Strategies for oral delivery and mitochondrial targeting of CoQ10

Sato Y., Mutoh H., Suzuki M., Takekuma Y., Iseki K., Sugawara M.

Coenzyme Q10 (CoQ10) is an essential component in the electron-transport systems of mitochondria and bacteria and is often used as a supplementary treatment for some diseases. We previously reported that the bioavailability of CoQ10 powder was less than 10%. In this study, we investigated various preparations to improve the intestinal absorption of CoQ10 with focus on the effect of emulsification. We prepared a suspension and some emulsions with four types of surfactants and investigated the plasma concentration profile after oral administration to rats. The absorption of CoQ10 was improved by an emulsion formulation although there was little absorption of CoQ10 when a suspension was administered. However, little CoQ10 was absorbed in the bile duct-ligated group even when the emulsion formulation was administered (about 50% of the control group). Bile and emulsion formulation are essential for absorption of CoQ10. When the preparations containing Tween20 (polysorbate (20) sorbitan monolaurate) and Tween80 (polyoxyethylene (20) sorbitan monooleate) were administered, plasma concentrations of CoQ10 were higher than those obtained with preparations containing Tween65 (polyoxyethylene (20) sorbitan tristearate) and Span20 (sorbitan monolaurate). Tween20 and Tween80 have higher hydrophile-lipophile balance (HLB) values than those Tween65 and Span20. Our study suggests that highly lipophilic compounds like CoQ10 would diffuse the unstirred water layer and would easily access the intestinal apical membrane by an emulsion containing a surfactant with a high HLB value. Attention must be given to CoQ10 supplementation for patients whose bile is not excreted to the intestine such as patients with cholestasis.

Barakat A., Shegokar R., Dittgen M., Müller R.H.

Coenzyme Q10 (Q10) has a poor bioavailability due to its very low aqueous solubility and high molecular weight. The purpose of this review is to discuss the different types of Q10 drug delivery systems (DDS) ranging from the simple oily dispersions to the nanotechnology-oriented systems such as nanocrystals, self-nanoemulsified drug delivery systems, etc. to overcome the solubility issue. The basics of these approaches were discussed in relationship to the effect of Q10 absorption. For that purpose, the percentage of the drug absorbed to the blood stream out of the administered dose was calculated as the fraction absorbed (Fa%). The Fa% for the nanoemulsions discussed in this article did not correlate with droplet size. In human studies most of the delivery systems had a low Fa% being in the range from 1.53 to 12.48 %. The highest Fa% value was found to be for the self-emulsified drug delivery systems (SEDDS). In dogs studies, the Fa% values ranged between 0.28 (cyclodextrin complex) and 4.8 %. In rat studies, some other DDS like emulsions and solubilized formulations showed Fa% of around 0.22 %. The relationship between the average Fa% in rats, dogs and humans was found to be 1:15:20. One recent study applied both oral and intravenous delivery of Q10; the orally tested SEDDS formulation had an absolute bioavailability of 2.2 % corresponding to Fa% = 0.04 %. The studies with Q10 formulations based only on in vitro data were also discussed and assessed regarding the influence of formulation on solubility, release and/or uptake.

Zhou H., Zhang J., Jin Q., Liu G., Long Y., Duan M., Xia Q.

d -alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS), a water-soluble derivative of natural vitamin E, has been intensively used in drug delivery systems. TPGS (CoQ10-NE-TPGS) and lecithin-based (CoQ10-NE-LC) coenzyme Q10-loaded nanoemulsions were prepared by hot high-pressure homogenization (HPH) and tested for their ability to target heart tissue. Both formulations yielded particles ~50 nm in diameter. CoQ10 in both the formulations was in a supercooled melt state without crystallization. CoQ10-NE-TPGS more effectively delivered CoQ10 to heart tissue than CoQ10-NE-LC after intravenous administration. CoQ10 concentration in the heart was 2.8-fold higher at 5 min after intravenous administration of CoQ10-NE-TPGS compared to CoQ10-NE-LC. Higher tissue levels were maintained for 90 min after injection. These data suggest that CoQ10-NE-TPGS could be a potential vehicle for rapid delivery of CoQ10 to heart tissue.

Littlefield N., Beckstrand R.L., Luthy K.E.

Mahlin D., Bergström C.A.

The purpose of this study was to investigate if rapidly measured physical properties can predict glass-forming ability and glass stability of drug compounds. A series of 50 structurally diverse drug molecules were studied with respect to glass-forming ability and, for glass-formers (n=24), the physical stability upon 1 month of storage was determined. Spray-drying and melt-cooling were used to produce the amorphous material and the solid state was analysed by Differential Scanning Calorimetry (DSC) and Powder X-ray Diffraction. Thermal properties and molecular weight (Mw) were used to develop predictive models of (i) glass-forming ability and (ii) physical stability. In total, the glass-forming ability was correctly predicted for 90% of the drugs from their Mw alone. As a rule of thumb, drugs with Mw greater than 300 g/mole are expected to be transformed to its amorphous state by using standard process technology. Glass transition temperature and Mw predicted the physical stability upon storage correctly for 78% of the glass-forming compounds. A strong sigmoidal relationship (R(2) of 0.96) was identified between crystallization temperature and stability. These findings have the potential to rationalize decisions schemes for utilizing and developing amorphous formulations, through early predictions of glass-forming ability from Mw and physical stability from simple DSC characterization.

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.

Fibromyalgia (FM) is a complex disorder that affects up to 5% of the general population worldwide. Its pathophysiological mechanisms are difficult to identify and current drug therapies demonstrate limited effectiveness. Both mitochondrial dysfunction and coenzyme Q10 (CoQ10) deficiency have been implicated in FM pathophysiology. We have investigated the effect of CoQ10 supplementation. We carried out a randomized, double-blind, placebo-controlled trial to evaluate clinical and gene expression effects of forty days of CoQ10 supplementation (300 mg/day) on 20 FM patients. This study was registered with controlled-trials.com (ISRCTN 21164124). An important clinical improvement was evident after CoQ10 versus placebo treatment showing a reduction of FIQ (p

Nanjwade B.K., Kadam V.T., Manvi F.V.

Nanostructured lipid carriers (NLC) developed from mixtures of solid lipid and spatially incompatible liquid lipid by solvent diffusion method. This new type of lipid nanoparticles offers the advantage of improved drug loading capacity and release properties. In this study, Glyceryl distearate and Glyceryl behenate were chosen as solid lipid and Glyceryl triacetate used as liquid lipid. Ubidecarenone used as model drug was incorporated into the NLC. The influences of different type of solid lipid and liquid lipid concentration on physiochemical properties of the NLC were characterized. As a result, the drug encapsulation efficiencies were improved by adding the liquid lipid into the solid lipid of nanoparticles. NLC had higher encapsulation efficiency and drug release. In addition, in vivo study showed that the antioxidant activity of the Ubidecarenone (Co. Q10 NLC) was more effective than the Ubidecarenone (Coenzyme Q10) solution form on DPPH scavenging, anti-lipid peroxidation, lowers the effect of amnesia induced by scopolamine and increased bioavailability observed in Cmax, Tmax, and AUC. These results indicated that nanostructured lipid formulation of Ubiquinone (Coenzyme Q10) has more antioxidant activity than that of solution form and it can be used to reduce the oxidative stress and to increase the antioxidant enzyme activity in many neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease etc.

Zhou H., Zhang J., Long Y., Liu G., Duan M., Xia Q.

Coenzyme Q10-loaded lecithin nanocapsules (CoQ10-LNCs), composed of a CoQ10/lecithin/ GTCC/glycerol aqueous solution, were prepared by high-pressure homogenization. The zeta potential of the CoQ10-LNCs above -60 mV was determined on a Malvern Zetasize 2000 (Malvern Instruments, UK). The spherical shape of the CoQ10-LNCs was observed by using freeze-fracture transmission electron microscopy (FF-TEM), and the particle size was found to be below 100 nm. The supercooled state of the CoQ10-LNCs was observed by differential scanning calorimetry (DSC). In an oral bioavailability study, the CoQ10 plasma level after administering CoQ10-LNCs was higher than that after administering a CoQ10 tablet over 24 hours, and the relative bioavailability of CoQ10 was improved to 176.6% in mice. Based on the above results, the LNC delivery system might be a potential vehicle for improving the oral bioavailability of CoQ10.

Onoue S., Uchida A., Kuriyama K., Nakamura T., Seto Y., Kato M., Hatanaka J., Tanaka T., Miyoshi H., Yamada S.

The present study was undertaken to develop a solid self-emulsifying drug delivery system of coenzyme Q(10) (CoQ(10)/s-SEDDS) with high photostability and oral bioavailability. The CoQ(10)/s-SEDDS was prepared by spray-drying an emulsion preconcentrate containing CoQ(10), medium-chain triglyceride, sucrose ester of fatty acid, and hydroxypropyl cellulose, and its physicochemical, photochemical, and pharmacokinetic properties were evaluated. The CoQ(10)/s-SEDDS powder with a diameter of ca. 15 μm was obtained by spray-drying, in which the CoQ(10) was mostly amorphized. The CoQ(10)/s-SEDDS exhibited immediate self-emulsification when introduced to aqueous media under gentle agitation, forming uniform fine droplets with a mean diameter of ca. 280 nm. There was marked generation of reactive oxygen species, in particular superoxide, from CoQ(10) exposed to simulated sunlight (250W/m(2)), suggesting potent photoreactivity. Nano-emulsified solution of CoQ(10) under light exposure underwent photodegradation with 22-fold higher degradation kinetics than crystalline CoQ(10), although the CoQ(10)/s-SEDDS was less photoreactive. After the oral administration of CoQ(10)/s-SEDDS (100 mg-CoQ(10)/kg) in rats, enhanced exposure of CoQ(10) was observed with increases in both C(max) and AUC of ca. 5-fold in comparison with those of orally administered crystalline CoQ(10). From the improved physicochemical and pharmacokinetic data, the s-SEDDS approach upon spray-drying might be a suitable dosage option for enhancing nutraceutical and pharmaceutical values of CoQ(10).

Wang J., Wang H., Zhou X., Tang Z., Liu G., Liu G., Xia Q.

Nanostructured lipid carrier (NLC) is prospective active ingredients delivery systems based on combinations of solid lipids and liquid oil. Aqueous dispersion of NLC was prepared via hot high pressure homogenization technique. The CoQ10-NLC aqueous dispersion was prepared in order to improve the water solubility, photo-stability of Coenzyme Q10 (CoQ10). The physicochemical characterization parameters of CoQ10-NLC have been explored regarding particle size, zeta potential, polydispersity index (PDI) value and stability of CoQ10, which is an antioxidant. HPLC was employed to monitor the loading of CoQ10 encapsulated in NLC system. Morphology profile and hydrophobicity/hydrophilicity were determined and analyzed using atomic force microscopy (AFM) and water contact angle measurements, respectively. Infrared (IR) spectrometry was exploited to confirm the possible interaction and complex formation between CoQ10 and lipids. The photo-stability of CoQ10 was powerfully improved by NLC, more than 80% of CoQ10 remained unchanged in one month under natural daylight, while the retention of free CoQ10 only 33.5% under the same conditions. CoQ10-NLC offered comparatively high protection. The retention of CoQ10 in NLC system was about 65% after five-month exposure to natural daylight, the retention of free CoQ10 only 13.3%. The CoQ10 in the NLC-based formulation showed considerably enhanced photo-stability compared with CoQ10 itself, and displayed the better protection of CoQ10. The obtained results opened new perspectives on the photo-stability of CoQ10. The MTT analysis determined CoQ10-NLC lower cytotoxicity. In conclusion, the present investigation demonstrated that the CoQ10-NLC significantly improved the water solubility, especially the enhancement of photo-stability of CoQ10 under natural daylight.

Sharma A., Soliman G.M., Al-Hajaj N., Sharma R., Maysinger D., Kakkar A.

Impairments of mitochondrial functions have been associated with failure of cellular functions in different tissues, leading to various pathologies. We report here a mitochondria-targeted nanodelivery system for coenzyme Q10 (CoQ10) that can reach mitochondria and deliver CoQ10 in adequate quantities. Multifunctional nanocarriers based on ABC miktoarm polymers (A = poly(ethylene glycol (PEG), B = polycaprolactone (PCL), and C = triphenylphosphonium bromide (TPPBr)) were synthesized using a combination of click chemistry with ring-opening polymerization, self-assembled into nanosized micelles, and were employed for CoQ10 loading. Drug loading capacity (60 wt %), micelle size (25-60 nm), and stability were determined using a variety of techniques. The micelles had a small critical association concentration and were colloidally stable in solution for more than 3 months. The extraordinarily high CoQ10 loading capacity in the micelles is attributed to good compatibility between CoQ10 and PCL, as indicated by the low Flory-Huggins interaction parameter. Confocal microscopy studies of the fluorescently labeled polymer analog together with the mitochondria-specific vital dye label indicated that the carrier did indeed reach mitochondria. The high CoQ10 loading efficiency allowed testing of micelles within a broad concentration range and provided evidence for CoQ10 effectiveness in two different experimental paradigms: oxidative stress and inflammation. Combined results from chemical, analytical, and biological experiments suggest that the new miktoarm-based carrier provides a suitable means of CoQ10 delivery to mitochondria without loss of drug effectiveness. The versatility of the click chemistry used to prepare this new mitochondria-targeting nanocarrier offers a widely applicable, simple, and easily reproducible procedure to deliver drugs to mitochondria or other intracellular organelles.

KATAYAMA K., FUJITA T.

The intestinal absorption of 1', 2', -(3H)-coenzyme Q10 (3H-Q-10) was studied in rats with cannulated thoracic duct and the effect of surface-active agents on the lymphatic absorption of 3H-Q-10 was determined. The amount of radioactivity absorbed via lymphatics during the first 48 hr was 1 % of the dose after oral administration of 3H-Q-10 dissolved in sesame oil or 20 mM sodium taurocholate, and was 1.5% of the dose of 3H-Q-10 dissolved by HCO-60. Assuming that the amount of radioactivity recovered from urine (0.481%) and liver (0.004%) might come from the radioactivity absorbed via portal vein, the total amount of the radioactivity absorbed via portal vein and lymphatics was approximately 2% of the dose of 3H-Q-10 dissolved by HCO-60 and the main route in absorption of 3H-Q-10 was lymphatics. The model for lymphatic absorption of 3H-Q-10 was proposed by kinetic analysis of the data.

KOMMURU T.R., ASHRAF M., KHAN M.A., REDDY I.K.

Coenzyme Q10 (CoQ10), a highly lipophilic compound present in the inner mitochondrial membrane, is essential for production of cellular energy in the form of ATP. CoQ10 is used as an antioxidant and also in the treatment of various cardiovascular disorders. The relative bioavailabilities of powder filled capsule (I) and oil-based formulation (II) of CoQ10 were compared in beagle dogs in an open, randomized, multiple dose, cross-over design. Poor and slow absorption characteristics were observed for both the formulations. The AUC, Cmax, and Tmax for formulation I and II are comparable (p < 0.05) where the values for formulation I are 22.84 +/- 6.3 micrograms ml-1 h, 0.51 +/- 0.11 microgram/ml, and 6.1 +/- 2.0 h whereas the values for formulation II are 24.32 +/- 5.6 micrograms ml-1 h, 0.55 +/- 0.16 microgram/ml, and 6.6 +/- 2.3 h, respectively. Stability of CoQ10 at various temperature and humidity conditions and its photostability were studied. Various antioxidants were evaluated to determine the type and amount of antioxidant(s) required to improve the stability of CoQ10. Large extent of degradation was observed at 45 degrees C and 55 degrees C. The effect of humidity conditions on degradation was insignificant. Among the various antioxidants studied, mixture of ascorbic acid (5%) and EDTA (0.1%) offered better protection than phenolic antioxidants such as butylated hydroxy anisole (BHA), butylated hydroxy toluene (BHT), or propyl gallate (PG). Further, increasing concentrations of phenolic antioxidants (from 0.1 to 0.3%) accelerated the degradation.

Venkatesh S., Durga K., Padmavathi Y., Reddy B., Mullangi R.

Piperine (CAS 94-62-2), an alkaloid obtained from Piper nigrum and P. longum, is a known inhibitor of various enzymes (CYP isozymes) responsible for biotransformation of drugs. By inhibiting the metabolism of drugs, piperine improves the bioavailability of drugs. In the present study piperine (10 mg/kg) significantly increased the dose-dependent antinociceptive activity of ibuprofen evaluated by both acetic acid writhing and formalin test, when it was administered with ibuprofen. Ibuprofen plasma concentration was also increased when it was administered with piperine. The synergistic antinociception activity of ibuprofen when administered with piperine can be attributed to increased plasma concentration of ibuprofen. From this study it can be concluded that piperine can be used as a bioenhancer along with ibuprofen.

Kawabata Y., Wada K., Nakatani M., Yamada S., Onoue S.

The poor oral bioavailability arising from poor aqueous solubility should make drug research and development more difficult. Various approaches have been developed with a focus on enhancement of the solubility, dissolution rate, and oral bioavailability of poorly water-soluble drugs. To complete development works within a limited amount of time, the establishment of a suitable formulation strategy should be a key consideration for the pharmaceutical development of poorly water-soluble drugs. In this article, viable formulation options are reviewed on the basis of the biopharmaceutics classification system of drug substances. The article describes the basic approaches for poorly water-soluble drugs, such as crystal modification, micronization, amorphization, self-emulsification, cyclodextrin complexation, and pH modification. Literature-based examples of the formulation options for poorly water-soluble compounds and their practical application to marketed products are also provided. Classification of drug candidates based on their biopharmaceutical properties can provide an indication of the difficulty of drug development works. A better understanding of the physicochemical and biopharmaceutical properties of drug substances and the limitations of each delivery option should lead to efficient formulation development for poorly water-soluble drugs.

Ergin A.D., Seçen E., Celik A., Uner B.

Leigh syndrome (LS), a severe neurometabolic disorder caused by mitochondrial dysfunction, is often linked to coenzyme Q10 (CoQ10) deficiency. This study investigated using dequalinium chloride to create CoQ10-loaded DQAsomes (liposome-like vesicles) to improve CoQ10 solubility and delivery to mitochondria. DQAsomes were characterized for size, charge, encapsulation efficiency, and yield. Further, drug release, dissolution, and effects on cell viability were studied in human pluripotent stem cells (HPP) and NDUFV gene-mutant cells (MDCi007-A). Techniques like RT-PCR, ELISA, immunostaining, and Western blotting were used to assess pluripotency markers, gene expression, and apoptosis. Results showed DQAsomes with sizes between 165.8 and 311.2 nm and a negative charge. Encapsulation efficiencies ranged from 34.03 to 82.48%. CoQ10-loaded DQAsomes significantly improved cell viability compared to CoQ10 in solution. Additionally, CoQ10-DQAsomes decreased pluripotency markers, suggesting potential effects on stem cell properties. In summary, the development of CoQ10-loaded DQAsomes offers a promising approach to enhance CoQ10 delivery, potentially improving cellular health in LS. This represents a significant step forward in exploring new treatments for this challenging condition.

Wang Y., Lilienfeldt N., Hekimi S.

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.

Pan P., Zhou N., Sun Y., Chen Z., Han J., Zhou W.

BackgroundCoenzyme Q10 (CoQ10) plays an important role in the electron transport chain within the human mitochondrial respiratory chain. The manifestations of this deficiency exhibit a diverse range. This study investigates the clinical manifestations of primary coenzyme Q10 deficiency in neonates with the COQ4 mutation to improve the diagnosis of the disease and the prognosis through targeted treatment.MethodsWe report 4 patients with primary coenzyme Q10 deficiency by COQ4 variants in neonates. A comprehensive literature search and review for original articles and case reports with COQ4 mutation published from January 1989 to November 2023 was performed through Pubmed. We review clinical manifestations, diagnostic approaches, and treatment monitoring in these and 20 previously reported patients.ResultsWithin the cohort of four cases examined, three females and one male were identified from two distinct families. Specifically, case 1 and 2 consisted of monoamniotic twins. Cases 3 and 4 were siblings. A comprehensive review of 20 cases involving neonatal-onset COQ4 mutation was conducted. Half of the cases are Chinese. There was no statistically significant difference in the mortality between Chinese (9/12, 75%) and other regions (11/12, 91.7%) (P = 0.27). The survival time for the 24 cases was 60.0 ± 98.0 days (95% confidence interval CI: 0–252.0 days). The incidence of prenatal abnormalities in preterm infants was significantly higher than that in full-term infants (66.7% vs. 16.7%, P = 0.02). Hyperlactatemia was one of the most common manifestations, accounting for 75% of cases (18/24). Twenty of the 24 cases were diagnosed by whole exome sequencing. Only 9 patients received exogenous coenzyme Q10 treatment, and all the 4 surviving patients received coenzyme Q10 supplementation.ConclusionThe prognosis of COQ4 mutation in the neonatal period indicates a low survival rate and an poor prognosis. This may be due to the incomplete understanding of the mechanism of how COQ4 gene defects lead to coenzyme Q10 deficiency and why CoQ10 supplementation does not respond well to treatment. To improve the diagnostic rate, in addition to genetic testing, mitochondrial functional verification should be prioritized in southern China, where the incidence is relatively high. It will facilitate more in-depth mechanistic studies.

Kacar G.

Understanding properties of materials at the molecular level are crucial to develop novel nano-carriers for the purpose of drug delivery. To that purpose, we perform mesoscopic simulations to study the formation mechanism and properties of lecithin liposomes encapsulating coenzyme Q10. The self-assembly process of the liposomes is monitored as well as the structural properties such as RDFs, Voronoi volumes and vesicle sizes. We found that increasing the concentration of lecithin leads to increasing vesicles size, but similar total Voronoi volumes and a decrease in the interactions between liposome and coenzyme Q10 as the number of lecithin molecules increase in solution. Moreover, steered MD simulations are performed to estimate the strength of interactions between encapsulated material and liposomes by applying a mechanical force to coenzyme Q10 beads. The computed values are observed to not to be influenced by the lecithin concentration. Finally, the computed radial density and pressure profiles indicate that the liposomal bilayer is quite homogenous in density, but exhibit interfacial pressure excess, which drives the bilayer to form spherical liposomal vesicles. The release properties of coenzyme Q10 are characterized and found that the Weibull’s model is able to represent the release character as a result of the mechanical force. Our findings in this work would hopefully stimulate a better understanding of liposomal systems while introducing new computational tools to study properties of these materials.

Chen K., Jackson N.J., Kelesidis T.

An ongoing important need exists to rapidly develop novel therapeutics for COVID-19 that will retain antiviral efficacy in the setting of rapidly evolving SARS-CoV-2 variants and potential future development of resistance of SARS-COV-2 to remdesivir and protease inhibitors. To date, there is no FDA-approved treatment for post-exposure prophylaxis against SAR-CoV-2. We have shown that the mitochondrial antioxidant mitoquinone/mitoquinol mesylate (Mito-MES), a dietary supplement, has antiviral activity against SARS-CoV-2 in vitro and in SARS-CoV-2 infected K18-hACE2 mice.In this exploratory, pragmatic open label clinical trial (ClinicalTrials.gov identifier NCT05381454), we studied whether Mito-MES is an effective post-exposure prophylaxis treatment in people who had high-grade unmasked exposures to SARS-CoV-2 within 5 days prior to study entry. Participants were enrolled in real-world setting in Los Angeles, United States between May 1 and December 1, 2022 and were assigned to either mito-MES 20 mg daily for 14 days (n = 40) or no mito-MES (controls) (n = 40). The primary endpoint was development of SARS-CoV-2 infection based on 4 COVID-19 diagnostic tests [rapid antigen tests (RATs) or PCR] performed during the study period (14 days post exposure).Out of 40 (23 females; 57.5%) study participants who took Mito-MES, 12 (30%) developed SARS-CoV-2 infection compared to 30 of the 40 controls (75%) (difference -45.0%, 95% confidence intervals (CI): -64.5%, -25.5%). Out of 40 (19 females; 47.5%) study participants in the control group, 30 (75.0%) had at least one positive COVID-19 diagnostic test and 23 (57.5%) were symptomatic. With regards to key secondary outcomes, among symptomatic SARS-CoV-2 infections, the median duration of viral symptoms was lower in the Mito-MES group (median 3.0, 95% CI 2.75, 3.25) compared to the control group (median 5.0, 95% CI 4.0, 7.0). None of the study participants was hospitalized or required oxygen therapy. Mito-MES was well tolerated and no serious side effect was reported in any study participant.This work describes antiviral activity of mito-MES in humans. Mito-MES was well tolerated in our study population and attenuated transmission of SARS-CoV-2 infection. Given established safety of Mito-MES in humans, our results suggest that randomized control clinical trials of Mito-MES as post-exposure prophylaxis against SARS-CoV-2 infection are warranted.This work was supported in part by National Institutes of Health grant R01AG059501 (TK), National Institutes of Health grant R01AG059502 04S1 (TK), NIH/National Center for Advancing Translational Sciences (NCATS) UCLA CTSI Grant Number UL1TR001881 and California HIV/AIDS Research Program grant OS17-LA-002 (TK).

Hsu C., Lee W.

Coenzyme Q10 (CoQ10) is one of the essential substances for mitochondrial energy synthesis and extra-mitochondrial vital function. Primary CoQ10 deficiency is a rare disease resulting from interruption of CoQ10 biosynthetic pathway and biallelic COQ4 variants are one of the genetic etiologies recognized in this hereditary disorder. The clinical heterogenicity is broad with wide onset age from prenatal period to adulthood. The typical manifestations include early pharmacoresistant seizure, severe cognition and/or developmental delay, dystonia, ataxia, and spasticity. Patients may also have multisystemic involvements such as cardiomyopathy, lactic acidosis or gastro-esophageal regurgitation disease. Oral CoQ10 supplement is the major therapeutic medication currently. Among those patients, c.370G > A variant is the most common pathogenic variant detected, especially in Asian population. This phenomenon also suggests that this specific allele may be the founder variants in Asia. In this article, we report two siblings with infantile onset seizures, developmental delay, cardiomyopathy, and diffuse brain atrophy. Genetic analysis of both two cases revealed homozygous COQ4 c.370G > A (p.Gly124Ser) variants. We also review the clinical manifestations of primary CoQ10 deficiency patients and possible treatment categories, which are still under survey. As oral CoQ10 supplement may improve or stabilize disease severity, early precise diagnosis of primary CoQ10 deficiency and early treatment are the most important issues. This review article helps to further understand clinical spectrum and treatment categories of primary CoQ10 deficiency with COQ4 variant.

ERGİN A.D., ÜNER B., BALCI Ş., DEMİRBAĞ Ç., Benetti C., OLTULU Ç.

Coenzyme Q10 (CoQ10) is a fat-soluble vitamin-with a benzoquinone-like structure. CoQ10 plays a role in membrane stability, energy conversion, and ATP production. It is also one of the important antioxidants in the body. The bioavailability of exogenous CoQ10 is extremely low due to its poor aqueous solubility and large molecular mass. In this study, mixed proniosomal drug delivery systems have been used to increase solubility and bioavailability of CoQ10. Arginine (semi-essential amino acid) was incorporated in the formulation composition to achieve higher efficacy by boosting nitric oxide presence, endothelial dysfunction, and cellular uptake. Proniosomes were investigated in terms of particle size, polydispersity index, zeta potential, encapsulation efficiency, and process yield, and optimization studies were carried on by utilizing STATISTICA 8.0 software considering dependent factors (carrier amount, drug amount, and surfactant ratio). Optimum proniosome formulation (particle size 187.5 ± 16.35 nm, zeta potential: -44.7 ± 12.8 mV, encapsulation efficiency 99.05±0.30%, and product yield: 90.55%) was evaluated for thermal analysis, in-vitro drug release using microcentrifuge method. In-vitro cytotoxicity studies of proniosomes were performed on intestinal Epithelial Cells (Cellartis®, ChiPSC18) and no cytotoxic effects was seen during the 72 h. Besides, anti Alzheimer effect was investigated on APPSL-GFP lentivirus-infected human neural cells (APPSL-GFP-l-HNC) and Alzheimer biomarkers (p-tau181 and p-tau217). While CoQ10’s relative bioavailability was statistically increased by proniosome compared to CoQ10 suspension (p

Ergin A.D., Üner B.

Alzheimer's disease (AD) is a neurological disorder that causes dementia and a progressive loss of thinking, social, and memory abilities. Afterwards, this worsening induces the person incapable of doing even the most fundamental duties. Recent research have proven that Coenzyme-q10 (CoQ10), one of the endogenous fatty acids, suppresses phosphorylated Tau protein which is GM1-ganglioside-bound amyloid β-protein (GM1-Aβ), and inhibiting the formation of amyloid plaques in Alzheimer's disease. Unfortunately, CoQ10 is poorly absorbed due to its high molecular weight (863.34 g/mol) and high lipophilicity, and its bioavailability is quite low. Therefore, we developed the CoQ10-loaded, cholesterol-free liposomes to get across the limitations. Liposomes were developed by ether injection method, and physicochemical characterization of the liposomes were evaluated in terms of particle size, size distribution (PDI), zeta potential, encapsulation efficiency (% EE), and process recovery as well. Release study, DSC analysis, morphological analysis, and cytotoxicity assay were performed with optimized formulations. The particle size, PDI, zeta potential, EE%, and process recovery of the formulations ranged from 343.8 to 167.9 nm; 0.269 to 0.431; (−56) to (−31.7); 18.15–93.48%; 74.63 to 99.62, respectively. According to cytotoxicity tests, liposomes have no significant toxic effect on cells while having decreased p-tau 181 and p-tau 231 proteins (p > 0.05). As a result, the novel cholesterol-free liposome formulation were proved that it might be candidate of including the therapeutical guideline for the future alzheimer's disease treatment with these substantial results.

Mthembu S.X., Orlando P., Silvestri S., Ziqubu K., Mazibuko-Mbeje S.E., Mabhida S.E., Nyambuya T.M., Nkambule B.B., Muller C.J., Basson A.K., Tiano L., Dludla P.V.

Dyslipidemia is one of the major risk factors for the development of cardiovascular disease (CVD) in patients with type 2 diabetes (T2D). This metabolic anomality is implicated in the generation of oxidative stress, an inevitable process involved in destructive mechanisms leading to myocardial damage. Fortunately, commonly used drugs like statins can counteract the detrimental effects of dyslipidemia by lowering cholesterol to reduce CVD-risk in patients with T2D. Statins mainly function by blocking the production of cholesterol by targeting the mevalonate pathway. However, by blocking cholesterol synthesis, statins coincidently inhibit the synthesis of other essential isoprenoid intermediates of the mevalonate pathway like farnesyl pyrophosphate and coenzyme Q10 (CoQ10). The latter is by far the most important co-factor and co-enzyme required for efficient mitochondrial oxidative capacity, in addition to its robust antioxidant properties. In fact, supplementation with CoQ10 has been found to be beneficial in ameliorating oxidative stress and improving blood flow in subjects with mild dyslipidemia.. Beyond discussing the destructive effects of oxidative stress in dyslipidemia-induced CVD-related complications, the current review brings a unique perspective in exploring the mevalonate pathway to block cholesterol synthesis while enhancing or maintaining CoQ10 levels in conditions of dyslipidemia. Furthermore, this review disscusses the therapeutic potential of bioactive compounds in targeting the downstream of the mevalonate pathway, more importantly, their ability to block cholesterol while maintaining CoQ10 biosynthesis to protect against the destructive complications of dyslipidemia.

Yalgın A., Köse F.A., Gökçe E.H.

The aim of this study was to use a 3D printer for developing human auricular models. Alginate, polylactic acid (PLA) and polyvinyl alcohol (PVA) were printed by Ultimaker-2 printer with two different methods. Their suitability for NIH-3T3 fibroblast cell growth was evaluated in the presence of Cyclosporine A (CycA) and Co-enzyme Q10 (Q10) SLNs. SLNs were prepared by high shear homogenization and their effect was investigated by MTT assay. CycA-SLNs had a PS of 218.1 ± 4.4 nm and Q10-SLNs were 142.4 ± 7.9 nm with PDI below 0.3. ZP of CycA-SLN was −23.6 ± 0.65 mV while the value for Q10-SLN was −13.7 ± 1.3 mV. The encapsulation efficiencies were 95.3 ± 0.5% for CycA-SLNs and 90.2 ± 3.8 for Q10-SLNs. Although the viability of cells was higher for alginate hydrogels indicating proliferation, due to mechanical instability, nanoparticles could be incorporated only to PLA model. The lowest viability was observed with CycA-SLN as 76.5%. Q10-SLNs increased the proliferation significantly (164%). CycA-SLNs on PLA models showed a viability of 82.55%. When Q10-SLNs were added in this combination the viability was enhanced to 114%. As a result of this study, it was concluded that Q10-SLNs increases the proliferation of cells on stable PLA auricular model and protects from toxicity.

Gasmi A., Bjørklund G., Mujawdiya P.K., Semenova Y., Piscopo S., Peana M.

Coenzyme Q10 (CoQ10) is an essential component of the electron transport chain. It also acts as an antioxidant in cellular membranes. It can be endogenously produced in all cells by a specialized mitochondrial pathway. CoQ10 deficiency, which can result from aging or insufficient enzyme function, has been considered to increase oxidative stress. Some drugs, including statins and bisphosphonates, often used by older individuals, can interfere with enzymes responsible for endogenous CoQ10 synthesis. Oral supplementation with high doses of CoQ10 can increase both its circulating and intracellular levels and several clinical trials observed that its administration provided beneficial effects on different disorders such as cardiovascular disease and inflammation which have been associated with low CoQ10 levels and high oxidative stress. Moreover, CoQ10 has been suggested as a promising therapeutic agent to prevent and slow the progression of other diseases including metabolic syndrome and type 2 diabetes, neurodegenerative and male infertility. However, there is still a need for further studies and well-designed clinical trials involving a large number of participants undergoing longer treatments to assess the benefits of CoQ10 for these disorders.

Staufer T., Schulze M.L., Schmutzler O., Körnig C., Welge V., Burkhardt T., Vietzke J., Vogelsang A., Weise J.M., Blatt T., Dabrowski O., Falkenberg G., Brückner D., Sanchez-Cano C., Grüner F.

X-ray fluorescence (XRF) imaging is a highly sensitive non-invasive imaging method for detection of small element quantities in objects, from human-sized scales down to single-cell organelles, using various X-ray beam sizes. Our aim was to investigate the cellular uptake and distribution of Q10, a highly conserved coenzyme with antioxidant and bioenergetic properties. Q10 was labeled with iodine (I2-Q10) and individual primary human skin cells were scanned with nano-focused beams. Distribution of I2-Q10 molecules taken up inside the screened individual skin cells was measured, with a clear correlation between individual Q10 uptake and cell size. Experiments revealed that labeling Q10 with iodine causes no artificial side effects as a result of the labeling procedure itself, and thus is a perfect means of investigating bioavailability and distribution of Q10 in cells. In summary, individual cellular Q10 uptake was demonstrated by XRF, opening the path towards Q10 multi-scale tracking for biodistribution studies.

Maneu V., Lax P., De Diego A.M., Cuenca N., García A.G.

This review focuses on retina degeneration occurring during glaucoma, age-related macular degeneration (AMD), diabetic retinopathy (DR), and retinitis pigmentosa (RP), and on the potential therapeutic use of triads of repositioned medicines, addressed to distinct but complementary targets, to prevent, delay or stop retina cell death. Although myriad pathogenic mechanisms have been implicated in these disorders, common signaling pathways leading to apoptotic cell death to all of them, and to all neurodegenerative diseases are (i) calcium dyshomeostasis/excitotoxicity; (ii) oxidative stress/mitochondrial dysfunction, and (iii) neuroinflammation/P2X7 receptor activation. From a therapeutic point of view, it is relevant to consider the multitarget approach based on the use of combined medicines acting on complementary pathogenic mechanisms that has been highly successful in the treatment of chronic diseases such as cancer, AIDS, pain, hypertension, Parkinson’s disease, cardiac failure, depression, or the epilepsies as the basic mechanisms of cell death do not differ between the different CNS degenerative diseases. We suggest the multi-target therapy approach could be more effective compared with single-drug treatments. Used at doses lower than standard, these triads may also be safer and more efficient. After the establishment of a proof-of-concept in animal models of retinal degeneration, potential successful preclinical trials of such combinations may eventually drive to test this concept in clinical trials in patients, first to evaluate the safety and efficacy of the drug combinations in humans and then their therapeutic advantages, if any, seeking the prevention and/or the delay of retina degeneration and blindness. • Eye diseases leading to retinal degeneration have pathogenic pathways common with neurodegenerative diseases. • Common pathogenic pathways in neurodegeneration are excitotoxicity, oxidative stress and inflammation. • Combined drug triads acting on different targets may afford more effective neuroprotection.

Xie J., Jiang J., Guo Q.

Primary Coenzyme Q10 Deficiency-7 (COQ10D7) is a rare mitochondrial disorder caused by pathogenic COQ4 variants. In this review, we discuss the correlation of COQ4 genotypes, particularly the East Asian-specific c.370G &gt; A variant, with the clinical presentations and therapeutic effectiveness of coenzyme Q10 supplementation from an exon-dependent perspective. Pathogenic COQ4 variants in exons 1–4 are associated with less life-threating presentations, late onset, responsiveness to CoQ10 therapy, and a relatively long lifespan. In contrast, pathogenic COQ4 variants in exons 5–7 are associated with early onset, unresponsiveness to CoQ10 therapy, and early death and are more fatal. Patients with the East Asian-specific c.370G &gt; A variant displays intermediate disease severity with multi-systemic dysfunction, which is between that of the patients with variants in exons 1–4 and 5–7. The mechanism underlying this exon-dependent genotype-phenotype correlation may be associated with the structure and function of COQ4. Sex is shown unlikely to be associated with disease severity. While point-of-care high-throughput sequencing would be useful for the rapid diagnosis of pathogenic COQ4 variants, whereas biochemical analyses of the characteristic impairments in CoQ10 biosynthesis and mitochondrial respiratory chain activity, as well as the phenotypic rescue of the CoQ10 treatment, are necessary to confirm the pathogenicity of suspicious variants. In addition to CoQ10 derivatives, targeted drugs and gene therapy could be useful treatments for COQ10D7 depending on the in-depth functional investigations and the development of gene editing technologies. This review provides a fundamental reference for the sub-classification of COQ10D7 and aim to advance our knowledge of the pathogenesis, clinical diagnosis, and prognosis of this disease and possible interventions.

Rizzardi N., Liparulo I., Antonelli G., Orsini F., Riva A., Bergamini C., Fato R.

Coenzyme Q10 (CoQ10) is a lipid-soluble molecule with a dual role: it transfers electrons in the mitochondrial transport chain by promoting the transmembrane potential exploited by the ATPase to synthesize ATP and, in its reduced form, is a membrane antioxidant. Since the high CoQ10 hydrophobicity hinders its bioavailability, several formulations have been developed to facilitate its cellular uptake. In this work, we studied the bioenergetic and antioxidant effects in I407 and H9c2 cells of a CoQ10 phytosome formulation (UBIQSOME®, UBQ). We investigated the cellular and mitochondrial content of CoQ10 and its redox state after incubation with UBQ. We studied different bioenergetic parameters, such as oxygen consumption, ATP content and mitochondrial potential. Moreover, we evaluated the effects of CoQ10 incubation on oxidative stress, membrane lipid peroxidation and ferroptosis and highlighted the connection between the intracellular concentration of CoQ10 and its antioxidant potency. Finally, we focused on the cellular mechanism that regulates UBQ internalization. We showed that the cell lines used in this work share the same uptake mechanism for UBQ, although the intestinal cell line was less efficient. Given the limitations of an in vitro model, the latter result supports that intestinal absorption is a critical step for the oral administration of Coenzyme Q10 formulations.