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2.2. Participants | pain | MAY | Healthy Japanese participants with mild pain of the knee joint(s) were recruited from 18 May 2021 to 21 August 2021, by Ortho Medico (Tokyo, Japan), a contracted research organization, using a website ( | PMC10346176 |
2.3. Study Design | knee pain | This study was a randomized, double-blind, placebo-controlled trial. Participants were randomly assigned to two groups, namely, an MSM consumption group and a placebo control group, with a 1:1 ratio. The details of this study were explained, and written informed consent was obtained from all participants. Both groups of participants took 10 tablets per day, five tablets each at breakfast and dinner for 12 weeks. The dominant ingredient of the tablets of the MSM consumption group was 200 mg MSM per tablet and that of the placebo control group was the same amount of lactose. Lactose was adopted as a placebo, referring to a clinical trial of supplement intake for knee pain [This study was conducted in accordance with the principles of the Declaration of Helsinki. The trial protocol and any amendments were approved by the ethics committee of the Takara Clinic, Medical Corporation Seishinkai (approval number: 2204-00145-0004-0E-TC), and statistical analysis was performed by Ortho Medico. This trial has been registered in the UMIN Clinical Trials Registry (UMIN000044258). | PMC10346176 | |
2.4. Outcomes | SECONDARY | The measured values of the total score of JKOM at 12 weeks after the test sample consumption were considered the primary outcome of this study. The secondary outcomes were as follows: (1) the measured values of the total score of JKOM at 4 and 8 weeks after consumption; (2) the differences in the total score of JKOM between screening (0 weeks) and 4, 8, or 12 weeks; (3) the measured values at 4, 8, and 12 weeks and amounts of changes between screening (0 weeks) and 4, 8, or 12 weeks after assessment of VAS [The JKOM questionnaire was written in Japanese and an English translation had been published [Diets three days before each test date were surveyed. The diet study used the Calorie and Nutrition Diary (CAND), developed by Ortho Medico [ | PMC10346176 | |
2.5. Sample Size and Statistical Analysis | Kawasaki | KAWASAKI | The target sample size was 80, assuming an ineligibility rate of approximately 10%. The sample size was calculated with the following assumptions: Cohen’s d = 0.80, type I error rate = 0.05, power = 80%, and the ratio of the two groups = 1:1. All participants, physicians, investigators, and analysts were blinded to the allocation information. The staff of Ortho Medico provided computer-generated random numbers using Statlight#11 Ver. 2.10 software (Yukms, Kawasaki, Japan). Data were described as means and SDs, median and minimum to maximum, or 95% confidence interval. The Chi-square test was used to compare sex and K-L grade between the two groups. Mean differences between two individual groups were analyzed by Welch’s | PMC10346176 |
3. Results | PMC10346176 | |||
3.1. Participant Flow | pain | MAY | From 25 May 2021 to 21 August 2021, 163 healthy Japanese participants with mild pain of the knee joint(s) were screened for enrollment ( | PMC10346176 |
3.2. JKOM Scores, JOA Scores, and Inflammation Markers | The measured values of JKOM scores and JOA scores are shown in The results of inflammatory markers and type II collagen biomarkers are shown in | PMC10346176 | ||
3.3. Questionaries | pain | The JKOM questionnaire consists of a total of 25 items: Q1 to Q8 for pain and stiffness in knees, Q9 to Q18 for conditions in daily life, Q19 to Q23 for general activities, and Q24 to Q25 for health conditions. Answers for each question were chosen from a scale of 0 to 4: 0 for no pain at all or good condition, and 4 for most severe or bad condition. Only four items with significant changes in scores were observed during the study period, and the results are shown in | PMC10346176 | |
3.4. Safety Evaluation | ADVERSE EVENTS | The results of physical examination, urine analysis, peripheral blood test, and medical interview revealed no health problems during the study period, and no adverse events were reported ( | PMC10346176 | |
4. Discussion | Depressive, comorbidity, OA, inflammation, morning pain, KOA, pain, knee pain | OBESE, INFLAMMATION, DEGENERATIVE, PATHOPHYSIOLOGY, OXIDATIVE STRESS | This is the first clinical trial of MSM oral consumption in healthy participants who felt mild pain in the knee joint rather than patients with OA. The JKOM total scores at 12 weeks after test sample consumption in the MSM group were significantly lower than those in the placebo group. The health conditions of the JKOM of the MSM group at 12 weeks were also significantly lower than those of the placebo group. Decreases in the JKOM total scores and the health condition scores indicated improvement of the knee and systemic health conditions of the participants by MSM consumption. The MSM group showed significant improvements compared to placebo at 12 weeks, in terms of morning pain, pain while standing, and health condition in the JKOM questionnaires. These results indicate that MSM alleviates wake-up pain and standing pain and improves general health and quality of life in healthy individuals with knee mild pain in daily life.OA is common in the hands, knees, hips, and spine and manifests as inflammation, stiffness, and loss of range of motion [The JKOM score is a questionnaire on the QOL of KOA based on Japanese lifestyle [The pathophysiology of KOA includes inflammatory and degenerative processes associated with oxidative stress. Mild inflammation may be caused by aging, which may contribute to local inflammation and affect the knee joint [As for changes in serum cytokine levels, studies have investigated the effects of MSM on serum cytokines in obese individuals [In recent years, it has been suggested that there is a gender difference in the association of knee pain inflammatory cytokines [Depressive symptoms are a major comorbidity in elderly OA patients. Depressive symptoms are known to be a factor associated with both knee pain and physical function, especially self-reported physical function, in KOA patients [This study had several limitations. JKOM is associated with WOMAC and SF-36 and is a scientifically valid questionnaire to assess QOL related to KOA [ | PMC10346176 |
5. Conclusions | pain | This study indicated that MSM oral consumption improved knee conditions and systemic health conditions in healthy participants who were experiencing mild pain in the knee joint. | PMC10346176 | |
Supplementary Materials | The following supporting information can be downloaded at: Click here for additional data file. | PMC10346176 | ||
Author Contributions | A.T. and N.N. conceived and designed the study. A.T., N.N. and A.Y. analyzed the data and drafted the manuscript. T.K. and A.Y. supervised the study. All authors have read and agreed to the published version of the manuscript. | PMC10346176 | ||
Institutional Review Board Statement | This study was conducted in accordance with the principles of the Declaration of Helsinki. The trial protocol and any amendments were approved by the ethics committee of the Takara Clinic, Medical Corporation Seishinkai (approval number: 2204-00145-0004-0E-TC), and statistical analysis was performed by Ortho Medico. This trial has been registered in the UMIN Clinical Trials Registry (UMIN000044258). | PMC10346176 | ||
Informed Consent Statement | Informed consent was obtained from all patients involved in this study. | PMC10346176 | ||
Data Availability Statement | The data used to support the findings of this study are available from the corresponding author upon reasonable request. | PMC10346176 | ||
Conflicts of Interest | The authors declare no conflict of interest. | PMC10346176 | ||
References | KNEE OSTEOARTHRITIS | Consort flow diagram.Effect of MSM consumption on JKOM questions. (Background of the study participants.PPS, Per protocol set; SAF, Safety analysis population; Japanese Knee Osteoarthritis Measure (JKOM) and Japanese Orthopaedic Association (JOA) scores from weeks 0 to 12.CI, confidence interval; Plasma concentrations of IL-1β, IL-6, Hs-CRP, CIICP, and C2C from 0 to 12 weeks.CI, confidence interval; Comparison of the amount of change in PIICP at each week from week 0.CI, confidence interval; | PMC10346176 | |
1. Introduction | obesity, muscle mass, weight gain, overweight, mitochondrial dysfunction, weight loss | OBESITY, OBESE, INFLAMMATION, MITOCHONDRIAL DYSFUNCTION, OXIDATIVE STRESS, PATHOGENESIS | Background: Despite the growing recognition of the obesity crisis, its rates continue to rise. The current first-line therapies, such as dietary changes, energy restriction, and physical activity, are typically met with poor adherence. Novel nutritional interventions can address the root causes of obesity, including mitochondrial dysfunction, and facilitate weight loss. Objective: The objective of this study was to investigate the effects of a multi-ingredient nutritional supplement designed to facilitate mitochondrial function and metabolic health outcomes over a 12 wk period. Methods: Fifty-five overweight and/or obese participants (age (mean ± SEM): 26 ± 1; body mass index (BMI) (kg/mThe obesity epidemic continues to grow unabated on a global scale. Over the last 30 years, the incidence of obesity has nearly tripled [Ultimately, the development of obesity can stem from an increased energy intake concomitant with reduced energy expenditure [Another factor in the etiology of obesity is excessive energy intake, which can cause oxidative stress [To address the constellation of factors underlying obesity, a multi-faceted approach must be taken. To counteract the cycle of ROS-associated weight gain, mitochondrial dysfunction, and subsequent inflammation, several natural ingredients have exhibited antioxidant properties. Supplementation with coenzyme Q10, an intermediate in the electron transport chain (ETC), has been shown to rescue pro-oxidative markers in serum and lower lipid peroxidation [While these ingredients have often been examined individually, there is limited utilization regarding the potential for a multi-ingredient supplementation strategy targeting the multiple pathways known to be involved in the pathogenesis of obesity. Our pre-clinical data suggested that such a strategy lowered body fat, preserved muscle mass, and improved mitochondrial function in white adipose tissue [ | PMC10490028 |
2. Materials and Methods | PMC10490028 | |||
2.1. Participant Screening & Recruitment | overweight, Overweight | OBESE | Overweight and obese men and women were recruited for the current study. Potential participants were first screened by email or telephone to confirm that they were a male or female between the ages 18 and 50 y, were overweight (BMI 25–29.9 kg/m | PMC10490028 |
2.2. Experimental Design | Participants were randomly allocated to receive either the multi-ingredient nutritional supplement (MIS) consisting of 7 ingredients (The following assessments were performed on eligible participants at the initiation of the study and after completion of the 12 wk supplement period: DXA scan, blood pressure, antecubital blood draw, grip strength, aerobic capacity (VOTo assess the progress between study initiation and completion (i.e., 12 wk), participants returned for testing at the 2 wk and 5 wk mark from the study initiation to perform a DXA scan and anthropometric measurements. Weekly phone calls and/or emails were conducted throughout the study period to ensure participant compliance. At the onset of the study, all participants received a copy of the Canada Food Guide and the evidence-based Canadian Society for Exercise Physiology (CSEP) Movement Guidelines [ | PMC10490028 | ||
2.3. Nutritional Supplementation | The exact composition of and nutrition information for the MIS and PLA capsules is provided in | PMC10490028 | ||
2.4. Anthropometric Measurements and Body Composition | Participants were weighed at baseline and at each follow-up study visit. Weight was measured using a Health-O-Meter 2600KL Digital Wheelchair Scale (Pelstar, McCook, IL, USA), and height was measured using a stadiometer (Perspective Enterprises, Portage, MI, USA). Waist and measurements for the calculation of WHR [ | PMC10490028 | ||
2.5. Measurement of Blood Pressure | Participants were fitted with a FlexiPort™ reusable blood pressure cuff (WelchAllyn, Inc., Okumoto, NY, USA) to measure blood pressure while the participant was relaxed and seated for 15 min. Measurements were obtained with an automated blood pressure machine (Spot Vital Signs Device, WelchAllyn). | PMC10490028 | ||
2.6. Venous Blood Sampling and Analysis | dyslipidemia | BLOOD, INSULIN RESISTANCE, DYSLIPIDEMIA | Blood was collected in the morning following an overnight 10 h fast (no food or caffeine) and the participants were instructed to consume 250 mL of water prior to arrival. Blood was taken from the antecubital vein and drawn into evacuated tubes with heparin for plasma collection, ethylenediaminetetraacetic acid (EDTA) for plasma collection, and non-treated tubes were used to collect serum. Serum and plasma samples were immediately taken to the Core Laboratory at McMaster University Medical Centre for the analysis of the following panel of tests for general blood biochemistry: complete blood count (CBC), gamma-glutamyl transferase (GGT), bilirubin, alanine aminotransferase (ALT), creatine kinase (CK), creatinine, and C-reactive protein (CRP). Markers of dyslipidemia (i.e., triglycerides, total cholesterol, LDL cholesterol, and HDL cholesterol) and blood sugar control (i.e., glucose, insulin) were measured. Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) was calculated as the equation [fasting insulin (U/L) × fasting glucose (nmol/L)/22.5] [ | PMC10490028 |
2.7. Isolation of Extracellular Vesicles | Exactly 400 µL of serum was initially subjected to two consecutive centrifugation spins at 2000× | PMC10490028 | ||
2.8. miRNA Extraction and RT-PCR | The MagMAX™ | PMC10490028 | ||
2.9. Metabolic Measures and Resting Metabolic Rate (RMR) | Participants were placed in a supine position while connected to a metabolic cart with an online gas collection system (Moxus Modular Oxygen Uptake System, AEI Technologies, Pittsburgh, PA, USA), and the system acquired oxygen consumption (VO | PMC10490028 | ||
2.10. Maximal Voluntary VO | Participants completed a double-leg incremental peak oxygen uptake (VO | PMC10490028 | ||
2.11. Maximal Voluntary Handgrip Assessment | Handgrip strength was measured using an isometric dynamometer (JAMAR | PMC10490028 | ||
2.12. Questionnaires | The RAND 36-Item Health Survey Version 1.0 is used extensively as a survey instrument for assessing participant health-related quality of life (HRQOL). We examined scales pertaining to physical functioning and role limitations due to health problems instead of the total score [ | PMC10490028 | ||
2.13. Dietary Intake | Three-day food records (recording 2 weekdays and 1 weekend day) were collected and analyzed using the MyFitnessPal smartphone app (MyFitnessPal, Under Armour, Baltimore, MD, USA.) and website that tracks diet and exercise. If participants were not comfortable with utilizing the smartphone application, they were provided with a paper diet log. Participants were given instructions on how to record their intake of any food and beverages. Diet logs were completed at periods before the participant began the study protocol, at the study midpoint (5 wk), and final timepoint (12 wk). | PMC10490028 | ||
2.14. Activity Tracking | Study participants were provided with a pedometer (Omron HJ-321, Omron, Kyoto, Japan) to record their daily step counts for three separate 7 d periods within the study to determine average daily step count. Daily step count for a 7 d period was recorded at periods before the participant began the study protocol, at the study midpoint (5 wk), and final timepoint (12 wk). | PMC10490028 | ||
2.15. Sample Size Calculation | The MIS was comprised of 7 separate ingredients, with aspects featuring a potential varied or synergistic [ | PMC10490028 | ||
2.16. Statistical Analysis | Post-intervention differences between treatment arms in outcome variables were compared using a one-way analysis of covariance (ANCOVA), implementing the corresponding pre-intervention variables as covariates. If data were not normally distributed, logarithmic transformations were performed. Endpoints that were intractably non-normal were assessed using the Mann–Whitney U test. Within-group analysis was performed utilizing a paired | PMC10490028 | ||
3. Results | PMC10490028 | |||
3.1. Study Information and Compliance | A total of 65 participants were randomized: 55 completed the study, five dropped out ( | PMC10490028 | ||
3.2. Baseline Characteristics | overweight | OBESE | Fifty-five participants (23 men, 32 women) with a mean age of 25.9 ± 1.1 y (mean ± SEM) completed the study. The participants were overweight to obese, with a mean BMI of 30.5 ± 0.6 kg/m | PMC10490028 |
3.3. Co-Primary Outcomes Utilizing Modified ITT | For the examination of weight and fat mass (co-primary outcomes) exclusively, we utilized a modified ITT analysis. After adjustment for pre-intervention body weight, there was a statistically significant difference in post-intervention body weight between the PLA and MIS interventions, | PMC10490028 | ||
3.4. Anthropometry and Body Composition | After adjustment for pre-intervention body weight, there was a statistically significant difference in post-intervention weight between the treatment arms (After adjustment for pre-intervention fat mass, there was a significant difference in post-intervention fat mass between the treatment arms (There was no significant difference in the post-intervention total fat-free mass between the treatment arms (The ratio of fat-free mass (kg) to fat mass (kg), termed herein the Body Composition Index (BCI), was significantly different between the intervention arms (The BMI adjusted for pre-intervention values was significantly different between the treatment arms (Following adjustment for pre-intervention data, there was no significant difference in the post-intervention waist-to-height ratio between the treatment arms (There were significant differences detected between the treatment arms in the post-intervention regional fat mass in the trunk and gynoid regions ( | PMC10490028 | ||
3.5. Clinical Biochemistry | Following adjustment for pre-intervention ALT, there was a significant difference in post-intervention ALT between the treatment arms (Following adjustment for the respective baseline variables, there were no significant differences in post-intervention serum creatinine (There were no significant differences between the treatment arms in GGT, CRP, or bilirubin ( | PMC10490028 | ||
3.6. Markers of Dyslipidemia and Glucose Metabolism | There were no significant differences between the treatment arms with respect to total cholesterol, low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglycerides ( | PMC10490028 | ||
3.7. Hematology | After adjustment for pre-intervention circulating eosinophil cell population, there was a statistically significant difference in post-intervention data between the treatment arms ( | PMC10490028 | ||
3.8. Indices of Physical Health, Metabolism and Function | No statistically significant differences were found between the two treatment arms in post-intervention systolic blood pressure, diastolic blood pressure, resting heart rate, or bone mineral density, adjusted for the corresponding pre-intervention variable data ( | PMC10490028 | ||
3.9. Diet, Activity Level, and Self-Reported Quality of Life | At baseline, there was no significant difference between the treatment arms in terms of energy intake, caffeine consumption, and 7-day pedometer-derived average daily step count ( | PMC10490028 | ||
3.10. Molecular Signalling Factors and Antioxidant Capacity | EV-associated | Post-intervention growth differentiation factor 15 (GDF15) was significantly different between the two treatment arms, following adjustment for pre-intervention data (The circulating EV-associated miRNA species miR-34a (Oxygen Radical Absorbance Capacity (ORAC) within the blood plasma was not significantly different the between treatment arms ( | PMC10490028 | |
4. Discussion | obesity, liver disease, obesity-related glomerulopathy, Fatty liver disease, overweight, mitochondrial dysfunction, weight loss, impairment of kidney function | OBESITY, OBESE, LIVER DISEASE, MITOCHONDRIAL DYSFUNCTION, PATHOGENESIS | We report that the daily consumption of a multi-ingredient supplement (MIS) designed to facilitate weight loss and mitochondrial function [Amongst an overweight population, there is a significantly lower mortality risk for individuals who are classified as overweight (BMI of 25.0–29.9 kg/mBy design, it is not possible to isolate which individual aspects of the seven-component MIS contributed to our observations; each has been shown to independently facilitate weight loss and/or improve mitochondrial function. We have previously reported that 5-, 7-, and 10-component MIS significantly reduced body weight and fat mass, and improved markers of in vivo metabolism in a murine model [The composition of MIS was designed to also include bioactive compounds that could facilitate mitochondrial function, given the established relationship between mitochondrial dysfunction and the pathogenesis of obesity. Increased consumption of food can lead to increased circulating lipids and carbohydrates, providing an ‘over-supply’ of energy substrates in metabolic tissues, which in turn stimulates the production of ROS [Fatty liver disease, when the triglyceride content of the liver organ weight surpasses 5%, is the most common liver disease associated with individuals who are obese [To examine the potential mechanisms of improved hepatic biomarkers, we performed additional molecular analysis. Growth differentiation factor-15 (GDF-15) is a novel cytokine member of the transforming growth factor β superfamily, whose expression increases in response to a variety of stimuli, including metabolic stress [Another potential mechanism via which the MIS may elicit metabolic and hepatic benefits is via circulating miRNAs contained within extracellular vesicles. EVs are emerging mechanisms of intercellular communication through the release or shedding of vesicles by various cells [Our examination of clinical hematology revealed a significant difference between the MIS and PLA treatment arms, with a significantly lower eosinophil count following 12 wks of MIS. Interestingly, eosinophil count has been previously shown to be positively correlated with BMI up to a plateau of 40 kg/mAn impairment of kidney function, specifically obesity-related glomerulopathy [We acknowledge several limitations of the current study. A possible limitation of this study is that we did not have full control of physical activity and/or dietary intake during the experimental period. At the onset of the study, we provided simple diet information (the Canadian Food Guide) and only provided diet and activity guidelines at the inception to determine the potential effect of an MIS in a free-living scenario without intensive behavioral intervention. The lack of strict dietary and/or exercise controls and the impact of COVID-19 in the third inception cohort were also factors that may have contributed to the increase in body weight in the control group and may represent a potential attenuation of weight loss in the MIS group. Finally, the current study was conducted for 12 wks and thus we could not observe the sustainability of the effects over a longer period. Future studies should address interventions with longer durations. | PMC10490028 |
5. Conclusions | In conclusion, the provision of 12 wks of MIS comprising ingredients known to facilitate mitochondrial function, increase lipid metabolism, and enhance body re-composition [ | PMC10490028 | ||
Supplementary Materials | The following supporting information can be downloaded at: Click here for additional data file. | PMC10490028 | ||
Author Contributions | J.P.N.: Conceptualization, Methodology, Validation, Formal Analysis, Investigation, Writing—Original Draft, Visualization, and Project Administration. A.J.M.: Formal Analysis, Investigation, Reviewing, and Project Administration. D.X.: Formal Analysis, Investigation, Writing, and Reviewing. A.D.C.: Formal Analysis, Investigation, and Reviewing. K.M.: Formal Analysis, Investigation, and Reviewing. M.R.F.: Formal Analysis, Investigation, and Reviewing M.A.T.: Supervision of all aspects, Writing, Reviewing, and Editing. All authors have read and agreed to the published version of the manuscript. | PMC10490028 | ||
Institutional Review Board Statement | The study was approved by the Hamilton Health Sciences Integrated Research Ethics Board (HIREB-5754), conformed to the guidelines outlined in the Declaration of Helsinki, and complied with the guidelines set out in the Canadian Tri-Council policy statement on ethical conduct for research involving humans. The trial was registered at clinicaltrials.gov (NCT03812211). The study was conducted under Good Clinical Practice (GCP) guidelines. | PMC10490028 | ||
Informed Consent Statement | All participants were informed of the nature of the study and its potential risks before providing their written informed consent. | PMC10490028 | ||
Data Availability Statement | Not applicable. | PMC10490028 | ||
Conflicts of Interest | GENETIC DISORDERS, FOUNDER, CHRONIC DISEASES | Exerkine Corporation is a biotechnology company that develops and commercializes therapies based on supplements, exercise-derived factors (‘exerkines’), and extracellular vesicles to treat genetic disorders, chronic diseases, and aging. MAT is the founder, CEO, and CSO of Exerkine Corporation. At the time of publication submission, a Canadian patent (CA 3050823) was granted for the supplement described herein. The author warrants that the COI did not impact the execution of the research, including data collection, analyses, and interpretation, or in the decision to publish the manuscript. | PMC10490028 | |
References | ± SE | INFLAMMATION | Characterization of anthropometric changes following 12 wks of a multi-ingredient supplement (MIS, Characterization of plasma and circulating molecular signaling factors following 12 wks of a multi-ingredient supplement (MIS, green bars) compared to placebo (PLA, pink bars). (Characterization of plasma antioxidant content and capacity following 12 wks of a multi-ingredient supplement (MIS, green bars) compared to placebo (PLA, pink bars). (Nutritional composition of the multi-ingredient supplement (MIS) and placebo (PLA) control supplement.The quantities listed represent the complete daily serving of the MIS or PLA. Participants consumed servings of the supplement during the 12 wk intervention period (7 d/wkBaseline participant characteristics in both treatment arms.Data are presented as means ± SE. BMI: body mass index.Anthropometric measurements following 12 wks of treatment, adjusted for baseline variables.Post-intervention data are presented as adjusted means ± SEs. Post-intervention variables were compared using one-way ANCOVA, with corresponding baseline variables as covariates. Within-group comparisons were made using a paired Post-intervention clinical biochemistry, fasting glucose, and blood lipids following 12 wks of treatment, adjusted for baseline variables.Post-intervention data are presented as adjusted means ± SEs. Post-intervention variables were compared using one-way ANCOVA, with corresponding baseline variables as covariates. Within-group comparisons were made using a paired Post-intervention hematology following 12 wks of treatment, adjusted for baseline variables.Post-intervention data are presented as adjusted means ± SEs. Post-intervention variables were compared using one-way ANCOVA, with corresponding baseline variables as covariates. Within-group comparisons were made using a paired Post-intervention indices of physical health, function, and metabolism following 12 wks of treatment, adjusted for baseline variables.Post-intervention data are presented as adjusted means ± SEs. Post-intervention variables were compared using one-way ANCOVA, with corresponding baseline variables as covariates. Within-group comparisons were made using a paired Post-intervention indices of molecular markers of inflammation, metabolism, and antioxidant capacity following 12 wks of treatment, adjusted for baseline variables.Post-intervention data are presented as adjusted means ± SEs. Post-intervention variables were compared using one-way ANCOVA, with corresponding baseline variables as covariates. Within-group comparisons were made using a paired | PMC10490028 |
Background | Choline, as a neurotransmitter acetylcholine precursor, is reportedly associated with cognitive function. Although there are several cohort and animal studies on choline-containing foods and cognitive function, only a few interventional studies were reported. Egg yolk is a rich source of different choline-containing chemical forms, such as phosphatidylcholine (PC), lysophosphatidylcholine (LPC), and α-glycerophosphocholine (α-GPC). This study aimed to investigate the effect of consuming 300 mg of egg yolk choline per day on cognitive function of Japanese adults. | PMC10280906 | ||
Methods | dementia | MOS | A 12-week, randomized, double-blind, placebo-controlled, parallel-group study was conducted in 41 middle-aged and elderly males and females (43.9% female) aged ≥ 60 years and ≤ 80 years without dementia. Participants were randomly assigned to placebo and choline groups. The choline group received a supplement containing egg yolk choline (300 mg/day), and the placebo group received an egg yolk supplement free from choline for 12 weeks. Assessments of Cognitrax, Trail Making Tests (TMT) part A and B, the MOS 36-Item Short-Form Health Survey (SF-36), the Simplified Japanese Version of the WHO-Five Well-Being Index (WHO-5), and plasma choline levels were performed before and 6 and 12 weeks after supplement intake. In the present study, 19 subjects (9 in the placebo group and 10 in the choline group) were excluded due to the violation of the discontinuation criteria or participant compliance, and 41 subjects were analyzed. | PMC10280906 |
Results | The change amount of verbal memory scores and verbal memory test-correct hit (delay) was significantly higher in the choline group than in the placebo group at baseline-6 and baseline-12 weeks. The plasma free choline level was significantly higher in the choline group compared with the placebo group at 6 weeks. Conversely, the choline group showed significantly lower Cognitrax processing speed scores, symbol digit coding testing correct responses, and SF-36 physical quality of life summary scores compared to the placebo group at 6 weeks. | PMC10280906 | ||
Conclusions | The results suggested that continued 300 mg/day intake of egg yolk choline improved verbal memory, which is a part of cognitive functions. To confirm the observed effects of egg yolk choline, more well-designed and large-scale studies are warranted. | PMC10280906 | ||
Trial registration | Study protocols were pre-registered in the Clinical Trials Registration System (UMIN-CTR) (UMIN 000045050). | PMC10280906 | ||
Keywords | PMC10280906 | |||
Background | forgetfulness, dementia | Recently, population aging has progressed worldwide. The number of people aged ≥ 60 years is expected to increase by 2 billion till 2050 [Exercise habituation, smoking cessation, nutritional intervention, and social activity are recommended to reduce the risk of developing dementia [PC, one of the choline compound in the egg yolk, is the popular source of choline, a precursor to the neurotransmitter acetylcholine, which is hypothesized to help maintain cognitive function [The choline compounds in egg yolk are composed primarily PC, and its metabolites, LPC and α-GPC . They are collectively called egg yolk choline. Although there are various chemical forms of choline, we focused on egg yolk choline because of the high proportion of PC, the phospholipid form in foods.Therefore, a 12-week, randomized, double-blind, placebo-controlled, parallel-group study was conducted to investigate the effect of continuous intake of egg yolk choline on cognitive function. Subjects were healthy, middle-aged, and elderly Japanese males and females aged 60 to 80 years without dementia who were concerned or had been pointed out by others about their forgetfulness. | PMC10280906 | |
Methods | PMC10280906 | |||
Subjects | forgetfulness, dementia, ill | The participants were 60 middle-aged and elderly Japanese males and females aged 60–80 years without dementia who had been made aware of their forgetfulness or had it pointed out by others. Moreover, they were judged not to be ill by a clinical investigator and with 26 points or more on the Mini-Mental State Examination-Japanese (MMSE-J) screening test [The sample size was determined according to a previous pilot study [ | PMC10280906 | |
Study design | The study was conducted at KSO Inc. (Tokyo, Japan) from August to December 2021, under the supervision of Iwama Y. as the principal investigator with support from a project team composed of a doctor, a clinical laboratory technician, and a nutritionist. This 12-week, randomized, double-blind, placebo-controlled, parallel-group study divided the participants into the placebo and choline groups by the block-randomization method.The Cognitrax test [There were no dropouts during the study period, but five participants were excluded due to a substantial change in the living environment during the study period, a violation of study limitations, and a lack of reliability. One participant could not take the 12-weeks test on that day due to illness, and only a safety evaluation was conducted six days later. Furthermore, 14 subjects were excluded because they had 10% or more changes in the clinical test that have been reported to be associated with cognitive function [Flow chart | PMC10280906 | ||
Primary endpoint | As the primary endpoint, the Cognitrax test (Health Solution Inc., Tokyo, Japan), a computer-based cognitive test with a Japanese version developed by CNS Vital Signs, LLC. (USA) [ | PMC10280906 | ||
Secondary endpoints | SECONDARY | As secondary endpoints, five tests were conducted. All tests other than safety evaluations were conducted before the test and 6 and 12 weeks after intake. Safety evaluations were conducted before the test and 12 weeks after intake. | PMC10280906 | |
Trail making test | TMT part A (TMT-A) and part B (TMT-B) were performed to assess attention and executive function. Participants were asked to connect the numbers from 1 to 25 in TMT-A and to connect the numbers from 1 to 13 and the 12 Japanese letters alternatively in TMT-B as early as possible. The time taken to perform the test and the number of errors were assessed. | PMC10280906 | ||
SF-36 | pain | SF-36 consisted of 36 questions to measure eight health concept subscales (physical functioning, physical role, bodily pain, general health, vitality, social functioning, emotional role, and mental health). Additionally, physical component summary scores (PCS), mental component summary scores, and role/social component summary scores were calculated from eight subscales. | PMC10280906 | |
WHO-5 | cheerful | WHO-5 consisted of five questions (cheerful and in good spirits, calm and relaxed, active and vigorous, wake up feeling fresh and rested, things that interest me) to assess the condition in the last 2 weeks, and each score and total score were calculated. | PMC10280906 | |
Plasma choline level | Plasma free and fat-soluble choline levels were analyzed, respectively. 100 μL of plasma was mixed with 900 μL of methanol. Following sonication for 10 minutes, the samples were centrifuged at 15,000 rpm for 10 min. at 4°C, and the supernatant was aliquoted. Filter filtration was performed immediately before the analysis, and plasma free choline levels was measured by LC/MS/MS quantitative analysis (Waters, QTRAP4500, 40 °C, A: acetonitrile /B:5 mM ammonium acetate [pH 4.0]), and fat-soluble choline levels were also measured by LC/MS/MS quantitative analysis (BRUKER, micrOTOF-QII, 30°C, A: acetonitrile /B:5 mM ammonium acetate [pH4.0]). The analyses were conducted by the specialist in charge of the analyses of Kewpie Corporation (Tokyo, Japan). | PMC10280906 | ||
Dietary survey with BDHQs | overeating or undereating | This was performed to ensure that subjects were not overeating or undereating, which would negatively influence the evaluation of the effects of functional foods. | PMC10280906 | |
Safety evaluation | high-density lipoprotein-cholesterol, occult blood reaction | ADVERSE EVENTS, BLOOD | As a safety evaluation, it was performed that, physical measurement (height, weight, and body mass index), physical examination (systolic blood pressure, diastolic blood pressure, and pulse), hematological tests (leukocyte count, erythrocyte count, hematocrit, and platelet count), blood biochemistry tests (total protein, albumin, total bilirubin, indirect bilirubin, alkaline phosphatase, aspartate transaminase, alanine transaminase, L-lactate dehydrogenase, gamma-glutamyl transpeptidase, total cholesterol, triglycerol, high-density lipoprotein-cholesterol, urea-nitrogen, creatinine, sodium, potassium, chloride, blood glucose, and hemoglobin A1C), urinalysis (protein, glucose, and occult blood reaction), and medical interviews. Blood and urine analyses were conducted at BML, Inc. (Saitama, Japan). Blood collection was performed after fasting for 4 h or more. The participants completed daily life diaries to investigate the status of consumption of the supplements and the presence of adverse events. | PMC10280906 |
Ethical approval | The study was conducted after obtaining approval from the Nihonbashi Cardiology Clinic Institutional Review Board (approval number: NJI-021-07-01, approval date: July 27, 2021), in accordance with the principles of the Declaration of Helsinki by the World Medical Association and the ethical guidelines for bioscience and medical research involving human subjects set forth by Ministry of Education, Culture, Sports, Science and Technology, Ministry of Health, Labour and Welfare, and Ministry of Economic, Trade, and Industry. The study protocol was pre-registered with the Clinical Trials Registry System (UMIN-CTR) (UMIN 000045050). | PMC10280906 | ||
Statistical analysis | Allocation-adjustment factors were age, sex, egg consumption, plasma free choline level, Cognitrax short version total and verbal memory scores, MMSE-J score, and GDS-S-J score. The reason why the verbal memory score was added to the adjustment factor is that the function was confirmed by previous research [The test results are presented as the mean ± standard error of the amount of change. The statistical significance level was set at | PMC10280906 | ||
Results | PMC10280906 | |||
Subject characteristics | SE | Participant characteristics are shown in Table Participant characteristicsMean ± SE of 20 or 21 subjects. The | PMC10280906 | |
TMT | SE | The results of the TMT scores are shown in Table Effects of egg yolk choline on ⊿TMT test scores in subjectsMean ± SE of 20 or 21 subjects. The | PMC10280906 | |
QOL survey | SF-36 revealed significantly lower PCS 12 weeks post-ingestion in the choline group compared with the placebo group (1.88 ± 1.1vs. −1.76 ± 1.19; | PMC10280906 | ||
Discussion | forgetfulness, dementia | This study evaluated the effects of continuous egg yolk choline ingestion at 300 mg on cognitive function in middle-aged and older adults who were aware of healthy forgetfulness but not dementia or who had been indicated by others for forgetfulness. The results showed that there was a significant improvement in the choline group compared with the placebo group in verbal memory ability, a part of the cognitive function.In this test, plasma choline concentration was measured. Previous studies revealed that phosphatidylcholine ingestion increases plasma free choline and brain acetylcholine levels [The ingested egg yolk choline is well absorbed in the small intestine by a complex mechanism. PC is degraded to LPC by pancreatic phospholipase A2 in the small intestine [The processing speed score and SDC test used to calculate the rate of processing efficiency were significantly higher in the placebo group after 6 weeks, although these parameters have been reported to be a function related to cholinergic nerves [Soybean is also a well-known source of phospholipids, but egg yolk phospholipids have a high level of PC of approximately 80% compared with an approximately 30% in soybean [ | PMC10280906 | |
Strength and limitation | The appearance of significant differences in VBM score (at 6 weeks: In the future, to assess the effects of choline intake more accurately, dietary choline intake will need to be investigated in Japan, or intervention tests will need to be conducted in the area where choline is listed in the dietary reference intake information. Its effect on different age groups or populations other than the Japanese are yet to be elucidated. | PMC10280906 | ||
Conclusions | dementia | This study showed that in middle-aged and older Japanese males and females, ingestion of 300 mg/day egg yolk choline increased plasma free choline levels and improved verbal memory, a part of cognitive function. It has been proposed that the consumption of egg yolk choline could potentially maintain cognitive function in individuals without dementia. However, it remains unclear that whether the intake of egg yolk choline could prevent or reduce the incidence of dementia. Nevertheless, it has been suggested that incorporating regular consumption of egg yolk choline into the diet is an effective strategy for maintaining brain function in adults who are free of dementia. | PMC10280906 | |
Acknowledgements | We gratefully acknowledge the individuals who participated in this test. We also thank Enago ( | PMC10280906 | ||
Authors’ contributions | S.Y., N.K., W.W., K.S., M.K., Y.T., and R.M. conceived the study concept and design. M.K., Y.T., and R.M. as principal investigator was responsible for study logistics, data acquisition. Y.S. and N.K. prepared the manuscript. S.Y., N.K., K.S., Y.T., and Y.I. were responsible for conducting the trial, and data collection. S.Y., N.K., Y.T., and R.M. carried out the statistical analysis. Y.I. contributed to the test as clinical investigator. Y.M. and M.S. supervised the study design and commented on the manuscript. All authors reviewed the manuscript. | PMC10280906 | ||
Funding | This research and was funded by Kewpie Corporation (Tokyo, Japan). | PMC10280906 | ||
Availability of data and materials | The dataset supporting the conclusions of this article is included within the article. | PMC10280906 | ||
Declarations | PMC10280906 | |||
Ethics approval and consent to participate | The study was conducted after obtaining approval from the Nihonbashi Cardiology Clinic Institutional Review Board (approval number: NJI-021-07-01, approval date: July 27, 2021) and registering with the University Hospital Medical Information Network (UMIN) Center, (UMIN 000045050; registration date: August 4, 2021) following the Declaration of Helsinki (the World Medical Association) and the ethical guidelines for bioscience and medical research in the spirit for human subjects (Ministry of Education, Culture, Sports, Science and Technology, Ministry of Health, Labor and Welfare, and Ministry of Economic, Trade, and Industry). | PMC10280906 | ||
Consent for publication | Not applicable. | PMC10280906 | ||
Competing interests | S.Y., N.K., W.W., K.S., Y.T., M.K., and R.M. are employees of Kewpie Corporation. The remaining authors have no other conflicts of interest to report in this work. | PMC10280906 | ||
References | PMC10280906 | |||
Introduction | lung cancer, cancer, Lung cancer, death | LUNG CANCER, CANCER, LUNG CANCER | Lung cancer remains the leading cause of death from cancer, worldwide. Developing early detection diagnostic methods, especially non-invasive methods, is a critical component to raising the overall survival rate and prognosis for lung cancer. The purpose of this study is to evaluate two protocols of a novel in vitro cellular immune response test to detect lung cancer. The test specifically quantifies the glycolysis metabolism pathway, which is a biomarker for the activation level of immune cells. It summarizes the results of two clinical trials, where each deploys a different protocol's version of this test for the detection of lung cancer. In the later clinical trial, an improved test protocol is applied. | PMC9927051 |
Method | Lung cancer | BLOOD, LUNG CANCER, LUNG TUMOR | The test platform is based on changes in the metabolic pathways of the immune cells following their activation by antigenic stimuli associated with Lung cancer. Peripheral Blood Mononuclear Cells are loaded on a multiwell plate together with various lung tumor associated antigens and a fluorescent probe that exhibits a pH-dependent absorption shift. The acidification process in the extracellular fluid is monitored by a commercial fluorescence plate reader device in continuous reading for 3 h at 37 °C to document the fluorescent signal received from each well. | PMC9927051 |
Results | lung cancer stage | In the later clinical trial, an improved test protocol was applied and resulted in increased test accuracy. Specificity of the test increased to 94.0% and test sensitivity increased to 97.3% in lung cancer stage I, by using the improved protocol. | PMC9927051 | |
Conclusion | lung cancer | LUNG CANCER | The improved protocol of the novel cellular immune metabolic response based test detects stage I and stage II of lung cancer with high specificity and sensitivity, with low material costs and fast results. | PMC9927051 |
Keywords | PMC9927051 | |||
Background | cancer, Lung cancer, death, MLC | DISEASE, CANCER, LUNG CANCER | Lung cancer (LC) remains the worldwide leading cause of death from cancer. Unfortunately, approximately 75% of patients are diagnosed at an advanced stage of the disease (III, IV) [Current diagnostic methods (e.g., Computed Tomography—CT, Positron Emission Tomography—PET, Low-dose CT- LDCT, radiography) have high sensitivity but low specificity. False positive rates of 96.4% for LDCT and 94% for radiography [Studies show that activation of immune cells requires changes in the way metabolic energy (ATP molecules) is generated. Immune system cells alter their energy generation in order to obtain an effector function. Usually, the shift is from the oxidative phosphorylation cycle into an aerobic glycolysis cycle. This shift provides immediate energy that gives the immune system the ability to attack the foreign antigen [This article describes an improved immunometabolism blood test that measures the function of the immune cells in response to antigenic stimuli based on changes in the metabolic pathways of cells. There are several classical methods to test lymphocytes’ function. Mixed leukocyte culture (MLC) determines histocompatibility by co-culturing PBMCs of a potential donor with those of an allograft recipient. MLC takes 3–8 days to get results and involves the use of HIn a previous publication, we presented a novel, non-invasive, cancer detection platform [ | PMC9927051 |
Methods | PMC9927051 | |||
Metabolic activity test | PMC9927051 |
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