OBJECTIVES: Primary tumor treatment through surgical resection and adjuvant therapy has been extensively studied, but there is a lack of effective strategies and drugs for the treatment of tumor metastases. Here, we describe a functional product based on a combination of compounds, which can be used as an adjuvant therapy and has well-known mechanisms for inhibiting cancer metastases, improving anti-cancer treatment, and enhancing immunity and antioxidant capacity. Our designed combination, named MVBL, consists of four inexpensive compounds: L-selenium-methylselenocysteine (MSC), D-‍α‍-tocopheryl succinic acid (VES), β‍-carotene (β‍-Ca), and L-lysine (Lys). METHODS: The effects of MVBL on cell viability, cell cycle, cell apoptosis, cell migration, cell invasion, reactive oxygen species (ROS), and paclitaxel (PTX)-combined treatment were studied in vitro. The inhibition of tumor metastasis, antioxidation, and immune enhancement capacity of MVBL were determined in vivo. RESULTS: MVBL exhibited higher toxicity to tumor cells than to normal cells. It did not significantly affect the cell cycle of cancer cells, but increased their apoptosis. Wound healing, adhesion, and transwell assays showed that MVBL significantly inhibited tumor cell migration, adhesion, and invasion. MVBL sensitized MDA-MB-231 breast cancer cells to PTX, indicating that it can be used as an adjuvant to enhance the therapeutic effect of chemotherapy drugs. In mice, experimental data showed that MVBL inhibited tumor metastasis, prolonged their survival time, and enhanced their antioxidant capacity and immune function. CONCLUSIONS This study revealed the roles of MVBL in improving immunity and antioxidation, preventing tumor growth, and inhibiting metastasis in vitro and in vivo. MVBL may be used as an adjuvant drug in cancer therapy for improving the survival and quality of life of cancer patients.
Mice ; Animals ; beta Carotene ; Lysine/pharmacology* ; Antioxidants/pharmacology* ; Quality of Life ; Paclitaxel/pharmacology* ; Apoptosis ; alpha-Tocopherol ; Succinates/pharmacology* ; Cell Line, Tumor ; Cell Proliferation ; Neoplasms

OBJECTIVES: Pentoxifylline (PTX) is a methylxanthine derivative that has been implicated in the pathogenesis of peripheral vessel disease and intermittent lameness. The purpose of this study was to investigate the effect of PTX and tocopherol in patients diagnosed with osteoradionecrosis (ORN), bisphosphonate-related osteonecrosis of the jaw (BRONJ), and chronic osteomyelitis using digital panoramic radiographs.MATERIALS AND METHODS: This study was performed in 25 patients who were prescribed PTX and tocopherol for treatment of ORN, BRONJ, and chronic osteomyelitis between January 2014 and May 2018 in Seoul National University Dental Hospital. Radiographic densities of the dental panorama were compared prior to starting PTX and tocopherol, at 3 months, and at 6 months after prescription. Radiographic densities were measured using Adobe Photoshop CS6 (Adobe System Inc., USA). Blood sample tests showing the degree of inflammation at the initial visit were considered the baseline and compared with results after 3 to 6 months. Statistical analysis was performed using the Mann–Whitney test and repeated measurement ANOVA using IBM SPSS 23.0 (IBM Corp., USA).RESULTS: Eight patients were diagnosed with ORN, nine patients with BRONJ, and the other 8 patients with chronic osteomyelitis. Ten of the 25 patients were men, average age was 66.32±14.39 years, and average duration of medication was 151.8±80.65 days (range, 56–315 days). Statistically significant increases were observed in the changes between 3 and 6 months after prescription (P<0.05). There was no significant difference between ORN, BRONJ, and chronic osteomyelitis. Only erythrocyte sedimentation rate (ESR) was statistically significantly lower than before treatment (P<0.05) among the white blood cell (WBC), ESR, and absolute neutrophil count (ANC).CONCLUSION: Long-term use of PTX and tocopherol can be an auxiliary method in the treatment of ORN, BRONJ, or chronic osteomyelitis in jaw.
Bisphosphonate-Associated Osteonecrosis of the Jaw ; Blood Sedimentation ; Humans ; Inflammation ; Jaw ; Leukocytes ; Male ; Methods ; Neutrophils ; Osteomyelitis ; Osteoradionecrosis ; Pentoxifylline ; Prescriptions ; Radiography, Panoramic ; Seoul ; Tocopherols

Hesperetin, an abundant bioactive component of citrus fruits, is poorly water-soluble, resulting in low oral bioavailability. We developed new formulations to improve the water solubility, antioxidant activity, and oral absorption of hesperetin. Two nano-based formulations were developed, namely hesperetin-TPGS (D-α-tocopheryl polyethylene glycol 1000 succinate) micelles and hesperetin-phosphatidylcholine (PC) complexes. These two formulations were prepared by a simple technique called solvent dispersion, using US Food and Drug Administration (FDA)-approved excipients for drugs. Differential scanning calorimetry (DSC) and dynamic light scattering (DLS) were used to characterize the formulations' physical properties. Cytotoxicity analysis, cellular antioxidant activity assay, and a pharmacokinetic study were performed to evaluate the biological properties of these two formulations. The final weight ratios of both hesperetin to TPGS and hesperetin to PC were 1:12 based on their water solubility, which increased to 21.5- and 20.7-fold, respectively. The hesperetin-TPGS micelles had a small particle size of 26.19 nm, whereas the hesperetin-PC complexes exhibited a larger particle size of 219.15 nm. In addition, the cellular antioxidant activity assay indicated that both hesperetin-TPGS micelles and hesperetin-PC complexes increased the antioxidant activity of hesperetin to 4.2- and 3.9-fold, respectively. Importantly, the in vivo oral absorption study on rats indicated that the micelles and complexes significantly increased the peak plasma concentration (C_max) from 2.64 μg/mL to 20.67 and 33.09 μg/mL and also increased the area under the concentration-time curve of hesperetin after oral administration to 16.2- and 18.0-fold, respectively. The micelles and complexes increased the solubility and remarkably improved the in vitro antioxidant activity and in vivo oral absorption of hesperetin, indicating these formulations' potential applications in drugs and healthcare products.
Administration, Oral ; Animals ; Antioxidants/chemistry* ; Biological Availability ; Calorimetry, Differential Scanning ; Dogs ; Dose-Response Relationship, Drug ; Drug Carriers ; Female ; Hep G2 Cells ; Hesperidin/chemistry* ; Humans ; Light ; Madin Darby Canine Kidney Cells ; Micelles ; Phosphatidylcholines/chemistry* ; Polyethylene Glycols/chemistry* ; Rats ; Rats, Sprague-Dawley ; Scattering, Radiation ; Solubility ; Solvents ; Vitamin E/chemistry* ; Water/chemistry* ; alpha-Tocopherol/chemistry*

BACKGROUND/OBJECTIVES: Korea is quickly becoming an aged society. Dementia is also becoming a vital public health problem in Korea. Cognitive impairment as a pre-stage of dementia shares most risk factors for dementia. The aim of the present study was to determine associations of serum levels of vitamins A, C, and E with the risk of cognitive impairment among elderly Koreans. SUBJECTS/METHODS: In this cross-sectional study, a total of 230 participants aged 60–79 years from Yangpyeong cohort were included. Cognitive function was assessed by the Korean version of the Mini-Mental State Examination for Dementia Screening. The logistic multivariable regression model was applied to determine the effect of serum vitamins A, C, and E on the risk of cognitive impairment. RESULTS: There was no significant association between the risk of cognitive impairment and serum levels of vitamin A and vitamin C. There was a significant odd ratio when the second tertile group of beta-gamma tocopherol level was compared to the first tertile group [odds ratio (OR) = 0.37, 95% confidence interval (CI) = 0.14–0.98, P for trend = 0.051]. In subgroup analyses, there were significant negative associations between beta-gamma tocopherol level and the risk of cognitive impairment in men (OR = 0.17, 95% CI = 0.03–0.87, P for trend = 0.028), non-drinkers or former drinkers (OR = 0.13, 95% CI = 0.02–0.66, P for trend = 0.025), and non-smokers or former smokers (OR = 0.27, 95% CI = 0.09–0.82, P for trend = 0.017). CONCLUSION: Serum beta-gamma tocopherol levels tended to be inversely associated with the risk of cognitive impairment. Further prospective large-scaled studies are needed to examine this association.
Aged* ; Ascorbic Acid ; Cognition ; Cognition Disorders* ; Cohort Studies ; Cross-Sectional Studies ; Dementia ; Humans ; Korea ; Male ; Mass Screening ; Prospective Studies ; Public Health ; Risk Factors ; Tocopherols ; Vitamin A ; Vitamin E ; Vitamins*

PURPOSE: This study examined the association between the antioxidant vitamin intake and obesity in Korean women. METHODS: Adult women aged ≥19 years who completed a health examination and nutrition survey from the Korea National Health and Nutrition Examination Survey between 2007 ~ 2016 were selected for the study (n = 30,425). A BMI ≥25 kg/m2 and waist circumference ≥85 cm were defined as obesity and abdominal obesity, respectively. The individual antioxidant vitamin intake was estimated by linking the antioxidant vitamin composition database of commonly consumed foods and the subjects' 24-hour recall food consumption data. Carotenoids, retinol, vitamin A (retinol activity equivalent), vitamin C, tocopherols, and vitamin E (α-tocopherol equivalent) were included in the analysis. Each vitamin intake was converted to the nutrient density per 1,000 kcal. Odds ratio (ORs) and 95% confidence interval (CI) for obesity according to each tertile of the nutrient density was obtained from multiple logistic regression adjusted for age, household income, education level, smoking, alcohol consumption, and physical activity. RESULTS: The mean intake of α-carotene, retinol, vitamin E, α-tocopherol, and γ-tocopherol per 1,000 kcal was significantly lower in the obese group than in the normal group. A higher intake of lycopene was inversely associated with obesity (highest vs. lowest; OR = 0.89, 95% CI: 0.83–0.96) and abdominal obesity (highest vs. lowest; OR = 0.88, 95% CI: 0.81–0.95). Higher intakes of α-carotene, total carotenoids, vitamin A, and γ-tocopherol also had a negative relationship with abdominal obesity. The antioxidant vitamin intakes from eggs, milk and dairy products, seasoning, and grains were significantly lower in the obese group than in the normal group. CONCLUSION: This study showed that the dietary intake of antioxidant vitamins was inversely associated with obesity and abdominal obesity among Korean women. Further study will be needed to examine the causal relationship between the antioxidant vitamin and obesity.
Adult ; Alcohol Drinking ; Ascorbic Acid ; Carotenoids ; Education ; Eggs ; Family Characteristics ; Female ; Humans ; Korea* ; Logistic Models ; Milk ; Motor Activity ; Nutrition Surveys* ; Obesity* ; Obesity, Abdominal ; Odds Ratio ; Ovum ; Seasons ; Smoke ; Smoking ; Tocopherols ; Vitamin A ; Vitamin E ; Vitamins* ; Waist Circumference

PURPOSE: The purpose of this study was to determine trends in dietary vitamin E intakes and contributing food groups among Korean adults. METHODS: This study included 66,695 subjects aged ≥ 19 years who completed a nutrition survey as part of the Korea National Health and Nutrition Examination Survey (1998, 2001, 2005, 2007~2009, 2010~2012, 2013~2015). We estimated individual daily intakes of α-, β-, γ-, δ-tocopherol, and total vitamin E by linking food consumption data with a vitamin E database of commonly consumed foods. RESULTS: Daily vitamin E intake significantly increased from 6.4 mg α-TE/d in 1998 to 7.7 mg α-TE/d in 2013~2015 (p for trend < 0.0001) among men as well as from 5.4 mg α-TE/d in 1998 to 6.5 mg α-TE/d in 2013~2015 among women (p for trend < 0.0001). However, the intake of vitamin E was lower than the adequate intake (AI) of Dietary Reference Intakes for Koreans 2015 (2015 KDRI). In 2013~2015, men consumed 6.5 mg/d of α-tocopherol, 0.5 mg/d of β-tocopherol, 6.0 mg/d of γ-tocopherol, and 3.9 mg/d of δ-tocopherol, whereas women consumed 5.7 mg/d of α-tocopherol, 0.4 mg/d of β-tocopherol, 4.8 mg/d of γ-tocopherol, and 2.8 mg/d of δ-tocopherol. The major food groups contributing to vitamin E intake were vegetables (men: 23.3%, women: 22.7%), grains (men: 14.5%, women: 13.9%), and eggs (men: 13.0%, women: 12.5%). CONCLUSION: This study provides scientific evidence for vitamin E intake in Korean adults. Since the current intake of vitamin E was lower than the reference intakes set by 2015 KDRI, dietary vitamin E intake should be monitored regularly among Korean adults.
Adult* ; Eggs ; Female ; Humans ; Korea* ; Male ; Nutrition Surveys* ; Ovum ; Recommended Dietary Allowances ; Tocopherols ; Vegetables ; Vitamin E* ; Vitamins*

BACKGROUND/OBJECTIVES: A pivotal role of oxidative stress has been emphasized in the pathogenesis as well as in the disease progression of Parkinson's disease (PD). We aimed at investigating serum levels of antioxidant vitamins and elucidating whether they could be associated with the pathogenesis and progression of PD. MATERIALS/METHODS: Serum levels of retinol, α- and γ-tocopherols, α- and β-carotenes, lutein, lycopene, zeaxanthin and β-cryptoxanthin were measured and compared between 104 patients with idiopathic PD and 52 healthy controls matched for age and gender. In order to examine the relationship between antioxidant vitamins and the disease progression, multiple group comparisons were performed among the early PD (Hoehn and Yahr stage I and II, N = 47), advanced PD (stage III and IV, N = 57) and control groups. Separate correlation analyses were performed between the measured antioxidant vitamins and clinical variables, such as Hoehn and Yahr stage and Unified Parkinson's Disease Rating Scale (UPDRS) motor score. RESULTS: Compared to controls, PD patients had lower levels of α- and β-carotenes and lycopene. α-carotene, β-carotene and lycopene levels were significantly reduced in advanced PD patients relative to early PD patients and were negatively correlated with Hoehn and Yahr stage and UPDRS motor score in PD patients. No significant differences were found in serum levels of retinol, α- and γ-tocopherols, and other carotenoids between PD patients and controls. No significant correlations were found between these vitamin levels and clinical variables in PD patients. CONCLUSIONS: We found that serum levels of some carotenoids, α-carotene, β-carotene and lycopene, were lower in PD patients, and that these carotenoids inversely correlated with clinical variables representing disease progression. Our findings suggest that decreases in serum α-carotene, β-carotene and lycopene may be associated with the pathogenesis as well as progression of PD.
Carotenoids ; Disease Progression ; Humans ; Lutein ; Oxidative Stress ; Parkinson Disease* ; Tocopherols* ; Vitamin A* ; Vitamins ; Zeaxanthins

Phytantriol (PT), ethanol (ET) and water were used to prepare in situ cubic liquid crystal (ISV2). The pseudo-ternary phase diagram of PT-ET-water was constructed and isotropic solution formulations were chosen for further optimization. The physicochemical properties of isotropic solution formulations were evaluated to optimize the composition of ISV2. In situ hexagonal liquid crystals (ISH2) were prepared based on the composition of ISV2 with the addition of vitamin E acetate (VitEA) and the amount of VitEA was optimized by in vitro release behavior. The phase structures of liquid crystalline gels formed by ISV2 and ISH2 in excess water were confirmed by crossed polarized light microscopy and small angle X-ray scattering, respectively. Rheological properties of ISV2 and ISH2 were studied by a DHR-2 rheometer. In vitro drug release studies were conducted by using a dialysis membrane diffusion method. Pharmacokinetics was investigated by determination of sinomenine hydrochloride (SMH) concentration in synovial membrane after intra-articular injection of SMH-loaded ISH2 in adjuvant-induced arthritis rats. The optimal ISV2 (PT/ET/water, 64 : 16 : 20, w/w/w) loaded with 6 mg x g(-1) of SMH showed a suitable pH, injectable and formed a cubic liquid crystalline gel in situ with minimum water absorption in the shortest time. The optimal ISV2 was able to sustain the drug release for 144 h. The optimal ISH2 system was prepared by addition of 5% VitEA into PT in the optimal ISV2 system. This ISH2 (PT/VitEA/ET/water, 60.8 : 3.2 : 16 : 20, w/w/w/w) was an injectable isotropic solution with suitable pH. The new ISH2 was able to sustain the drug release for more than 240 h. Local pharmacokinetics study indicated that the retention time and AUC(0-∞) of ISH2 group were increased significantly compared with that of SMH solution group and the AUC(0-∞) of ISH2 group was 6.01 times higher than that of SMH solution group. The developed ISH2 was suitable for intra-articular injection that may apply to patients in the treatment of rheumatoid arthritis.
Animals ; Chemistry, Pharmaceutical ; Diffusion ; Ethanol ; Fatty Alcohols ; Gels ; Injections, Intra-Articular ; Liquid Crystals ; Morphinans ; administration & dosage ; chemistry ; Rats ; Rheology ; Water ; alpha-Tocopherol

BACKGROUND/OBJECTIVES: Diabetes mellitus (DM) is a major chronic disease which increases global health problems. Diabetes-induced renal damage is associated with inflammation and fibrosis. Alpha (AT) and gamma-tocopherols (GT) have shown antioxidant and anti-inflammatory effects in inflammation-mediated injuries. The primary aim of this study was to investigate effects of AT and GT supplementations on hyperglycemia induced acute kidney inflammation in alloxan induced diabetic mice with different levels of fasting blood glucose (FBG). MATERIALS/METHODS: Diabetes was induced by injection of alloxan monohydrate (150 mg/kg, i.p) in ICR mice (5.5-week-old, male) and mice were subdivided according to their FBG levels and treated with different diets for 2 weeks; CON: non-diabetic mice, m-DMC: diabetic control mice with mild FBG levels (250 mg/dl < or = FBG < or = 450 mg/dl), m-AT: m-DM mice fed AT supplementation (35 mg/kg diet), m-GT: m-DM mice with GT supplementation (35 mg/kg diet), s-DMC: diabetic control mice with severe FBG levels (450 mg/dl < FBG), s-AT: s-DM mice with AT supplementation, s-GT: s-DM mice with GT supplementation. RESULTS: Both AT and GT supplementations showed similar beneficial effects on NFkappaB associated inflammatory response (phosphorylated inhibitory kappa B-alpha, interleukin-1beta, C-reactive protein, monocyte chemotactic protein-1) and pre-fibrosis (tumor growth factor beta-1 and protein kinase C-II) as well as an antioxidant emzyme, heme oxygenase-1 (HO-1) in diabetic mice. On the other hands, AT and GT showed different beneficial effects on kidney weight, FBG, and oxidative stress associated makers (malondialdehyde, glutathione peroxidase, and catalase) except HO-1. In particular, GT significantly preserved kidney weight in m-DM and improved FBG levels in s-DM and malondialdehyde and catalase in m- and s-DM, while AT significantly attenuated FBG levels in m-DM and improved glutathione peroxidase in m- and s-DM. CONCLUSIONS: The results suggest that AT and GT with similarities and differences would be considered as beneficial nutrients to modulate hyperglycemia induced acute renal inflammation. Further research with careful approach is needed to confirm beneficial effects of tocopherols in diabetes with different FBG levels for clinical applications.
Alloxan ; alpha-Tocopherol* ; Animals ; Blood Glucose ; C-Reactive Protein ; Catalase ; Chronic Disease ; Diabetes Mellitus ; Diet ; Fasting ; Fibrosis ; gamma-Tocopherol* ; Glutathione Peroxidase ; Hand ; Heme Oxygenase-1 ; Hyperglycemia* ; Inflammation* ; Interleukin-1beta ; Kidney* ; Malondialdehyde ; Mice ; Mice, Inbred ICR ; Monocytes ; Oxidative Stress* ; Protein Kinases ; Tocopherols

OBJECTIVETo investigate the regulation of &alpha;-Tocopherol on NFκB and Nrf2 signaling pathway at early stage of N-nitrosomethylbenzylamine (NMBzA)-induced human esophageal carcinogenesis.

METHODSHuman normal esophageal HET-1A cells were treated with NMBzA at 50 µmol/L, 100 µmol/L for 24 h to intimate the initiation of esophageal carcinogenesis. For intervention groups, HET-1A cells were pre-treated with &alpha;-T at 25, 50, 100 µmol/L for 3 h and then co-treated with NMBzA (100 µmol/L) for 24 h. In comparison with HET-1A cells, human esophageal cancer EC109 cells were treated with &alpha;-T at corresponding concentrations. Cells treated with 0.1% DMSO were used as negative control. Immunofluorence staining was used for the determination of distribution and activation of NFκB p65 and Nrf2 in the cell. Real time PCR and Western blot were used to determine the expression levels of target genes including cyclinD1, KI67, proliferating cell nuclear antigen (PCNA), cyclo-oxygen-ase 2 (COX2), 5LOX, HO-1, NQO1 and GCLC. Flow cytometry was utilized to analyze the reactive oxygen species contents in the cells.

RESULTSAs compared to the control group (1.00 ± 0.08), the expression of CyclinD1 (2.99 ± 0.15), KI67 (2.35 ± 0.38) and PCNA (2.46 ± 0.25) in HET-1A were all markedly increased by NMBzA treatment (F values were 97.23, 65.28, 34.62, P < 0.001). Also, the proportion of cells with nucleus translocation of NFκB p65 (71.0%, 98/138) or Nrf2 (36.3%, 49/135) were significantly increased (χ² values were 194.71, 133.72, P < 0.001), and the expression of COX2 (3.22 ± 0.17), 5LOX (2.87 ± 0.12) as well as HO-1 (1.87 ± 0.22), NQO1 (2.14 ± 0.08), GCLC (2.63 ± 0.41) at protein levels were elevated (F values were 72.35, 43.87, 69.23, 71.34, 85.79, P values were 0.013, 0.015, 0.010, 0.011, 0.002). Under the treatment with 50 µmol/L &alpha;-T, comparing with the control group(59.1%,65/110),the nuclear translocation of NFκB p65 (77.7%, 8/104) was clearly inhibited (χ² = 148.1, P < 0.001), and protein expression levels of COX2 (0.74 ± 0.19) and 5LOX (0.42 ± 0.13) were decreased (F values were 56.31, 73.25, P values were 0.003, 0.001). However, no changes on Nrf2 signaling pathway were observed; &alpha;-T showed little impact on NFκB or Nrf2 pathway in EC109 cells.

CONCLUSIONSAt the early stage of NMBz-induced esophageal cancer, &alpha;-T could block the initiation of carcinogenesis through suppressing the activation of NFκB signaling pathway. It might be the major mechanism by which &alpha;-T is potentially chemopreventive to esophageal cancer. During the progression of esophageal cancer, the cells may acquire the adaptive functions to accommodate oxidative stress via activating Nrf2 pathway.

Carcinogenesis ; Cyclooxygenase 2 ; Dimethylnitrosamine ; analogs & derivatives ; Esophageal Neoplasms ; Heme Oxygenase-1 ; Humans ; NAD(P)H Dehydrogenase (Quinone) ; NF-E2-Related Factor 2 ; NF-kappa B ; Oxidative Stress ; Reactive Oxygen Species ; Signal Transduction ; alpha-Tocopherol