Life Extension Magazine®

Issue: Jun 2010

Vitamin D

Sex steroids to maintain cognitive function in women after the menopause: A meta-analyses of treatment trials.

It is still debated whether estrogen treatment after the menopause could result in improved cognitive function in women. This debate is based on many animal and cell culture data showing that estrogens can positively affect the aging brain. Observational data also show a halved risk of dementia in women who took estrogens around the age of menopause. However, large treatment trials have shown negative effects of long-term treatment with estrogens in older women. The present meta-analyses included 36 randomised treatment trials and tested various hypotheses which have been developed to attempt to explain discrepant data. Results indicated that, contrary to expectations, age of women and duration of time elapsed when treatment was initiated since menopause (‘window of opportunity’ hypothesis) did not significantly affect treatment outcome, nor did it matter whether women were symptomatic or not. It was not clear whether bilateral oophorectomy affected the outcome, as this effect was based on only a few studies from the same group and some observational studies show negative effects on cognition in surgical menopausal women treated with hormones for more than 10 years. Duration of treatment overall significantly affected outcome. More negative effects were seen in longer studies, where positive effects were mainly seen in short term studies (<4 months). Treatment with combined estrogens and progestagens also negatively affected the outcome. Whether women with symptoms should be treated for a couple of months or using other (intermittent) modes of treatment and whether this could have long-term positive consequences remains to be investigated.

Maturitas. 2010 Mar 2

Lepidium meyenii (Maca) increases litter size in normal adult female mice.

BACKGROUND: Lepidium meyenii, known as Maca, grows exclusively in the Peruvian Andes over 4,000 m altitude. It has been used traditionally to increase fertility. Previous scientific studies have demonstrated that Maca increases spermatogenesis and epididymal sperm count. The present study was aimed to investigate the effects of Maca on several fertility parameters of female mice at reproductive age. METHODS: Adult female Balb/C mice were divided at random into three main groups: i) Reproductive indexes group, ii) Implantation sites group and iii) Assessment of uterine weight in ovariectomized mice. Animals received an aqueous extract of lyophilized Yellow Maca (1 g/Kg BW) or vehicle orally as treatment. In the fertility indexes study, animals received the treatment before, during and after gestation. The fertility index, gestation index, post-natal viability index, weaning viability index and sex ratio were calculated. Sexual maturation was evaluated in the female pups by the vaginal opening (VO) day. In the implantation study, females were checked for implantation sites at gestation day 7 and the embryos were counted. In ovariectomized mice, the uterine weight was recorded at the end of treatment. RESULTS: Implantation sites were similar in mice treated with Maca and in controls. All reproductive indexes were similar in both groups of treatment. The number of pups per dam at birth and at postnatal day 4 was significantly higher in the group treated with Maca. VO day occurred earlier as litter size was smaller. Maca did not affect VO day. In ovariectomized mice, the treatment with Maca increased significantly the uterine weights in comparison to their respective control group. CONCLUSION: Administration of aqueous extract of Yellow Maca to adult female mice increases the litter size. Moreover, this treatment increases the uterine weight in ovariectomized animals. Our study confirms for the first time some of the traditional uses of Maca to enhance female fertility.

Reprod Biol Endocrinol. 2005 May 3;3:16

Effect of three different cultivars of Lepidium meyenii (Maca) on learning and depression in ovariectomized mice.

BACKGROUND: Lepidium meyenii Walp. (Brassicaceae), known as Maca, is a Peruvian hypocotyl growing exclusively between 4,000 and 4,500 m altitude in the central Peruvian Andes, particularly in Junin plateau and is used traditionally to enhance fertility. Maca is a cultivated plant and different cultivars are described according to the color of the hypocotyls. METHODS: The study aimed to elucidate the effect of Yellow, Red, and Black Maca on cognitive function and depression in ovariectomized (OVX) mice. In all experiments OVX mice were treated during 21 days and divided in four groups: control group, Yellow Maca, Red Maca and Black Maca. Latent learning was assessed using the water finding task and the antidepressant activity of the three varieties of Maca was evaluated using the forced swimming test. Animals were sacrificed at the end of each treatment and the uterus were excised and weighed. RESULTS: Black Maca was the variety that showed the best response in the water finding task, particularly in the trained mice. The three varieties were effective to reduce finding latency in non trained and trained mice (P < 0.05). In the force swimming test, all varieties assessed reduced the time of immobility and increased uterine weight in OVX mice. CONCLUSION: Black Maca appeared to have more beneficial effects on latent learning in OVX mice; meanwhile, all varieties of Maca showed antidepressant activity.

BMC Complement Altern Med. 2006 Jun 23;6:23

The influence of maca (Lepidium meyenii) on antioxidant status, lipid and glucose metabolism in rat.

This work focused on the effect of Maca on lipid, anti-oxidative, and glucose parameters in hereditary hypertriglyceridemic (HHTg) rat. Maca (1%) was administred to rats as a part of a high-sucrose diet (HSD) for 2 weeks. Rosiglitazone (0.02%) was used as a positive control. Maca significantly decreased the levels of VLDL (very low density lipoproteins), LDL (low density lipoproteins), and total cholesterol, and also the level of TAG (triacylglycerols) in the plasma, VLDL, and liver. Maca, as well as rosiglitazone, significantly improved glucose tolerance, as the decrease of AUC (area under the curve) of glucose showed, and lowered levels of glucose in blood. The activity of SOD (superoxide dismutase) in the liver, the GPX (glutathione peroxidase) in the blood, and the level of GSH (glutathione) in liver increased in all cases significantly. Results demonstrate that maca seems to be promising for a positive influence on chronic human diseases (characterized by atherogenous lipoprotein profile, aggravated antioxidative status, and impaired glucose tolerance), and their prevention.

Plant Foods Hum Nutr. 2007 Jun;62(2):59-63

Aqueous Extract of Black Maca (Lepidium meyenii) on Memory Impairment Induced by Ovariectomy in Mice.

The present study aims to test two different doses of aqueous extract of black maca on learning and memory in ovariectomized (OVX) mice and their relation with malonalehyde (MDA), acetylcholinesterase (Ache) and monoamine oxidase (MAO) brain levels. Female mice were divided into five groups: (i) naive (control), (ii) sham, (iii) OVX mice and OVX mice treated with (iv) 0.50 g kg(-1) and (v) 2.00 g kg(-1) black maca. Mice were orally treated with distilled water or black maca during 35 days starting 7 days after surgery. Memory and learning were assessed using the water Morris maze (from day 23-27) and the step-down avoidance test (days 34 and 35). At the end of each treatment, mice were sacrificed by decapitation and brains were dissected out for MDA, Ache and MAO determinations. Black maca (0.5 and 2.0 g/kg) increased step-down latency when compared to OVX control mice. Black maca decreased MDA and Ache levels in OVX mice; whereas, no differences were observed in MAO levels. Finally, black maca improved experimental memory impairment induced by ovariectomy, due in part, by its antioxidant and Ache inhibitory activities.

Evid Based Complement Alternat Med. 2008 Oct 9

Healthcare seeking and treatment for menopausal symptoms in the United States.

OBJECTIVES: A population-based study was used to describe healthcare seeking behavior for menopausal symptoms and treatment among women 40-65 years old in the United States. METHODS: Participants were recruited into the Menopause Epidemiology Study from the KnowledgePanel(SM), which is selected by random digit dialing and probability sampling from the US population. From this source, 6,201 women 40-65 years old were contacted and 4,402 women participated. From the 3,135 peri- and postmenopausal women, detailed information was obtained on menopausal symptoms, healthcare seeking, medication usage, and symptom relief from the medication. RESULTS: Many women (60%) reported seeking health care for their menopausal symptoms. More than half of these women sought health care in the past 12 months. Vasomotor symptoms were the most frequently reported menopause symptoms across all races/ethnicities, and the most common symptoms discussed with a health care professional. One-third of the women (34%) used only hormone therapies, 12% used complementary and/or alternative medicines, and 16% used both for treatment of menopausal symptoms. CONCLUSIONS: This study has shown that a large number of women consult healthcare providers for menopausal symptoms, indicating these symptoms are bothersome. Yet, in the United States, there is considerable variation in the symptomatology, healthcare seeking, and use of therapies for menopausal symptoms across cultures. To alleviate these symptoms women have tried alternative treatments as well as hormone therapies, yet many women did not get complete relief of specific symptoms.

Maturitas. 2007 Dec 20;58(4):348-58

Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial.

CONTEXT: Despite decades of accumulated observational evidence, the balance of risks and benefits for hormone use in healthy postmenopausal women remains uncertain. OBJECTIVE: To assess the major health benefits and risks of the most commonly used combined hormone preparation in the United States. DESIGN: Estrogen plus progestin component of the Women’s Health Initiative, a randomized controlled primary prevention trial (planned duration, 8.5 years) in which 16,608 postmenopausal women aged 50-79 years with an intact uterus at baseline were recruited by 40 US clinical centers in 1993-1998. INTERVENTIONS: Participants received conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102). MAIN OUTCOMES MEASURES: The primary outcome was coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome. A global index summarizing the balance of risks and benefits included the 2 primary outcomes plus stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, and death due to other causes. RESULTS: On May 31, 2002, after a mean of 5.2 years of follow-up, the data and safety monitoring board recommended stopping the trial of estrogen plus progestin vs placebo because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic supported risks exceeding benefits. This report includes data on the major clinical outcomes through April 30, 2002. Estimated hazard ratios (HRs) (nominal 95% confidence intervals [CIs]) were as follows: CHD, 1.29 (1.02-1.63) with 286 cases; breast cancer, 1.26 (1.00-1.59) with 290 cases; stroke, 1.41 (1.07-1.85) with 212 cases; PE, 2.13 (1.39-3.25) with 101 cases; colorectal cancer, 0.63 (0.43-0.92) with 112 cases; endometrial cancer, 0.83 (0.47-1.47) with 47 cases; hip fracture, 0.66 (0.45-0.98) with 106 cases; and death due to other causes, 0.92 (0.74-1.14) with 331 cases. Corresponding HRs (nominal 95% CIs) for composite outcomes were 1.22 (1.09-1.36) for total cardiovascular disease (arterial and venous disease), 1.03 (0.90-1.17) for total cancer, 0.76 (0.69-0.85) for combined fractures, 0.98 (0.82-1.18) for total mortality, and 1.15 (1.03-1.28) for the global index. Absolute excess risks per 10 000 person-years attributable to estrogen plus progestin were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10,000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the global index was 19 per 10,000 person-years. CONCLUSIONS: Overall health risks exceeded benefits from use of combined estrogen plus progestin for an average 5.2-year follow-up among healthy postmenopausal US women. All-cause mortality was not affected during the trial. The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases, and the results indicate that this regimen should not be initiated or continued for primary prevention of CHD.

JAMA.2002 Jul 17;288(3):321-33

Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial.

CONTEXT: Despite decades of use and considerable research, the role of estrogen alone in preventing chronic diseases in postmenopausal women remains uncertain. OBJECTIVE: To assess the effects on major disease incidence rates of the most commonly used postmenopausal hormone therapy in the United States. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled disease prevention trial (the estrogen-alone component of the Women’s Health Initiative [WHI]) conducted in 40 US clinical centers beginning in 1993. Enrolled were 10,739 postmenopausal women, aged 50-79 years, with prior hysterectomy, including 23% of minority race/ethnicity. INTERVENTION: Women were randomly assigned to receive either 0.625 mg/d of conjugated equine estrogen (CEE) or placebo. MAIN OUTCOME MEASURES: The primary outcome was coronary heart disease (CHD) incidence (nonfatal myocardial infarction or CHD death). Invasive breast cancer incidence was the primary safety outcome. A global index of risks and benefits, including these primary outcomes plus stroke, pulmonary embolism (PE), colorectal cancer, hip fracture, and deaths from other causes, was used for summarizing overall effects. RESULTS: In February 2004, after reviewing data through November 30, 2003, the National Institutes of Health (NIH) decided to end the intervention phase of the trial early. Estimated hazard ratios (HRs) (95% confidence intervals [CIs]) for CEE vs placebo for the major clinical outcomes available through February 29, 2004 (average follow-up 6.8 years), were: CHD, 0.91 (0.75-1.12) with 376 cases; breast cancer, 0.77 (0.59-1.01) with 218 cases; stroke, 1.39 (1.10-1.77) with 276 cases; PE, 1.34 (0.87-2.06) with 85 cases; colorectal cancer, 1.08 (0.75-1.55) with 119 cases; and hip fracture, 0.61 (0.41-0.91) with 102 cases. Corresponding results for composite outcomes were: total cardiovascular disease, 1.12 (1.01-1.24); total cancer, 0.93 (0.81-1.07); total fractures, 0.70 (0.63-0.79); total mortality, 1.04 (0.88-1.22), and the global index, 1.01 (0.91-1.12). For the outcomes significantly affected by CEE, there was an absolute excess risk of 12 additional strokes per 10,000 person-years and an absolute risk reduction of 6 fewer hip fractures per 10 000 person-years. The estimated excess risk for all monitored events in the global index was a nonsignificant 2 events per 10 000 person-years. CONCLUSIONS: The use of CEE increases the risk of stroke, decreases the risk of hip fracture, and does not affect CHD incidence in postmenopausal women with prior hysterectomy over an average of 6.8 years. A possible reduction in breast cancer risk requires further investigation. The burden of incident disease events was equivalent in the CEE and placebo groups, indicating no overall benefit. Thus, CEE should not be recommended for chronic disease prevention in postmenopausal women.

JAMA. 2004 Apr 14;291(14):1701-12

A double-blind, randomized, pilot dose-finding study of maca root (L. meyenii) for the management of SSRI-induced sexual dysfunction.

We sought to determine whether maca, a Peruvian plant, is effective for selective-serotonin reuptake inhibitor (SSRI)-induced sexual dysfunction. We conducted a double-blind, randomized, parallel group dose-finding pilot study comparing a low-dose (1.5 g/day) to a high-dose (3.0 g/day) maca regimen in 20 remitted depressed outpatients (mean age 36+/-13 years; 17 women) with SSRI-induced sexual dysfunction. The Arizona Sexual Experience Scale (ASEX) and the Massachusetts General Hospital Sexual Function Questionnaire (MGH-SFQ) were used to measure sexual dysfunction. Ten subjects completed the study, and 16 subjects (9 on 3.0 g/day; 7 on 1.5 g/day) were eligible for intent-to-treat (ITT) analyses on the basis of having had at least one postbaseline visit. ITT subjects on 3.0 g/day maca had a significant improvement in ASEX (from 22.8+/-3.8 to 16.9+/-6.2; z=-2.20, P=0.028) and in MGH-SFQ scores (from 24.1+/-1.9 to 17.0+/-5.7; z=-2.39, P=0.017), but subjects on 1.5 g/day maca did not. Libido improved significantly (P<0.05) for the ITT and completer groups based on ASEX item #1, but not by dosing groups. Maca was well tolerated. Maca root may alleviate SSRI-induced sexual dysfunction, and there may be a dose-related effect. Maca may also have a beneficial effect on libido.

CNS Neurosci Ther. 2008 Fall;14(3):182-91

Beneficial effects of Lepidium meyenii (Maca) on psychological symptoms and measures of sexual dysfunction in postmenopausal women are not related to estrogen or androgen content.

OBJECTIVE: To examine the estrogenic and androgenic activity of Lepidium meyenii (Maca) and its effect on the hormonal profile and symptoms in postmenopausal women. DESIGN: Fourteen postmenopausal women completed a randomized, double-blind, placebo-controlled, crossover trial. They received 3.5 g/day of powered Maca for 6 weeks and matching placebo for 6 weeks, in either order, over a total of 12 weeks. At baseline and weeks 6 and 12 blood samples were collected for the measurement of estradiol, follicle-stimulating hormone, luteinizing hormone, and sex hormone-binding globulin, and the women completed the Greene Climacteric Scale to assess the severity of menopausal symptoms. In addition, aqueous and methanolic Maca extracts were tested for androgenic and estrogenic activity using a yeast-based hormone-dependent reporter assay. RESULTS: No differences were seen in serum concentrations of estradiol, follicle-stimulating hormone, luteinizing hormone, and sex hormone-binding globulin between baseline, Maca treatment, and placebo (P > 0.05). The Greene Climacteric Scale revealed a significant reduction in scores in the areas of psychological symptoms, including the subscales for anxiety and depression and sexual dysfunction after Maca consumption compared with both baseline and placebo (P < 0.05). These findings did not correlate with androgenic or alpha-estrogenic activity present in the Maca as no physiologically significant activity was observed in yeast-based assays employing up to 4 mg/mL Maca extract (equivalent to 200 mg/mL Maca). CONCLUSIONS: Preliminary findings show that Lepidium meyenii (Maca) (3.5 g/d) reduces psychological symptoms, including anxiety and depression, and lowers measures of sexual dysfunction in postmenopausal women independent of estrogenic and androgenic activity.

Menopause. 2008 Nov-Dec;15(6):1157-62

Safety and tolerability of donepezil, rivastigmine and galantamine for patients with Alzheimer’s disease: systematic review of the ‘real-world’ evidence.

BACKGROUND/AIMS: The purpose of this systematic review was to compare the safety and tolerability of the cholinesterase inhibitors (ChEIs) donepezil, rivastigmine and galantamine for treating mild to moderate Alzheimer’s disease (AD) patients in routine clinical practice. METHODS: Electronic databases (Cochrane Library, Med-line, EMBASE; accessed October 2008) and manual bibliographic searches were conducted to identify head-to-head non-randomised studies examining ChEIs for the treatment of AD. Data were extracted by 2 independent reviewers. RESULTS: Twelve head-to-head studies comparing ChEIs met the pre-specified inclusion criteria; 6 retrospective analyses and 6 prospective cohort studies. Donepezil was the most widely studied treatment and galantamine the least widely prescribed therapy. Fewer donepezil-treated subjects withdrew due to adverse events (AEs) compared with rivastigmine and galantamine-treated subjects. The incidence of gastrointestinal (GI) AEs was lower following treatment with donepezil compared with rivastigmine and galantamine. Non-GI (CNS and cardiovascular) AEs occurred at a low frequency, and had a similar incidence in subjects treated with the different ChEIs. CONCLUSIONS: Subjects with mild to moderate AD treated in routine clinical practice with donepezil were more adherent to pharmacotherapy, and had a lower risk of GI AEs compared with rivastigmine or galantamine. This finding accords with results reported in the randomised clinical trial literature.

Dement Geriatr Cogn Disord. 2009;28(5):389-403

Black raspberry components inhibit proliferation, induce apoptosis, and modulate gene expression in rat esophageal epithelial cells.

We have shown that a diet containing freeze-dried black raspberries (BRB) inhibits the development of chemically induced cancer in the rat esophagus. To provide insights into possible mechanisms by which BRB inhibit esophageal carcinogenesis, we evaluated an ethanol (EtOH) extract of BRB, and two component anthocyanins (cyanidin-3-O-glucoside and cyanidin-3-O-rutinoside) in BRB, for their effects on growth, apoptosis, and gene expression in rat esophageal epithelial cell lines. The EtOH extract and both anthocyanins selectively caused significant growth inhibition and induction of apoptosis in a highly tumorigenic cell line (RE-149 DHD) but not in a weakly tumorigenic line (RE-149). The uptake of anthocyanins from the EtOH extract into RE-149 DHD cells far exceeded their uptake into RE-149 cells, which may have accounted for the selective effects of the extract on growth and apoptosis of RE-149 DHD cells. The growth inhibitory and proapoptotic effects were enhanced by the daily addition of the EtOH extract and the anthocyanins to the medium. Interestingly, the EtOH extract did not alter cyclooxygenase-2 (COX-2) and nitric oxide synthase (i-NOS) expression in RE-149 DHD cells, whereas both anthocyanins downregulated the expressions of these genes. This differential effect may have been related to the relative amounts of anthocyanins in the extract vs. when they were added individually to the medium. We conclude that the selective effects of the EtOH extract on growth and apoptosis of highly tumorigenic rat esophageal epithelial cells in vitro may be due to preferential uptake and retention of its component anthocyanins, and this may also be responsible for the greater inhibitory effects of freeze-dried whole berries on tumor cells in vivo.

Nutr Cancer. 2009 Nov;61(6):816-26

Induction of apoptosis in human colon cancer HCT-116 cells by anthocyanins through suppression of Akt and activation of p38-MAPK.

Anthocyanins belong to a class of flavonoids that exhibit important anti-oxidant and anti-inflammatory actions as well as chemotherapeutic effects. However, little is known concerning the molecular mechanisms by which these activities are exerted. In this study, we investigated the anthocyanins isolated from Vitis coignetiae Pulliat for their potential anti-proliferative and apoptotic effects on human colon cancer HCT-116 cells. These anthocyanins inhibited cell viability and induce apoptotic cell death of HCT-116 cells in a dose-dependent manner. The apoptotic cell death was caspase-dependent and the anthocyanins regulated anti-apoptotic proteins (IAPs). In addition, apoptosis was associated with activation of p38-MAPK and suppression of Akt. In conclusion, this study suggests that the anthocyanins isolated from Vitis coignetiae Pulliat induce apoptosis might at least in part through activating p38-MAPK and suppressing Akt in human colon cancer HCT-116 cells.

Int J Oncol. 2009 Dec;35(6):1499-504

Induction of apoptosis and inhibition of invasion in human hepatoma cells by anthocyanins from meoru.

Anthocyanins belong to a class of flavonoids exhibiting antioxidant and anti-inflammatory actions as well as a variety of chemotherapeutic effects. However, little is known about the cellular and molecular mechanism of anticancer activity. In this study, we investigated if the anthocyanins (delphinidin-3,5-diglucoside: cyanidin-3,5-diglucoside: petunidin-3,5-diglucoside: delphinidin-3-glucoside: malvdin-3,5-diglucoside: peonidin-3,5-diglucoside: cyanidin-3-glucoside: petunidin-3-glucoside: peonidin-3- glucoside: malvidin-3- glucoside = 27:63:8.27:1:2.21:2.21:6.7:1.25:5.72:1.25) [corrected] isolated from meoru (Vitis coignetiae Pulliat) exerted antiproliferative and anti-invasive and apoptotic effects on human hepatoma Hep3B cells. It was found that the anthocyanins could inhibit cell growth by 75% at the concentration of 400 microg/mL for 48 h. Flow cytometric analysis showed that the anthocyanins increased the amount of DNA fragments (sub-G1 fraction) in a dose-dependent manner, which is closely related to mitochondrial dysfunction and reduction in antiapoptotic proteins (Bcl-2, xIAP, cIAP-1, and cIAP-2). The anthocyanins also significantly inhibited the migration and invasion of Hep3B cells through a matrigel-coated chamber. Taken together this study indicates that the anthocyanins from meoru have antiproliferative and anti-invasive effects and may induce apoptosis through the activation of the mitochondrial pathway and inhibition of antiapoptotic proteins. This study provides evidence that the anthocyanins isolated from meoru might be useful in the treatment of human hepatitis B-associated hepatoma.

Ann N Y Acad Sci. 2009 Aug;1171:137-48

Chronic dietary intake of plant-derived anthocyanins protects the rat heart against ischemia-reperfusion injury.

Consumption of flavonoid-rich foods and beverages is thought to reduce the risk of cardiovascular diseases. Whereas the biological activities of flavonoids have been characterized in vitro, there are no clear experimental data demonstrating that chronic dietary intake and intestinal absorption of flavonoids actually protects the heart against ischemia-reperfusion injury. We tested whether long-term consumption of specific flavonoids (anthocyanins) included in normal food could render the heart of rats more resistant to myocardial infarction. Maize kernels that differed specifically in their accumulation of anthocyanins were used to prepare rodent food in which anthocyanins were either present or absent. Male Wistar rats were fed the anthocyanin-rich (ACN-rich) or the anthocyanin-free (ACN-free) diet for a period of 8 wk. Anthocyanins were significantly absorbed and detected in the blood and urine of only rats fed the ACN-rich diet. In Langendorff preparations, the hearts of rats fed the ACN-rich diet were more resistant to regional ischemia and reperfusion insult. Moreover, on an in vivo model of coronary occlusion and reperfusion, infarct size was reduced in rats that ate the ACN-rich diet than in those that consumed the ACN-free diet (P < 0.01). Cardioprotection was associated with increased myocardial glutathione levels, suggesting that dietary anthocyanins might modulate cardiac antioxidant defenses. Our findings suggest important potential health benefits of foods rich in anthocyanins and emphasize the need to develop anthocyanin-rich functional foods with protective activities for promoting human health.

J Nutr. 2008 Apr;138(4):747-52

Berry meals and risk factors associated with metabolic syndrome.

Background/Objectives: Nonalcoholic fatty liver disease is commonly associated with obesity, insulin resistance, dyslipidemia and type 2 diabetes, and can thus be regarded as the hepatic manifestation of metabolic syndrome. In this study we compared the effects of lifestyle intervention with and without industrial berry products, on risk factors associated with metabolic syndrome on slightly overweight women. Subjects/Methods: Sixty-one female volunteers (average age 42.9 years) were recruited and randomized for a 20-week dietary intervention trial with two parallel treatment groups, one lifestyle intervention group with berry products equaling with an average daily dose of 163 g of northern berries (berry group, diet 1, N=31, of which 28 completed the study) and the other group with lifestyle intervention only (control group, diet 2, N=30, of which 22 completed the study). Results:Increased berry consumption as part of the normal daily diet was the only lifestyle difference between the two intervention groups. The major effects achieved by diet 1 were changes in the levels of alanine aminotransferase (ALAT) and adiponectin (at P-values <0.001 and 0.002, respectively). A statistically significant difference between the two intervention groups was the higher decrease in the ALAT value in the berry group (P=0.003).Conclusions: The 23% decrease in the ALAT value, from 20.29 to 15.66 U/l in the berry group may be regarded as nutritionally significant by enhancing the liver function. This may contribute positively to the low-grade systemic inflammation in body and decrease the risk of cardiovascular diseases.

Eur J Clin Nutr. 2010 Mar 3

Berries modify the postprandial plasma glucose response to sucrose in healthy subjects.

Sucrose increases postprandial blood glucose concentrations, and diets with a high glycaemic response may be associated with increased risk of obesity, type 2 diabetes and CVD. Previous studies have suggested that polyphenols may influence carbohydrate digestion and absorption and thereby postprandial glycaemia. Berries are rich sources of various polyphenols and berry products are typically consumed with sucrose. We investigated the glycaemic effect of a berry purée made of bilberries, blackcurrants, cranberries and strawberries, and sweetened with sucrose, in comparison to sucrose with adjustment of available carbohydrates. A total of twelve healthy subjects (eleven women and one man, aged 25-69 years) with normal fasting plasma glucose ingested 150 g of the berry purée with 35 g sucrose or a control sucrose load in a randomised, controlled cross-over design. After consumption of the berry meal, the plasma glucose concentrations were significantly lower at 15 and 30 min (P < 0.05, P < 0.01, respectively) and significantly higher at 150 min (P < 0.05) compared with the control meal. The peak glucose concentration was reached at 45 min after the berry meal and at 30 min after the control meal. The peak increase from the baseline was 1.0 mmol/l smaller (P = 0.002) after ingestion of the berry meal. There was no statistically significant difference in the 3 h area under the glucose response curve. These results show that berries rich in polyphenols decrease the postprandial glucose response of sucrose in healthy subjects. The delayed and attenuated glycaemic response indicates reduced digestion and/or absorption of sucrose from the berry meal.

Br J Nutr. 2009 Nov 24:1-4

Ingestion of black chokeberry fruit extract leads to intestinal and systemic changes in a rat model of prediabetes and hyperlipidemia.

This report presents a complex analysis of changes proceeding in the gut, blood and internal organs of rats with induced oxidative stress, glucose intolerance and hyperlipidemia after dietary supplementation with an extract from black chokeberry (Aronia melanocarpa) fruit, that is a condensed source of polyphenols (714 mg/g), especially anthocyanin glycosides (56.6%). The disturbances mimicking those observed in metabolic syndrome were induced by a high-fructose diet and simultaneous single injection of streptozotocin (20 mg/kg). Dietary supplementation with the chokeberry fruit extract (0.2%) decreased activity of maltase and sucrase as well as increased activity of lactase in the mucosa of the small intestine. Its ingestion led also to the improvement of antioxidant status, especially, the concentration of a lipid peroxidation indicator (TBARS) in organ tissues (liver, kidney, and lung) was normalized; some cholesterol-lowering and distinct hypoglycemic actions were also observed. The mechanism of glucose reduction is likely to be multifactorial, and we suggest the factors related with the decreased activity of mucosal disaccharidases important for further investigation. In conclusion, chokeberry fruit derivatives may act as a promising supplementary therapeutic option in the prevention and treatment of disorders occurring in metabolic syndrome, as well as their complications.

Plant Foods Hum Nutr. 2008 Dec;63(4):176-82

Antioxidant capacity and other bioactivities of the freeze-dried Amazonian palm berry, Euterpe oleraceae mart. (acai).

The fruit of Euterpe oleraceae, commonly known as acai, has been demonstrated to exhibit significantly high antioxidant capacity in vitro, especially for superoxide and peroxyl scavenging, and, therefore, may have possible health benefits. In this study, the antioxidant capacities of freeze-dried acai fruit pulp/skin powder (OptiAcai) were evaluated by different assays with various free radical sources. It was found to have exceptional activity against superoxide in the superoxide scavenging (SOD) assay, the highest of any food reported to date against the peroxyl radical as measured by the oxygen radical absorbance capacity assay with fluorescein as the fluorescent probe (ORACFL), and mild activity against both the peroxynitrite and hydroxyl radical by the peroxynitrite averting capacity (NORAC) and hydroxyl radical averting capacity (HORAC) assays, respectively. The SOD of acai was 1,614 units/g, an extremely high scavenging capacity for O2*-, by far the highest of any fruit or vegetable tested to date. Total phenolics were also tested as comparison. In the total antioxidant (TAO) assay, antioxidants in acai were differentiated into “slow-acting” and “fast-acting” components. An assay measuring inhibition of reactive oxygen species (ROS) formation in freshly purified human neutrophils showed that antioxidants in acai are able to enter human cells in a fully functional form and to perform an oxygen quenching function at very low doses. Furthermore, other bioactivities related to anti-inflammation and immune functions were also investigated. Acai was found to be a potential cyclooxygenase (COX)-1 and COX-2 inhibitor. It also showed a weak effect on lipopolysaccharide (LPS)-induced nitric oxide but no effect on either lymphocyte proliferation and phagocytic capacity.

J Agric Food Chem. 2006 Nov 1;54(22):8604-10

Total oxidant scavenging capacities of Euterpe oleracea Mart. (Açaí) fruits.

The antioxidant capacities of 11 commercial and non-commercial samples of Euterpe oleracea Mart. (açaí) fruit pulp were studied with the total oxidant scavenging capacity assay in a modified and automated version against three reactive oxygen species. The antioxidant capacities of all purple açaí samples were found to be excellent against peroxyl radicals, good against peroxynitrite and poor against hydroxyl radicals compared with common European fruit and vegetable juices recently analysed. In all cases the correlation between sample concentration and antioxidant capacities was non-linear. The antioxidant capacities against all three reactive oxygen species of the fruit pulp from one white açaí variety were very low. The phenolic compounds in purple açaí fruit pulp were identified by high-performance liquid chromatography-mass spectrometry, and the two major anthocyanins, cyanidin-3-glucoside and cyanidin-3-rutinoside, were quantified by high-performance liquid chromatography-visible spectrometry. The contributions of the anthocyanins to the overall antioxidant capacities of the fruit were estimated to be only approximately 10%. Obviously, compounds not yet identified are responsible for the major part of the antioxidant capacities of the açaí fruit pulp.

Int J Food Sci Nutr. 2005 Feb;56(1):53-64

Phytochemical and nutrient composition of the freeze-dried amazonian palm berry, Euterpe oleraceae mart. (acai).

Euterpe oleraceae is a large palm tree indigenous to the Amazon River and its tributaries and estuaries in South America. Its fruit, known as acai, is of great economic value to native people. In this study, a standardized freeze-dried acai fruit pulp/skin powder was used for all analyses and tests. Among many findings, anthocyanins (ACNs), proanthocyanidins (PACs), and other flavonoids were found to be the major phytochemicals. Two ACNs, cyandin 3-glucoside and cyanidin 3-rutinoside were found to be predominant ACNs; three others were also found as minor ACNs. The total content of ACNs was measured as 3.1919 mg/g dry weight (DW). Polymers were found to be the major PACs. The concentration of total PACs was calculated as 12.89 mg/g DW. Other flavonoids, namely, homoorientin, orientin, isovitexin, scoparin, and taxifolin deoxyhexose, along with several unknown flavonoids, were also detected. Resveratrol was found but at a very low concentration. In addition, components including fatty acids, amino acids, sterols, minerals, and other nutrients were analyzed and quantified. Total polyunsaturated fatty acid, total monounsaturated fatty acid, and total saturated fatty acids contributed to 11.1%, 60.2%, and 28.7% of total fatty acid. Oleic acid (53.9%) and palmitic acid (26.7%) were found to be the two dominant fatty acids. Nineteen amino acids were found; the total amino acid content was determined to be 7.59% of total weight. The total sterols accounted for 0.048% by weight of powder. The three sterols B-sitosterol, campesterol, and sigmasterol were identified. A complete nutrient analysis is also presented. Microbiological analysis was also performed.

J Agric Food Chem. 2006 Nov 1;54(22):8598-603

Anthocyanins, phenolics, and antioxidant capacity in diverse small fruits: vaccinium, rubus, and ribes.

Fruits from 107 genotypes of Vaccinium L., Rubus L., and Ribes L., were analyzed for total anthocyanins (ACY), total phenolics (TPH), and antioxidant capacities as determined by oxygen radical absorbing capacity (ORAC) and ferric reducing antioxidant power (FRAP). Fruit size was highly correlated (r = 0.84) with ACY within Vaccinium corymbosum L., but was not correlated to ACY across eight other Vaccinium species, or within 27 blackberry hybrids. Certain Vaccinium and Ribes fruits with pigmented flesh were lower in ACY, TPH, ORAC, and FRAP compared to those values in berries with nonpigmented flesh. ORAC values ranged from 19 to 131 micromol Trolox equivalents/g in Vaccinium, from 13 to 146 in Rubus, and from 17 to 116 in Ribes. Though ACY may indicate TPH, the range observed in ACY/TPH ratios precludes prediction of ACY from TPH and vice versa for a single genotype. In general, TPH was more highly correlated to antioxidant capacity than ACY was. This study demonstrates the wide diversity of phytochemical levels and antioxidant capacities within and across three genera of small fruit.

J Agric Food Chem. 2002 Jan 30;50(3):519-25

Pharmacokinetics of anthocyanins and antioxidant effects after the consumption of anthocyanin-rich acai juice and pulp (Euterpe oleracea Mart.) in human healthy volunteers.

The acai berry is the fruit of the acai palm and is traditionally consumed in Brazil but has gained popularity abroad as a food and functional ingredient, yet little information exists on its health effect in humans. This study was performed as an acute four-way crossover clinical trial with acai pulp and clarified acai juice compared to applesauce and a non-antioxidant beverage as controls. Healthy volunteers (12) were dosed at 7 mL/kg of body weight after a washout phase and overnight fast, and plasma was repeatedly sampled over 12 h and urine over 24 h after consumption. Noncompartmental pharmacokinetic analysis of total anthocyanins quantified as cyanidin-3-O-glucoside showed Cmax values of 2,321 and 1,138 ng/L at t max times of 2.2 and 2.0 h, and AUC last values of 8,568 and 3,314 ng h L(-1) for pulp and juice, respectively. Nonlinear mixed effect modeling identified dose volume as a significant predictor of relative oral bioavailability in a negative nonlinear relationship for acai pulp and juice. Plasma antioxidant capacity was significantly increased by the acai pulp and applesauce. Individual increases in plasma antioxidant capacity of up to 2.3- and 3-fold for acai juice and pulp, respectively were observed. The antioxidant capacity in urine, generation of reactive oxygen species, and uric acid concentrations in plasma were not significantly altered by the treatments. Results demonstrate the absorption and antioxidant effects of anthocyanins in acai in plasma in an acute human consumption trial.

J Agric Food Chem. 2008 Sep 10;56(17):7796-802

Bilberry (Vaccinium myrtillus) anthocyanins modulate heme oxygenase-1 and glutathione S-transferase-pi expression in ARPE-19 cells.

PURPOSE: To determine whether anthocyanin-enriched bilberry extracts modulate pre- or posttranslational levels of oxidative stress defense enzymes heme-oxygenase (HO)-1 and glutathione S-transferase-pi (GST-pi) in cultured human retinal pigment epithelial (RPE) cells. METHODS: Confluent ARPE-19 cells were preincubated with anthocyanin and nonanthocyanin phenolic fractions of a 25% enriched extract of bilberry (10(-6)-1.0 mg/mL) and, after phenolic removal, cells were oxidatively challenged with H(2)O(2). The concentration of intracellular glutathione was measured by HPLC and free radical production determined by the dichlorofluorescin diacetate assay. HO-1 and GST-pi protein and mRNA levels were determined by Western blot and RT-PCR, respectively. RESULTS: Preincubation with bilberry extract ameliorated the intracellular increase of H(2)O(2)-induced free radicals in RPE, though H(2)O(2) cytotoxicity was not affected. By 4 hours, the extract had upregulated HO-1 and GST-pi protein by 2.8- and 2.5-fold, respectively, and mRNA by 5.5- and 7.1-fold, respectively, in a dose-dependent manner. Anthocyanin and nonanthocyanin phenolic fractions contributed similarly to mRNA upregulation. CONCLUSIONS: Anthocyanins and other phenolics from bilberry upregulate the oxidative stress defense enzymes HO-1 and GST-pi in RPE, suggesting that they stimulate signal transduction pathways influencing genes controlled by the antioxidant response element.

Invest Ophthalmol Vis Sci. 2007 May;48(5):2343-9

Activity of anthocyanins from fruit extract of Ribes nigrum L. against influenza A and B viruses.

Earlier, we have detected antiviral activity in an extract from Ribes nigrum L. fruits (“Kurokarin”, name of the one species of black currant in Japanese) against influenza A and B viruses, and herpes simplex virus 1 (Knox et al., Food Processing 33, 21-23, 1998). In the present study, the antiviral activity of constituents of a Kurokarin extract and the mechanism of its antiviral action were examined. Kurokarin extracts were separated to fractions A to D by column chromatography. The major constituents of the fraction D were estimated as anthocyanins. The fraction D was further fractionated by thin-layer chromatography (TLC) to fractions A’ to G’. The fraction E’ consisted of 3-O-alpha-L-rhamnopyranosyl-beta-D-glucopyranosyl-cyanidin and 3-O-beta-D-glucopyra-nosyl-cyanidin, and the fraction F’ consisted of 3-O-alpha-L-rhamno-

pyranosyl-beta-D-glucopyranosyl-delphinidin and 3-O-beta-D-glucopyranosyl-delphinidin, identified by high performance liquid chromatography (HPLC) with standards and by high resolution mass spectrometry. The fractions D’ to G’ showed potent antiviral activity against influenza viruses A and B. The additive antiviral effect of a combination of the fractions E’ and F’ was assessed. Anthocyanins in the fraction F’ did not directly inactivate influenza viruses A and B, but they inhibited virus adsorption to cells and also virus release from infected cells.

Acta Virol. 2001;45(4):209-15

Cytotoxic Effects of Bilberry Extract on MCF7-GFP-Tubulin Breast Cancer Cells.

Bilberry (European blueberry) has been reported to have many biological effects, including anticancer activity. In this study, we investigated the antiproliferative effects of bilberry extract in relation to its ability to induce apoptosis and affect microtubule assembly and organization in MCF7 human breast cancer cells. We observed that bilberry extract inhibited cell proliferation in a concentration-dependent fashion with a 50% inhibitory concentration of 0.3-0.4 mg/mL, in concert with induction of apoptotic cell death. At these concentrations there was no selective inhibition of mitosis or any other cell cycle stage, nor was there any apparent effect on the microtubule or actin cytoskeletons. However, somewhat higher extract concentrations (0.5-0.9 mg/mL) did cause an increase in the fraction of cells at the G(2)/M phase of the cell cycle, together with destruction of microtubules and formation of punctate tubulin aggregates in the cells. Bilberry extract at 0.3-0.4 mg/mL did not appreciably inhibit microtubule polymerization in vitro, but significant inhibition of polymerization (approximately 30%) did occur at higher extract concentrations (0.5-1 mg/mL). We conclude that bilberry extract as ingested by humans, not just the purified anthocyanins it contains, inhibits proliferation of and induces apoptosis in breast cancer cells at its lowest effective concentrations via a mechanism that does not involve action on microtubules or on mitosis. We further conclude that at somewhat higher concentrations the extract modifies microtubule organization in cells and causes accumulation of cells at mitosis by a direct action on microtubules.

J Med Food. 2010 Feb 4

Vitamin D and the skin.

The keratinocytes of the skin are unique in being not only the primary source of vitamin D for the body, but also possessing the enzymatic machinery to metabolize vitamin D to active metabolites [in particular, 1,25 dihydroxyvitamin D (1,25(OH)(2)D)] and the vitamin D receptor (VDR) that enables the keratinocytes to respond to the 1,25(OH)(2)D they produce. Numerous functions of the skin are regulated by vitamin D and/or its receptor: these include inhibition of proliferation, stimulation of differentiation including formation of the permeability barrier, promotion of innate immunity, regulation of the hair follicle cycle, and suppression of tumor formation. Regulation of these actions is exerted by a number of different coregulators including the coactivators DRIP and SRC, a less well known inhibitor, hairless, and beta-catenin. Different coregulators appear to be involved in different VDR-regulated functions. This review examines the various functions of vitamin D and its receptor, and to the extent known explores the mechanisms by which these functions are regulated.

J Bone Miner Metab. 2010 Mar;28(2):117-30

Vitamin D and the skin.

Along with other organs like prostate, bones and kidney, skin is capable of vitamin D synthesis. Primarily keratinocytes but also macrophages and fibroblasts synthesize active vitamin D from cholesterol precursors by photochemical activation. The synthesized vitamin D functions by binding to nuclear vitamin D receptors. Vitamin D deficiency usually manifests as rickets in childhood although it is today only relevant in diseases characterized by malabsorption due to today’s recommended vitamin D prophylaxis. Excessive doses of vitamin D are the usual cause of increased levels. The most common therapeutic target of vitamin D is psoriasis. Here, topical preparations are usually employed; their anti-proliferative and cell differentiation-promoting action is mediated via binding to cutaneous vitamin D receptors.

Hautarzt. 2008 Sep;59(9):737-42

Vitamin D receptor and coactivators SRC2 and 3 regulate epidermis-specific sphingolipid production and permeability barrier formation.

The vitamin D receptor (VDR) is a nuclear hormone receptor that controls transcription of target genes. It exerts its biological effects through transcriptional coactivators. Previously, we identified two distinct classes of VDR coactivators, VDR-interacting protein (DRIP) and steroid receptor coactivator (SRC) at different stages of keratinocyte differentiation. Here, we determined the functions of VDR and coactivators in lipid production and permeability barrier formation. Silencing of either VDR, SRC2, or SRC3 resulted in decreases in specific glucosylceramide (GlcCer) species but not other lipids such as cholesterol and free fatty acids. Their silencing also caused decreased transcription of fatty acid elongase and ceramide glucosyltransferase, which are critical for the synthesis of epidermis-unique GlcCer species, and defects in lamellar body formation associated with decreased expression of the lipid transporter ATP-binding cassette transporter protein 12. VDR null mice exhibit abnormal barrier function with altered lipid composition in vivo. These results demonstrate that VDR and coactivators SRC2 and SRC3, which are also involved in other nuclear receptors as well, are critical for epidermis-specific sphingolipid production and barrier formation. In contrast, DRIP silencing had no apparent effect on these processes indicating that the two classes of coactivators are differentially utilized. J Invest Dermatol. 2009 Jun;129(6):1367-78

Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis.

The purpose of this review is to put into perspective the many health benefits of vitamin D and the role of vitamin D deficiency in increasing the risk of many common and serious diseases, including some common cancers, type 1 diabetes, cardiovascular disease, and osteoporosis. Numerous epidemiologic studies suggest that exposure to sunlight, which enhances the production of vitamin D(3) in the skin, is important in preventing many chronic diseases. Because very few foods naturally contain vitamin D, sunlight supplies most of our vitamin D requirement. 25-hydroxyvitamin D [25(OH)D] is the metabolite that should be measured in the blood to determine vitamin D status. Vitamin D deficiency is prevalent in infants who are solely breastfed and who do not receive vitamin D supplementation and in adults of all ages who have increased skin pigmentation or who always wear sun protection or limit their outdoor activities. Vitamin D deficiency is often misdiagnosed as fibromyalgia. A new dietary source of vitamin D is orange juice fortified with vitamin D. Studies in both human and animal models add strength to the hypothesis that the unrecognized epidemic of vitamin D deficiency worldwide is a contributing factor of many chronic debilitating diseases. Greater awareness of the insidious consequences of vitamin D deficiency is needed. Annual measurement of serum 25(OH)D is a reasonable approach to monitoring for vitamin D deficiency. The recommended adequate intakes for vitamin D are inadequate, and, in the absence of exposure to sunlight, a minimum of 1,000 IU vitamin D/d is required to maintain a healthy concentration of 25(OH)D in the blood.

Am J Clin Nutr. 2004 Mar;79(3):362-71

Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease.

Most humans depend on sun exposure to satisfy their requirements for vitamin D. Solar ultraviolet B photons are absorbed by 7-dehydrocholesterol in the skin, leading to its transformation to previtamin D3, which is rapidly converted to vitamin D3. Season, latitude, time of day, skin pigmentation, aging, sunscreen use, and glass all influence the cutaneous production of vitamin D3. Once formed, vitamin D3 is metabolized in the liver to 25-hydroxyvitamin D3 and then in the kidney to its biologically active form, 1,25-dihydroxyvitamin D3. Vitamin D deficiency is an unrecognized epidemic among both children and adults in the United States. Vitamin D deficiency not only causes rickets among children but also precipitates and exacerbates osteoporosis among adults and causes the painful bone disease osteomalacia. Vitamin D deficiency has been associated with increased risks of deadly cancers, cardiovascular disease, multiple sclerosis, rheumatoid arthritis, and type 1 diabetes mellitus. Maintaining blood concentrations of 25-hydroxyvitamin D above 80 nmol/L (approximately 30 ng/mL) not only is important for maximizing intestinal calcium absorption but also may be important for providing the extrarenal 1alpha-hydroxylase that is present in most tissues to produce 1,25-dihydroxyvitamin D3. Although chronic excessive exposure to sunlight increases the risk of nonmelanoma skin cancer, the avoidance of all direct sun exposure increases the risk of vitamin D deficiency, which can have serious consequences. Monitoring serum 25-hydroxyvitamin D concentrations yearly should help reveal vitamin D deficiencies. Sensible sun exposure (usually 5-10 min of exposure of the arms and legs or the hands, arms, and face, 2 or 3 times per week) and increased dietary and supplemental vitamin D intakes are reasonable approaches to guarantee vitamin D sufficiency.

Am J Clin Nutr. 2004 Dec;80(6 Suppl):1678S-88S

Comparative effectiveness of vitamin D3 and dietary vitamin E on peroxidation of lipids and enzymes of the hepatic antioxidant system in Sprague—Dawley rats.

The vitamin D-endocrine system has mostly been studied for its role in calcium and phosphorus metabolism and its possible role as an antioxidant has been neglected. This study attempts to elucidate the antioxidative properties of the prohormone with respect to vitamin E, a membrane antioxidant. Results herein show that D3 treatment brought about similar reduction in the extent of lipid peroxidation and induction in superoxide dismutase (SOD) activity, as with vitamin E supplementation. While selenium dependent glutathione peroxidase (Sedep. GPx) activity reflected no change with vitamin D3 treatment, total GPx activity was more significantly influenced by vitamin D3 than by vitamin E. The glutathione (GSH) content in the experimental rats also reflected similar changes. Vitamin E supplementation caused 8.57% increase in glutathione reductase (GR) activity, while vitamin D3 decreased the concerned enzymes activity by 11.11%. Vitamin D3 treatment also caused 25% increase in glucose 6-phosphate dehydrogenase (G6PD) activity. These data thus suggest that vitamin D3 may function as an antioxidant in the liver in vivo and illustrate an effectiveness higher than that observed with vitamin E supplementation.

Int J Vitam Nutr Res. 1996;66(1):39-45

Involvement of endogenously produced 1,25-dihydroxyvitamin D-3 in the growth and differentiation of human keratinocytes.

In this study, we investigated the possibility that cultured keratinocytes from normal human adult skin produce 1,25-dihydroxyvitamin D-3 (1,25(OH)2D3, a biologically active form of vitamin D-3) from 25-hydroxyvitamin D-3 [25(OH)D3], and that 1,25(OH)2D3 endogenously produced by keratinocytes is involved in the self regulation of their growth and differentiation. To determine whether 1,25(OH)2D3 is produced from 25(OH)D3 by skin keratinocytes, 25(OH)[3H]D3 was added to keratinocyte cultures and incubated for 1 h and 5 h. The intracellular and extracellular metabolites were analyzed by three chromatographic systems. The three chromatograms revealed that the major metabolite produced from 25(OH)D3 was 1,25(OH)2D3. Most of the 1,25(OH)2D3 endogenously produced from 25(OH)D3 remained within the cells. To examine the time course of 1,25(OH)2D3 production, the amount of 1,25(OH)[3H]D3 was measured at 15 min, 1 h, 5 h and 10 h, being at a maximum 1 h after the addition of 25(OH)D3. These data indicate that keratinocytes rapidly convert 25(OH)D3 to 1,25(OH)2D3 and that 1,25(OH)2D3 is not released into the medium. To determine whether endogenously produced 1,25(OH)2D3 is involved in the regulation of growth and differentiation of normal human keratinocytes, we examined the effects of 1,25(OH)2D3 and 25(OH)D3 on their growth and differentiation. Keratinocyte growth was inhibited to 52.6% and 23.4% by 10(-8) M and 10(-7) M 1,25(OH)2D3 and to 80.5% and 23.9% by 10(-8) M and 10(-7) M 25(OH)D3, respectively. Differentiation of these cells was evaluated by quantifying the number which express involucrin, a precursor protein of cornified envelope. The population of involucrin expressing cells (differentiated cells) increased from 6.2% to 14.5% by 2.5.10(-7) M 1,25(OH)2D3, and to 11.8% by 2.5.10(-7) M 25(OH)D3. These results clearly indicate that 25(OH)D3 is as effective on human keratinocytes as 1,25(OH)2D3 in inhibiting growth and inducing differentiation, although to a slightly lesser extent than 1,25(OH)2D3. The possibility that the effect of 25(OH)D3 is mediated through binding to the 1,25(OH)2D3 receptor can be excluded, since a competitive binding assay revealed that the affinity of 25(OH)D3 for the 1,25(OH)2D3 receptor in a cytosolic extract of keratinocytes was 100-times lower than that of 1,25(OH)2D3. Thus, these results suggest that 1,25(OH)2D3 endogenously produced in keratinocytes from 25(OH)D3 is involved in the regulation of their growth and differentiation in vitro.

Biochim Biophys Acta. 1991 May 17;1092(3):311-8

Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D-dependent mechanism.

An essential element of the innate immune response to injury is the capacity to recognize microbial invasion and stimulate production of antimicrobial peptides. We investigated how this process is controlled in the epidermis. Keratinocytes surrounding a wound increased expression of the genes coding for the microbial pattern recognition receptors CD14 and TLR2, complementing an increase in cathelicidin antimicrobial peptide expression. These genes were induced by 1,25(OH)2 vitamin D3 (1,25D3; its active form), suggesting a role for vitamin D3 in this process. How 1,25D3 could participate in the injury response was explained by findings that the levels of CYP27B1, which converts 25OH vitamin D3 (25D3) to active 1,25D3, were increased in wounds and induced in keratinocytes in response to TGF-beta1. Blocking the vitamin D receptor, inhibiting CYP27B1, or limiting 25D3 availability prevented TGF-beta1 from inducing cathelicidin, CD14, or TLR2 in human keratinocytes, while CYP27B1-deficient mice failed to increase CD14 expression following wounding. The functional consequence of these observations was confirmed by demonstrating that 1,25D3 enabled keratinocytes to recognize microbial components through TLR2 and respond by cathelicidin production. Thus, we demonstrate what we believe to be a previously unexpected role for vitamin D3 in innate immunity, enabling keratinocytes to recognize and respond to microbes and to protect wounds against infection.

J Clin Invest. 2007 Mar;117(3):803-11

Dermal toxicity and environmental contamination: electron transfer, reactive oxygen species, oxidative stress, cell signaling, and protection by antioxidants.

Large numbers of chemicals are known to produce diverse types of skin injury, and these substances fit into a wide variety of both organic and inorganic chemical classes. Skin contact with toxins is difficult to avoid, because they are widely distributed, e.g., in industrial substances, agricultural chemicals, household products, and plants. Although various hypotheses have been advanced, there is no universal agreement as to how dermal toxins act to produce their effects. In this review, we provide evidence and numerous literature citations to support the view that oxidative stress (OS) and electron transfer (ET) comprise a portion of a key mechanism, and perhaps unifying theme that underlie the action of dermatotoxins. We apply the concept that ET and OS are key elements in the induction of dermatotoxic effects to all of the main classes of toxins, and to other toxins, as well. We believe it is not coincidental that the vast majority of dermatotoxic substances incorporate recurrent ET chemical functionalities (i.e., quinone, metal complexes, ArNO2, or conjugated iminium), either per se or as metabolites; such entities potentially give rise to reactive oxygen species (ROS) by redox cycling. However, in some categories, wherein agents cause dermal damage, e.g., peroxides and radiation, it appears that ROS are generated by non-ET routes. As expected, if ET and oxidative process do constitute the mechanistic framework by which most dermal toxins act, then antioxidants (AOs), if present, should prevent or mitigate effects. This is exactly what has been discovered to occur. Because ET and OS either cause or contribute to dermal toxicity, and AOs may offer protection therefrom, policy makers and researchers may be better positioned to prevent human dermatotoxicity.

Rev Environ Contam Toxicol. 2010;203:119-38

Delivery of vitamin E to the skin by a novel liquid skin cleanser: comparison of topical versus oral supplementation.

Topical supplementation represents an attractive approach to mitigate environmentally induced deficiencies of skin vitamin E (alpha-tocopherol). We report here the impact of natural sunlight on stratum corneum (SC) vitamin E and also compare the effectiveness of dietary supplementation to topical application as a way to increase vitamin E in the superficial layers of the SC. The effects of natural sunlight, 30 minutes of midday sunlight, were measured on two separate occasions. Vitamin E in the surface layers of the SC was measured by HPLC after ethanol extraction. Under these relevant conditions, vitamin E in the superficial SC was reduced in a dose-dependent manner by 50-65%. In a followup study, panelists entered into a randomized, double-blind, vehicle-controlled study. In this study, one group washed their skin once daily for one minute with a commercially available body wash containing 0.15% vitamin E and 0.10% vitamin E acetate, while the second group used a body wash without vitamin E but also supplemented their diet with 400 IU alpha-tocopherol (18 x RDI). Not surprisingly, only dietary supplementation increased serum vitamin E (approximately twofold). Although both treatment modalities increased SC vitamin E, topical delivery was significantly more effective (53-fold vs baseline) than dietary delivery (eightfold vs baseline). Moreover, only topical delivery increased SC vitamin E acetate (19-fold vs baseline). The results reported here indicate that vitamin E in the superficial layers of the SC is depleted readily by even a brief exposure to sunlight and that use of a vitamin E body wash can substantially increase the vitamin E in this superficial layer more effectively than dietary supplementation.

J Cosmet Sci. 2004 Mar-Apr;55(2):177-87

Vitamin D is a membrane antioxidant. Ability to inhibit iron-dependent lipid peroxidation in liposomes compared to cholesterol, ergosterol and tamoxifen and relevance to anticancer action.

Vitamin D is a membrane antioxidant: thus Vitamin D3 (cholecalciferol) and its active metabolite 1,25-dihydroxycholecalciferol and also Vitamin D2 (ergocalciferol) and 7-dehydrocholesterol (pro-Vitamin D3) all inhibited iron-dependent liposomal lipid peroxidation. Cholecalciferol, 1,25-dihydroxycholecalciferol and ergocalciferol were all of similar effectiveness as inhibitors of lipid peroxidation but were less effective than 7-dehydrocholesterol; this was a better inhibitor of lipid peroxidation than cholesterol, though not ergosterol. The structural basis for the antioxidant ability of these Vitamin D compounds is considered in terms of their molecular relationship to cholesterol and ergosterol. Furthermore, the antioxidant ability of Vitamin D is compared to that of the anticancer drug tamoxifen and its 4-hydroxy metabolite (structural mimics of cholesterol) and discussed in relation to the anticancer action of this vitamin.

FEBS Lett. 1993 Jul 12;326(1-3):285-8

Oxidative stress associated with exercise, psychological stress and life-style factors.

Oxidative stress is a cellular or physiological condition of elevated concentrations of reactive oxygen species that cause molecular damage to vital structures and functions. Several factors influence the susceptibility to oxidative stress by affecting the antioxidant status or free oxygen radical generation. Here, we review the effect of alcohol, air pollution, cigarette smoke, diet, exercise, non-ionizing radiation (UV and microwaves) and psychological stress on the development of oxidative stress. Regular exercise and carbohydrate-rich diets seem to increase the resistance against oxidative stress. Air pollution, alcohol, cigarette smoke, non-ionizing radiation and psychological stress seem to increase oxidative stress. Alcohol in lower doses may act as an antioxidant on low density lipoproteins and thereby have an anti-atherosclerotic property.

Chem Biol Interact. 1996 Sep 27;102(1):17-36

The role of redox regulation in the normal physiology and inflammatory diseases of skin.

Skin is the largest organ which contains complex and tightly regulated redox network of the reactive oxygen/nitrogen/lipid species producing components as well as the redox damage protective systems. This redox balancing system has evolved to regulate normal physiological processes and to protect skin and the internal organs against environmental damage. Exposure to some physical, chemical, and biological agents results in the excessive formation of free radicals and non-radical redox active species within the skin. Normally, skin reacts to this overproduction by sacrificing non-enzymatic antioxidants and by adaptive induction of both protective detoxifying and damage-eliminating systems. Thus, fast restoration of redox balance necessary to maintain normal skin structure and functioning occurs. In the case of excessive exposure or defects in the adaptive reactions, redox damage to skin components occurs. Here, we focus on the role of redox status in the acute inflammatory response to wounding and chronic inflammatory skin diseases such as psoriasis, atopic and contact dermatitis. Redox-mediated chronic inflammation and immunosuppression as risk factors for tumorigenesis are also reviewed.

Front Biosci (Elite Ed). 2009 Jun 1;1:123-41

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