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Background Mitochondrial Diseases (MDs) refers to a heterogeneous group of inherited metabolic disorders resulting in defective cellular energy production due to abnormal oxidative phosphorylation (OXPHOS) caused by pathogenic mitochondrial DNA or nuclear DNA variants. As mitochondria are pivotal for cell bioenergetics, MDs could potentially affect multisystem, leaving a devastating and life-threatening impact. The treatment of MDs present significant challenges due to the complexity of the disease and the wide heterogeneity of its molecular defects. Thus, the need for innovative and more comprehensive therapeutic approaches is evident. Methods This longitudinal, open-label study was a pilot trial involving 9 paediatric MD patients, aiming to gain a better understanding on the impact of hydroxytyrosol (HT) on the clinical outcomes of MD patients and to assess the feasibility and logistics of using HT as a dietary supplement for MD patients. Subjects received HT daily as dietary supplements for 12 months. Following this period, patients were then randomly assigned to either discontinue HT or continue receiving HT as their dietary supplements for an additional 6 months. Outcome measures that were assessed included the International Paediatric Mitochondrial Disease Scores, biochemical parameters, and quality of life assessments. Results Among the outcome measures assessed, HT supplementation demonstrated the most considerable impact on improving the health-related quality of life according to the PedsQL scoring system and potential effects on a subgroup of MD patients with Mitochondrial encephalopathy, lactic acidosis, and stroke-like episode (MELAS). Discussion This study demonstrated that HT supplementation resulted in improvement in health-related quality of life in MD patients, while the subgroup of MELAS patients showed additional potential beneficial effect from HT use. As a pilot trial, this study importantly highlighted HT’s tolerability in MD patients, which would facilitate trials of larger scale to be performed in the future. Conclusion This study highlights the use of HT as a health supplement and its potential therapeutic effects in paediatric patients diagnosed with MDs, especially in MELAS patients. The results lay the foundation for future large-scale clinical trials. Consequently, further clinical intervention studies and investigations into HT’s potential therapeutic mechanisms at the molecular and intercellular levels are strongly encouraged.

Background: Metabolic syndrome (MetS) patients have impaired hypothalamic regulatory functions involved in food intake and energy expenditure and suffer from a state of meta-inflammation. Pre-clinical studies demonstrated that ultramicronized palmitoylethanolamide (PEA) acts both on the adipose tissue and the central nervous system, while hydroxytyrosol (HTyr) counteracts several types of dysmetabolism. Objectives: The aim of our randomized crossover double-blind placebo-controlled pilot study was to evaluate the potential effects of a food supplement (FS) containing a co-micronized formulation of PEA and rutin along with HTyr, combined with a tailored calorie-controlled Mediterranean diet, in patients with MetS. Methods: Nineteen patients were enrolled and block-randomized to an eight-week MD together with the FS or placebo. After a two-week washout period, the treatments were reversed. Data on laboratory parameters and those detected by capillary sampling, anthropometry, body composition analysis, ultrasound examination, blood pressure monitoring, the 36-Item Short-Form Health Survey questionnaire, handgrip strength test, and physical performance tests were collected at each time point (protocol code R.S. 262.22, registered on 20 December 2022). Results: At the end of the study, patients supplemented with the FS showed a significant reduction in body weight, body mass index, fat mass, and inflammation biomarkers (CRP and ESR), compared to placebo-supplemented patients. In contrast, the fat-free mass, phase angle, and body cell mass were increased in FS compared to placebo patients. Conclusions: Although preliminary, the results of our clinical study suggest that co-micronized PEA–rutin and HTyr may be of help against adiposopathy in patients with MetS.

Beer and wine contains the simple phenol tyrosol (TYR) which is endogenously converted into hydroxytyrosol (HT), one of the strongest dietary antioxidants, by CYP2A6 and CYP2D6 polymorphic enzymes. We investigated in humans the rate of this bioconversion after beer and red wine (RW) intake. In a single blind, randomized, crossover, controlled clinical trial (n = 20 healthy subjects), we evaluated TYR absorption and biotransformation into HT following a single dose of (i) RW, (ii) Indian pale ale beer (IPA), (iii) blonde beer, and (iv) non-alcoholic beer (free). Individuals were genotyped for CYP2A6 and CYP2D6, and a polygenic activity score (PAS) was derived. RW triggered the highest increase in total TYR recovered, followed by IPA, blonde, and free beers. Although the HT content in beer was minimal, an increase in HT production was observed in all beers following TYR in a dose-response manner, confirming TYR to HT biotransformation. Sex differences were identified in the rate of the conversion following RW. PAS scores correlated linearly with the recoveries of HT (HT:TYR ratios) after RW intake. In conclusion, after beer and RW consumption, TYR is absorbed and endogenously biotransformed into HT. This mechanism could be modulated by sex, genetics, and matrix components.

Hydroxytyrosol (HT) is a natural antioxidant found in olive products and characterized by well-documented beneficial effects on human health. Several research studies are ongoing that aim to investigate its potency and molecular mechanism of action. The present study aimed to investigate the potential effect of HT on human obesity through a randomized double-blind prospective design. HT in two different doses (15 and 5 mg/day) and a placebo capsule was administered to 29 women with overweight/obesity for six months and their weight and fat mass were monitored at three time points (baseline, 4, 12 and 24 weeks). Statistically significant weight and visceral fat mass loss (%weight loss: p = 0.012, %visceral fat loss: p = 0.006) were observed in the group receiving the maximum HT dosage versus placebo after 4 weeks of the intervention, with attenuation of these findings at 12 and 24 weeks of the study. Urine samples were collected during the intervention and analyzed via liquid chromatography–high-resolution mass spectrometry for untargeted metabolomic purposes and comparisons between study groups were performed. HT administration was safe and well-tolerated. To the best of our knowledge, this is the first human cohort investigating the effects of HT on obesity for a prolonged study period.

Hydroxytyrosol (HT) and punicalagin (PC) exert cardioprotective and antiatherosclerotic effects. This study evaluated the effect of an oral supplement containing HT and PC (SAx) on dyslipidemia in an adult population. A randomized, double-blind, controlled, crossover trial was conducted over a 20-week period. SAx significantly reduced the plasma levels of triglycerides (TG) in subjects with hypertriglyceridemia (≥150 mg/dL) (from 200.67 ± 51.38 to 155.33 ± 42.44 mg/dL; p < 0.05), while no such effects were observed in these subjects after the placebo. SAx also significantly decreased the plasma levels of low-density lipoprotein cholesterol (LDL-C) in subjects with high plasma levels of LDL-C (≥160 mg/dL) (from 179.13 ± 16.18 to 162.93 ± 27.05 mg/dL; p < 0.01), while no such positive effect was observed with the placebo. In addition, the placebo significantly reduced the plasma levels of high-density lipoprotein cholesterol (HDL-C) in the total population (from 64.49 ± 12.65 to 62.55 ± 11.57 mg/dL; p < 0.05), while SAx significantly increased the plasma levels of HDL-C in subjects with low plasma levels of HDL-C (<50 mg/dL) (from 44.25 ± 3.99 to 48.00 ± 7.27 mg/dL; p < 0.05). In conclusion, the supplement containing HT and PC exerted antiatherosclerotic and cardio-protective effects by considerably improving dyslipidemia in an adult population, without co-adjuvant treatment or adverse effects.

PurposeEnrichment of wheat bread with either α-cyclodextrin (α-CD) or an inclusion complex of hydroxytyrosol (HT) and α-CD was performed to examine potential postprandial benefits.MethodsTen healthy normoglycaemic adults were provided with either a glucose solution (reference food, GS), white wheat bread (WB), wheat bread enriched with α-CD (α-CDB) or wheat bread enriched with HT/α-CD complex ((HT + α-CD)B), with 1-week intervals in amounts that yielded 50 g of available carbohydrates. Venous blood samples were collected before consumption and at 15, 30, 45, 60, 90, 120 and 180 min, postprandially. Glycaemic, insulinaemic and appetite hormone responses as well as glycaemic index (GI) and subjective appetite ratings were evaluated.ResultsBoth enriched breads were characterized as low GI foods (α-CDB:49.7, (HT + α-CD)B:40.0) and presented similar reduction in glucose, insulin and GLP-1 responses. Significant differences were found in glucose values 45 min after (HT + α-CD)B consumption compared to α-CDB (P < 0.05) as well as in serum ghrelin, 120 min postprandially, between (HT + α-CD)B and WB in (− 90.55 ± 29.17 and 16.53 ± 21.78 pg/dL, respectively, P < 0.05). Neither of the enriched breads prevailed regarding the induced self-reported satiety. However, their consumption led to a lower desire for the next meal compared to WB.ConclusionEnrichment of bread with α-CD resulted in positive effects on postprandial glycaemia and induced satiety. Incorporation of encapsulated HT offered similar overall acceptability, due to the bitter taste-masking effect provided by α-CD, and a slightly additional positive effect in postprandial glycaemia and satiety. The development of foods with favorable metabolic effects is of great importance for the prevention of chronic diseases. The study was prospectively registered in clinicaltrials.gov (NCT04725955, date: 27th January 2021).

Collecting dietary intake data is associated with challenges due to the subjective nature of self–administered instruments. Biomarkers may objectively estimate the consumption of specific dietary items or help assess compliance in dietary intervention studies. Our aim was to use a panel of plasma and urine biomarkers to assess the validity of self-reported dietary intake using a modified Mediterranean Diet Scale (mMDS) among firefighters participating in Feeding America’s Bravest (FAB), an MD cluster-randomized controlled trial. In our nested biomarker pilot study, participants were randomly selected from both the MD intervention group (n = 24) and the control group (n = 24) after 12-months of dietary intervention. At baseline data collection for the pilot study (t = 12-months of FAB), participants in the control group crossed-over to receive the MD intervention (active intervention) for 6-months. Participants in the intervention group continued in a self-sustained continuation phase (SSP) of the intervention. Food frequency questionnaires (FFQ), 13-item-mMDS questionnaires, 40 plasma fatty acids, inflammatory biomarkers and urinary hydroxytyrosol and tyrosol were analyzed at both time points. Spearman’s correlation, t-tests and linear regression coefficients were calculated using SAS software. Overall, the mMDS derived from the FFQ was highly correlated with the specific 13-domain-mMDS (r = 0.74). The concordance between the two questionnaires for low and high adherence to MD was high for all the participants in the parent trial (κ = 0.76). After 6 months of intervention in the pilot study, plasma saturated fatty acid decreased in both groups (active intervention: −1.3 ± 1.7; p = 0.002; SSP: −1.12 ± 1.90; p = 0.014) and oleic acid improved in the SSP (p = 0.013). Intake of olive oil was positively associated with plasma omega-3 (p = 0.004) and negatively with TNF-α (p < 0.001) at baseline. Choosing olive oil as a type of fat was also associated with higher levels of plasma omega-3 (p = 0.019) at baseline and lower TNF-α (p = 0.023) at follow up. Intake of red and processed meats were associated with lower serum omega-3 (p = 0.04) and fish consumption was associated with lower IL-6 at baseline (p = 0.022). The overall mMDS was associated with an increase in plasma omega-3 (p = 0.021). Good correlation was found between nutrient intake from the FFQ and the corresponding plasma biomarkers (omega-3, EPA and DHA). In this MD randomized controlled trial, some key plasma biomarkers were significantly associated with key MD diet components and the overall mMDS supporting the validity of the mMDS questionnaire as well as compliance with the intervention.

Inclusion of biophenols in traditional foods transforms them into functional foods that may help to decrease CVD risk. The aim of the present study was to determine whether the consumption of hydroxytyrosol-enriched sunflower oil (HSO) improves certain CVD biomarker values. A total of twenty-two healthy volunteers participated in a cross-over study involving two 3-week periods, separated by a 2-week washout period, in which volunteers consumed 10–15 g/d of either HSO (45–50 mg/d of hydroxytyrosol) or non-enriched (control) sunflower oil. Total cholesterol, LDL-cholesterol, HDL-cholesterol, arylesterase activity, oxidised LDL and soluble vascular cell adhesion molecule (sVCAM-1) levels were measured in the plasma obtained at the beginning and at the end of each treatment period. The HSO group displayed a significantly higher level (P < 0·01) of arylesterase activity and significantly lower levels of oxidised LDL and sVCAM-1 (both P < 0·05) than the control group. These results suggest that HSO may help prevent CVD.

Objective: The purpose of this study was to assess the efficacy and safety of edivoxetine (LY2216684), a selective norepinephrine reuptake inhibitor, in pediatric patients with attention-deficit/hyperactivity disorder (ADHD). Method: A fixed-dose, randomized, double-blind, 8 week study was conducted in patients 6–17 years of age, who were randomized by two strata: 1) Patients with prior stimulant use randomized to placebo, edivoxetine 0.1 mg/kg/day, 0.2 mg/kg/day, or 0.3 mg/kg/day arms in a 1:1:1:1 ratio; 2) Stimulant-naïve patients randomized to placebo, edivoxetine 0.1mg/kg/day, 0.2 mg/kg/day, 0.3 mg/kg/day, or osmotic-release oral system methylphenidate (OROS MPH) (18–54 mg/day based on body weight) arms in a 1:1:1:1:1 ratio. The primary efficacy measure was baseline-to-week 8 change of ADHD Rating Scale (ADHD-RS) total score for edivoxetine 0.2 mg/kg/day and 0.3 mg/kg/day. Results: A total of 340 patients were randomized to placebo (n=78); edivoxetine 0.1 mg/kg/day (n=76), 0.2 mg/kg/day (n=75), or 0.3 mg/kg/day (n=75); or OROS MPH (n=36). In the stimulant-naïve stratum, the positive control, OROS MPH, was significantly superior to placebo in mean ADHD-RS total score change at end-point (−19.46, p=0.015). The edivoxetine 0.2 mg/kg/day and 0.3 mg/kg/day arms had statistically significantly greater improvement than the placebo arm in mean ADHD-RS total score change at end-point (placebo −10.35; edivoxetine 0.2 mg/kg/day −16.09, p<0.010; edivoxetine 0.3 mg/kg/day −16.39, p<0.010) and Clinical Global Impressions-Improvement score (placebo 3.05; edivoxetine 0.1 mg/kg/day 3.01, p=0.860; edivoxetine 0.2 mg/kg/day 2.54, p=0.013; edivoxetine 0.3 mg/kg/day 2.53, p=0.013). In the overall efficacy-analyses data set (n=270), the effect size estimates for edivoxetine doses 0.1 mg/kg/day, 0.2 mg/kg/day and 0.3 mg/kg/day at the week 8 time point were 0.17, 0.51, and 0.54, respectively (for the stimulant-naïve stratum, the effect size estimate for OROS MPH was 0.69). Compared with placebo, edivoxetine treatment was associated with statistically significant increases in blood pressure and pulse (p<0.050), and a smaller increase or slight decrease in weight. Conclusions: Edivoxetine at doses of 0.2 mg/kg/day and 0.3 mg/kg/day demonstrated efficacy in ADHD treatment, despite the presence of a sizeable placebo response. No unexpected adverse events were identified. Clinical Trial Registry identifier: NCT00922636

The aim of this study was to determine the efficacy and safety profile of tratinterol hydrochloride tablets in the treatment of bronchial asthma. This multicenter, randomized, double-blind clinical research study was completed at 6 centers in the People’s Republic of China from March 2009 to June 2010, and a randomized trial of procaterol hydrochloride tablets produced by Otsuka Pharmaceutical Co Ltd was conducted. The study was approved by the Medical Ethics Committee of the First Hospital of China Medical University. The clinical trial registration number is 2007L04263. A total of 223 patients were selected for this study, with 112 patients in the treatment group and 111 in the control group. The lung function of the 2 groups after treatment significantly increased in all (P < 0.05); however, there was no significant difference in the changes between the 2 groups (P > 0.05). The occurrence of related adverse events at varying degrees in the control group was higher than in the treatment group. It is safe and effective to use tratinterol hydrochloride tablets to treat bronchial asthma.