Clin. Nutr. 2019, 38, 982–995. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  176. Muss, C.; Mosgoeller, W.; Endler, T. Prevention of “nitrosative stress” by a nutritional supplement (LaVita®)—A randomized placebo controlled double blind clinical trial with healthy volunteers. Neuro Endocrinol. Lett. 2016, 37, 345–352. [Google Scholar] [PubMed]
  177. Kopets, R.; Kuibida, I.; Chernyavska, I.; Cherepanyn, V.; Mazo, R.; Fedevych, V.; Gerasymov, S. Dietary supplementation with a novel l-carnitine multi-micronutrient in idiopathic male subfertility involving oligo-, astheno-, teratozoospermia: A randomized clinical study. Andrology 2020, 8, 1184–1193. [Google Scholar] [CrossRef] [PubMed]
  178. Salas-Huetos, A.; Rosique-Esteban, N.; Becerra-Tomás, N.; Vizmanos, B.; Bulló, M.; Salas-Salvadó, J. The Effect of Nutrients and Dietary Supplements on Sperm Quality Parameters: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. Adv. Nutr. 2018, 9, 833–848. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  179. Buhling, K.; Schumacher, A.; Eulenburg, C.Z.; Laakmann, E. Influence of oral vitamin and mineral supplementation on male infertility: A meta-analysis and systematic review. Reprod. Biomed. Online 2019, 39, 269–279. [Google Scholar] [CrossRef] [Green Version]
  180. Nielsen, A.N.; Mizuno, M.; Ratkevicius, A.; Mohr, T.; Rohde, M.; Mortensen, S.A.; Quistorff, B. No effect of antioxidant supplementation in triathletes on maximal oxygen uptake, 31P-NMRS detected muscle energy metabolism and muscle fatigue. Int. J. Sports Med. 1999, 20, 154–158. [Google Scholar] [CrossRef]
  181. Davison, G.W.; Hughes, C.M.; Bell, R.A. Exercise and mononuclear cell DNA damage: The effects of antioxidant supplementation. Int. J. Sport Nutr. Exerc. Metab. 2005, 15, 480–492. [Google Scholar] [CrossRef]
  182. Kaikkonen, J.; Kosonen, L.; Nyyssönen, K.; Porkkala-Sarataho, E.; Salonen, R.; Korpela, H.; Salonen, J.T. Effect of combined coenzyme Q10 and d-alpha-tocopheryl acetate supplementation on exercise-induced lipid peroxidation and muscular damage: A placebo-controlled double-blind study in marathon runners. Free Radic. Res. 1998, 29, 85–92. [Google Scholar] [CrossRef]
  183. Tauler, P.; Ferrer, M.D.; Sureda, A.; Pujol, P.; Drobnic, F.; Tur, J.A.; Pons, A. Supplementation with an antioxidant cocktail containing coenzyme Q prevents plasma oxidative damage induced by soccer. Eur. J. Appl. Physiol. 2008, 104, 777–785. [Google Scholar] [CrossRef]
  184. Vasankari, T.J.; Kujala, U.M.; Vasankari, T.M.; Vuorimaa, T.; Ahotupa, M. Increased serum and low-density-lipoprotein antioxidant potential after antioxidant supplementation in endurance athletes. Am. J. Clin. Nutr. 1997, 65, 1052–1056. [Google Scholar] [CrossRef] [Green Version]
  185. Wolters, M.; Hahn, A. Plasma ubiquinone status and response to six-month supplementation combined with multivitamins in healthy elderly women--results of a randomized, double-blind, placebo-controlled study. Int. J. Vitam. Nutr. Res. 2003, 73, 207–214. [Google Scholar] [CrossRef] [PubMed]
  186. Alehagen, U.; Johansson, P.; Aaseth, J.; Alexander, J.; Brismar, K. Increase in insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 1 after supplementation with selenium and coenzyme Q10. A prospective randomized double-blind placebo-controlled trial among elderly Swedish citizens. PLoS ONE 2017, 12, e0178614. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  187. Alehagen, U.; Johansson, P.; Aaseth, J.; Alexander, J.; Surowiec, I.; Lundstedt-Enkel, K.; Lundstedt, T. Significant Changes in Metabolic Profiles after Intervention with Selenium and Coenzyme Q10 in an Elderly Population. Biomolecules 2019, 9, 553. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  188. Johansson, P.; Dahlström, Ö.; Dahlström, U.; Alehagen, U. Improved Health-Related Quality of Life, and More Days out of Hospital with Supplementation with Selenium and Coenzyme Q10 Combined. Results from a Double Blind, Placebo-Controlled Prospective Study. J. Nutr. Health Aging 2015, 19, 870–877. [Google Scholar] [CrossRef]
  189. Negro, M.; Perna, S.; Spadaccini, D.; Castelli, L.; Calanni, L.; Barbero, M.; Cescon, C.; Rondanelli, M.; D’Antona, G. Effects of 12 Weeks of Essential Amino Acids (EAA)-Based Multi-Ingredient Nutritional Supplementation on Muscle Mass, Muscle Strength, Muscle Power and Fatigue in Healthy Elderly Subjects: A Randomized Controlled Double-Blind Study. J. Nutr. Health Aging 2019, 23, 414–424. [Google Scholar] [CrossRef]
  190. Feher, J.; Kovacs, B.; Kovacs, I.; Schveoller, M.; Papale, A.; Balacco Gabrieli, C. Improvement of visual functions and fundus alterations in early age-related macular degeneration treated with a combination of acetyl-L-carnitine, n-3 fatty acids, and coenzyme Q10. Ophthalmologica 2005, 219, 154–166. [Google Scholar] [CrossRef]
  191. Qu, J.; Kaufman, Y.; Washington, I. Coenzyme Q10 in the human retina. Investig. Ophthalmol. Vis. Sci. 2009, 50, 1814–1818. [Google Scholar] [CrossRef]
  192. Pirro, M.; Mannarino, M.R.; Bianconi, V.; Simental-Mendía, L.E.; Bagaglia, F.; Mannarino, E.; Sahebkar, A. The effects of a nutraceutical combination on plasma lipids and glucose: A systematic review and meta-analysis of randomized controlled trials. Pharmacol. Res. Off. J. Ital. Pharmacol. Soc. 2016, 110, 76–88. [Google Scholar] [CrossRef]
  193. Mazza, A.; Schiavon, L.; Rigatelli, G.; Torin, G.; Lenti, S. The Effects of a New Generation of Nutraceutical Compounds on Lipid Profile and Glycaemia in Subjects with Pre-hypertension. High Blood Press. Cardiovasc. Prev. Off. J. Ital. Soc. Hypertens. 2019, 26, 345–350. [Google Scholar] [CrossRef]
  194. Cicero, A.F.; Colletti, A.; Fogacci, F.; Bove, M.; Rosticci, M.; Borghi, C. Effects of a Combined Nutraceutical on Lipid Pattern, Glucose Metabolism and Inflammatory Parameters in Moderately Hypercholesterolemic Subjects: A Double-blind, Cross-over, Randomized Clinical Trial. High Blood Press. Cardiovasc. Prev. Off. J. Ital. Soc. Hypertens. 2017, 24, 13–18. [Google Scholar] [CrossRef] [Green Version]
  195. Mazza, A.; Lenti, S.; Schiavon, L.; Di Giacomo, E.; Tomasi, M.; Manunta, R.; Torin, G.; Townsend, D.M.; Rubello, D. Effect of Monacolin K and COQ10 supplementation in hypertensive and hypercholesterolemic subjects with metabolic syndrome. Biomed. Pharmacother. Biomed. Pharmacother. 2018, 105, 992–996. [Google Scholar] [CrossRef] [PubMed]
  196. Cicero, A.F.G.; Kennedy, C.; Knežević, T.; Bove, M.; Georges, C.M.G.; Šatrauskienė, A.; Toth, P.P.; Fogacci, F. Efficacy and Safety of Armolipid Plus(®): An Updated PRISMA Compliant Systematic Review and Meta-Analysis of Randomized Controlled Clinical Trials. Nutrients 2021, 13, 638. [Google Scholar] [CrossRef] [PubMed]
  197. Domanico, D.; Fragiotta, S.; Cutini, A.; Carnevale, C.; Zompatori, L.; Vingolo, E.M. Circulating levels of reactive oxygen species in patients with nonproliferative diabetic retinopathy and the influence of antioxidant supplementation: 6-month follow-up. Indian J. Ophthalmol. 2015, 63, 9–14. [Google Scholar] [CrossRef] [PubMed]
  198. Kayiklik, A.; Guvenmez, O. Application of Vitamin E + Coenzyme Q Therapy During FAKO + IOL Implantation. Med. Arch. 2019, 73, 109–112. [Google Scholar] [CrossRef]
  199. Parisi, V.; Centofanti, M.; Gandolfi, S.; Marangoni, D.; Rossetti, L.; Tanga, L.; Tardini, M.; Traina, S.; Ungaro, N.; Vetrugno, M.; et al. Effects of coenzyme Q10 in conjunction with vitamin E on retinal-evoked and cortical-evoked responses in patients with open-angle glaucoma. J. Glaucoma 2014, 23, 391–404. [Google Scholar] [CrossRef]
  200. Kendler, B.S. Supplemental conditionally essential nutrients in cardiovascular disease therapy. J. Cardiovasc. Nurs. 2006, 21, 9–16. [Google Scholar] [CrossRef] [Green Version]
  201. Parsi, E.; Bitterlich, N.; Winkelmann, A.; Rösler, D.; Metzner, C. Dietary intervention with a specific micronutrient combination for the treatment of patients with cardiac arrhythmias: The impact on insulin resistance and left ventricular function. BMC Cardiovasc. Disord. 2018, 18, 220. [Google Scholar] [CrossRef]
  202. Witte, K.K.; Nikitin, N.P.; Parker, A.C.; von Haehling, S.; Volk, H.D.; Anker, S.D.; Clark, A.L.; Cleland, J.G. The effect of micronutrient supplementation on quality-of-life and left ventricular function in elderly patients with chronic heart failure. Eur. Heart J. 2005, 26, 2238–2244. [Google Scholar] [CrossRef] [Green Version]
  203. Fumagalli, S.; Fattirolli, F.; Guarducci, L.; Cellai, T.; Baldasseroni, S.; Tarantini, F.; Di Bari, M.; Masotti, G.; Marchionni, N. Coenzyme Q10 terclatrate and creatine in chronic heart failure: A randomized, placebo-controlled, double-blind study. Clin. Cardiol. 2011, 34, 211–217. [Google Scholar] [CrossRef]
  204. Kumar, A.; Singh, R.B.; Saxena, M.; Niaz, M.A.; Josh, S.R.; Chattopadhyay, P.; Mechirova, V.; Pella, D.; Fedacko, J. Effect of carni Q-gel (ubiquinol and carnitine) on cytokines in patients with heart failure in the Tishcon study. Acta Cardiol. 2007, 62, 349–354. [Google Scholar] [CrossRef]
  205. Fukuda, S.; Koyama, H.; Kondo, K.; Fujii, H.; Hirayama, Y.; Tabata, T.; Okamura, M.; Yamakawa, T.; Okada, S.; Hirata, S.; et al. Effects of nutritional supplementation on fatigue, and autonomic and immune dysfunction in patients with end-stage renal disease: A randomized, double-blind, placebo-controlled, multicenter trial. PLoS ONE 2015, 10, e0119578. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  206. De Benedetto, F.; Pastorelli, R.; Ferrario, M.; de Blasio, F.; Marinari, S.; Brunelli, L.; Wouters, E.F.M.; Polverino, F.; Celli, B.R. Supplementation with Qter(®) and Creatine improves functional performance in COPD patients on long term oxygen therapy. Respir. Med. 2018, 142, 86–93. [Google Scholar] [CrossRef] [PubMed]
  207. Barden, A.E.; Shinde, S.; Burke, V.; Puddey, I.B.; Beilin, L.J.; Irish, A.B.; Watts, G.F.; Mori, T.A. The effect of n-3 fatty acids and coenzyme Q10 supplementation on neutrophil leukotrienes, mediators of inflammation resolution and myeloperoxidase in chronic kidney disease. Prostaglandins Other Lipid Mediat. 2018, 136, 1–8. [Google Scholar] [CrossRef] [PubMed]
  208. Kharaeva, Z.; Gostova, E.; De Luca, C.; Raskovic, D.; Korkina, L. Clinical and biochemical effects of coenzyme Q(10), vitamin E, and selenium supplementation to psoriasis patients. Nutrition 2009, 25, 295–302. [Google Scholar] [CrossRef]
  209. Castro-Marrero, J.; Cordero, M.D.; Segundo, M.J.; Sáez-Francàs, N.; Calvo, N.; Román-Malo, L.; Aliste, L.; Fernández de Sevilla, T.; Alegre, J. Does oral coenzyme Q10 plus NADH supplementation improve fatigue and biochemical parameters in chronic fatigue syndrome? Antioxid. Redox Signal. 2015, 22, 679–685. [Google Scholar] [CrossRef] [Green Version]
  210. Castro-Marrero, J.; Sáez-Francàs, N.; Segundo, M.J.; Calvo, N.; Faro, M.; Aliste, L.; Fernández de Sevilla, T.; Alegre, J. Effect of coenzyme Q10 plus nicotinamide adenine dinucleotide supplementation on maximum heart rate after exercise testing in chronic fatigue syndrome—A randomized, controlled, double-blind trial. Clin. Nutr. 2016, 35, 826–834. [Google Scholar] [CrossRef] [Green Version]
  211. Gaul, C.; Diener, H.C.; Danesch, U. Improvement of migraine symptoms with a proprietary supplement containing riboflavin, magnesium and Q10: A randomized, placebo-controlled, double-blind, multicenter trial. J. Headache Pain 2015, 16, 516. [Google Scholar] [CrossRef]
  212. Hajihashemi, P.; Askari, G.; Khorvash, F.; Reza Maracy, M.; Nourian, M. The effects of concurrent Coenzyme Q10, L-carnitine supplementation in migraine prophylaxis: A randomized, placebo-controlled, double-blind trial. Cephalalgia 2019, 39, 648–654. [Google Scholar] [CrossRef]
  213. Parohan, M.; Sarraf, P.; Javanbakht, M.H.; Foroushani, A.R.; Ranji-Burachaloo, S.; Djalali, M. The synergistic effects of nano-curcumin and coenzyme Q10 supplementation in migraine prophylaxis: A randomized, placebo-controlled, double-blind trial. Nutr. Neurosci. 2021, 24, 317–326. [Google Scholar] [CrossRef]
  214. Fedacko, J.; Pella, D.; Fedackova, P.; Hänninen, O.; Tuomainen, P.; Jarcuska, P.; Lopuchovsky, T.; Jedlickova, L.; Merkovska, L.; Littarru, G.P. Coenzyme Q(10) and selenium in statin-associated myopathy treatment. Can. J. Physiol. Pharmacol. 2013, 91, 165–170. [Google Scholar] [CrossRef]
  215. Bogsrud, M.P.; Langslet, G.; Ose, L.; Arnesen, K.E.; Sm Stuen, M.C.; Malt, U.F.; Woldseth, B.; Retterstøl, K. No effect of combined coenzyme Q10 and selenium supplementation on atorvastatin-induced myopathy. Scand. Cardiovasc. J. SCJ 2013, 47, 80–87. [Google Scholar] [CrossRef] [PubMed]
  216. Shojaei, M.; Djalali, M.; Khatami, M.; Siassi, F.; Eshraghian, M. Effects of carnitine and coenzyme Q10 on lipid profile and serum levels of lipoprotein(a) in maintenance hemodialysis patients on statin therapy. Iran. J. Kidney Dis. 2011, 5, 114–118. [Google Scholar] [PubMed]
  217. Galasko, D.R.; Peskind, E.; Clark, C.M.; Quinn, J.F.; Ringman, J.M.; Jicha, G.A.; Cotman, C.; Cottrell, B.; Montine, T.J.; Thomas, R.G.; et al. Antioxidants for Alzheimer disease: A randomized clinical trial with cerebrospinal fluid biomarker measures. Arch. Neurol. 2012, 69, 836–841. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  218. Hertz, N.; Lister, R.E. Improved survival in patients with end-stage cancer treated with coenzyme Q(10) and other antioxidants: A pilot study. J. Int. Med. Res. 2009, 37, 1961–1971. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  219. Premkumar, V.G.; Yuvaraj, S.; Vijayasarathy, K.; Gangadaran, S.G.D.; Sachdanandam, P. Serum Cytokine Levels of Interleukin-1β, -6, -8, Tumour Necrosis Factor-α and Vascular Endothelial Growth Factor in Breast Cancer Patients Treated with Tamoxifen and Supplemented with Co-Enzyme Q10, Riboflavin and Niacin. Basic Clin. Pharmacol. Toxicol. 2007, 100, 387–391. [Google Scholar] [CrossRef] [PubMed]
  220. Premkumar, V.G.; Yuvaraj, S.; Shanthi, P.; Sachdanandam, P. Co-enzyme Q10, riboflavin and niacin supplementation on alteration of DNA repair enzyme and DNA methylation in breast cancer patients undergoing tamoxifen therapy. Br. J. Nutr. 2008, 100, 1179–1182. [Google Scholar] [CrossRef] [Green Version]
  221. Iwase, S.; Kawaguchi, T.; Yotsumoto, D.; Doi, T.; Miyara, K.; Odagiri, H.; Kitamura, K.; Ariyoshi, K.; Miyaji, T.; Ishiki, H.; et al. Efficacy and safety of an amino acid jelly containing coenzyme Q10 and L-carnitine in controlling fatigue in breast cancer patients receiving chemotherapy: A multi-institutional, randomized, exploratory trial (JORTC-CAM01). Support. Care Cancer 2016, 24, 637–646. [Google Scholar] [CrossRef]
  222. Grammatikopoulou, M.G.; Gkiouras, K.; Papageorgiou, S.; Myrogiannis, I.; Mykoniatis, I.; Papamitsou, T.; Bogdanos, D.P.; Goulis, D.G. Dietary Factors and Supplements Influencing Prostate Specific-Antigen (PSA) Concentrations in Men with Prostate Cancer and Increased Cancer Risk: An Evidence Analysis Review Based on Randomized Controlled Trials. Nutrients 2020, 12, 2985. [Google Scholar] [CrossRef]
  223. Hoenjet, K.M.; Dagnelie, P.C.; Delaere, K.P.; Wijckmans, N.E.; Zambon, J.V.; Oosterhof, G.O. Effect of a nutritional supplement containing vitamin E, selenium, vitamin c and coenzyme Q10 on serum PSA in patients with hormonally untreated carcinoma of the prostate: A randomised placebo-controlled study. Eur. Urol. 2005, 47, 433–439; discussion 439–440. [Google Scholar] [CrossRef]
  224. Ames, B.N. Musings in the twilight of my career. Free Radic. Biol. Med. 2022, 178, 219–225. [Google Scholar] [CrossRef]
  225. Ames, B.N. Optimal micronutrients delay mitochondrial decay and age-associated diseases. Mech. Ageing Dev. 2010, 131, 473–479. [Google Scholar] [CrossRef] [PubMed]
  226. McCann, J.C.; Ames, B.N. Vitamin K, an example of triage theory: Is micronutrient inadequacy linked to diseases of aging? Am. J. Clin. Nutr. 2009, 90, 889–907. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  227. Ames, B.N. Low micronutrient intake may accelerate the degenerative diseases of aging through allocation of scarce micronutrients by triage. Proc. Natl. Acad. Sci. USA 2006, 103, 17589–17594. [Google Scholar] [CrossRef] [PubMed]
Nutrients 14 04383 g001 550
Figure 1. The PRISMA flow diagram.
Figure 1. The PRISMA flow diagram.
Nutrients 14 04383 g001
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Figure 2. The integrated antioxidant defenses against lipid peroxidation. The nutrient network halts the propagation of lipid peroxyl radicals while their redox interactions maintain their reduction states. These nutrients include coenzyme Q10, α tocopherol, vitamin C, α lipoic acid, glutathione, and the micronutrients that support the activities of antioxidant enzymes such as selenium, manganese, copper, and zinc (not shown in the figure). O2•—superoxide anion radical, H2O2—hydrogen peroxide, Fe2+/3+—ferrous or ferric iron, PUFA—polyunsaturated fatty acids, GSH—reduced glutathione, GSSG—glutathione disulfide, GPx—glutathione peroxidase, CAT—catalase, H2O—water, O2—oxygen, α TOH—reduced α tocopherol, α TO•—oxidized α tocopherol.
Figure 2. The integrated antioxidant defenses against lipid peroxidation. The nutrient network halts the propagation of lipid peroxyl radicals while their redox interactions maintain their reduction states. These nutrients include coenzyme Q10, α tocopherol, vitamin C, α lipoic acid, glutathione, and the micronutrients that support the activities of antioxidant enzymes such as selenium, manganese, copper, and zinc (not shown in the figure). O2•—superoxide anion radical, H2O2—hydrogen peroxide, Fe2+/3+—ferrous or ferric iron, PUFA—polyunsaturated fatty acids, GSH—reduced glutathione, GSSG—glutathione disulfide, GPx—glutathione peroxidase, CAT—catalase, H2O—water, O2—oxygen, α TOH—reduced α tocopherol, α TO•—oxidized α tocopherol.
Nutrients 14 04383 g002
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Tippairote, T.; Bjørklund, G.; Gasmi, A.; Semenova, Y.; Peana, M.; Chirumbolo, S.; Hangan, T. Combined Supplementation of Coenzyme Q10 and Other Nutrients in Specific Medical Conditions. Nutrients 2022, 14, 4383. https://doi.org/10.3390/nu14204383

AMA Style

Tippairote T, Bjørklund G, Gasmi A, Semenova Y, Peana M, Chirumbolo S, Hangan T. Combined Supplementation of Coenzyme Q10 and Other Nutrients in Specific Medical Conditions. Nutrients. 2022; 14(20):4383. https://doi.org/10.3390/nu14204383

Chicago/Turabian Style

Tippairote, Torsak, Geir Bjørklund, Amin Gasmi, Yuliya Semenova, Massimiliano Peana, Salvatore Chirumbolo, and Tony Hangan. 2022. "Combined Supplementation of Coenzyme Q10 and Other Nutrients in Specific Medical Conditions" Nutrients 14, no. 20: 4383. https://doi.org/10.3390/nu14204383

APA Style

Tippairote, T., Bjørklund, G., Gasmi, A., Semenova, Y., Peana, M., Chirumbolo, S., & Hangan, T. (2022). Combined Supplementation of Coenzyme Q10 and Other Nutrients in Specific Medical Conditions. Nutrients, 14(20), 4383. https://doi.org/10.3390/nu14204383

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