Abstract
Background
Chronic fatigue deleteriously affects the quality of life, thereby impairing physical and social functions and subsequently leading to financial and social problems. This study investigated the anti-fatigue effects of Korean Red Ginseng (KRG) extract in healthy middle-aged Japanese adults.
Methods
Forty-six participants were randomly divided into two groups (KRG and placebo). KRG (960 mg) or placebo capsules were administered for 3 weeks. The effect of KRG on fatigue was evaluated using visual analogue scale (VAS), plasma lactic acid, and cortisol levels.
Results and conclusions
Three-week consumption of KRG extract resulted in a significant decrease in the fatigue VAS score compared to the placebo group (p = 0.035). No significant difference was found in plasma cortisol and lactic acid levels between the groups. There were no differences between groups in the incidence of adverse events and the results of urinalysis, hematology, and biochemistry. These findings suggest the potential of KRG extract in mitigating fatigue and the safety of KRG extracts in healthy adults.
Keywords: Anti-Fatigue, Chronic fatigue, Korean Red Ginseng
Graphical abstract
1. Introduction
Fatigue, a ubiquitous phenomenon experienced by a multitude of individuals, has yet to find a comprehensive conceptualization or precise diagnostic approach despite persistent endeavors. In the Korean context, a noteworthy 29.5 % of patients seeking care in primary healthcare settings report substantial fatigue [1]. The heightened occurrence of prolonged or chronic fatigue (CF) has garnered renewed attention within the realm of general medicine, casting a challenge upon the prevailing classification schemes encompassing prevalent manifestations of depression, anxiety, and somatic distress syndromes. CF is assumed when fatigue lasts more than one month with or without comorbid conditions elucidating fatigue, whereas chronic fatigue syndrome can be diagnosed when fatigue lasts more than six months without physical or mental illness as the main reason for fatigue. CF has different characteristics than other common psychological and somatic forms of distress. The essential components of CF are mental and physical fatigue, neurocognitive symptoms, and musculoskeletal pain. Prolonged states of fatigue exert a deleterious impact upon quality of life, thereby impairing individual functioning and subsequently engendering financial ramifications and social seclusion. Findings from a comprehensive nationwide epidemiological study focused on CF within South Korea unveiled a prevalence rate of 57.70 ± 12.20 cases per 100,000 individuals [2]. Consequently, timely intervention for CF assumes paramount significance, poised to engender a resilient and productive societal milieu.
Recent advances in molecular biology and immunology have led to the formulation of a hypothesis regarding the intricate interplay between CF and metabolic processes. This speculation underscores the significance of metabolic aberrations, encompassing oxidative stress, perturbations in amino acids, nucleotides, nitrogen, and hormones, alongside anomalous immune activations, particularly alterations in NK and T cell. Of noteworthy emphasis are oxidative stress and hormonal imbalances. Several studies demonstrated the pivotal role played by oxidative stress in the pathogenesis of CF, concurrently proposing the plausible utility of antioxidants as a prospective therapeutic avenue [3]. Some studies have investigated the linkage between altered cortisol levels and CF, comparing cortisol excretion patterns among CF patients, depressive individuals, and healthy counterparts [4]. Therapeutic interventions targeting CF have revealed significant advancements, marked by the introduction of diverse treatment modalities. In this context, the anti-fatigue properties of ginseng have garnered research attention, with animal models corroborating the anti-fatigue efficacy and postulating potential mechanisms underlying polysaccharides derived from ginseng [5,6]. Despite the potential effects of Korean Red Ginseng (KRG) on fatigue, there is limited clinical evidence supporting its use for CF.
Ginseng, a time-honored botanical with a rich historical pedigree, occupies a revered position as a medicinal agent and dietary constituent, notable for its safe usage profile devoid of significant side effects sequelae. As for adverse events, both the German Commission E and Expanded Commission E document state “none known”. However, Ginseng Abuse Syndrome has been reported in cases of higher than normal doses of ginseng (>15 g/day) [7]. The noted side effects manifest mildly and tend to dissipate following the cessation of ginseng usage. Results emanating from a comprehensive safety study encompassing red ginseng, white ginseng, and American ginseng administration among Korean and Chinese cohorts revealed a uniform absence of disparities in overall symptoms and side effects, irrespective of ginseng type or study participants' nationality [8]. Dosing healthy subjects with white ginseng, red ginseng, or American ginseng at a prescribed daily dosage of 3 g for a duration of 35 days compellingly demonstrated an absence of both adverse effects and perturbations in blood parameters and biochemistry test outcomes [9]. A study targeting postmenopausal women elucidated enhancements in sexual function, concurrently reporting isolated instances of vaginal bleeding within the red ginseng cohort [10]. Other investigations involving postmenopausal women did not record any untoward events. Notably, vaginal bleeding within the red ginseng cohort could not be linked to hormonal fluctuations, as demonstrated by the inertness of hormone levels and estrogen receptors to the influence of red ginseng [11]. In cumulative consideration, the potency of ginseng in conferring beneficial outcomes supersedes the prospect of risks, thereby suggesting as a recommendation for future therapeutic explorations for CF.
A comprehensive understanding of the underlying physiological mechanisms of chronic fatigue remains a challenging endeavor. The underlying physiological underpinnings of chronic fatigue continue to elude comprehensive understanding. However, the potential roles of antioxidants and hormones to chronic fatigue, based on a substantial amount of previous investigations, warrant thorough investigation. Kennedy et al. reported decreased high-density lipoprotein (HDL), increased oxidized low-density lipoprotein (oxLDL), and increased F2 alpha-isoprostane levels in CF patients compared to healthy subjects. Importantly, the study also identified a relationship between isoprostane levels and CF symptoms, with a particular focus on symptoms such as joint pain and post-exercise discomfort [3]. Cleare et al. conducted a study assessing urinary free cortisol secretion, implicating hypocortisolism as a potential contributor to chronic fatigue syndrome (CFS) [12]. In the present study, we hypothesize that KRG has anti-fatigue effects and has great potential to prevent prolonged or CF. Based on the previous findings, visual analogue scale (VAS) of fatigue and cortisol levels were adopted to assess the effect of KRG for CF [12,13]. This study aimed to assess the anti-fatigue effects of Korean Red Ginseng (KRG) in a cohort of healthy Japanese adults, encompassing individuals of different age groups and genders. Additionally, this investigation rigorously assessed the safety and effectiveness of KRG.
2. Materials and methods
2.1. Participants and randomization
A total of 46 Japanese male and female individuals were recruited via the website (https://www.go106.jp/) managed by ORTHOMEDICO Inc. (Tokyo, Japan). Medical history and demographic data including sex, age, body weight, body height, body mass index (BMI) and habits were recorded during general screening of participants on visit 1 (day 0). Each subject underwent a complete evaluation of VAS of fatigue, physical examination, anthropometric measurement, urinalysis, and peripheral blood examination. The target number of participants was set at 42 as the maximum number of patients. In addition, in consideration of dropouts during the study period, 2 more patients per group were enrolled, and the number of participants to be enrolled was 46. Subject screening was conducted to meet the following inclusion criteria for this trial: (1) aged between 40 and 60 years, (2) healthy, (3) feel fatigue daily, and (4) VAS of fatigue are relatively high.
Exclusion criteria encompassed individuals undergoing medical treatment or with a medical history involving malignant tumors, heart failure, or myocardial infarction. Participants with pacemakers or implantable cardioverter defibrillators (ICDs) were also deemed ineligible. Individuals undergoing treatment for chronic conditions such as cardiac arrhythmia, liver or kidney disease, cerebrovascular disorder, rheumatism, diabetes mellitus, dyslipidemia, hypertension, or any other chronic ailment were excluded from participation. Additionally, individuals incorporating "Food for Specified Health Uses," "Food with Functional Claims," or other functional food/beverages, including Ginseng products, into their daily regimen, as well as those regularly utilizing medications (including herbal medicines and supplements), individuals with allergies to medications and/or test-food related products, pregnant or breastfeeding individuals, those planning pregnancy, individuals infected with COVID-19, and participants who had been enrolled in other clinical trials within 28 days prior to agreeing to participate in this trial or planning to enroll in another clinical trial during the trial period, were excluded.
The allocation process aimed to balance participant numbers across two groups and was executed using the computerized random-number generator, StarLight #11 Version 2.10 (Yukms Co., Ltd., Kanagawa, Japan), based on the unique identification number assigned to the test-food. Stratified randomization was employed for allocation, considering factors such as VAS of fatigue, gender, and age. The randomization were strictly kept confidential to maintain blinding during the clinical trial. Neither the participants nor any researchers, including investigators and investigational site personnel, knew which groups the participants belonged to in the conduct of this clinical trials. The allocation information remained undisclosed to sponsors, organizations, and individuals until the trial's conclusion. Consequently, participants were randomly assigned to either the placebo or KRG extracts group, each comprising 23 subjects. A priori power analysis for the analysis of variance was conducted using G∗Power version 3.1.9.7. Commencing on June 01, 2022, with the first enrollee, the study reached completion on October 07, 2022.
2.2. Study design and approval
The protocol was registered on https://center6.umin.ac.jp/cgi-openbin/ctr_e/ctr_view.cgi?recptno=R000054637. The main objective of this trial was to investigate the anti-fatigue effects of a 3-week, continuous daily consumption of KRG extracts on healthy Japanese adults. This clinical trial was reviewed and approved and the Ethical committee of the Takara Clinic of the Seishinkai Medical Corporation (2205-06008-0006-15-TC) and conformed to the Helsinki Declaration 2013 and the Ethical Guidelines for Medical and Health Research Involving Human Subjects. Before screening, all subjects were informed of the nature and purpose of the study, including the participation/withdrawal conditions. The participating subjects had to provide written informed consent explanation documents.
After obtaining written informed consent forms from the subjects, approved by the institutional ethics committee, screening was conducted and healthy participants, whose VAS of fatigue are relatively high, were enrolled into the study, in accordance with our inclusion and exclusion criteria. Participants were randomized into one of the two treatment groups: the placebo group and KRG extracts group. All 46 subjects received either the placebo or KRG extracts in the ratio of 1:1 for a period of 3 weeks, two tablet per day taken with water at any time during the day. Participants took daily reports during intervention to indicate their ingestion of test-food and menses. Meal intake during the three days prior to each examination (visit 1 and visit 2) was reported on a meal record form (Calorie and Nutrition Diary; CAND) specially designed by the CRO. Their respective VAS of fatigue values as primary efficacy endpoint and plasma cortisol and lactate levels values as secondary efficacy endpoint on visit 1 and visit 2 were measured and analyzed. The efficacy of daily doses of 500 mg of KRG extracts was evaluated and compared with the efficacy of the placebo in improving VAS of fatigue values in healthy volunteers over a period of three weeks.
2.3. Preparation of KRG and its placebo tablet
The main constituents of the KRG extracts (500 mg/tablet) tablet were red ginseng powder (480 mg), additional ingredients included avicel 101 (7.5 mg), and magnesium stearate (12.5 mg). The red ginseng placebo tablet was composed solely by the following additional ingredients: crystalline cellulose (200 mg), corn starch (150 mg), lactose (142.5 mg), magnesium stearate (5 mg), and red ginseng flavor (2.5 mg) without red ginseng extracts. To ensure that blinding was as effective as possible, the characteristics (shape, weight, taste) of the placebo group were the precisely same as the characteristics of the KRG extracts group.
2.4. Efficacy and safety outcomes
The primary efficacy parameter in this study was fatigue, assessed through a questionnaire survey utilizing the VAS of fatigue, a methodology endorsed by the Japanese Society of Fatigue Science. Secondary efficacy parameters included plasma cortisol and lactate levels. Venous blood samples were drawn from participants at the Takara Clinics of the Seishinkai Medical Corporation, and the collected samples were subsequently analyzed by the LSI Medicine Corporation.
Safety parameters in this study included incidence of adverse events, physical measurements, physical examinations (systolic and diastolic blood pressure), urinalysis (protein, glucose, pH, and occult blood), and peripheral blood examination (leukocyte count, erythrocyte count, hemoglobin, hematocrit, platelet count, aspartate aminotransferase, alanine aminotransferase, -glutamyl transpeptidase, bilirubin, total protein, urea nitrogen, creatinine, uric acid, Na, K, Cl, serum amylase, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, glucose, and hemoglobin A1c). All measurements and examinations were conducted on visit 1 and visit 2. Any medical condition that was present during screening was considered baseline. During the trial, if a participant exhibits any clinically significant “new symptoms of abnormality” or “aggravation” in his/her physical signs and symptoms, the subject was considered to have an adverse event and was recorded by the day when the adverse event appeared and disappeared. Severity was graded as mild, moderate, and severe according to the severity of the event, and its relationship to the treatment was classified as associated or not associated. If no adverse event occurred during the trial, a follow-up survey was performed and the results were recorded.
2.5. Data management and monitoring
Input, import, and management of all collected data were conducted by the CRO. Each of the involved medical institutions, the organization of affiliation of the ethics committee, the CRO, and the sponsor of this trial will retain the documents for two years after completion of the trial. Biological samples (blood and urine) collected from participants were not used for purposes other than measurement and analysis and were discarded as anonymized medical waste afterward. Storage and disposal of the samples were outsourced to the LSI Medience Corporation, and disposal timing of the sample followed the LSI Medience Corporation rules. The medical institution responded to the request of the sponsor for investigation or direct browsing of the source documents (i.e., the consent form, daily report, and other records submitted by participants) for investigation or validation of the records upon request. However, sufficient consideration from the perspective of protecting the privacy of participants was taken in case of direct browsing of source documents, and/or information.
The data monitoring committee formed from the ethical committee of Takara Clinic. The person in charge of monitoring confirmed the registration and acquisition of consent of the trial participants, the status of compliance, records and procedures, procedures of the ethics committee, and the continuation of the implementation system, and handled adverse events of the trial participants. The results of monitoring were reported to the ethics committee periodically.
2.6. Statistical analysis
All values of VAS items, plasma cortisol, and lactate levels were presented as mean and standard deviation, and comparisons between groups were made using analysis of covariance (ANCOVA) with baseline (value at screening and baseline assessment) as the covariate. If other tests such as unpaired t-test are necessary for data analysis from multifaceted perspectives, those were adopted and the efficacy evaluation of the test-food was performed accordingly.
Data analysis set was safety analysis population (SAF). Incidences of side effects and adverse events were tabulated on an individual participant basis. In addition, the 95 % confidence interval of the incidence rate and the intergroup incidence rate were calculated. Furthermore, the incidence rates of side effects and adverse events were compared using Fisher's exact test.
All statistical analyses were performed using IBM SPSS Statistics (Version 23, Armonk, NY, USA) and a p-value lower than 5 % was considered to be statistically significant. As the analysis or primary endpoint was the priority in this trial, multiplicity derived from making multiple hypotheses for secondary endpoints were not considered.
3. Results
3.1. Disposition of subjects
Of the 65 subjects who agreed to participate in the study, 46 who met the eligibility criteria were included and evenly divided, randomly allocating to either test-food (KRG extracts) or placebo groups, respectively (n = 23 each group). All subjects completed this study and non-compliance was not identified. Thus, the total number of subjects for both intention to treat (ITT) and SAF was 46. The flow chart of participants is presented in Fig. 1, and the participants background in each analysis data set is shown in Table 1.
Fig. 1.
Flow chart of participants.
Table 1.
Participants background.
| Item | Unit | ITT, SAF |
||
|---|---|---|---|---|
| Placebo group | Test-food group | |||
| Sex | – | n | 23 | 23 |
| Male | 9 (39.1 %) | 8 (34.8 %) | ||
| Female | 14 (60.9 %) | 15 (65.2 %) | ||
| Age | – | n | 23 | 23 |
| Mean (SD) | 50.9 (6.2) | 50.0 (5.7) | ||
| Med | 51.0 | 50.0 | ||
| Min-Max | 40–60 | 41–60 | ||
| Body height | cm | n | 23 | 23 |
| Mean (SD) | 162.8 (8.2) | 163.4 (7.6) | ||
| Med | 162.20 | 162.90 | ||
| Min-Max | 149.7–183.5 | 152.6–176.5 | ||
| Body weight | kg | n | 23 | 23 |
| Mean (SD) | 58.2 (8.8) | 57.0 (13.8) | ||
| Med | 60.60 | 55.60 | ||
| Min-Max | 38.9–71.7 | 30.4–84.9 | ||
| BMI | kg/m2 | n | 23 | 23 |
| Mean (SD) | 22.0 (3.2) | 21.1 (3.7) | ||
| Med | 21.90 | 21.00 | ||
| Min-Max | 14.8–27.4 | 13.1–27.6 | ||
| Systolic blood pressure | mmHg | n | 23 | 23 |
| Mean (SD) | 116.3 (13.0) | 115.9 (17.3) | ||
| Med | 119.0 | 111.0 | ||
| Min-Max | 94–148 | 92–145 | ||
| Diastolic blood pressure | mmHg | n | 23 | 23 |
| Mean (SD) | 75.9 (10.0) | 76.0 (11.9) | ||
| Med | 74.0 | 73.0 | ||
| Min-Max | 59–93 | 59–98 | ||
n, Number of cases; SD, Standard Deviation; Med, Median; Min, Minimum; Max, Maximum; ITT, Intention to treat; SAF, Safety analysis population.
3.2. Efficacy of KRG
Mean ± SD, Med, Min, Max, the difference between groups (Δ) and its SE, 95 % CI, as well as p-value of the efficacy endpoint outcomes including VAS of fatigue, lactic acid, and plasma cortisol level values are summarized in Table 2A. Of all the time points at which significant differences in fatigue score were found, the measured values were found to be lower in the test-food group (38.8 ± 18.9 mm) compared to the placebo group (placebo group: 50.1 ± 15.8 mm) at visit 2, revealing a difference between groups of −11.2 mm [−21.6, −0.8] (P = 0.035) (Fig. 2). Plasma cortisol and lactic acid levels demonstrated little difference between the groups.
Table 2.
Summary of the efficacy (A), primary safety (B), and secondary safety (C) endpoints.
| (A) | ||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Item | Unit | Time point | Placebo group |
Test-food group |
Group comparison |
|||||||||||||||
| n | Mean | SD | Med | Min | Max | n | Mean | SD | Med | Min | Max | ⊿ | SE | 95 % CI- | 95 % CI+ | P | ||||
| Fatigue (VAS) | mm | VISIT1 | ∗ | 23 | 64.1 | 11.2 | 69.0 | 41.0 | 76.0 | 23 | 63.3 | 12.6 | 65.0 | 36.0 | 81.0 | −0.8 | 3.5 | −7.9 | 6.3 | 0.816 |
| VISIT2 | #, † | 23 | 50.1 | 15.8 | 50.0 | 26.0 | 81.0 | 23 | 38.8 | 18.9 | 34.0 | 9.0 | 79.0 | −11.2 | 5.2 | −21.6 | −0.8 | 0.035 | ||
| Lactic acid | mg/dL | VISIT1 | ∗ | 23 | 12.1 | 5.3 | 11.7 | 4.1 | 24.4 | 23 | 11.7 | 4.9 | 10.2 | 3.6 | 19.6 | −0.4 | 1.5 | −3.4 | 2.6 | 0.783 |
| VISIT2 | # | 23 | 11.6 | 4.8 | 9.9 | 4.2 | 23.7 | 23 | 11.0 | 3.6 | 10.3 | 6.1 | 21.4 | −0.5 | 1.1 | −2.6 | 1.6 | 0.652 | ||
| Cortisol (plasma) | μg/dL | VISIT1 | ∗ | 23 | 8.7 | 2.7 | 8.3 | 4.7 | 16.3 | 23 | 8.4 | 3.0 | 8.6 | 3.7 | 13.2 | −0.3 | 0.8 | −1.9 | 1.4 | 0.759 |
| VISIT2 | # | 23 | 8.7 | 2.6 | 9.2 | 3.7 | 13.7 | 23 | 8.9 | 3.2 | 8.1 | 4.6 | 19.1 | 0.3 | 0.8 | −1.2 | 1.8 | 0.717 | ||
| (B) | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Item | Placebo group |
Test-food group |
Group comparison ∗∗ |
|||||||
| n | Number of cases | Incidence rate (%) | n | Number of cases | Incidence rate (%) | ⊿ (%) | 95 % CI- | 95 % CI+ | P | |
| Adverse events | 23 | 2 | 8.7 | 23 | 1 | 4.3 | −4.3 | −18.6 | 9.9 | 1.000 |
| (C) | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Item | Time point | Placebo group |
Test-food group |
Group comparison ∗∗ |
|||||||
| n | Number of cases | Percentage of cases (%) | n | Number of cases | Percentage of cases (%) | ⊿ (%) | 95 % CI- | 95 % CI+ | P | ||
| Urinary protein | VISIT2 | 23 | 0 | 0.0 | 23 | 2 | 8.7 | 8.7 | −3.1 | 20.5 | 0.489 |
| Urinary glucose | VISIT2 | 23 | 0 | 0.0 | 23 | 0 | 0.0 | 0.0 | NA | NA | NA |
| Urinary pH | VISIT2 | 23 | 1 | 4.3 | 23 | 1 | 4.3 | 0.0 | −11.8 | 11.8 | 1.000 |
| Urinary occult blood | VISIT2 | 23 | 2 | 8.7 | 23 | 3 | 13.0 | 4.3 | −13.6 | 223 | 1.000 |
| Leukocyte count (WBC) | VISIT2 | 23 | 1 | 4.3 | 23 | 0 | 0.0 | −4.3 | −128 | 4.1 | 1.000 |
| Erythrocyte count (RBC) | VISIT2 | 23 | 2 | 8.7 | 23 | 2 | 8.7 | 0.0 | −16.3 | 16.3 | 1.000 |
| Hemoglobin (Hb) | VISIT2 | 23 | 0 | 0.0 | 23 | 2 | 8.7 | 8.7 | −3.1 | 20.5 | 0.489 |
| Hematocrit (Ht) | VISIT2 | 23 | 0 | 0.0 | 23 | 3 | 13.0 | 13.0 | −1.2 | 27.3 | 0.233 |
| Platelet count (PLT) | VISIT2 | 23 | 1 | 4.3 | 23 | 0 | 0.0 | −4.3 | −128 | 4.1 | 1.000 |
| Aspartate aminotransferase | VISIT2 | 23 | 1 | 4.3 | 23 | 0 | 0.0 | −4.3 | −128 | 4.1 | 1.000 |
| Alanine aminotransferase (ALT) | VISIT2 | 23 | 1 | 4.3 | 23 | 0 | 0.0 | −4.3 | −128 | 4.1 | 1.000 |
| γ -glutamyl transpeptidase (γ -GT) | VISIT2 | 23 | 0 | 0.0 | 23 | 0 | 0.0 | 0.0 | NA | NA | NA |
| Total bilirubin (T-BIL) | VISIT2 | 23 | 1 | 4.3 | 23 | 0 | 0.0 | −4.3 | −128 | 4.1 | 1.000 |
| Total protein (TP) | VISIT2 | 23 | 2 | 8.7 | 23 | 2 | 8.7 | 0.0 | −16.3 | 16.3 | 1.000 |
| Urea nitrogen (UN) | VISIT2 | 23 | 1 | 4.3 | 23 | 0 | 0.0 | −4.3 | −128 | 4.1 | 1.000 |
| Creatinine (CRE) | VISIT2 | 23 | 0 | 0.0 | 23 | 2 | 8.7 | 8.7 | −3.1 | 20.5 | 0.489 |
| Uric acid (UA) | VISIT2 | 23 | 1 | 4.3 | 23 | 0 | 0.0 | −4.3 | −128 | 4.1 | 1.000 |
| Sodium (Na) | VISIT2 | 23 | 0 | 0.0 | 23 | 0 | 0.0 | 0.0 | NA | NA | NA |
| Potassium (K) | VISIT2 | 23 | 0 | 0.0 | 23 | 2 | 8.7 | 8.7 | −3.1 | 20.5 | 0.489 |
| Chlorine (CI) | VISIT2 | 23 | 0 | 0.0 | 23 | 0 | 0.0 | 0.0 | NA | NA | NA |
| Serum amylase (AMY/S) | VISIT2 | 23 | 0 | 0.0 | 23 | 0 | 0.0 | 0.0 | NA | NA | NA |
| Total cholesterol (T-Cho) | VISIT2 | 23 | 2 | 8.7 | 23 | 0 | 0.0 | −8.7 | −20.5 | 3.1 | 0.489 |
| High-density lipoprotein (HDL) cholesterol | VISIT2 | 23 | 2 | 8.7 | 23 | 0 | 0.0 | −8.7 | −20.5 | 3.1 | 0.489 |
| Low-density lipoprotein (LDL) cholesterol | VISIT2 | 23 | 1 | 4.3 | 23 | 1 | 4.3 | 0.0 | −11.8 | 11.8 | 1.000 |
| Triglycerides (TG) | VISIT2 | 23 | 2 | 8.7 | 23 | 0 | 0.0 | −8.7 | −20.5 | 3.1 | 0.489 |
| Glucose (GLU) | VISIT2 | 23 | 0 | 0.0 | 23 | 0 | 0.0 | 0.0 | NA | NA | NA |
| Hemoglobin A1c (HbA1c: NGSP) | VISIT2 | 23 | 0 | 0.0 | 23 | 0 | 0.0 | 0.0 | NA | NA | NA |
n, Number of cases; SD, Standard Deviation; Med, Median; Min, Minimum; Max, Maximum; ⊿, Group differences (Test-food minus Placebo); SE, Standard Error; 95%CI−, Lower limit of 95 % Confidence Interval for group differences; 95%CI+; Upper limit of 95 % Confidence Interval for group differences; P, p-value (Statistical Significance); VISIT1, Screening and baseline assessment; VISIT2, Examination at week 3 after consumption; †, Primary outcome; ∗, Group comparison using Welch's t-test; ∗∗, Group comparison using Fisher's exact test; #, Group comparison using ANCOVA where baseline is treated as covariate and group as factor (⊿ indicates the group differences of Estimated Marginal Means); Bold, P < 0.05.
Fig. 2.
Efficacy endpoint outcomes: (a) VAS of fatigue, (b) lactic acid plasma, and (c) cortisol level.
3.3. Safety of KRG
The incidence rates of adverse events and the adverse events identified during the study are listed in Table 2B. While some participants were found to have developed adverse events, they recovered after using medications. There was no causal relationship between the adverse events and the study products. Percentage of cases in which urinalysis and blood test measurements were within the reference values at the screening, but their values exceeded the reference values after the intervention. The number of cases in this category, the percentage of such cases in each group, and statistical analysis outcomes are summarized in Table 2C. No items were shown to have significant difference between the groups.
The complete data including anthropometric measurement and physical examination are shown in Table 3A. The results of urinalysis and peripheral blood examination (hematology and biochemistry) are displayed in Table 3, Table 4, respectively. These safety outcomes were reviewed individually and confirmed that none of the changes that occurred upon consumption of the study products (test-food and placebo) were clinically significant.
Table 3.
Summary of the anthropometric measurement and physical examinations (A) and the urinalysis (B).
| (A) | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Item | Unit | Time point | n | Lower limit of reference range | Upper limit of reference range | Placebo group |
Test-food group |
||||||||||||||
| n | Mean | SD | Med | Min | Max | 95 % CI- | 95 % CI+ | n | Mean | SD | Med | Min | Max | 95 % CI- |
95 % CI+ | ||||||
| Body height | cm | VISIT1 | 23 | 162.8 | 8.2 | 162.2 | 149.7 | 183.5 | 159.3 | 166.3 | 23 | 163.4 | 7.6 | 162.9 | 152.6 | 176.5 | 160.1 | 166.8 | VISIT1 | 23 | 162.8 |
| VISIT2 | 0 | – | – | – | – | – | – | – | 0 | – | – | – | – | – | – | – | VISIT2 | 0 | – | ||
| Body weight | kg | VISIT1 | 23 | 58.2 | 8.8 | 60.6 | 38.9 | 71.7 | 54.4 | 62.0 | 23 | 57.0 | 13.8 | 55.6 | 30.4 | 84.9 | 51.0 | 62.9 | VISIT1 | 23 | 58.2 |
| VISIT2 | 23 | 57.6 | 8.7 | 58.4 | 38.9 | 69.8 | 53.8 | 61.4 | 23 | 56.7 | 13.9 | 55.4 | 31.5 | 85.1 | 50.7 | 62.8 | VISIT2 | 23 | 57.6 | ||
| BMI | kg/m2 | VISIT1 | 23 | 22.0 | 3.2 | 21.9 | 14.8 | 27.4 | 20.6 | 23.4 | 23 | 21.1 | 3.7 | 21.0 | 13.1 | 27.6 | 19.5 | 22.7 | VISIT1 | 23 | 22.0 |
| VISIT2 | 23 | 21.7 | 3.0 | 21.9 | 14.8 | 26.6 | 20.5 | 23.0 | 23 | 21.0 | 3.8 | 20.9 | 13.5 | 27.7 | 19.4 | 22.6 | VISIT2 | 23 | 21.7 | ||
| Systolic blood | mmHg | VISIT1 | 23 | 116.3 | 13.0 | 119.0 | 94.0 | 148.0 | 110.7 | 122.0 | 23 | 115.9 | 17.3 | 111.0 | 92.0 | 145.0 | 108.4 | 123.4 | VISIT1 | 23 | 116.3 |
| pressure | VISIT2 | 23 | 118.6 | 14.1 | 120.0 | 88.0 | 142.0 | 112.5 | 124.7 | 23 | 113.2 | 15.5 | 113.0 | 87.0 | 137.0 | 106.5 | 119.9 | VISIT2 | 23 | 118.6 | |
| Diastolic blood | mmHg | VISIT1 | 23 | 75.9 | 10.0 | 74.0 | 59.0 | 93.0 | 71.6 | 80.2 | 23 | 76.0 | 11.9 | 73.0 | 59.0 | 98.0 | 70.9 | 81.2 | VISIT1 | 23 | 75.9 |
| pressure | VISIT2 | 23 | 78.7 | 11.0 | 83.0 | 55.0 | 94.0 | 73.9 | 83.4 | 23 | 73.2 | 11.9 | 73.0 | 57.0 | 95.0 | 68.1 | 78.4 | VISIT2 | 23 | 78.7 | |
| (B) | ||||||
|---|---|---|---|---|---|---|
| Group | Time point | Result | Placebo group |
Test-food group |
||
| Number of cases | Percentage of cases (%) | Number of cases | Percentage of cases (%) | |||
| Urinary protein | VISIT1 | (−) | 22 | 95.7 | 22 | 95.7 |
| (±) | 0 | 0.0 | 1 | 4.3 | ||
| (+) | 1 | 4.3 | 0 | 0.0 | ||
| (2+) | 0 | 0.0 | 0 | 0.0 | ||
| (3+) | 0 | 0.0 | 0 | 0.0 | ||
| VISIT2 | (−) | 23 | 100.0 | 21 | 91.3 | |
| (±) | 0 | 0.0 | 2 | 8.7 | ||
| (+) | 0 | 0.0 | 0 | 0.0 | ||
| (2+) | 0 | 0.0 | 0 | 0.0 | ||
| (3+) | 0 | 0.0 | 0 | 0.0 | ||
| Urinary glucose | VISIT1 | (−) | 23 | 100.0 | 23 | 100.0 |
| (±) | 0 | 0.0 | 0 | 0.0 | ||
| (+) | 0 | 0.0 | 0 | 0.0 | ||
| (2+) | 0 | 0.0 | 0 | 0.0 | ||
| (3+) | 0 | 0.0 | 0 | 0.0 | ||
| VISIT2 | (−) | 23 | 100.0 | 23 | 100.0 | |
| (±) | 0 | 0.0 | 0 | 0.0 | ||
| (+) | 0 | 0.0 | 0 | 0.0 | ||
| (2+) | 0 | 0.0 | 0 | 0.0 | ||
| (3+) | 0 | 0.0 | 0 | 0.0 | ||
| Urinary pH | VISIT1 | <5.0 | 0 | 0.0 | 0 | 0.0 |
| 5.0–7.5 | 22 | 95.7 | 23 | 100.0 | ||
| >7.5 | 1 | 4.3 | 0 | 0.0 | ||
| VISIT2 | <5.0 | 0 | 0.0 | 0 | 0.0 | |
| 5.0–7.5 | 22 | 95.7 | 22 | 95.7 | ||
| >7.5 | 1 | 4.3 | 1 | 4.3 | ||
| Urinary occult blood | VISIT1 | (−) | 22 | 95.7 | 22 | 95.7 |
| (±) | 0 | 0.0 | 1 | 4.3 | ||
| (+) | 1 | 4.3 | 0 | 0.0 | ||
| (2+) | 0 | 0.0 | 0 | 0.0 | ||
| (3+) | 0 | 0.0 | 0 | 0.0 | ||
| VISIT2 | (−) | 21 | 91.3 | 19 | 82.6 | |
| (±) | 0 | 0.0 | 3 | 13.0 | ||
| (+) | 1 | 4.3 | 0 | 0.0 | ||
| (2+) | 0 | 0.0 | 0 | 0.0 | ||
| (3+) | 1 | 4.3 | 1 | 4.3 | ||
n, Number of cases; SD, Standard Deviation; Med, Median; Min, Minimum; Max, Maximum; 95%CI−, Lower limit of 95 % Confidence Interval for group differences; 95%CI+, Upper limit of 95 % Confidence Interval for group differences; VISIT1, Screening and baseline assessment; VISIT2, Examination at week 3 after consumption.
Table 4.
Summary of the peripheral blood examination (Hematological and biochemical tests).
| Item | Unit | Time point | Sex | Lower limit of reference range | Upper limit of reference range | Placebo group |
Test-food group |
||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| n | Mean | SD | Med | Min | Max | 95 % CI- | 95 % CI+ | n | Mean | SD | Med | Min | Max | 95 % CI- | 95 % CI+ | ||||||
| Leukocyte count (WBC) | μL | VISIT1 | MIX | 3300 | 9000 | 23 | 5217.4 | 1326.5 | 4700.0 | 3100.0 | 8600.0 | 4643.8 | 5791.0 | 23 | 5026.1 | 1414.6 | 4700.0 | 2000.0 | 8000.0 | 4414.4 | 5637.8 |
| VISIT2 | MIX | 3300 | 9000 | 23 | 5017.4 | 1230.9 | 5000.0 | 3200.0 | 8100.0 | 4485.1 | 5549.7 | 23 | 4995.7 | 1341.5 | 4600.0 | 2700.0 | 7900.0 | 4415.6 | 5575.7 | ||
| Erythrocyte count (RBC) | ×104/μL | VISIT1 | MIX | – | – | 23 | 450.6 | 38.3 | 440.0 | 378.0 | 531.0 | 434.0 | 467.1 | 23 | 435.7 | 39.6 | 432.0 | 384.0 | 546.0 | 418.5 | 452.8 |
| M | 430 | 570 | 9 | 467.3 | 42.9 | 471.0 | 391.0 | 531.0 | 434.4 | 500.3 | 8 | 446.0 | 42.6 | 435.0 | 407.0 | 546.0 | 410.4 | 481.6 | |||
| F | 380 | 500 | 14 | 439.8 | 32.2 | 437.0 | 378.0 | 503.0 | 421.2 | 458.3 | 15 | 430.1 | 38.3 | 415.0 | 384.0 | 523.0 | 408.9 | 451.3 | |||
| VISIT2 | MIX | – | – | 23 | 450.5 | 41.9 | 448.0 | 368.0 | 545.0 | 432.4 | 468.6 | 23 | 426.4 | 41.7 | 420.0 | 335.0 | 520.0 | 408.3 | 444.4 | ||
| M | 430 | 570 | 9 | 466.2 | 52.2 | 476.0 | 380.0 | 545.0 | 426.1 | 506.3 | 8 | 429.9 | 52.5 | 439.5 | 335.0 | 510.0 | 386.0 | 473.8 | |||
| F | 380 | 500 | 14 | 440.4 | 31.8 | 443.5 | 368.0 | 484.0 | 422.0 | 458.7 | 15 | 424.5 | 36.7 | 420.0 | 382.0 | 520.0 | 404.2 | 444.9 | |||
| Hemoglobin (Hb) | g/dL | VISIT1 | MIX | – | – | 23 | 13.4 | 1.6 | 13.5 | 7.9 | 16.2 | 12.7 | 14.1 | 23 | 13.2 | 1.2 | 13.2 | 10.8 | 16.1 | 12.7 | 13.8 |
| M | 13.5 | 17.5 | 9 | 14.3 | 1.3 | 14.5 | 11.7 | 16.2 | 13.3 | 15.4 | 8 | 13.9 | 1.1 | 13.9 | 12.6 | 16.1 | 13.0 | 14.9 | |||
| F | 11.5 | 15.0 | 14 | 12.9 | 1.6 | 13.2 | 7.9 | 14.4 | 12.0 | 13.8 | 15 | 12.9 | 1.1 | 12.9 | 10.8 | 15.1 | 12.2 | 13.5 | |||
| VISIT2 | MIX | – | – | 23 | 13.6 | 1.6 | 13.7 | 8.8 | 16.5 | 12.9 | 14.3 | 23 | 13.0 | 1.3 | 12.7 | 10.5 | 15.3 | 12.5 | 13.5 | ||
| M | 13.5 | 17.5 | 9 | 14.4 | 1.6 | 14.7 | 11.6 | 16.5 | 13.1 | 15.6 | 8 | 13.6 | 1.2 | 13.7 | 11.3 | 15.3 | 12.6 | 14.6 | |||
| F | 11.5 | 15.0 | 14 | 13.1 | 1.4 | 13.5 | 8.8 | 14.3 | 12.3 | 13.9 | 15 | 12.7 | 1.2 | 12.4 | 10.5 | 14.9 | 12.0 | 13.3 | |||
| Hematocrit (Ht) | % | VISIT1 | MIX | – | – | 23 | 42.7 | 4.3 | 42.3 | 30.7 | 49.8 | 40.9 | 44.6 | 23 | 41.9 | 3.7 | 41.1 | 36.0 | 50.8 | 40.3 | 43.5 |
| M | 39.7 | 52.4 | 9 | 45.0 | 4.5 | 46.4 | 35.7 | 49.8 | 41.5 | 48.4 | 8 | 43.5 | 3.6 | 43.4 | 39.7 | 50.8 | 40.5 | 46.4 | |||
| F | 34.8 | 45.0 | 14 | 41.3 | 3.6 | 42.1 | 30.7 | 45.5 | 39.2 | 43.4 | 15 | 41.0 | 3.6 | 40.8 | 36.0 | 50.2 | 39.1 | 43.0 | |||
| VISIT2 | MIX | – | – | 23 | 42.9 | 4.5 | 42.3 | 31.9 | 50.6 | 40.9 | 44.8 | 23 | 40.8 | 3.4 | 40.7 | 34.2 | 47.6 | 39.3 | 42.3 | ||
| M | 39.7 | 52.4 | 9 | 45.0 | 5.2 | 47.7 | 35.2 | 50.6 | 41.1 | 49.0 | 8 | 41.8 | 3.8 | 42.5 | 34.2 | 47.0 | 38.6 | 45.1 | |||
| F | 34.8 | 45.0 | 14 | 41.5 | 3.5 | 42.3 | 31.9 | 45.3 | 39.4 | 43.5 | 15 | 40.3 | 3.2 | 39.6 | 35.7 | 47.6 | 38.5 | 42.1 | |||
| Platelet count (PLT) | ×104/μL | VISIT1 | MIX | 14 | 34 | 23 | 27.2 | 5.3 | 26.1 | 17.3 | 40.3 | 24.8 | 29.5 | 23 | 25.7 | 5.0 | 25.6 | 18.3 | 39.5 | 23.5 | 27.8 |
| VISIT2 | MIX | 14 | 34 | 23 | 26.4 | 5.8 | 25.6 | 17.0 | 38.4 | 23.9 | 29.0 | 23 | 24.6 | 4.4 | 25.7 | 16.2 | 32.9 | 22.7 | 26.5 | ||
| Aspartate aminotransferase | U/L | VISIT1 | MIX | 10 | 40 | 23 | 18.8 | 4.3 | 18.0 | 11.0 | 27.0 | 16.9 | 20.6 | 23 | 22.0 | 6.4 | 20.0 | 14.0 | 35.0 | 19.2 | 24.7 |
| (AST) | VISIT2 | MIX | 10 | 40 | 23 | 18.5 | 5.5 | 17.0 | 9.0 | 30.0 | 16.1 | 20.9 | 23 | 21.2 | 6.5 | 19.0 | 13.0 | 40.0 | 18.4 | 24.0 | |
| Alanine aminotransferase | U/L | VISIT1 | MIX | 5 | 45 | 23 | 16.9 | 7.4 | 16.0 | 9.0 | 39.0 | 13.7 | 20.1 | 23 | 17.3 | 7.9 | 15.0 | 9.0 | 42.0 | 13.9 | 20.8 |
| (ALT) | VISIT2 | MIX | 5 | 45 | 23 | 18.7 | 11.0 | 18.0 | 7.0 | 50.0 | 13.9 | 23.4 | 23 | 17.0 | 7.4 | 13.0 | 9.0 | 37.0 | 13.8 | 20.1 | |
| γ-glutamyl transpeptidase | U/L | VISIT1 | MIX | – | – | 23 | 34.6 | 45.3 | 19.0 | 10.0 | 231.0 | 15.0 | 54.2 | 23 | 26.2 | 25.7 | 18.0 | 8.0 | 109.0 | 15.1 | 37.3 |
| (γ-GT) | VISIT2 | M | 0 | 80 | 9 | 50.2 | 71.1 | 19.0 | 10.0 | 231.0 | −4.4 | 104.8 | 8 | 44.3 | 37.2 | 32.5 | 12.0 | 109.0 | 13.2 | 75.3 | |
| F | 0 | 30 | 14 | 24.5 | 9.6 | 20.5 | 15.0 | 45.0 | 19.0 | 30.0 | 15 | 16.6 | 7.7 | 15.0 | 8.0 | 34.0 | 12.3 | 20.9 | |||
| MIX | – | – | 23 | 36.0 | 50.5 | 24.0 | 11.0 | 259.0 | 14.2 | 57.9 | 23 | 26.3 | 27.4 | 17.0 | 9.0 | 123.0 | 14.4 | 38.1 | |||
| M | 0 | 80 | 9 | 55.8 | 79.0 | 20.0 | 11.0 | 259.0 | −4.9 | 116.5 | 8 | 44.1 | 41.0 | 26.5 | 11.0 | 123.0 | 9.9 | 78.4 | |||
| F | 0 | 30 | 14 | 23.4 | 5.4 | 25.0 | 14.0 | 30.0 | 20.2 | 26.5 | 15 | 16.7 | 7.8 | 15.0 | 9.0 | 38.0 | 12.4 | 21.0 | |||
| Total bilirubin (T-BIL) | mg/dL | VISIT1 | MIX | 0.2 | 1.2 | 23 | 0.8 | 0.3 | 0.8 | 0.6 | 1.4 | 0.7 | 1.0 | 23 | 0.9 | 0.4 | 0.8 | 0.4 | 1.7 | 0.7 | 1.0 |
| VISIT2 | MIX | 0.2 | 1.2 | 23 | 0.8 | 0.3 | 0.9 | 0.4 | 1.6 | 0.7 | 1.0 | 23 | 0.8 | 0.3 | 0.7 | 0.4 | 1.6 | 0.7 | 1.0 | ||
| Total protein (TP) | g/dL | VISIT1 | MIX | 6.7 | 8.3 | 23 | 7.0 | 0.3 | 7.0 | 6.5 | 7.5 | 6.9 | 7.2 | 23 | 7.1 | 0.4 | 7.0 | 6.3 | 8.1 | 6.9 | 7.2 |
| VISIT2 | MIX | 6.7 | 8.3 | 23 | 7.0 | 0.3 | 6.9 | 6.4 | 7.7 | 6.8 | 7.1 | 23 | 7.0 | 0.3 | 7.1 | 6.4 | 7.7 | 6.9 | 7.2 | ||
| Urea nitrogen (UN) | mg/dL | VISIT1 | MIX | 8.0 | 20.0 | 23 | 13.6 | 4.2 | 13.7 | 6.6 | 24.3 | 11.8 | 15.5 | 23 | 13.8 | 4.0 | 12.8 | 6.9 | 22.5 | 12.1 | 15.6 |
| VISIT2 | MIX | 8.0 | 20.0 | 23 | 12.3 | 3.4 | 12.3 | 5.5 | 20.5 | 10.8 | 13.8 | 23 | 12.8 | 3.2 | 12.6 | 8.1 | 18.1 | 11.4 | 14.2 | ||
| Creatinine (CRE) | mg/dL | VISIT1 | MIX | – | – | 23 | 0.7 | 0.2 | 0.7 | 0.5 | 1.2 | 0.6 | 0.8 | 23 | 0.8 | 0.2 | 0.8 | 0.5 | 1.2 | 0.7 | 0.8 |
| M | 0.61 | 1.04 | 9 | 0.9 | 0.1 | 0.9 | 0.7 | 1.2 | 0.8 | 1.0 | 8 | 1.0 | 0.1 | 0.9 | 0.8 | 1.2 | 0.9 | 1.1 | |||
| F | 0.47 | 0.79 | 14 | 0.6 | 0.1 | 0.6 | 0.5 | 0.7 | 0.6 | 0.6 | 15 | 0.6 | 0.1 | 0.6 | 0.5 | 0.9 | 0.6 | 0.7 | |||
| VISIT2 | MIX | – | – | 23 | 0.7 | 0.1 | 0.6 | 0.5 | 1.0 | 0.6 | 0.7 | 23 | 0.7 | 0.2 | 0.7 | 0.4 | 1.1 | 0.7 | 0.8 | ||
| M | 0.61 | 1.04 | 9 | 0.8 | 0.1 | 0.8 | 0.7 | 1.0 | 0.8 | 0.9 | 8 | 0.9 | 0.1 | 0.9 | 0.7 | 1.1 | 0.8 | 1.0 | |||
| F | 0.47 | 0.79 | 14 | 0.6 | 0.1 | 0.6 | 0.5 | 0.8 | 0.6 | 0.6 | 15 | 0.6 | 0.1 | 0.6 | 0.4 | 0.9 | 0.6 | 0.7 | |||
| Uric acid (UA) | mg/dL | VISIT1 | MIX | – | – | 23 | 4.8 | 1.5 | 4.6 | 2.6 | 9.1 | 4.2 | 5.5 | 23 | 4.3 | 1.3 | 4.6 | 1.5 | 6.5 | 3.8 | 4.8 |
| M | 3.8 | 7.0 | 9 | 6.0 | 1.6 | 5.9 | 4.4 | 9.1 | 4.8 | 7.2 | 8 | 5.1 | 1.3 | 5.4 | 2.9 | 6.5 | 3.9 | 6.2 | |||
| F | 2.5 | 7.0 | 14 | 4.1 | 0.8 | 4.1 | 2.6 | 5.5 | 3.6 | 4.6 | 15 | 3.9 | 1.0 | 4.0 | 1.5 | 5.2 | 3.3 | 4.5 | |||
| VISIT2 | MIX | – | – | 23 | 4.7 | 1.4 | 4.3 | 3.0 | 7.9 | 4.1 | 5.3 | 23 | 4.5 | 1.5 | 4.7 | 2.0 | 7.0 | 3.9 | 5.1 | ||
| M | 3.8 | 7.0 | 9 | 5.8 | 1.5 | 5.8 | 4.2 | 7.9 | 4.7 | 7.0 | 8 | 5.5 | 1.7 | 6.1 | 2.8 | 7.0 | 4.1 | 6.9 | |||
| F | 2.5 | 7.0 | 14 | 4.0 | 0.7 | 4.0 | 3.0 | 5.1 | 3.6 | 4.4 | 15 | 4.0 | 1.1 | 4.2 | 2.0 | 5.3 | 3.4 | 4.6 | |||
| Sodium (Na) | mEq/L | VISIT1 | MIX | 137 | 147 | 23 | 141.1 | 1.8 | 141.0 | 137.0 | 144.0 | 140.3 | 141.9 | 23 | 140.3 | 1.9 | 141.0 | 136.0 | 145.0 | 139.5 | 141.2 |
| VISIT2 | MIX | 137 | 147 | 23 | 140.9 | 1.5 | 141.0 | 138.0 | 143.0 | 140.2 | 141.5 | 23 | 140.8 | 1.7 | 141.0 | 137.0 | 144.0 | 140.0 | 141.5 | ||
| Potassium (K) | mEq/L | VISIT1 | MIX | 3.5 | 5.0 | 23 | 4.0 | 0.3 | 4.0 | 3.5 | 4.5 | 3.9 | 4.1 | 23 | 3.9 | 0.3 | 3.9 | 3.5 | 4.6 | 3.8 | 4.1 |
| VISIT2 | MIX | 3.5 | 5.0 | 23 | 3.9 | 0.3 | 3.9 | 3.5 | 4.5 | 3.8 | 4.0 | 23 | 3.9 | 0.3 | 3.9 | 3.3 | 4.4 | 3.7 | 4.0 | ||
| Chlorine (Cl) | mEq/L | VISIT1 | MIX | 98 | 108 | 23 | 103.7 | 1.7 | 104.0 | 101.0 | 107.0 | 103.0 | 104.4 | 23 | 102.7 | 2.0 | 103.0 | 99.0 | 106.0 | 101.8 | 103.6 |
| VISIT2 | MIX | 98 | 108 | 23 | 103.4 | 2.3 | 103.0 | 101.0 | 108.0 | 102.4 | 104.4 | 23 | 102.9 | 1.3 | 103.0 | 101.0 | 106.0 | 102.3 | 103.5 | ||
| Serum amylase (AMY/S) | U/L | VISIT1 | MIX | 40 | 122 | 23 | 79.5 | 32.3 | 73.0 | 34.0 | 171.0 | 65.6 | 93.5 | 23 | 93.8 | 36.7 | 86.0 | 39.0 | 163.0 | 77.9 | 109.7 |
| VISIT2 | MIX | 40 | 122 | 23 | 77.1 | 25.3 | 78.0 | 35.0 | 139.0 | 66.2 | 88.0 | 23 | 96.7 | 47.1 | 86.0 | 43.0 | 232.0 | 76.3 | 117.0 | ||
| Total cholesterol (T-Cho) | mg/dL | VISIT1 | MIX | 120 | 219 | 23 | 213.4 | 36.0 | 219.0 | 144.0 | 288.0 | 197.8 | 229.0 | 23 | 222.4 | 42.9 | 219.0 | 158.0 | 326.0 | 203.8 | 240.9 |
| VISIT2 | MIX | 120 | 219 | 23 | 215.1 | 35.9 | 215.0 | 158.0 | 295.0 | 199.5 | 230.6 | 23 | 214.6 | 43.1 | 217.0 | 122.0 | 295.0 | 196.0 | 233.2 | ||
| High-density lipoprotein | mg/dL | VISIT1 | MIX | – | – | 23 | 66.1 | 15.8 | 66.0 | 36.0 | 111.0 | 59.3 | 73.0 | 23 | 79.8 | 19.5 | 79.0 | 49.0 | 113.0 | 71.4 | 88.2 |
| (HDL) cholesterol | VISIT2 | M | 40 | 85 | 9 | 60.9 | 8.2 | 56.0 | 53.0 | 74.0 | 54.6 | 67.2 | 8 | 65.5 | 20.4 | 60.5 | 49.0 | 113.0 | 48.5 | 82.5 | |
| F | 40 | 95 | 14 | 69.5 | 18.7 | 68.5 | 36.0 | 111.0 | 58.7 | 80.3 | 15 | 87.4 | 14.5 | 84.0 | 69.0 | 112.0 | 79.4 | 95.4 | |||
| MIX | – | – | 23 | 66.9 | 15.1 | 66.0 | 33.0 | 100.0 | 60.4 | 73.4 | 23 | 79.0 | 18.3 | 79.0 | 50.0 | 117.0 | 71.1 | 86.9 | |||
| M | 40 | 85 | 9 | 64.4 | 10.0 | 65.0 | 55.0 | 87.0 | 56.8 | 72.1 | 8 | 68.3 | 22.3 | 58.5 | 50.0 | 117.0 | 49.6 | 86.9 | |||
| F | 40 | 95 | 14 | 68.5 | 17.8 | 72.0 | 33.0 | 100.0 | 58.2 | 78.8 | 15 | 84.8 | 13.2 | 83.0 | 68.0 | 110.0 | 77.5 | 92.1 | |||
| Low-density lipoprotein | mg/dL | VISIT1 | MIX | 65 | 139 | 23 | 126.0 | 33.8 | 125.0 | 67.0 | 203.0 | 111.4 | 140.6 | 23 | 126.7 | 38.6 | 120.0 | 79.0 | 211.0 | 110.0 | 143.4 |
| (LDL) cholesterol | VISIT2 | MIX | 65 | 139 | 23 | 130.7 | 33.5 | 122.0 | 83.0 | 210.0 | 116.2 | 145.2 | 23 | 125.1 | 38.7 | 121.0 | 57.0 | 202.0 | 108.4 | 141.9 | |
| Triglycerides (TG) | mg/dL | VISIT1 | MIX | 30 | 149 | 23 | 113.3 | 79.8 | 90.0 | 23.0 | 332.0 | 78.7 | 147.8 | 23 | 93.1 | 112.5 | 62.0 | 33.0 | 578.0 | 44.5 | 141.8 |
| VISIT2 | MIX | 30 | 149 | 23 | 100.8 | 59.1 | 77.0 | 26.0 | 227.0 | 75.2 | 126.4 | 23 | 75.1 | 49.5 | 59.0 | 33.0 | 280.0 | 53.7 | 96.5 | ||
| Glucose (GLU) | mg/dL | VISIT1 | MIX | 70 | 109 | 23 | 88.7 | 9.0 | 86.0 | 72.0 | 111.0 | 84.9 | 92.6 | 23 | 86.3 | 7.3 | 86.0 | 74.0 | 102.0 | 83.1 | 89.4 |
| VISIT2 | MIX | 70 | 109 | 23 | 87.0 | 6.8 | 85.0 | 77.0 | 100.0 | 84.1 | 89.9 | 23 | 87.8 | 8.0 | 88.0 | 72.0 | 109.0 | 84.3 | 91.3 | ||
| Hemoglobin A1c | % | VISIT1 | MIX | 4.6 | 6.2 | 23 | 5.4 | 0.3 | 5.3 | 4.9 | 6.1 | 5.3 | 5.5 | 23 | 5.4 | 0.3 | 5.3 | 5.0 | 5.9 | 5.2 | 5.5 |
| (HbA1c: NGSP) | VISIT2 | MIX | 4.6 | 6.2 | 23 | 5.4 | 0.2 | 5.3 | 5.0 | 6.0 | 5.3 | 5.5 | 23 | 5.4 | 0.2 | 5.3 | 5.0 | 6.0 | 5.3 | 5.5 | |
n, Number of cases; SD, Standard Deviation; Med, Median; Min, Minimum; Max, Maximum; 95%CI−, Lower limit of 95 % Confidence Interval for group differences; 95%CI+, Upper limit of 95 % Confidence Interval for group differences; VISIT1, Screening and baseline assessment; VISIT2, Examination at week 3 after consumption; MIX, Male and female; M, Male; F, Female.
4. Discussion
The primary objective of this clinical trial was to investigate the anti-fatigue effects of a 3-week, continuous daily consumption of KRG extracts among a group of healthy Japanese adults. The underlying hypothesis postulates that fatigue is linked to oxidative stress induced by the presence of reactive oxygen species (ROS). The mitochondria, responsible for adenosine triphosphate (ATP) synthesis, the quintessential energy currency in humans, concurrently generate ROS as a byproduct during this process [14]. Excessive ROS accumulation leads to oxidative injury within the mitochondria, resulting in a reduction in energy production from these vital organelles. This energy deficit ultimately contributes to systemic energy depletion, consequently leading to the onset of fatigue [5]. Hence, the critical objective is to mitigate mitochondrial oxidative impairment, achieved by reducing ROS levels through antioxidative mechanisms, effectively alleviating fatigue [15]. Moreover, it is essential to meticulously examine the complex interrelation between fatigue resulting from inadequate sleep and the demands of both physical and psychological stress, extending this scrutiny to its consequential impact on motivation and vitality [16]. Fatigue stemming from physical exertion is categorized as physical fatigue, whereas fatigue originating from increased psychological, emotional, or volitional engagements falls under the classification of mental fatigue [17,18]. Of particular import, mental fatigue plays a pivotal role in the development of chronic fatigue, a condition characterized by its persistence for a duration exceeding six months, and accompanied by a wide spectrum of symptoms encompassing profound fatigue, myalgia, sleep disturbances, and compromised concentration [19,20]. Therefore, the concept of antioxidant supplementation occupies a crucial position in alleviating mental fatigue, orchestrating the scavenging of ROS within the physiological environment, and consequently contributing to the prophylaxis against the onset of chronic fatigue.
Ginsenosides Rb1, Rg1, and Rg3 are components of red ginseng that exhibit antioxidant activity [[21], [22], [23]]. Triggering ginsenoside Rb1 via protein kinase B (Akt) phosphorylation, a controller intricately linked to cellular growth and proliferation, leads to an upregulation of nuclear factor E2-related factor 2 (NrF2) levels [24]. This molecular cascade subsequently enhances the expression of superoxide dismutase (SOD), resulting in a reduction in serum levels of ROS and malondialdehyde (MDA) concentrations, a well-recognized indicator of lipid peroxidation [25,26]. Ginsenoside Rg1 enhances the production of antioxidants, including SOD, by through the upregulation of NrF2 expression [27]. Furthermore, it has been revealed that ginsenoside Rg3 elicits the activation of silent information regulator of transcription 1 (SIRT1), resulting in the subsequent stimulation of proliferator-activated receptor gamma coactivator-1α (PGC-1α) expression, followed by facilitating the augmentation of SOD synthesis [28,29]. Based on the preceding discussion, the presence of antioxidant-rich constituents within ginseng suggests a potential pathway for alleviating fatigue. In practice, an empirical investigation involving a 4-week sustained regimen of red ginseng (enriched with ginsenosides) among individuals suffering from chronic fatigue syndrome (CFS) revealed a substantial reduction in fatigue levels by the fourth week within the intervention group, demonstrating significant improvement in comparison to the placebo group [30].
The inclusion of ginsenosides Rb1, Rg1, and Rg3 within the test-food underscored an anticipated mechanism for fatigue reduction upon ingestion, supported by consistent findings within the existing literature. Fatigue, as defined by Ko et al., is a subjective feeling of exhaustion resulting from physical, mental, and neurosensory labor [31]. To assess fatigue in this study, the Visual Analog Scale (VAS), a widely used tool for measuring subjective symptoms such as pain, fatigue, and quality of life [32], was employed. The analysis of the VAS scores was based on predefined parameters, including an effect size of 0.75, α error probability of 0.05, and 1-β error probability of 0.95. According to these parameters, a sample size of at least 21 participants per group was determined to achieve sufficient statistical power. The baseline VAS fatigue scores were 63.3 ± 12.6 mm for the test-food group and 64.1 ± 11.2 mm for the placebo group. After 3 weeks of consumption, the mean VAS fatigue scores dropped to 38.8 ± 18.9 mm for the test-food group and 50.1 ± 15.8 mm for the placebo group. This difference of 11.2 mm (95 % CI [21.6, 0.8]) was statistically significant, indicating a meaningful reduction in fatigue in the test-food group compared to the placebo. The test-food group clearly demonstrated a statistically significant decrease in fatigue compared to the placebo group (P = 0.035) (Table 2B). A comprehensive systematic review and meta-analysis encompassing the literature from January 2010 to December 2020 aimed to elucidate the efficacy of ginseng-containing supplements, encompassing American ginseng, Asian ginseng, Korean ginseng, and Korean Red Ginseng, in addressing disease-induced fatigue [33]. Within the 12 studies analyzed, three studies employed VAS to assess fatigue levels [13,33]. The only trial that showed a significant group difference was conducted by Kim et al. [13], in which participants suffering from sudden onset showed an average VAS fatigue score of 58.0 ± 13.0 mm in the placebo group following a 4-week intervention, while the group receiving the Panax ginseng Meyer extract intervention demonstrated a significantly lower score of 44.0 ± 18.0 mm, indicating a substantial inter-group difference of 14.0 mm. This outcome is consistent with the concurrent reduction in oxidative stress level, acknowledged as an etiological factor for chronic fatigue, in the P. ginseng extract intake group. These findings offer insights into the potential underlying mechanism for fatigue improvement following the consumption of P. ginseng extract. While the present study involved healthy subjects and thus a direct comparison with the study conducted by Kim et al. [13] is not exactly feasible, it is important to highlight that the disparity in fatigue VAS score between the test-food and placebo groups was comparable in both studies, underscoring the clinical significance of the substantial group difference. In light of the paucity of prior observational or correlated investigations employing the fatigue VAS within cohorts of healthy subjects, the inclusion of healthy participants in this trial introduced limitations in the precise assessment of their experienced tiredness. Even if fatigue levels of the participants remained within the range of health, an accurate quantification of their exhaustion under these experimental conditions remains challenging. Consequently, the findings of this study should be primarily considered in the context of individuals displaying similar fatigue VAS scores. Moreover, considering the presumed correlation between lower fatigue VAS scores and diminished levels of ROS, comparable effectiveness is anticipated within such a subgroup. Conversely, individuals with higher VAS scores would require further validation of these findings through the initiation of new investigations.
In the present study, lactic acid was employed as an objective metric to quantify physical fatigue, while plasma cortisol levels were measured to provide an objective evaluation of mental fatigue. However, the post-intervention analysis (Table 2A) revealed no statistically significant difference in either of these parameters. Lactic acid and plasma cortisol are widely recognized as established biomarkers indicative of acute stress, undergoing alterations in response to both physical and psychological burdens [[34], [35], [36]]. In a clinical trial conducted in China, a group of healthy young males (mean age: 23.0 ± 1.6 years) were subjected to a 4-week regimen of American ginseng supplementation to investigate changes in blood lactate levels during exercise stress in comparison to a placebo-controlled group [35]. The findings underscored a substantial reduction in blood lactate levels among the American ginseng recipients during exercise, while no significant disparities detected prior to exercise. In another research conducted in the United States, subjects including males (mean age: 41.2 ± 9.7 years) and females (mean age: 38.7 ± 7.8 years) were subjected to a 14-day regimen of ginseng-containing supplements, and their plasma cortisol levels exhibited a significant reduction following exposure to an exercise load [37]. Considering the absence of physical or mental stress interventions in the present study, a comprehensive evaluation of the impact of the test-food on lactic acid and plasma cortisol remains limited. Additionally, a previous study has indicated a lack of correlation between subjective and objective fatigue measures [38], emphasizing the need for further investigations to elucidate the influence of test-food consumption on objective assessments.
Within the scope of this investigation, it was firmly established that the consumption of the test-food yielded a clear reduction in subjective fatigue levels. This observation is most likely attributed to the antioxidative effects of ginsenosides Rb1, Rg1, and Rg3. Considering the intricate nature of fatigue experiences in daily life, it is important to investigate methods for indirectly validating the effectiveness of the test food. This exploration could encompass the assessment of changes in quality of life and mood, both of which are directly impacted by fatigue. To achieve this, well-established evaluation instruments such as the MOS Short-Form 36-Item Health Survey [39] or the Profile of Mood States Second Edition [40] can be utilized. In order to elucidate the specific mechanism responsible for the mitigation of fatigue through the consumption of the test food, the integration of assessments related to oxidative stress markers needs to be incorporated, including derivatives-reactive oxygen metabolites (d-ROMs), biological antioxidant potential (BAP), SOD, and MDA tests [15,25,41,42]. These measurements will enable a comprehensive evaluation of the antioxidative properties of the test-food.
The principal focus of this study was to assess the safety profile of the test food. While there were no reported adverse reactions during the study period, a subset of participants did report experiencing adverse events (Table 2B). It is imperative to emphasize that no causal relationship between these adverse events and the consumption of the test food was established. The proportion of instances in which urinalysis and peripheral blood assessment measurements initially conformed to reference values during screening subsequently revealed deviations beyond these reference values post-intervention (Table 2C). This comprehensive examination encompassed individual and collective physical assessments, urinalysis, and peripheral blood tests (Table 3, Table 4), demonstrating the absence of any significant clinical events subsequent to the consumption of the test-food.
5. Conclusion
The primary objective of this study was to investigate the potential anti-fatigue resulting from the sustained daily consumption of KRG extracts over a 3-week period in a cohort of healthy Japanese adults. The consumption of the test-food resulted in a significant reduction in the fatigue VAS score, indicating its potential efficacy in a role in mitigating fatigue. Furthermore, the safety profile of KRG extracts was established within the scope of this study.
Conflict of interest
The authors declare no conflict of interest.
Acknowledgements
This work was supported by Korea Institute of Planning and Evaluation for Technology in Food, Agriculture and Forestry (IPET) through Agri-Food Export Business Model Development Program, funded by the Republic of Korea Ministry of Agriculture, Food and Rural Affairs (MAFRA) (Project No: 320104-03)
Contributor Information
Yeong-Geun Lee, Email: lyg629@nate.com.
Hyunggun Kim, Email: hkim.bme@skku.edu.
Se Chan Kang, Email: sckang@khu.ac.kr.
References
- 1.Kim S., Bae W.K., Kim J.Y., Jang M., Kim J.H., Noh H.H. Validation of the Korean version of schedule of fatigue and anergia: general physician questionnaire. J Korean Med Sci. 2016;31(2):159–163. doi: 10.3346/jkms.2016.31.2.159. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Lim E.J., Lee J.S., Lee E.J., Jeong S.J., Park H.Y., Ahn Y.C., et al. Nationwide epidemiological characteristics of chronic fatigue syndrome in South Korea. J Transl Med. 2021;19(1):502. doi: 10.1186/s12967-021-03170-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Sung W.S., Kang H.R., Jung C.Y., Park S.S., Lee S.H., Kim E.J. Efficacy of Korean red ginseng (Panax ginseng) for middle-aged and moderate level of chronic fatigue patients: a randomized, double-blind, placebo-controlled trial. Compl Ther Med. 2020;48 doi: 10.1016/j.ctim.2019.102246. [DOI] [PubMed] [Google Scholar]
- 4.Morris M.C., Kouros C.D., Mielock A.S., Rao U. Depressive symptom composites associated with cortisol stress reactivity in adolescents. J Affect Disord. 2017;210:181–188. doi: 10.1016/j.jad.2016.12.023. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Lu G., Liu Z., Wang X., Wang C. Recent advances in Panax ginseng C.A. Meyer as a herb for anti-fatigue: an effects and mechanisms review. Foods. 2021;10(5):1030. doi: 10.3390/foods10051030. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Shin I.S., Kim D.H., Jang E.Y., Kim H.Y., Yoo H.S. Anti-fatigue properties of cultivated wild ginseng distilled extract and its active component panaxydol in rats. J Pharmacopuncture. 2019;22(2):68–74. doi: 10.3831/KPI.2019.22.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.World Health O. World Health Organization; Geneva: 2010. WHO monographs on medicinal plants commonly used in the Newly Independent States (NIS) pp. 141–160. [Google Scholar]
- 8.Kim Y.S., Woo J.Y., Han C.K., Chang I.M. Safety analysis of Panax ginseng in randomized clinical trials: a systematic review. Medicines (Basel) 2015;2(2):106–126. doi: 10.3390/medicines2020106. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Yang H., In Bok J., Lian Xue Z., Dong Hwi K., Yong Hua X., Young Chang K., et al. Clinical study on food safety evaluation of Panax ginseng. Korean Journal of Medicinal Crop Science. 2015;23(3):185–189. [Google Scholar]
- 10.Oh K.J., Chae M.J., Lee H.S., Hong H.D., Park K. Effects of Korean red ginseng on sexual arousal in menopausal women: placebo-controlled, double-blind crossover clinical study. J Sex Med. 2010;7(4):1469–1477. doi: 10.1111/j.1743-6109.2009.01700.x. [DOI] [PubMed] [Google Scholar]
- 11.So S.H., Lee J.W., Kim Y.S., Hyun S.H., Han C.K. Red ginseng monograph. Journal of Ginseng Research. 2018;42(4):549–561. doi: 10.1016/j.jgr.2018.05.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Cleare A.J., Blair D., Chambers S., Wessely S. Urinary free cortisol in chronic fatigue syndrome. Am J Psychiatr. 2001;158(4):641–643. doi: 10.1176/appi.ajp.158.4.641. [DOI] [PubMed] [Google Scholar]
- 13.Kim H.G., Cho J.H., Yoo S.R., Lee J.S., Han J.M., Lee N.H., et al. Antifatigue effects of Panax ginseng ca meyer: a randomised, double-blind, placebo-controlled trial. PLoS One. 2013;8(4) doi: 10.1371/journal.pone.0061271. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Annesley S.J., Fisher P.R. Mitochondria in health and disease. Cells. 2019;8(7):680. doi: 10.3390/cells8070680. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Wang Y., Branicky R., Noe A., Hekimi S. Superoxide dismutases: dual roles in controlling ROS damage and regulating ROS signaling. J Cell Biol. 2018;217(6):1915–1928. doi: 10.1083/jcb.201708007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Rosenthal T.C., Majeroni B.A., Pretorius R., Malik K. Fatigue: an overview. Am Fam Physician. 2008;78(10):1173–1180. [PubMed] [Google Scholar]
- 17.Huang L.Z., Huang B.K., Ye Q., Qin L.P. Bioactivity-guided fractionation for anti-fatigue property of Acanthopanax senticosus. J Ethnopharmacol. 2011;133(1):213–219. doi: 10.1016/j.jep.2010.09.032. [DOI] [PubMed] [Google Scholar]
- 18.Lamou B., Taiwe G.S., Hamadou A., Abene Houlray J., Atour M.M., et al. Antioxidant and antifatigue properties of the aqueous extract of Moringa oleifera in rats subjected to forced swimming endurance test. Oxid Med Cell Longev. 2016;2016 doi: 10.1155/2016/3517824. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Mizuno K., Tanaka M., Yamaguti K., Kajimoto O., Kuratsune H., Watanabe Y. Mental fatigue caused by prolonged cognitive load associated with sympathetic hyperactivity. Behav Brain Funct. 2011;7:17. doi: 10.1186/1744-9081-7-17. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Galland-Decker C., Marques-Vidal P., Vollenweider P. Prevalence and factors associated with fatigue in the Lausanne middle-aged population: a population-based, cross-sectional survey. BMJ Open. 2019;9(8) doi: 10.1136/bmjopen-2018-027070. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Koh E.J., Kim K.J., Choi J., Jeon H.J., Seo M.J., Lee B.Y. Ginsenoside Rg1 suppresses early stage of adipocyte development via activation of C/EBP homologous protein-10 in 3T3-L1 and attenuates fat accumulation in high fat diet-induced obese zebrafish. J Ginseng Res. 2017;41(1):23–30. doi: 10.1016/j.jgr.2015.12.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Lan T.H., Xu Z.W., Wang Z., Wu Y.L., Wu W.K., Tan H.M. Ginsenoside Rb1 prevents homocysteine-induced endothelial dysfunction via PI3K/Akt activation and PKC inhibition. Biochem Pharmacol. 2011;82(2):148–155. doi: 10.1016/j.bcp.2011.04.001. [DOI] [PubMed] [Google Scholar]
- 23.Nabavi S.F., Sureda A., Habtemariam S., Nabavi S.M. Ginsenoside Rd and ischemic stroke; a short review of literatures. J Ginseng Res. 2015;39(4):299–303. doi: 10.1016/j.jgr.2015.02.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Shaukat A., Yang C., Yang Y., Guo Y.F., Jiang K., Guo S., et al. Ginsenoside Rb 1: a novel therapeutic agent in staphylococcusaureus-induced acute lung injury with special reference to oxidative stress and apoptosis. Microb Pathog. 2020;143 doi: 10.1016/j.micpath.2020.104109. [DOI] [PubMed] [Google Scholar]
- 25.Grotto D., Maria L.S., Valentini J., Paniz C., Schmitt G., Garcia S.C., et al. Importance of the lipid peroxidation biomarkers and methodological aspects for malondialdehyde quantification. Quim Nova. 2009;32(1):169–174. [Google Scholar]
- 26.Zhuang C.L., Mao X.Y., Liu S., Chen W.Z., Huang D.D., Zhang C.J., et al. Ginsenoside Rb1 improves postoperative fatigue syndrome by reducing skeletal muscle oxidative stress through activation of the PI3K/Akt/Nrf2 pathway in aged rats. Eur J Pharmacol. 2014;740:480–487. doi: 10.1016/j.ejphar.2014.06.040. [DOI] [PubMed] [Google Scholar]
- 27.Gao Y., Chu S.F., Shao Q.H., Zhang M.J., Xia C.Y., Wang Y.Y., et al. Antioxidant activities of ginsenoside Rg1 against cisplatin-induced hepatic injury through Nrf2 signaling pathway in mice. Free Radic Res. 2017;51(1):1–13. doi: 10.1080/10715762.2016.1234710. [DOI] [PubMed] [Google Scholar]
- 28.Yang Q.Y., Lai X.D., Ouyang J., Yang J.D. Effects of Ginsenoside Rg3 on fatigue resistance and SIRT1 in aged rats. Toxicology. 2018;409:144–151. doi: 10.1016/j.tox.2018.08.010. [DOI] [PubMed] [Google Scholar]
- 29.Valle I., Alvarez-Barrientos A., Arza E., Lamas S., Monsalve M. PGC-1 alpha regulates the mitochondrial antioxidant defense system in vascular endothelial cells. Cardiovasc Res. 2005;66(3):562–573. doi: 10.1016/j.cardiores.2005.01.026. [DOI] [PubMed] [Google Scholar]
- 30.Zhang L., Chen X.Y., Cheng Y.Q., Chen Q.L., Tan H.S., Son D., et al. Safety and antifatigue effect of Korean Red Ginseng: a randomized, double-blind, and placebo-controlled clinical trial. Journal of Ginseng Research. 2019;43(4):676–683. doi: 10.1016/j.jgr.2019.05.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Ko H.J., Kim M.A., Kwan Y.S., Kim C.N., Park K.M., Park J.S. The fatigue experience of shift work nurses. J Korean Acad Community Health Nurs. 2004;18(1):103–118. [Google Scholar]
- 32.Miller M.D., Ferris D.G. Measurement of subjective phenomena in primary care research: the visual analogue scale. Fam Pract Res J. 1993;13:15–24. [PubMed] [Google Scholar]
- 33.Zhu J.X., Xu X.R., Zhang X., Zhuo Y., Chen S.T., Zhong C.W., et al. Efficacy of ginseng supplements on disease-related fatigue: a systematic review and meta-analysis. Medicine. 2022;101(26) doi: 10.1097/MD.0000000000029767. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Zarabi L., Arazi H., Izadi M. The effects of Panax ginseng supplementation on growth hormone, cortisol and lactate response to high-intensity resistance exercise. Biomed Hum Kinet. 2018;10(1):8–14. [Google Scholar]
- 35.Hsu C.C., Ho M.C., Lin L.C., Su B., Hsu M.C. American ginseng supplementation attenuates creatine kinase level induced by submaximal exercise in human beings. World J Gastroenterol. 2005;11(34):5327–5331. doi: 10.3748/wjg.v11.i34.5327. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Adam E.K., Quinn M.E., Tavernier R., McQuillan M.T., Dahlke K.A., Gilbert K.E. Diurnal cortisol slopes and mental and physical health outcomes: a systematic review and meta-analysis. Psychoneuroendocrinology. 2017;83:25–41. doi: 10.1016/j.psyneuen.2017.05.018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Flanagan S.D., DuPont W.H., Caldwell L.K., Hardesty V.H., Barnhart E.C., Beeler M.K., et al. The effects of a Korean ginseng, GINST15, on hypo-pituitary-adrenal and oxidative activity induced by intense work stress. J Med Food. 2018;21(1):104–112. doi: 10.1089/jmf.2017.0071. [DOI] [PubMed] [Google Scholar]
- 38.Khaengkhun P., Bhuanantanondh P., Mekhora K., Jalayondeja C. D8-2 association between subjective and objective assessment of fatigue. Jpn J Ergon. 2017;53(Supplement2):S652–S655. [Google Scholar]
- 39.Cooley K., Szczurko O., Perri D., Mills E.J., Bernhardt B., Zhou Q., et al. Naturopathic care for anxiety: a randomized controlled trial ISRCTN78958974. PLoS One. 2009;4(8) doi: 10.1371/journal.pone.0006628. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Konuma H., Hirose H., Yokoyama K. Relationship of the Japanese translation of the profile of mood states Second edition (POMS 2®) to the first edition (POMS®) Juntendo Medical Journal. 2015;61(5) 517-9. [Google Scholar]
- 41.Ishiwata S., Kato T., Kasai T., Sato A., Yatsu S., Matsumoto H., et al. Changes in self-reported physical activity and health-related quality of life following 3-month astaxanthin supplementation in patients with heart failure: results from a pilot study. Ann Palliat Med. 2021;10(2):1396–1403. doi: 10.21037/apm-20-1378. [DOI] [PubMed] [Google Scholar]
- 42.Sim M., Kim C.S., Shon W.J., Lee Y.K., Choi E.Y., Shin D.M. Hydrogen-rich water reduces inflammatory responses and prevents apoptosis of peripheral blood cells in healthy adults: a randomized, double-blind, controlled trial. Sci Rep. 2020;10(1) doi: 10.1038/s41598-020-68930-2. [DOI] [PMC free article] [PubMed] [Google Scholar]