Not all carotenoids can reduce the risk of gastric cancer: a systematic review with meta-analysis.

BACKGROUND: Gastric cancer is characterized by high invasiveness, heterogeneity, and late diagnosis, leading to high incidence and mortality rates. It is a significant public health concern globally. Early prevention is crucial in reducing the occurrence of gastric cancer, and dietary prevention, particularly focusing on carotenoids, has been considered a convenient and effective approach. However, the association between carotenoid intake and gastric cancer incidence remains controversial. METHODS: A systematic search was conducted in PubMed, Ovid Embase, Web of Science, and Cochrane databases from inception to January 5, 2023. Two reviewers independently screened search results, extracted relevant data, and evaluated study quality. Statistical analysis was performed using the "metan" command in STATA 16 software. Random-effects or fixed-effects models were chosen based on the magnitude of heterogeneity among studies. RESULTS: This study included a total of 35 publications, consisting of 23 case-control studies and 12 cohort studies. Meta-analysis of case-control studies showed that alpha-carotene (OR = 0.71, 95% CI: 0.55-0.92), beta-carotene (OR = 0.62, 95% CI: 0.53-0.72), and lutein (OR = 0.82, 95% CI: 0.69-0.97) significantly reduced the risk of gastric cancer, while beta-cryptoxanthin (OR = 0.88, 95% CI: 0.75-1.04) and lycopene (OR = 0.86, 95% CI: 0.73-1.00) showed no significant correlation. Meta-analysis of cohort studies indicated no significant associations between any of the five carotenoids and gastric cancer incidence (alpha-carotene: RR = 0.81, 95% CI: 0.54-1.23; beta-carotene: RR = 0.86, 95% CI: 0.64-1.16; beta-cryptoxanthin: RR = 0.86, 95% CI: 0.64-1.16; lutein: RR = 0.94, 95% CI: 0.69-1.29; lycopene: RR = 0.89, 95% CI: 0.69-1.14). CONCLUSIONS: The relationship between carotenoids and gastric cancer incidence may vary depending on the type of study conducted. Considering that evidence from cohort studies is generally considered stronger than evidence from case-control studies, and high-quality randomized controlled trials show no significant association between carotenoids and gastric cancer incidence, current evidence does not support the supplementation of carotenoids for gastric cancer prevention. Further targeted research is needed to explore the association between the two.

The effects of ß-carotene on osteoporosis: a systematic review and meta-analysis of observational studies.

PURPOSE: The aim is to evaluate the effect of ß-carotene for osteoporosis and provide quantitative evidence. METHOD: PubMed, Embase, Web of Science, and Cochrane Library were searched for eligible studies. Fifteen studies were included. Random-effect model was applied to pool the odds ratio (OR). The risk of osteoporosis and fracture were compared between low ß-carotene intake group and high ß-carotene intake group. RESULT: The intake of ß-carotene was unassociated with the overall risk of osteoporosis [OR = 0.733, 95% Cl (0.528, 1.018), p = 0.064]. Subgroup analysis showed that the intake of ß-carotene was negatively associated with the risk of osteoporosis in both male subgroup [OR = 0.7, 95% Cl (0.549, 0.893), I2 = 40.40%, p = 0.004] and female subgroup [OR = 0.684, 95% Cl (0.487, 0.960), I2 = 86.40%, p = 0.028]. There was also a negative association between ß-carotene intake and osteoporosis in Asia subgroup [OR = 0.512, 95% Cl (0.403, 0.650), I2 = 0.00%, p = 0], whereas no association was observed in Western subgroup [OR = 1.107, 95% Cl (0.908, 1.350), I2 = 2.30%, p = 0.314]. In addition, random-effect model was adopted to pool the standard mean difference (SMD), and the results showed that ß-carotene intake was positively associated with overall bone mineral density (BMD) [SMD = - 0.213, 95% Cl (- 0.391, - 0.034), I2 = 87.30%, p = 0.019]. Subgroup analysis showed that ß-carotene intake was positively associated with BMD in Asian participants [SMD = - 0.394, 95% Cl (- 0.461, - 0.328), I2 = 0, p = 0], while unassociated in Western participants [SMD = - 0.047, 95% Cl (- 0.314, 0.219), I2 = 78.9%, p = 0.727]. CONCLUSION: ß-carotene may improve BMD and reduce the risk of osteoporosis and fracture. However, these effects could vary by gender and race and need to be further validated by longitudinal studies.

Combining ß-Carotene with 5-FU via Polymeric Nanoparticles as a Novel Therapeutic Strategy to Overcome uL3-Mediated Chemoresistance in p53-Deleted Colorectal Cancer Cells.

Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. Despite recent therapeutic advancements, resistance to 5-fluorouracil (5-FU) remains a major obstacle to the successful treatment of this disease. We have previously identified the ribosomal protein uL3 as a key player in the cell response to 5-FU, and loss of uL3 is associated with 5-FU chemoresistance. Natural products, like carotenoids, have shown the ability to enhance cancer cell response to drugs and may provide a safer choice to defeat chemoresistance in cancer. Transcriptome analysis of a cohort of 594 colorectal patients revealed a correlation between uL3 expression and both progression-free survival and response to treatment. RNA-Seq data from uL3-silenced CRC cells demonstrated that a low uL3 transcriptional state was associated with an increased expression of specific ATP-binding cassette (ABC) genes. Using two-dimensional (2D) and three-dimensional (3D) models of 5-FU-resistant CRC cells stably silenced for uL3, we investigated the effect of a novel therapeutic strategy by combining ß-carotene and 5-FU using nanoparticles (NPs) as a drug delivery system. Our results indicated that the combined treatment might overcome 5-FU chemoresistance, inducing cell cycle arrest in the G2/M phase and apoptosis. Furthermore, the combined treatment significantly reduced the expression levels of analyzed ABC genes. In conclusion, our findings suggest that ß-carotene combined with 5-FU may be a more effective therapeutic approach for treating CRC cells with low levels of uL3.

USPSTF recommends against beta carotene or vitamin E supplements for preventing CVD or cancer in adults.

SOURCE CITATION: US Preventive Services Task Force; Mangione CM, Barry MJ, et al. Vitamin, mineral, and multivitamin supplementation to prevent cardiovascular disease and cancer: US Preventive Services Task Force Recommendation Statement. JAMA. 2022;327:2326-33. 35727271.

Re-remembering the influence of randomized ß-carotene on cognitive decline.

The wave of individuals impacted by dementia continues to rise rapidly as worldwide lifespan increases. Dietary strategies to slow cognitive decline and prolong time to clinical dementia remain understudied, but with potentially powerful public health consequences. Indeed, previously conducted large, randomized, placebo-controlled trials of micronutrients remain an under-leveraged resource to study changes in cognitive performance. As a motivating example, we highlight an ancillary report from the Physicians' Health Study, where subjects randomized to ß-carotene (a provitamin A carotenoid) had a more attenuated change in longitudinal global cognitive performance and verbal memory, as compared to subjects randomized to placebo. Despite mechanistic evidence from cell and animal studies supporting a vitamin A-mediated role in the biology associated with cognition, limited follow-up work has been conducted. We argue that dietary factors (including provitamin A) deserve a second look, leveraging multi-omic approaches, to elucidate how they may mitigate cognitive decline and dementia risk.

ß-Carotene inhibits NF-κB and restrains diethylnitrosamine-induced hepatic inflammation in Wistar rats.

ß-Carotene exhibits antioxidant and hepatoprotective activities via a multitude of biochemical mechanisms. However, the action mechanism involved in antioxidant and anti-inflammatory effects of this carotene in chronic liver diseases is not fully understood. In the present investigation, we have attempted to outline a plausible mechanism of ß-carotene action against liver fibrosis in albino Wistar rats. To induce hepatic fibrosis, diethylnitrosamine (DEN) was administered in experimental rats for two weeks. DEN treated rats were divided into four groups, wherein each group comprised of five rats. ß-Carotene supplement attenuated DEN-induced elevation in LFT markers (P < 0.05); averted depletion of glycogen (24%, P < 0.05) and, increased nitrite (P < 0.05), hydroxyproline (~67%, P < 0.05) and collagen levels (~65%, P < 0.05). Confocal microscopy of tissue sections stained with picrosirius red revealed accrued collagen in DEN-administered group, which was found to be reduced by ß-carotene supplementation. Furthermore, ß-carotene decreased the expression of iNOS/NOS-2 and NF-κB, as revealed by immunohistochemistry and Western immunoblotting. Collectively, these results demonstrate that ß-carotene mitigates experimental liver fibrosis via inhibition of iNOS and NF-κB in-vivo. Thus, ß-carotene may be suggested as a possible nutraceutical to curb experimental liver fibrosis.

Beta-Carotene derivatives as novel therapy for the prevention and treatment of autistic symptoms.

Autistic Spectrum Disorders (ASD) are neurodevelopmental disorders characterized by impaired social interaction & communication as well as restricted and repetitive behavior. The currently reported incidence of ASD is 1-2%, and it increases dramatically to 10-20% in families predisposed to ASD. To date, there is no effective way to treat or prevent ASD, and only symptomatic treatment with limited efficacy is available. Oxytocin (Oxt) enhances affiliative behavior and improves social cognition. Social deficits characteristic of autism may be related to dysfunctional Oxt neurotransmission. Thus, administration of Oxt may relieve ASD, however it has a short plasma half-life and poor Blood Brain Barrier (BBB) permeability. CD38, a multifunctional ecto-enzyme expressed in brain and immune cells, was found to be critical for social behavior via regulation of Oxt secretion. All-trans retinoic acid (ATRA) is a potent inducer of CD38 and improves social behavior, but it is toxic and teratogenic. We have shown that beta-carotene has a similar therapeutic effect. The present study aimed to investigate the activity of novel beta-carotene derivatives in rescuing low sociability found in BTBR mice, providing an in vivo "proof of principle" that beta-carotene derivatives are potential agents to prevent/ameliorate the reappearance of ASD in high-risk populations for ASD. Beta-carotene and its synthetic analogs were administered orally to newborn BTBR mice with ASD associated like behavior. After 2 months, they were tested (at dosages of 0.1 and 1.0 mg/kg) by cognitive (T-maze spontaneous alteration and neurological score) and behavioral tests (reciprocal social interaction, repetitive grooming / bedding behavior), previously shown as indicators for autistic behavior. The following biochemical and molecular biology parameters were also examined: serum Oxt; gene expression in hippocampus and hypothalamus of CD 38, Oxt, Oxt receptor, BDNF, and retinoic acid receptor. The new compounds were significantly more effective than control. The most effective compounds, both in the behavioral tests and in their biochemical effects, were (3R,3'R)-astaxanthin bis(N-Cbz-l-alanine ester) (3B(and (3S,3'S)-astaxanthin bis(N,N-dimethylglycine ester (5). They did not exert any neurological symptoms. Thus, beta-carotene derivatives may have the potential to prevent and/or ameliorate autistic symptoms when administered orally after birth to newborns of families predisposed to autism.

ß-Carotene improves intestinal barrier function by modulating proinflammatory cytokines and improving antioxidant capacity in ß-lactoglobulin-sensitized mice.

Increased intestinal permeability due to barrier dysfunction is supposed to cause several gastrointestinal diseases. We have previously demonstrated that a single ß-carotene (BC) dose protects against increase in anaphylactic response in ß-lactoglobulin (BLG)-sensitized mice with no effect on the epithelial permeability and weak recovery of villi length. Utilizing the same murine ex vivo intestinal model, the aim of this study was to investigate the effect of different BC doses on BLG-mediated intestinal epithelial barrier disturbances. Jejunum was harvested from BLG-sensitized mice pretreated with either one of three different doses of BC (5, 10 and 20 mg/ kg body weight) and mounted on Ussing Chambers. Transepithelial electrical resistance (TER) and short-circuit current (Isc) were recorded as indicators of intestinal epithelial barrier function. Histopathological analysis of the intestine was carried out for the control and experimental mice. TNF-α and IL-6 levels were determined in serum using ELISA, and the analysis of antioxidant activity was performed for reduced glutathione (GSH) and thiobarbituric acid reactive substances (TBARS). BC was capable of enhancing the intestinal barrier function, as indicated by the increased TER and the decreased Isc. Intestinal damage characterized by the shortening of villi and infiltration of intestinal lymphocytes was significantly reversed by BC pretreatment. Such effects of BC were accompanied by a reduction in the levels of IL-6 and TBARS and an increase of GSH. TNF-α levels were reduced only at the lowest BC dose. These findings may encourage the use of BC-based therapies for controlling the breakdown of the intestinal barrier in vivo.

Antibiotic adjuvant therapy for pulmonary infection in cystic fibrosis.

BACKGROUND: Cystic fibrosis is a multi-system disease characterised by the production of thick secretions causing recurrent pulmonary infection, often with unusual bacteria. This leads to lung destruction and eventually death through respiratory failure. There are no antibiotics in development that exert a new mode of action and many of the current antibiotics are ineffective in eradicating the bacteria once chronic infection is established. Antibiotic adjuvants - therapies that act by rendering the organism more susceptible to attack by antibiotics or the host immune system, by rendering it less virulent or killing it by other means, would be a significant therapeutic advance. This is an update of a previously published review. OBJECTIVES: To determine if antibiotic adjuvants improve clinical and microbiological outcome of pulmonary infection in people with cystic fibrosis. SEARCH METHODS: We searched the Cystic Fibrosis Trials Register which is compiled from database searches, hand searches of appropriate journals and conference proceedings. Date of most recent search: 16 January 2020. We also searched MEDLINE (all years) on 14 February 2019 and ongoing trials registers on 06 April 2020. SELECTION CRITERIA: Randomised controlled trials and quasi-randomised controlled trials of a therapy exerting an antibiotic adjuvant mechanism of action compared to placebo or no therapy for people with cystic fibrosis. DATA COLLECTION AND ANALYSIS: Two of the authors independently assessed and extracted data from identified trials. MAIN RESULTS: We identified 42 trials of which eight (350 participants) that examined antibiotic adjuvant therapies are included. Two further trials are ongoing and five are awaiting classification. The included trials assessed ß-carotene (one trial, 24 participants), garlic (one trial, 34 participants), KB001-A (a monoclonal antibody) (two trials, 196 participants), nitric oxide (two trials, 30 participants) and zinc supplementation (two trials, 66 participants). The zinc trials recruited children only, whereas the remaining trials recruited both adults and children. Three trials were located in Europe, one in Asia and four in the USA. Three of the interventions measured our primary outcome of pulmonary exacerbations (ß-carotene, mean difference (MD) -8.00 (95% confidence interval (CI) -18.78 to 2.78); KB001-A, risk ratio (RR) 0.25 (95% CI 0.03 to 2.40); zinc supplementation, RR 1.85 (95% CI 0.65 to 5.26). ß-carotene and KB001-A may make little or no difference to the number of exacerbations experienced (low-quality evidence); whereas, given the moderate-quality evidence we found that zinc probably makes no difference to this outcome. Respiratory function was measured in all of the included trials. ß-carotene and nitric oxide may make little or no difference to forced expiratory volume in one second (FEV1) (low-quality evidence), whilst garlic probably makes little or no difference to FEV1 (moderate-quality evidence). It is uncertain whether zinc or KB001-A improve FEV1 as the certainty of this evidence is very low. Few adverse events were seen across all of the different interventions and the adverse events that were reported were mild or not treatment-related (quality of the evidence ranged from very low to moderate). One of the trials (169 participants) comparing KB001-A and placebo, reported on the time to the next course of antibiotics; results showed there is probably no difference between groups, HR 1.00 (95% CI 0.69 to 1.45) (moderate-quality evidence). Quality of life was only reported in the two KB001-A trials, which demonstrated that there may be little or no difference between KB001-A and placebo (low-quality evidence). Sputum microbiology was measured and reported for the trials of KB001-A and nitric oxide (four trials). There was very low-quality evidence of a numerical reduction in Pseudomonas aeruginosa density with KB001-A, but it was not significant. The two trials looking at the effects of nitric oxide reported significant reductions in Staphylococcus aureus and near-significant reductions in Pseudomonas aeruginosa, but the quality of this evidence is again very low. AUTHORS' CONCLUSIONS: We could not identify an antibiotic adjuvant therapy that we could recommend for treating of lung infection in people with cystic fibrosis. The emergence of increasingly resistant bacteria makes the reliance on antibiotics alone challenging for cystic fibrosis teams. There is a need to explore alternative strategies, such as the use of adjuvant therapies. Further research is required to provide future therapeutic options.

Drugs for preventing lung cancer in healthy people.

BACKGROUND: This is the second update of this Cochrane Review. Some studies have suggested a protective effect of antioxidant nutrients and higher dietary levels of fruits and vegetables on lung cancer. OBJECTIVES: To determine whether vitamins and minerals and other potential agents, alone or in combination, reduce lung cancer incidence and lung cancer mortality in healthy populations. SEARCH METHODS: We searched CENTRAL, MEDLINE and Embase from 1974 to May 2019 and screened references included in published studies and reviews. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing vitamins or mineral supplements with placebo, administered to healthy people with the aim of preventing lung cancer. DATA COLLECTION AND ANALYSIS: Four review authors independently selected the trials to be included in the review, assessed their methodological quality and extracted data. For dichotomous outcomes we calculated risk ratios (RRs) and 95% confidence intervals (CIs) and pooled results using the random-effects model. We assessed the risk of bias using Cochrane's 'Risk of bias' assessment tool and certainty of evidence using the GRADE approach. MAIN RESULTS: In this update, we identified three new trials for a total of 12 studies. Six analysed vitamin A, three vitamin C, three combined vitamin D3 + calcium, four vitamin E combined with other products, one selenium supplements and nine studied combinations of two or more products. Four studies included only men and five only women. Vitamin A results in little to no difference in lung cancer incidence (RR 1.09, 95% CI 1.00 to 1.19; 5 RCTs, 212314 participants; high-certainty evidence) and lung cancer mortality (RR 1.06, 95% CI 0.81 to 1.38; 3 RCTs, 190118 participants; high-certainty evidence). But in smokers or asbestos workers vitamin A increases the risk of lung cancer incidence (RR 1.10, 95% CI 1.01 to 1.20; 3 RCTs, 43995 participants; high-certainty evidence), lung cancer mortality (RR 1.18, 95% CI 1.01 to 1.38; 2 RCTs, 29426 participants; high-certainty evidence) and all-cause mortality (RR 1.09, 95% CI 1.05 to 1.13; 2 RCTs, 32883 participants; high-certainty evidence). Vitamin A increases the risk of minor side effects, such as yellowing of the skin and minor gastrointestinal symptoms (high-certainty evidence). Vitamin C likely results in little to no difference in lung cancer incidence (RR 1.29, 95% CI 0.67 to 2.49; 2 RCTs, 14953 participants; moderate-certainty evidence). In women, vitamin C increases the risk of lung cancer incidence (RR 1.84, 95% CI 1.14 to 2.95; 1 RCT, 7627 participants; high-certainty evidence). In men, vitamin C results in little to no difference in mortality for lung cancer (RR 0.81, 95% CI 0.53 to 1.23; 1 RCT, 7326 participants; high-certainty evidence). Vitamin D + calcium may result in little to no difference in lung cancer incidence in postmenopausal women (RR 0.90, 95% CI 0.39 to 2.08; 3 RCTs, 37601 women; low-certainty evidence). Vitamin E results in little to no difference in lung cancer incidence (RR 1.01, 95% CI 0.90 to 1.14; 3 RCTs, 36841 participants; high-certainty evidence) or to lung cancer mortality (RR 0.96, 95% CI 0.77 to 1.18; 2 RCTs, 29214 participants; high-certainty evidence), but increases the risk of haemorrhagic strokes (hazard ratio (HR), 1.74, 95% CI 1.04 to 2.91; 1 RCT, 14641 participants; high-certainty evidence). Calcium results in little to no difference in lung cancer incidence in postmenopausal women (RR 0.65, 95% CI 0.13 to 3.18; 1 RCT, 733 participants) or in risk of renal calculi (RR 1.94, 95% CI 0.20 to 18.57; 1 RCT, 733 participants; low-certainty evidence). Selenium in men results in little to no difference in lung cancer incidence (RR 1.11, 95% CI 0.80 to 1.54; 1 RCT, 17448 participants; high-certainty evidence) and lung cancer mortality (RR 1.09, 95% CI 0.72 to 1.66; 1 RCT, 17448 participants; high-certainty evidence) and increases the risk for grade 1 to 2 dermatitis (RR 1.16, 95% CI 1.04 to 1.31; 1 RCT, 17448 participants; high-certainty evidence) and for alopecia (RR 1.28, 95% CI 1.07 to 1.53; 1 RCT, 17448 participants; high-certainty evidence). The combination of vitamins A, C, E + selenium + zinc results in little to no difference in lung cancer incidence (RR 0.64, 95% CI 0.28 to 1.48; 1 RCT, 12741 participants; high-certainty evidence). AUTHORS' CONCLUSIONS: Well-designed RCTs have shown no beneficial effect of supplements for the prevention of lung cancer and lung cancer mortality in healthy people. Vitamin A supplements increase lung cancer incidence and mortality in smokers or persons exposed to asbestos. Vitamin C increases lung cancer incidence in women. Vitamin E increases the risk of haemorrhagic strokes.

Acquired erythropoietic protoporphyria: A systematic review of the literature.

BACKGROUND: Erythropoietic protoporphyria (EPP) is a semi-dominantly inherited porphyria presenting with photosensitivity during early childhood. Acquired EPP has been reported; however, data regarding this rare disorder are scarce. PURPOSE: To evaluate the characteristics of acquired EPP. METHODS: A comprehensive search of PubMed, Google Scholar, ScienceDirect, and clinicaltrials.gov databases was performed by three reviewers. Studies describing patients with acquired EPP were included. Additionally, we present an index case of a 26-year-old patient who acquired clinically and biochemically typical EPP in association with myelodysplastic syndrome (MDS). RESULTS: We included 20 case reports describing 20 patients. Most (80%) patients were male of mean age 58 ± 13 years. In all patients, acquired EPP was associated with hematological disease, most commonly MDS (85%) followed by myeloproliferative disease (10%). In 86% of cases, hematological disease led to abnormality or somatic mutation in chromosome 18q (the locus of the ferrochelatase gene). The mean erythrocyte protoporphyrin IX concentration was very high (4286 µg/dL). Most (90%) patients presented with photosensitivity, 20% experienced blistering, and 25% presented with hepatic insufficiency, both uncommon in EPP. In 55% of patients, hematological disease was diagnosed after occurrence of cutaneous symptoms. Beta-carotene led to partial control of symptoms in 5 patients and resolution in another patient. Azacitidine treatment of MDS led to resolution of cutaneous symptoms in three patients. CONCLUSION: We present the distinct features of acquired EPP and highlight that any patient presenting with new-onset photosensitivity, irrespective of age should be evaluated for porphyria.

Effects of ß-carotene on oxazolone-induced atopic dermatitis in hairless mice.

Skin acts as a barrier, which protects internal tissues and promotes moisture retention. Atopic dermatitis (AD) is an inflammatory skin disease associated with a variety of genetic and environmental factors that involve helper T cells. ß-Carotene (provitamin A) exhibits antioxidant activity and activates the immune system. However, it is not clear whether inflammation in AD skin is improved by posttreatment with ß-carotene. In the current study, we investigated the effects of ß-carotene on the skin of hairless mice with oxazolone-induced inflammation/oedema (Ox-AD mice). We found that skin inflammation was significantly reduced by oral administration of ß-carotene. In addition, treatment with ß-carotene suppressed protein levels of TNF-α, IL-1ß and MCP-1, as well as mRNA expression associated with IL-1ß, IL-6, IL-4 and Par-2 in skin tissues. Furthermore, the mRNA and protein levels of filaggrin, a structural protein in the epidermal stratum corneum, were elevated by ß-carotene administration as compared with Ox-AD mice. ß-Carotene significantly reduced the activity of proMMP-9, but not proMMP-2. These results suggest that in Ox-AD mice, ß-carotene improves skin inflammation by suppressing the expression of inflammatory factors, promoting filaggrin expression and reducing MMP-9 activity. ß-Carotene is a potent anti-inflammatory agent that improves the barrier functions of AD skin.

Insulin-like growth factor I, binding proteins -1 and -3, risk of type 2 diabetes and macronutrient intakes in men.

The insulin-like growth factor (IGF) axis may be involved in the development of type 2 diabetes. We examined the associations of IGF-I and IGF binding proteins (IGFBP)-1 and -3 with diabetes risk and evaluated macronutrient intakes related to the observed associations. In a nested case-control study of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of Finnish male smokers aged 50-69 years, the IGF variables were measured from baseline serum samples for a random sample of 310 men with diabetes diagnosed during a 12-year follow-up and for 310 controls matched by age, recruitment day and intervention group. Diet at baseline was assessed using a validated FFQ. The associations of IGF proteins with diabetes risk were estimated using conditional logistic regression and the associations with macronutrient intakes using linear regression. IGF-I and IGFBP-3 were not associated with the incidence of diabetes. Higher IGFBP-1 was associated with lower diabetes risk in an unadjusted crude model (OR 0·25; 95 % CI 0·15, 0·42 in the highest quartile compared with the lowest), but not after adjustment for BMI (corresponding OR 0·76; 95 % CI 0·41, 1·40). Intakes of carbohydrates, plant protein and milk protein associated positively and intake of meat protein and fat negatively with IGFBP-1 (P<0·005). IGFBP-1 was inversely associated with diabetes risk, but the association was substantially dependent on BMI. The associations between macronutrient intakes and IGFBP-1 may reflect influences of nutrients or foods on insulin concentrations.

Serum Metabolomic Profiling of All-Cause Mortality: A Prospective Analysis in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study Cohort.

Tobacco use, hypertension, hyperglycemia, overweight, and inactivity are leading causes of overall and cardiovascular disease (CVD) mortality worldwide, yet the relevant metabolic alterations responsible are largely unknown. We conducted a serum metabolomic analysis of 620 men in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (1985-2013). During 28 years of follow-up, there were 435 deaths (197 CVD and 107 cancer). The analysis included 406 known metabolites measured with ultra-high-performance liquid chromatography/mass spectrometry-gas chromatography/mass spectrometry. We used Cox regression to estimate mortality hazard ratios for a 1-standard-deviation difference in metabolite signals. The strongest associations with overall mortality were N-acetylvaline (hazard ratio (HR) = 1.28; P < 4.1 × 10-5, below Bonferroni statistical threshold) and dimethylglycine, 7-methylguanine, C-glycosyltryptophan, taurocholate, and N-acetyltryptophan (1.23 ≤ HR ≤ 1.32; 5 × 10-5 ≤ P ≤ 1 × 10-4). C-Glycosyltryptophan, 7-methylguanine, and 4-androsten-3ß,17ß-diol disulfate were statistically significantly associated with CVD mortality (1.49 ≤ HR ≤ 1.62, P < 4.1 × 10-5). No metabolite was associated with cancer mortality, at a false discovery rate of <0.1. Individuals with a 1-standard-deviation higher metabolite risk score had increased all-cause and CVD mortality in the test set (HR = 1.4, P = 0.05; HR = 1.8, P = 0.003, respectively). The several serum metabolites and their composite risk score independently associated with all-cause and CVD mortality may provide potential leads regarding the molecular basis of mortality.

The Effects of Long-Term, Low- and High-Dose Beta-Carotene Treatment in Zucker Diabetic Fatty Rats: The Role of HO-1.

Nowadays, there is a growing interest in compounds derived from plants as potential raw materials for drug development. One of the most studied compounds is beta-carotene (BC). Several clinical studies can be found investigating the cardiovascular effects of BC, however, all these results are controversial. There is an increasing body of evidence showing that besides the well-known antioxidant properties, under strong oxidative circumstances, BC could become prooxidant as well. In this study, we investigated the effects of long-term, low- and high-dose BC treatment in ischemic/reperfused (ISA/REP) hearts isolated from Zucker diabetic fatty (ZDF) rats. The animals were treated with various daily doses of BC for 4 weeks and then hearts were isolated and subjected to 30 min of global ischemia (ISA) followed by 120 min of reperfusion (REP). Blood glucose levels were measured before, after two weeks, and at the end of the treatment. In isolated hearts, the myocardial function was registered. At the end of the reperfusion period, the infarct size (IS) and heme oxygenase-1 (HO-1) expression were measured. The results showed that a low dose of BC treatment significantly improved postischemic recovery, which was reflected in a decreased IS. Interestingly, when BC was applied at high concentrations, the observed protective effects were lost. Although BC treatment increased HO-1 expression, we did not observe a better heart function and/or decreased IS in the high-dose-treated group. Glucose tolerance tests showed a concentration-independent decrease in blood glucose levels. Our results suggest that long-term, low-dose BC treatment could be effective in the treatment of type-2-diabetes and related cardiovascular diseases.

Antioxidant Supplementation Is Not Associated with Long-term Quality of Life in Stage-II Colorectal Cancer Survivors: A Follow-up of the Study of Colorectal Cancer Survivors Cohort.

Cancer survivors are motivated to change lifestyle following diagnosis, but studies investigating the outcomes are scarce. The purpose of this study was to examine the associations between antioxidant supplementation and quality of life (QoL) in stage-II colorectal cancer survivors. Four-hundred-fifty-three survivors were enrolled from the North Carolina Cancer Registry from 2009 to 2011. Interview data on demography, treatment, health behaviors, and QoL were collected at diagnosis, and at 12 and 24 mo post-diagnosis. Antioxidant supplementation was self-reported as use of selenium, zinc, beta-carotene, vitamin A, vitamin E, or vitamin C at baseline. Two-hundred-sixty-one subjects completed the 24-mo interview. After adjusting for multiple confounders, there was no association between antioxidant use and the Functional Assessment of Cancer Treatment-Colorectal [ß = 1.41; 95% confidence interval (CI): -2.48, 5.30] or the medical outcomes 12-item short form (physical composite score: ß = 0.84; 95% CI: -1.39, 3.07; mental composite score: ß = -0.61; 95% CI: -2.65, 1.43). This study revealed no benefit of antioxidant use among survivors, possibly explained by a limited sample size of antioxidant users. More prospective studies are necessary to assess the benefits of antioxidants.

p53 and ki67 as biomarkers in determining response to chemoprevention for oral leukoplakia.

BACKGROUND: We performed a randomized controlled chemoprevention trial of oral leukoplakia by administrating a low dose of beta-carotene and vitamin C supplements. 17% of subjects in the experimental arm (4/23) demonstrated clinical remission (complete or partial response) at completion of the trial. The objective of this study was to determine whether baseline expression of p53 and ki67 demonstrated any differences between those responding or not responding to our intervention. A secondary objective was to elucidate any relationship between dietary factors and clinical responses. METHODS: For this biomarker study, we included all subjects in the experimental group (n = 23) who were non-smokers. Among 16 who completed the trial for 1 year of supplementation, there were four responders and 12 non-responders at 1-year follow-up. Following immuno-staining for p53 and ki67, the percentage of positive cell nuclei were analyzed as labeling index (LI). RESULTS: Expression of p53 was greater in basal layers than in para-basal layers. Mean para-basal LI of p53 was higher in non-responding (26.0) than in responding subjects (11.2) (P = 0.028). ki67 LIs were not significantly different in the two groups. CONCLUSIONS: Expression of p53 was inversely related to clinical response to the supplements. Other biomarkers that may recognize subject's responsiveness to chemoprevention require further study.

Effects of Vitamin and Antioxidant Supplements in Prevention of Bladder Cancer: a Meta-Analysis of Randomized Controlled Trials.

This study aimed to investigate the effects of vitamin and antioxidant supplements in the prevention of bladder cancer using a meta-analysis of randomized controlled trials (RCTs). Fourteen RCTs were included in the final analysis. In a fixed-effect meta-analysis, vitamin and antioxidant supplements showed no preventive effect for bladder cancer (relative risk [RR] = 1.04; 95% confidence interval [CI] 0.92-1.17; I² = 39.7%). Also, there was no preventive effect of these supplements in the subgroup meta-analyses by various factors such as type of supplements, type of cancer prevention, methodological quality, providers of supplements, type of control group, and number of participants. Among the subgroup analyses by type of supplements, beta-carotene supplementation alone marginally increased the risk of bladder cancer (RR = 1.44; 95% CI 1.00-2.09; I² = 0.0%; n = 3). The current meta-analysis found that vitamin and antioxidant supplements have no preventive effect against bladder cancer.

Phytoestrogen-Rich Natural Preparation for Treatment of Climacteric Syndrome and Atherosclerosis Prevention in Perimenopausal Women.

The present study evaluated the risks and benefits of phytoestrogen treatment in healthy perimenopausal women in relation to the dynamics of climacteric syndrome and progression of atherosclerosis. Study participants were treated with placebo or phytoestrogen-rich natural preparation Karinat based on grape (Vitis vinifera) seeds, green tea (Camellia sinensis) leaves, hop (Hunulus lupulus) cone powder and garlic (Allium sativum) powder. The dynamics of climacteric syndrome was evaluated by Kupperman Index and Utian Quality of Life Scale. Atherosclerosis progression was evaluated by measuring carotid intima-media thickness. Significant changes of climacteric syndrome's severity in both Karinat and placebo groups (p = 0.005 and p = 0.001) were obtained after 24 months of follow-up. Detailed analysis of Kupperman Index suggested that Karinat possessed a significant effect on nervousness (p = 0.010), weakness (p = 0.020) and formication (p = 0.010). A significant improvement of medical (p = 0.070) and emotional (p = 0.060) components of Kupperman Index and Utian Quality of Life Scale was also observed in Karinat group. However, difference in carotid intima-media thickness between the two groups was not statistically significant at follow-up. A slight positive effect of phytoestrogens on climacteric syndrome manifestations was demonstrated in this study. Karinat can be used for alleviation of climacteric syndrome and cardiovascular disease prevention in perimenopausal women. Copyright © 2017 John Wiley & Sons, Ltd.

Chemoprevention of oral cancer in leukoplakia patients: A systematic review and meta-analysis.

The systematic review and meta-analysis of published randomised controlled trials (RCTs) was conducted to review the effectiveness of current chemopreventive agents in the treatment of oral leukoplakia lesions (OPLs) and prevention of their progression to oral cancer. Material was identified through a retrospective literature search of the electronic PubMed database, Embase and Cochrane Library between 2008 and 2016.Eight RCTs were included for systematic review. The pooled estimate showed a 14% greater chance of responding for those randomised to interventions compared with placebo (Risk Ratio [RR] 1.14, 95% confidence interval [CI] 0.72 to 1.81). The CI from individual studies overlapped. The results suggested that there were no significant differences in comparing clinical responses between chemopreventive agents with placebo in treatment of OPLs. It is time to investigate new agents for oral cancer chemoprevention.