The vitamin E derivative garcinoic acid from Garcinia kola nut seeds attenuates the inflammatory response

Wallert M, Bauer J, Kluge S, Schmölz L, Chen YC, Ziegler M, Searle AK, Maxones A, Schubert M, Thürmer M, Pein H, Koeberle A, Werz O, Birringer M, Peter K, Lorkowski S

Redox Biol. 2019 Jun;24:101166. doi: 10.1016/j.redox.2019.101166. Epub 2019 Mar 12.

Abstract

The plant Garcinia kola is used in African ethno-medicine to treat various oxidation- and inflammation-related diseases but its bioactive compounds are not well characterized. Garcinoic acid (GA) is one of the few phytochemicals that have been isolated from Garcinia kola. We investigated the anti-inflammatory potential of the methanol extract of Garcinia kola seeds (NE) and purified GA, as a major phytochemical in these seeds, in lipopolysaccharide (LPS)-activated mouse RAW264.7 macrophages and its anti-atherosclerotic potential in high fat diet fed ApoE-/- mice. This study outlines an optimized procedure for the extraction and purification of GA from Garcinia kola seeds with an increased yield and a purity of >99%. We found that LPS-induced upregulation of iNos and Cox2 expression, and the formation of the respective signaling molecules nitric oxide and prostanoids, were significantly diminished by both the NE and GA. In addition, GA treatment in mice decreased intra-plaque inflammation by attenuating nitrotyrosinylation. Further, modulation of lymphocyte sub-populations in blood and spleen have been detected, showing immune regulative properties of GA. Our study provides molecular insights into the anti-inflammatory activities of Garcinia kola and reveals GA as promising natural lead for the development of multi-target drugs to treat inflammation-driven diseases.

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Vitamin C and E supplementation effects on secretory and molecular aspects of vascular endothelial growth factor derived from peritoneal fluids of patients with endometriosis

Ansariniya H, Hadinedoushan H, Javaheri A, Zare F

J Obstet Gynaecol. 2019 Jun 24:1-6. doi: 10.1080/01443615.2019.1601167. [Epub ahead of print]

Abstract

Endometriosis is an extremely heterogeneous disease and affects about ten percent of the female population during their reproductive years. Recent studies showed that endometriosis is an angiogenesis-dependent disease. Peritoneal macrophages are a well-characterised source of vascular endothelial growth factor (VEGF). The aim of this study was to determine the VEGF gene expression and production in peritoneal macrophages of patients with endometriosis under the effects of vitamins C and E in comparison with control. The lab trial study carried out on 50 patients undergoing laparoscopy and peritoneal fluid samples were collected from them. We compared the VEGF gene expression and production in peritoneal macrophages among groups by using real-time polymerase chain reaction and enzyme-linked immunosorbent assay methods, respectively. Our results showed that gene expressions influenced by vitamin C increased in different concentrations and incubation times, except for the incubation time after 48 h. In the case of vitamin E, this was evident with the exception of vitamin E 50 μM after 24 h and vitamin E 100 μM after 48 h. Our findings indicated that vitamin C and E in different concentrations and incubation times altered VEGF gene expression in the peritoneal macrophages but they had not affected on VEGF productions. Impact statement What is already known on this subject? Previous studies showed that antioxidants play a key role in the inhibition of oxidative stress-induced damages and the reduction of pelvic pain in patients with endometriosis. Vitamin E and vitamin C are the main components in neutralising free radicals. Also, antioxidant consumption such as vitamin C and vitamin E in women with endometriosis showed an inverse correlation between antioxidant intake and endometriosis pathology. What do the results of this study add? Vitamin C and E in different concentrations and times of incubation altered vascular endothelial growth factor gene expression and production in peritoneal macrophages. What are the implications of these findings for clinical practice and/or further research? Further studies are needed to determine the effects of C and E vitamins in different concentrations on vascular endothelial growth factor gene expression and production in peritoneal macrophages and the possible roles of these vitamins in treating endometriosis.

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COMT Effects on Vitamin E and Colorectal Cancer, in-vitro and in Two Randomized Trials (P15-005-19)

Hall K, Weinstein S, Buring J, Mukamal K, Moorthy MV, Ridker P, Albanes D, Cook N, Chasman D, Sesso H

Curr Dev Nutr. 2019 Jun 13;3(Suppl 1). pii: nzz037.P15-005-19. doi: 10.1093/cdn/nzz037.P15-005-19. eCollection 2019 Jun.

Abstract

OBJECTIVES:

Despite promising observational data and compelling mechanisms of action, vitamin E has failed to demonstrate evidence of benefit in randomized clinical trials (RCTs). In two large long-term placebo-controlled RCTs, we reported that vitamin E effects on total cancer were modified by genetic variation in catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines. Here we investigate COMT effects on colorectal cancer (CRC) in the two RCTs and a CRC cell line.

METHODS:

We analyzed COMT rs4680 association with rates of CRC in the Women’s Health Study (WHS), N = 23,294 and a case/control (N = 2396/2235) subset of the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study (ATBC). Cell survival and apoptosis were examined in-vitro in HCT116 cells treated with increasing doses of vitamin E when COMT gene expression was inhibited by silencing RNA (siRNA).

RESULTS:

Rates of CRC were higher with randomized vitamin E compared to placebo among COMT high-activity val/val homozygotes in ATBC (HR, [CI] = 3.00, [1.48-6.09]), but not WHS (HR, [CI] = 0.99, [0.63-1.57]). Among low-activity met/met homozygotes randomized to vitamin E compared to placebo, rates of CRC were borderline lower in WHS (HR, [CI] = 0.66, [0.44-1.01]), but not in ATBC (HR, [CI] = 0.93, [0.63-1.62]).In cell culture, vitamin E at 3 µg/ml and 10 µg/mL had no effect on cell viability or apoptosis. However, silencing COMT resulted in a modest apoptotic effect that vitamin E enhanced in a dose-dependent manner. Human apoptosis arrays indicated that in the absence of COMT expression, vitamin E induced protein expression related to the intrinsic apoptotic pathway through p53 activation, dysregulation of Bcl-2 family protein expression and down-regulation of IAP family protein expression.

CONCLUSIONS:

Differential COMT effects on vitamin E and CRC were similar to those previously reported for all invasive cancers, but were only significant for val/val homozygotes. Further, inhibiting COMT in the presence of vitamin E in a CRC in-vitro model, recapitulated the RCT observation that among individuals homozygous for the low-activity allele (met/met) vitamin E tended to reduce invasive cancer and here CRC.

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Chemoprevention of Azoxymethane-induced Colon Carcinogenesis by Delta-Tocotrienol

Husain K, Zhang A, Shivers S, Davis-Yadley A, Coppola D, Yang CS, Malafa MP

Cancer Prev Res (Phila). 2019 Jun;12(6):357-366. doi: 10.1158/1940-6207.CAPR-18-0290. Epub 2019 Apr 2.

Abstract

This study evaluated the preclinical activity of δ-tocotrienol (DT3), a bioactive form of vitamin E, in the inhibition of colorectal cancer growth and development in vitro and in vivo DT3 is the most bioactive isomer of vitamin E in inhibiting growth of colorectal cancer cells. However, it had little effect on the proliferation of normal colon mucosal cells NCM460. In HCT-116 and SW-620 colorectal cancer cells, DT3 (50 μmol/L) significantly inhibited malignant transformation (P < 0.02, P < 0.001), cell migration (P < 0.02, P < 0.05), and invasion (P < 0.05, P < 0.01) compared with vehicle. DT3 inhibited markers for epithelial (E-cadherin) to mesenchymal (vimentin) transition, metastasis (matrix metalloproteinase 9), angiogenesis VEGF, inflammation (NF-κB), and Wnt signaling (β-catenin) compared with vehicle in colorectal cancer cells. DT3 induced apoptosis selectively in colorectal cancer cells (SW-620 cells, HCT-116 cells, and HT-29) without affecting the normal colon cells. In the azoxymethane-induced colorectal carcinogenesis model in rats, DT3 (200 mg/kg orally twice a day) for 20 weeks significantly inhibited colorectal polyps by 70% and colorectal cancer by almost 99% compared with the vehicle treatment group (P < 0.02, P< 0.001), and the cancer inhibition effect was more potent than sulindac (50%). Taken together, these data demonstrate that DT3 is a potential chemopreventive agent in colorectal cancer, warranting further investigation into its clinical use in the prevention and treatment of colorectal cancer.

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Vitamin E – Objective Marker of Healthful Diet and Long-Term Mortality

Tobias DK

Circ Res. 2019 Jun 21;125(1):41-42. doi: 10.1161/CIRCRESAHA.119.315285. Epub 2019 Jun 20.

Abstract

Huang et al of the ATBC study (Alpha-Tocopherol, Beta-Carotene Cancer Prevention) reported a significant relationship between serum α-tocopherol with lower risks of all-cause and cause-specific mortality in men. The ATBC cohort analysis included 29 092 male smokers aged 50 to 69 years at baseline, and 23 787 deaths were observed over 31 years of follow-up. Compared with the bottom 20% of serum α-tocopherol concentrations, men in the top 20% experienced a 22% lower risk of total mortality. Their results were robust to several sensitivity and subgroup analyses and persisted over 31 years of observation.

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Relationship Between Serum Alpha-Tocopherol and Overall and Cause-Specific Mortality

Huang J, Weinstein SJ, Yu K, Männistö S, Albanes D

Circ Res. 2019 Jun 21;125(1):29-40. doi: 10.1161/CIRCRESAHA.119.314944. Epub 2019 May 6.

Abstract

RATIONALE:

Although there has been a long-standing interest in the human health effects of vitamin E, a comprehensive analysis of the association between circulating vitamin E and long-term mortality has not been conducted.

OBJECTIVE:

Determine whether serum α-tocopherol (the predominant form of vitamin E) is related to long-term overall and cause-specific mortality and elucidate the dose-response relationships with better quantification of the associations.

METHODS AND RESULTS:

We conducted a biochemical analysis of 29 092 participants in the ATBC Study (Alpha-Tocopherol, Beta-Carotene Cancer Prevention) that originally tested vitamin E and β-carotene supplementation. Serum α-tocopherol was measured at baseline using high-performance liquid chromatography, and during a 30-year follow-up we identified 23 787 deaths, including deaths from cardiovascular disease (9867), cancer (7687), respiratory disease (2161), diabetes mellitus (119), injuries and accidents (1255), and other causes (2698). After adjusting for major risk factors, we found that men with higher serum α-tocopherol had significantly lower all-cause mortality (hazard ratios=0.83, 0.79, 0.75, and 0.78 for quintile 2 (Q2)-Q5 versus Q1, respectively; Ptrend<0.0001), and significantly decreased mortality from cardiovascular disease, heart disease, stroke, cancer, respiratory disease, and other causes, with risk reductions from 17% to 47% for the highest versus lowest quintile. The α-tocopherol association with overall mortality was similar across subgroups of smoking intensity, years of smoking, alcohol consumption, trial supplementation, and duration of follow-up. The association was, however, significantly modified by baseline age and body mass index, with stronger inverse associations for younger men and men with a lower body mass index ( Pinteraction≤0.006).

CONCLUSIONS:

In this long-term prospective cohort study, higher baseline serum α-tocopherol biochemical status was associated with lower risk of overall mortality and mortality from all major causes. Our data support the long-term health benefits of higher serum α-tocopherol for overall and chronic disease mortality and should be replicated in other more diverse populations.

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Hepatic and renal tissue damage in Balb/c mice exposed to diisodecyl phthalate: The role of oxidative stress pathways

Chen Y, Li C, Song P, Yan B, Yang X, Wu Y, Ma P

Food Chem Toxicol. 2019 Jun 20;132:110600. doi: 10.1016/j.fct.2019.110600. [Epub ahead of print]

Abstract

Diisononyl phthalate (DIDP) is commonly used as a plasticizer in industrial and consumer products, however, its toxicity remains unclear. This study investigated the possible involvement of oxidative stress in DIDP-induced liver and kidney toxicity. Liver function and kidney function, tissue lesions, oxidative stress biomarkers, inflammatory mediators and apoptosis factors were investigated in this study. The results showed that oral exposure to DIDP induced a marked increase in lever of alanine aminotransferase (ALT), aspartate aminotransferase (AST), urinary nitrogen (UREA) and creatinine (CREA), decrease in albumin (ALB) level, as well as causing hepatic and renal histopathological change. Investigation of the role of oxidative stress pathways showed that DBP exposure could lead to a significant increase in levels of reactive oxygen species (ROS), malondialdehyde (MDA), 8-hydroxy-2-deoxyguanosine (8-OHdG), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and nuclear factor-κB (NF-κB), while a decrease in glutathione (GSH) levels were observed. Administration of vitamin E to DIDP-treated mice restored these biochemical parameters to within normal levels, and resulted in less damage to livers and kidneys. Overall, these results suggest that the oxidative stress pathway is involved in DIDP-induced toxicity.

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Vitamin E Promotes Bone Formation in a Distraction Osteogenesis Model

Akçay H, Kuru K, Tatar B, Şimşek F

J Craniofac Surg. 2019 Jun 20. doi: 10.1097/SCS.0000000000005685. [Epub ahead of print]

Abstract

The long consolidation period of distraction osteogenesis (DO) may lead to complications such as pain, infection, fracture, scar formation, malunion and delayed union. The aim of this study was to evaluate the effect of systemic Vitamin E application during mandibular DO on new bone regeneration in a rabbit model. 16 adult male 8 months old New Zealand rabbits underwent mandibular lengthening with a distractor for the study. After the latency period of 5 days, the distractor was activated at a rate of 0.5 mm/12 hours for 7 days. Experimental animals received 200 mg/kg injections of α-tocopherol intraperitoneally for 7 days starting with the operation. After the consolidation period of 30 days, rabbits were sacrificed. Lengthened mandibles were obtained and subjected to dual-energy X-ray absorptiometry (DXA), radiologic and histomorphometric analysis. Statistically, bone mineral density and bone mineral content values were found to be significantly higher in the experimental group than the control group during DXA analysis. Rabbits in the experimental group had statistically higher scores in terms of osteoblast, osteoclast, vessel numbers and newly formed bone area than the control group. Results of the present study showed that systemic Vitamin E application during DO may stimulate new bone formation in rabbits and thus results in shortened treatment time.

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Associations between fat-soluble vitamins and lipid profile in overweight population

Piran S, Sarmasti S, Shabani M, Kakavandi N, Hosseni B, Khosravi M, Resaee S, Soltanmohammadi E, Naseri F, Ghasempour G, Mohammadi A, Najafi M

Recent Pat Food Nutr Agric. 2019 Jun 18. doi: 10.2174/2212798410666190618152134. [Epub ahead of print]

Abstract

METHODS:

A total of 120 overweight subjects participated in this study. The circulating PCSK9 and vitamin D were measured by ELISA technique. The serum vitamin A and vitamin E amounts were simultaneously measured by HPLC method. The serum small dense LDL-Cholesterol (sdLDL-C) values were evaluated using heparin-Mg2+ precipitation technique. The lipid profile was measured by routine laboratory techniques.

RESULTS:

The serum vitamin E values correlated significantly to vitamin A (r=0.47, P= 0.0001), VLDL-C (r= 0.30, P= 0.002), total cholesterol (r=0.309, P= 0.001), PCSK9 (r=0.233, P=0.01) and total triglyceride (r= 0.61, P= 0.0001) values. The circulating PCSK9 values correlated significantly to LDL-C (r=0.17, P=0.05) and total cholesterol (r=0.23, P=0.009) values. However, there were not correlations between the levels of serum D and A vitamins, the serum LDL-C, sdLDL-C and total cholesterol values.

CONCLUSION:

The data showed the correlations between serum vitamin E and PCSK9-related LDL-C values lower than the normal range. Furthermore, the results suggested a nutritional need on the patents considering supplementation or fortification of vitamin E for the overweight subjects with higher LDL-C levels.

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Effect of vitamin E on severity and duration of cyclic mastalgia: A systematic review and meta-analysis

Hajizadeh K, Alizadeh Charandabi SM, Hasanzade R, Mirghafourvand M

Complement Ther Med. 2019 Jun;44:1-8. doi: 10.1016/j.ctim.2019.03.014. Epub 2019 Mar 22.

Abstract

OBJECTIVES:

A systematic review was conducted to assess the effect of vitamin E on the severity and duration of Cyclic Mastalgia compared to vitamin B6, fish oil, herbal medicines and placebo.

DESIGN:

A systematic review and meta-analysis of clinical trials.

METHODS:

A search was carried out in PubMed, Cochrane Library, Embase, Scopus and Google Scholar and Persian databases for articles published from 1980 to 2018. The data obtained were analyzed in RevMan and reported in forest plots. The Odds Ratio (OR) was used to find the effect for the dichotomous data and the Standardized Mean Difference (SMD) for the continuous data. The heterogeneity of the studies was assessed using I2 and the Random Effects Model was used instead of the Fixed Effects Model if I2>25%.

RESULTS:

A total of 1051 titles and abstracts were extracted. Fourteen articles ultimately remained, and 11 of them were entered into the meta-analysis. The meta-analysis showed significant differences between vitamin E and placebo in the severity (SMD=-0.51; 95% CI=-0.21 to -0.82) and duration (MD=-1.47; 95% CI=-0.91 to -2.57) of cyclic mastalgia, although herbal medicines had a greater effect on the severity of mastalgia than vitamin E (SMD = 0.51, 95% CI = 0.06 to 0.96).

CONCLUSION:

Although herbal medicines are more effective than vitamin Evitamin E reduces both the severity and duration of the disorder compared to placebos, which only reduce its severity, and can therefore be considered a treatment with minimum side-effects. Due to the high heterogeneity of the studies, the researchers recommend further research on the subject using a standard tool based on the CONSORT statement.

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