Bi-allelic variants in COQ8B, a gene involved in the biosynthesis of coenzyme Q10, lead to non-syndromic retinitis pigmentosa.

Retinitis pigmentosa (RP) is a Mendelian disease characterized by gradual loss of vision, due to the progressive degeneration of retinal cells. Genetically, it is highly heterogeneous, with pathogenic variants identified in more than 100 genes so far. Following a large-scale sequencing screening, we identified five individuals (four families) with recessive and non-syndromic RP, carrying as well bi-allelic DNA changes in COQ8B, a gene involved in the biosynthesis of coenzyme Q10. Specifically, we detected compound heterozygous assortments of five disease-causing variants (c.187C>T [p.Arg63Trp], c.566G>A [p.Trp189Ter], c.1156G>A [p.Asp386Asn], c.1324G>A [p.Val442Met], and c.1560G>A [p.Trp520Ter]), all segregating with disease according to a recessive pattern of inheritance. Cell-based analysis of recombinant proteins deriving from these genotypes, performed by target engagement assays, showed in all cases a significant decrease in ligand-protein interaction compared to the wild type. Our results indicate that variants in COQ8B lead to recessive non-syndromic RP, possibly by impairing the biosynthesis of coenzyme Q10, a key component of oxidative phosphorylation in the mitochondria.

Familial thrombotic microangiopathy in a child with coenzyme Q10 deficiency-associated glomerulopathy.

We report a child with biallelic COQ6 variants presenting with familial thrombotic microangiopathy (TMA). A Chinese boy presented with steroid-resistant nephrotic syndrome at 8 months old and went into kidney failure requiring peritoneal dialysis at 15 months old. He presented with hypertensive encephalopathy with the triad of microangiopathic haemolytic anaemia, thrombocytopenia, and acute on chronic kidney injury at 25 months old following a viral illness. Kidney biopsy showed features of chronic TMA. He was managed with supportive therapy and plasma exchanges and maintained on eculizumab. However, he had another TMA relapse despite complement inhibition a year later. Eculizumab was withdrawn, and supportive therapies, including ubiquinol (50 mg/kg/day) and vitamins, were optimized. He remained relapse-free since then for 4 years. Of note, his elder sister succumbed to multiple organ failure with histological evidence of chronic TMA at the age of 4. Retrospective genetic analysis revealed the same compound heterozygous variants in the COQ6 gene.

Genetic profiles of multiple system atrophy revealed by exome sequencing, long-read sequencing and spinocerebellar ataxia repeat expansion analysis.

BACKGROUND AND PURPOSE: Multiple system atrophy (MSA) is a progressive, adult-onset neurodegenerative disorder clinically characterized by combinations of autonomic failure, parkinsonism, cerebellar ataxia and pyramidal signs. Although a few genetic factors have been reported to contribute to the disease, its mutational profiles have not been systemically studied. METHODS: To address the genetic profiles of clinically diagnosed MSA patients, exome sequencing and triplet repeat detection was conducted in 205 MSA patients, including one familial case. The pathogenicity of variants was determined according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines. RESULTS: In the familial patient, a novel heterozygous COQ2 pathogenic variant (p.Ala351Thr) was identified in the MSA pedigree. In the sporadic patients, 29 pathogenic variants were revealed in 21 genes, and the PARK7 p.Ala104Thr variant was significantly associated with MSA (p = 0.0018). Moreover, burden tests demonstrated that the pathogenic variants were enriched in cerebellar ataxia-related genes in patients. Furthermore, repeat expansion analyses revealed that two patients carried the pathogenic CAG repeat expansion in the CACNA1A gene (SCA6), one patient carried the (ACAGG)exp/(ACAGG)exp expansion in RFC1 and one carried the GAA-pure expansion in FGF14 gene. CONCLUSION: In conclusion, a novel COQ2 pathogenic variant was identified in a familial MSA patient, and repeat expansions in CACNA1A, RFC1 and FGF14 gene were detected in four sporadic patients. Moreover, a PARK7 variant and the burden of pathogenic variants in cerebellar ataxia-related genes were associated with MSA.

Oxygen-Binding Sites of Enriched Gold Nanoclusters for Capturing Mitochondrial Reverse Electrons.

Reverse electron transfer (RET), an abnormal backward flow of electrons from complexes III/IV to II/I of mitochondria, causes the overproduction of a reduced-type CoQ to boost downstream production of mitochondrial superoxide anions that leads to ischemia-reperfusion injury (IRI) to organs. Herein, we studied low-coordinated gold nanoclusters (AuNCs) with abundant oxygen-binding sites to form an electron-demanding trapper that allowed rapid capture of electrons to compensate for the CoQ/CoQH2 imbalance during RET. The AuNCs were composed of only eight gold atoms that formed a Cs-symmetrical configuration with all gold atoms exposed on the edge site. The geometry and atomic configuration enhance oxygen intercalation to attain a d-band electron deficiency in frontier orbitals, forming an unusually high oxidation state for rapid mitochondrial reverse electron capture under a transient imbalance of CoQ/CoQH2 redox cycles. Using hepatic IRI cells/animals, we corroborated that the CoQ-like AuNCs prevent inflammation and liver damage from IRI via recovery of the mitochondrial function.

Associations between Long-Term Dietary Coenzyme Q10 Intake and New-Onset Hypertension in Adults: Insights from a Nationwide Prospective Cohort Study.

Coenzyme Q10 (CoQ10) supplementation appears to be associated with a lower blood pressure. Nevertheless, it remains unclear whether food-sourced CoQ10 will affect new-onset hypertension in general adults. This study investigated the relationship between dietary CoQ10 intake and new-onset hypertension among the general population. Participants without hypertension at baseline from the China Health and Nutrition Survey (CHNS) prospective cohort study were included (n = 11,428). Dietary CoQ10 intake was collected by validated dietary recalls and the food weighing method. Linear and non-linear relationships between dietary CoQ10 intake and new-onset hypertension were analyzed using multivariable Cox proportional hazards models and restricted cubic splines. During follow-up (median: 6 years), 4006 new-onset hypertension cases were documented. Compared with non-consumers, the hazard ratio (HR) and 95% confidence interval (CI) from quintile 2 to 4 total dietary CoQ10 were 0.83 (0.76, 0.91), 0.86 (0.78, 0.94) and 1.01 (0.92, 1.11); total plant-derived CoQ10 were 0.80 (0.73, 0.88), 1.00 (0.91, 1.09) and 1.10 (1.00, 1.20); and animal-derived CoQ10 were 0.65 (0.59, 0.71), 0.58 (0.53, 0.64) and 0.68 (0.62, 0.75). The lowest risk was found at moderate intake, with a non-linear relationship (P nonlinearity < 0.05). Furthermore, the overall inverse association was stronger among individuals without alcohol consumption or eating a low-fat diet. Moderate long-term dietary CoQ10 intake might be protective against new-onset hypertension. However, it follows a non-linear relationship and excessive intake may increase the risk of new-onset hypertension in the Chinese population.

DHODH Alleviates Heart Failure via the Modulation of CoQ-Related Ferroptotic Inhibition.

BACKGROUND: Heart failure (HF) is a clinical syndrome that seriously endangers human health and quality of life as the terminal stage of cardiovascular diseases. Ferroptosis as a new iron-dependent programmed cell death mode that is closely related to the occurrence and development of cardiovascular diseases. Dihydroorotate dehydrogenase (DHODH) has been found to play a crucial role in inhibiting ferroptosis and improving mitochondrial function, and its expression can be upregulated by estradiol (E2). Recent studies have found that DHODH can inhibit ferroptosis by reducing coenzyme Q (CoQ) to CoQH2. Therefore, this study aims to explore the effect of up-regulation of DHODH on the pathological hypertrophy and fibrosis of heart failure and its mechanisms. METHODS: The mouse heart failure model was established by transverse aortic constriction (TAC), surgery in mice. Two days after the operation, a subcutaneous injection of E2 or the same volume of sesame oil was given for 8 weeks. Then, the left ventricular systolic function related indicators of mice were measured by echocardiography, and the degree of myocardial fibrosis of mice was detected by histological analysis; the expression levels of heart failure markers were detected by quantitative polymerase chain reaction (q-PCR) and western blot (WB) analysis; the morphological changes of mitochondria in cardiac cells of mice were observed by transmission electron microscopy. Cell model were established by stimulating with phenylephrine for 96 hours. Ferroptosis markers were detected by kits and WB analysis. Mitochondrial function was verified by a JC-1 fluorescent probe, and 2',7'-Dichlorodihydrofluorescein diacetate (DCFH-DA) staining. The knockdown results were detected by WB analysis after transfection of small interfering RNA (siRNA) of CoQ. Fer-1 was added as a positive control to verify the ferroptosis-related changes of myocardial cells. RESULTS: In the animal model, we found that E2 treatment alleviates TAC-induced cardiac hypertrophy and fibrosis and suppresses cardiomyocyte ferroptosis by promotes DHODH upregulation in murine cardiomyocytes. In the cell model, DHODH upregulation protects against phenylephrine-induced cardiomyocytes with failure. However, the effect on up-regulating DHODH was inhibited by transfection to down-regulate CoQ expression. CONCLUSIONS: The up-regulation of DHODH could effectively ameliorate the manifestations of heart failure such as myocardial hypertrophy and fibrosis in mice after TAC surgery, inhibit ferroptosis of cardiac myocytes, and ameliorate mitochondrial function. The mechanism involves CoQ-related biological processes.

Evaluating the efficacy of ubiquinol in heart failure patients: a systematic review and meta-analysis.

Aim: We aim to analyze past literature to evaluate the efficacy of coenzyme Q10 (CoQ-10) in the population with heart failure (HF). Methods: A systematic literature search was conducted through MEDLINE (via PubMed) and Cochrane Library. The outcomes analyzed were a reduction in HF-related mortality, an improvement in exercise capacity, and the left ventricular ejection fraction (LVEF). Results: Among 16 studies, CoQ-10 significantly reduced HF-related mortality by 40% and improved exercise capacity in patients with HF, but demonstrated no significant difference in LVEF however, the potential of its efficacy on LVEF could not be ruled out. Conclusion: CoQ-10 significantly enhances exercise capacity and reduces HF-related mortality; however, its impact on patients with reduced LVEF requires further investigation.

[Box: see text].

Nrf2/FSP1/CoQ10 axis-mediated ferroptosis is involved in sodium aescinate-induced nephrotoxicity.

Sodium aescinate (SA), an active compound found in horse chestnut seeds, is widely used in clinical practice. Recently, the incidence of SA-induced adverse events, particularly renal impairment, has increased. Our previous work demonstrated that SA causes severe nephrotoxicity via nephrocyte ferroptosis; however, the underlying mechanism remains to be fully elucidated. In the current study, we investigated additional molecular pathways involved in SA-induced nephrotoxicity. Our results showed that SA inhibited cell viability, disrupted cellular membrane integrity, and enhanced reactive oxygen species (ROS), ferrous iron (Fe2+), and malondialdehyde (MDA) levels, as well as lipid peroxidation in rat proximal renal tubular epithelial cell line (NRK-52E) cells. SA also depleted coenzyme Q10 (CoQ10, ubiquinone) and nicotinamide adenine dinucleotide (NADH) and reduced ferroptosis suppressor protein 1 (FSP1) and polyprenyltransferase (coenzyme Q2, COQ2) activity, triggering lipid peroxidation and ROS accumulation in mouse kidneys and NRK-52E cells. The overexpression of COQ2, FSP1, or CoQ10 (ubiquinone) supplementation effectively attenuated SA-induced ferroptosis, whereas iFSP1 or 4-formylbenzoic acid (4-CBA) pretreatment exacerbated SA-induced nephrotoxicity. Additionally, SA decreased nuclear factor-erythroid-2-related factor 2 (Nrf2) levels and inhibited Nrf2 binding to the -1170/-1180 bp ARE site in FSP1 promoter, resulting in FSP1 suppression. Overexpression of Nrf2 or its agonist dimethyl fumarate (DMF) promoted FSP1 expression, thereby improving cellular antioxidant capacity and alleviating SA-induced ferroptosis. These results suggest that SA-triggers renal injury through oxidative stress and ferroptosis, driven by the suppression of the Nrf2/FSP1/CoQ10 axis.

Gastroprotective and microbiome-modulating effects of ubiquinol in rats with radiation-induced enteropathy.

Radiation enteritis is a frequently encountered issue for patients receiving radiotherapy and has a significant impact on cancer patients' quality of life. The gut microbiota plays a pivotal role in intestinal function, yet the impact of irradiation on gut microorganisms is not fully understood. This study explores the gastroprotective effect and gut microbiome-modulating potential of ubiquinol (Ubq), the reduced form of the powerful antioxidant CoQ-10. For this purpose, male albino rats were randomly assigned to four groups: Control, IRR (acute 7 Gy γ-radiation), Ubq_Post (Ubq for 7 days post-irradiation), and Ubq_Pre/Post (Ubq for 7 days pre and 7 days post-irradiation). The fecal microbiomes of all groups were profiled by 16S rRNA amplicon sequencing followed by bioinformatics and statistical analysis. Histopathological examination of intestinal tissue indicated severe damage in the irradiated group, which was mitigated by ubiquinol with enhanced regeneration, goblet cells, and intestinal alkaline phosphatase expression. Compared to the irradiated group, the Ubq-treated groups had a significant recovery of intestinal interleukin-1ß, caspase-3, nitric oxide metabolites, and thio-barbituric reactive substances to near-healthy levels. Ubq_Pre/Post group displayed elevated peroxisome proliferator-activated receptor (PPAR-γ) level, suggesting heightened benefits. Serum insulin reduction in irradiated rats improved post-Ubq treatment, with a possible anti-inflammatory effect on the pancreatic tissue. Fecal microbiota profiling revealed a dysbiosis state with a reduction of bacterial diversity post-irradiation, which was re-modulated in the Ubq treated groups to profiles that are indistinguishable from the control group. These findings underscore Ubq's gastroprotective effects against radiation-induced enteritis and its potential in restoring the gut microbiota's diversity and balance.

Alterations in coenzyme Q10 status in a cybrid line harboring the 3243A>G mutation of mitochondrial DNA is associated with abnormal mitochondrial bioenergetics and dysregulated mitochondrial biogenesis.

Mitochondrial DNA (mtDNA) mutations, including the m.3243A>G mutation that causes mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), are associated with secondary coenzyme Q10 (CoQ10) deficiency. We previously demonstrated that PPARGC1A knockdown repressed the expression of PDSS2 and several COQ genes. In the present study, we compared the mitochondrial function, CoQ10 status, and levels of PDSS and COQ proteins and genes between mutant cybrids harboring the m.3243A>G mutation and wild-type cybrids. Decreased mitochondrial energy production, defective respiratory function, and reduced CoQ10 levels were observed in the mutant cybrids. The ubiquinol-10:ubiquinone-10 ratio was lower in the mutant cybrids, indicating blockage of the electron transfer upstream of CoQ, as evident from the reduced ratio upon rotenone treatment and increased ratio upon antimycin A treatment in 143B cells. The mutant cybrids exhibited downregulation of PDSS2 and several COQ genes and upregulation of COQ8A. In these cybrids, the levels of PDSS2, COQ3-a isoform, COQ4, and COQ9 were reduced, whereas those of COQ3-b and COQ8A were elevated. The mutant cybrids had repressed PPARGC1A expression, elevated ATP5A levels, and reduced levels of mtDNA-encoded proteins, nuclear DNA-encoded subunits of respiratory enzyme complexes, MNRR1, cytochrome c, and DHODH, but no change in TFAM, TOM20, and VDAC1 levels. Alterations in the CoQ10 level in MELAS may be associated with mitochondrial energy deficiency and abnormal gene regulation. The finding of a reduction in the ubiquinol-10:ubiquinone-10 ratio in the MELAS mutant cybrids differs from our previous discovery that cybrids harboring the m.8344A>G mutation exhibit a high ubiquinol-10:ubiquinone-10 ratio.

New variants expand the neurological phenotype of COQ7 deficiency.

The protein encoded by COQ7 is required for CoQ10 synthesis in humans, hydroxylating 3-demethoxyubiquinol (DMQ10) in the second to last steps of the pathway. COQ7 mutations lead to a primary CoQ10 deficiency syndrome associated with a pleiotropic neurological disorder. This study shows the clinical, physiological, and molecular characterization of four new cases of CoQ10 primary deficiency caused by five mutations in COQ7, three of which have not yet been described, inducing mitochondrial dysfunction in all patients. However, the specific combination of the identified variants in each patient generated precise pathophysiological and molecular alterations in fibroblasts, which would explain the differential in vitro response to supplementation therapy. Our results suggest that COQ7 dysfunction could be caused by specific structural changes that affect the interaction with COQ9 required for the DMQ10 presentation to COQ7, the substrate access to the active site, and the maintenance of the active site structure. Remarkably, patients' fibroblasts share transcriptional remodeling, supporting a modification of energy metabolism towards glycolysis, which could be an adaptive mechanism against CoQ10 deficiency. However, transcriptional analysis of mitochondria-associated pathways showed distinct and dramatic differences between patient fibroblasts, which correlated with the extent of pathophysiological and neurological alterations observed in the probands. Overall, this study suggests that the combination of precise genetic diagnostics and the availability of new structural models of human proteins could help explain the origin of phenotypic pleiotropy observed in some genetic diseases and the different responses to available therapies.

Coenzyme Q10 and Vitamin E Regulate the Bioactivity of Human Corneal Fibroblast Cells.

Purpose: Corneal fibroblasts are involved in the wound healing of the cornea with proliferation, migration, and differentiation processes. Coenzyme Q10 (CoQ10) and vitamin E can enhance corneal wound healing when applied after a corneal lesion as an eye drop. Thus, this study was performed to determine the potential efficiency of a CoQ10 ophthalmical solution containing a CoQ10 and vitamin E D-α-tocopherol polyethylene glycol 1000 succinate (TPGS)-derived formulation in human corneal fibroblasts (HCFs) in vitro. Methods: Primary HCFs were obtained from cadaveric corneal tissue, and cell viability was determined using MTT assay at 24 and 72 h. Cell migration was evaluated using an in vitro wound healing assay, and mRNA expressions of collagen type I (COL-I), collagen type III (COL-III), lumican, hyaluronan, matrix metalloproteinase (MMP)-1, MMP-2, MMP-9, tissue inhibitors of MMP (TIMP)-1, TIMP-2, interleukin (IL)-1ß, IL-6, IL-8, and IL-10 were assessed using reverse transcription polymerase chain reaction at 24 and 72 h. Results: At various concentrations of CoQ10 ophthalmical solution (CoQ10-os), cell viability and wound healing rates of HCFs increased compared with the control group. The expressions of COL-I, COL-III, lumican, and hyaluronan were increased by CoQ10-os, whereas those of MMP-1, MMP-2, MMP-9, TIMP-1, TIMP-2, and TIMP-3 were not affected by CoQ10-os at 24 and 72 h. In treating HCFs with a CoQ10-os medium, IL-1ß, IL-6, and IL-8 decreased, whereas IL-10 was significantly increased in a time- and dose-dependent manner. Conclusions: The findings indicate that CoQ10 and vitamin E-TPGS are potent regulators of the bioactivity of HCFs, thus supporting their potential application as ophthalmical solutions in therapies aimed at the fast regeneration of damaged cornea tissues.

Role of Dietary Antioxidant Supplements in Male Infertility: A Review.

Infertility, which affects around 70 million couples globally, is the inability to conceive after at least a year of continuous, unprotected sexual activity. Male-related elements are involving half of all infertility cases globally. Male infertility has various characteristics, including oligospermia, asthenozoospermia, and teratozoospermia. The purpose of this study was to assess the impact of antioxidant-rich food supplements on the properties of semen, like concentration of sperm, morphology, motility, fertility rate, and damage of DNA. Terms such as coenzyme Q10, antioxidants, folic acid, vitamin C, vitamin E, male infertility, selenium and others, were used to search for relevant research papers in the PubMed database. The findings of this study demonstrated beneficial improvements in semen parameters among infertile men who consumed dietary supplements, particularly combining antioxidants like coenzyme Q10, vitamin C, and vitamin E.

Antioxidants and Fertility in Women with Ovarian Aging: A Systematic Review and Meta-Analysis.

Ovarian aging is a major factor for female subfertility. Multiple antioxidants have been applied in different clinical scenarios, but their effects on fertility in women with ovarian aging are still unclear. To address this, a meta-analysis was performed to evaluate the effectiveness and safety of antioxidants on fertility in women with ovarian aging. A total of 20 randomized clinical trials with 2617 participants were included. The results showed that use of antioxidants not only significantly increased the number of retrieved oocytes and high-quality embryo rates but also reduced the dose of gonadotropin, contributing to higher clinical pregnancy rates. According to the subgroup analysis of different dose settings, better effects were more pronounced with lower doses; in terms of antioxidant types, coenzyme Q10 (CoQ10) tended to be more effective than melatonin, myo-inositol, and vitamins. When compared with placebo or no treatment, CoQ10 showed more advantages, whereas small improvements were observed with other drugs. In addition, based on subgroup analysis of CoQ10, the optimal treatment regimen of CoQ10 for improving pregnancy rate was 30 mg/d for 3 mo before the controlled ovarian stimulation cycle, and women with diminished ovarian reserve clearly benefited from CoQ10 treatment, especially those aged <35 y. Our study suggests that antioxidant consumption is an effective and safe complementary therapy for women with ovarian aging. Appropriate antioxidant treatment should be offered at a low dose according to the patient's age and ovarian reserve. This study was registered at PROSPERO as CRD42022359529.

Glomerular basement membrane ultrastructural changes in a patient with COQ2 glomerulopathy: A case report.

Primary coenzyme Q10 deficiency-1, caused by COQ2 disease-causing variants, is an autosomal recessive disorder, and genetic testing is the gold standard for diagnosing this condition. A Chinese boy with steroid-resistant nephrotic syndrome, focal segmental glomerulosclerosis, and progressive kidney insufficiency was included in the study. Electron microscopy revealed the glomerular basement membrane with irregular thickness and lamellation with diffuse effacement of foot processes in the podocytes, and swollen mitochondria with abnormal cristae in the podocytes. Coenzyme Q10 supplementation started about 3 weeks after the onset of mild kidney dysfunction did not improve the proband's kidney outcome. Proband-only whole-exome sequencing and Sanger sequencing revealed two heteroallelic COQ2 variants: a maternally inherited novel variant c.1013G > A[p.(Gly338Glu)] in exon 6 and a variant of unknown origin c.1159C > T[p.(Arg387*)] in exon 7. Subsequent long-read sequencing demonstrated these two variants were located on different alleles. Our report extends the phenotypic and genotypic spectrum of COQ2 glomerulopathy.

The effect of coenzyme Q10 intake on metabolic profiles in women candidates for in-vitro fertilization: a randomised trial.

Objective: Infertility and the pathogenesis of polycystic ovarian syndrome (PCOS) are both influenced by insulin resistance and dyslipidemia. Presumably, adding coenzyme Q10 (CoQ10) to these patients' diets will be beneficial. Therefore, this study aimed to examine the effects of CoQ10 supplementation on metabolic profiles in women candidates for in-vitro fertilization (IVF). Trial design and methods: For this randomized, double-blinded, parallel, placebo-controlled clinical experiment, 40 PCOS-positive infertile women who were IVF candidates were included. They ranged in age from 18 to 40. The 20 participants in the two intervention groups received either CoQ10 or a placebo for 8 weeks. The expression of glucose transporter 1 (GLUT-1), peroxisome proliferator-activated receptor gamma (PPAR-γ), low-density lipoprotein receptor (LDLR), as well as metabolic profiles such as insulin metabolism and lipid profiles were evaluated. Quantitative RT-PCR determined the expression of GLUT-1, PPAR-γ, and LDLR on peripheral blood mononuclear cells. Lipid profiles and fasting glucose were assessed using enzymatic kits, and insulin was determined using Elisa kit. Results: In comparison to the placebo, CoQ10 supplementation significantly reduced blood insulin levels (-0.3±1.0 vs. 0.5±0.7, P=0.01) and insulin resistance (-0.1±0.2 vs. 0.1±0.2, P=0.01), and increased PPAR-γ expression (P=0.01). In infertile PCOS patients' candidates for IVF, CoQ10 supplementation showed no appreciable impact on other metabolic profiles. Also, CoQ10 supplementation revealed no significant impact on GLUT-1 (P=0.30), or LDLR (P=0.27) expression. Within-group changes in insulin levels (P=0.01) and insulin resistance (P=0.01) showed a significant elevation in the placebo group. When we adjusted the analysis for baseline BMI, baseline values of variables, and age, our findings were not affected. Conclusions: Eight weeks of CoQ10 supplementation demonstrated positive benefits on PPAR-γ expression, insulin resistance, and serum insulin in infertile PCOS women candidates for IVF.

Coenzyme Q0 inhibited the NLRP3 inflammasome, metastasis/EMT, and Warburg effect by suppressing hypoxia-induced HIF-1α expression in HNSCC cells.

Coenzyme Q0 (CoQ0), a quinone derivative from Antrodia camphorata, has antitumor capabilities. This study investigated the antitumor effect of noncytotoxic CoQ0, which included NLRP3 inflammasome inhibition, anti-EMT/metastasis, and metabolic reprogramming via HIF-1α inhibition, in HNSCC cells under normoxia and hypoxia. CoQ0 suppressed hypoxia-induced ROS-mediated HIF-1α expression in OECM-1 and SAS cells. Under normoxia and hypoxia, the inflammatory NLRP3, ASC/caspase-1, NFκB, and IL-1ß expression was reduced by CoQ0. CoQ0 reduced migration/invasion by enhancing epithelial marker E-cadherin and suppressing mesenchymal markers Twist, N-cadherin, Snail, and MMP-9, and MMP-2 expression. CoQ0 inhibited glucose uptake, lactate accumulation, GLUT1 levels, and HIF-1α-target gene (HK-2, PFK-1, and LDH-A) expressions that are involved in aerobic glycolysis. Notably, CoQ0 reduced ECAR as well as glycolysis, glycolytic capability, and glycolytic reserve and enhanced OCR, basal respiration, ATP generation, maximal respiration, and spare capacity in OECM-1 cells. Metabolomic analysis using LC-ESI-MS showed that CoQ0 treatment decreased the levels of glycolytic intermediates, including lactate, 2/3-phosphoglycerate, fructose 1,6-bisphosphate, and phosphoenolpyruvate, and increased the levels of TCA cycle metabolites, including citrate, isocitrate, and succinate. HIF-1α silencing reversed CoQ0-mediated anti-metastasis (N-Cadherin, Snail, and MMP-9) and metabolic reprogramming (GLUT1, HK-2, and PKM-2) under hypoxia. CoQ0 prevents cancer stem-like characteristics (upregulated CD24 expression and downregulated CD44, ALDH1, and OCT4) under normoxia and/or hypoxia. Further, in IL-6-treated SG cells, CoQ0 attenuated fibrosis by inhibiting TGF-ß and Collagen I expression and suppressed EMT by downregulating Slug and upregulating E-cadherin expression. Interesting, CoQ0 inhibited the growth of OECM-1 tumors in xenografted mice. Our results advocate CoQ0 for the therapeutic application against HNSCC.

Preparation and characterization of novel nanostructured lipid carriers (NLC) and solid lipid nanoparticles (SLN) containing coenzyme Q10 as potent antioxidants and antityrosinase agents.

We developed novel and optimal Q10-NLC/SLN formulations as antioxidant and anti-tyrosinase agents. The formulations were analyzed for particle size, morphology, entrapment efficiency (EE %), and long-term stability. The in vitro drug release and in vivo skin penetration were evaluated using dialysis bag diffusion and Sprague Dawley (SD) rats, respectively. Cytotoxicity and protecting effects were assessed by AlamarBlue® assay, ROS level by DCFH-DA, and tyrosinase activity by l-DOPA assay, measuring the absorbance at 470 nm. The selected formulations had optimal surface characterizations, including Z-average size, PDI, and Zeta potential ranging from 125 to 207 nm, 0.09-0.22, and -7 to -24, respectively. They also exhibited physiochemical stability for up to 6 months and EE% above 80 %. The lipids ratio and co-Q10 amount as variable factors significantly affected particle size and zeta potential but were insignificant on PDI. The in vitro release diagram showed that Q10-NLC/SLN revealed a fast release during the first 8 h and prolonged release afterward. The in vivo skin permeation revealed a higher accumulative uptake of co-Q10 in the skin for Q10-NLC/SLN compared to Q10 emulsions. Both selected Q10-NLC and Q10-SLN could reduce intracellular ROS after exposure to H2O2. The Q10-NLC was found to be more potent for inhibiting the tyrosinase activity compared to O10-SLN. The results suggest that the new formulations are promising carriers for topical delivery of co-Q10 as an anti-aging and skin-whitening agent.

Mini-encyclopedia of mitochondria-relevant nutraceuticals protecting health in primary and secondary care-clinically relevant 3PM innovation.

Despite their subordination in humans, to a great extent, mitochondria maintain their independent status but tightly cooperate with the "host" on protecting the joint life quality and minimizing health risks. Under oxidative stress conditions, healthy mitochondria promptly increase mitophagy level to remove damaged "fellows" rejuvenating the mitochondrial population and sending fragments of mtDNA as SOS signals to all systems in the human body. As long as metabolic pathways are under systemic control and well-concerted together, adaptive mechanisms become triggered increasing systemic protection, activating antioxidant defense and repair machinery. Contextually, all attributes of mitochondrial patho-/physiology are instrumental for predictive medical approach and cost-effective treatments tailored to individualized patient profiles in primary (to protect vulnerable individuals again the health-to-disease transition) and secondary (to protect affected individuals again disease progression) care. Nutraceuticals are naturally occurring bioactive compounds demonstrating health-promoting, illness-preventing, and other health-related benefits. Keeping in mind health-promoting properties of nutraceuticals along with their great therapeutic potential and safety profile, there is a permanently growing demand on the application of mitochondria-relevant nutraceuticals. Application of nutraceuticals is beneficial only if meeting needs at individual level. Therefore, health risk assessment and creation of individualized patient profiles are of pivotal importance followed by adapted nutraceutical sets meeting individual needs. Based on the scientific evidence available for mitochondria-relevant nutraceuticals, this article presents examples of frequent medical conditions, which require protective measures targeted on mitochondria as a holistic approach following advanced concepts of predictive, preventive, and personalized medicine (PPPM/3PM) in primary and secondary care.

Understanding coenzyme Q.

Coenzyme Q (CoQ), also known as ubiquinone, comprises a benzoquinone head group and a long isoprenoid side chain. It is thus extremely hydrophobic and resides in membranes. It is best known for its complex function as an electron transporter in the mitochondrial electron transport chain (ETC) but is also required for several other crucial cellular processes. In fact, CoQ appears to be central to the entire redox balance of the cell. Remarkably, its structure and therefore its properties have not changed from bacteria to vertebrates. In metazoans, it is synthesized in all cells and is found in most, and maybe all, biological membranes. CoQ is also known as a nutritional supplement, mostly because of its involvement with antioxidant defenses. However, whether there is any health benefit from oral consumption of CoQ is not well established. Here we review the function of CoQ as a redox-active molecule in the ETC and other enzymatic systems, its role as a prooxidant in reactive oxygen species generation, and its separate involvement in antioxidant mechanisms. We also review CoQ biosynthesis, which is particularly complex because of its extreme hydrophobicity, as well as the biological consequences of primary and secondary CoQ deficiency, including in human patients. Primary CoQ deficiency is a rare inborn condition due to mutation in CoQ biosynthetic genes. Secondary CoQ deficiency is much more common, as it accompanies a variety of pathological conditions, including mitochondrial disorders as well as aging. In this context, we discuss the importance, but also the great difficulty, of alleviating CoQ deficiency by CoQ supplementation.