Trace elements under the spotlight: A powerful nutritional tool in cancer.

Cancer is the second leading cause of death worldwide. Research on the relationships between trace elements (TE) and the development of cancer or its prevention is a field that is gaining increasing relevance. This review provides an evaluation of the effects of TE (As, Al, B, Cd, Cr, Cu, F, I, Pb, Li, Mn, Hg, Mo, Ni, Se, Si, Sn, V and Zn) intake and supplementation in cancer risk and prevention, as well as their interactions with oncology treatments. Advancements in the knowledge of TE, their dietary interactions and their main food sources can provide patients with choices that will help them to improve their quality of life and therapy outcomes. This approach could open new opportunities for treatments based on the integration of conventional therapies (chemotherapy, radiotherapy, and immunotherapy) and dietary interventions that provide advanced personalized treatments.

Antioxidant Supplements versus Health Benefits of Brief/Intermittent Exposure to Potentially Toxic Physical or Chemical Agents.

Although antioxidants can act locally to react with an oxidant, oral administration of "antioxidants" is quite useless in treating oxidative stress in tissues. Furthermore, it does not make sense to consider a vitamin as an antioxidant, but vitamin B3 leads to the in vivo formation of compounds that are essential for reducing this stress. A rigorous treatment of the subject indicates that to deal with oxidative stress, the most direct approach is to enhance the innate antioxidant mechanisms. The question is whether this is possible through daily activities. Diets can contain the necessary components for these mechanisms or may induce the expression of the genes involved in them. Another possibility is that pro-oxidant molecules in food increase the sensitivity and power of the detoxification pathways. This option is based on well-known DNA repair mechanisms after exposure to radiation (even from the Sun), or strong evidence of induction of antioxidant capacity after exposure to powerful pro-oxidants such as H2O2. More experimental work is required to test whether some molecules in food can increase the expression of antioxidant enzymes and/or improve antioxidant mechanisms. Identifying effective molecules to achieve such antioxidant power is critical to the food and nutraceutical industries. The potential of diet-based interventions to combat oxidative stress must be viewed from a new perspective.

Molecular predictors of prevention of recurrence in HCC with sorafenib as adjuvant treatment and prognostic factors in the phase 3 STORM trial.

OBJECTIVE: Sorafenib is the standard systemic therapy for advanced hepatocellular carcinoma (HCC). Survival benefits of resection/local ablation for early HCC are compromised by 70% 5-year recurrence rates. The phase 3 STORM trial comparing sorafenib with placebo as adjuvant treatment did not achieve its primary endpoint of improving recurrence-free survival (RFS). The biomarker companion study BIOSTORM aims to define (A) predictors of recurrence prevention with sorafenib and (B) prognostic factors with B level of evidence. DESIGN: Tumour tissue from 188 patients randomised to receive sorafenib (83) or placebo (105) in the STORM trial was collected. Analyses included gene expression profiling, targeted exome sequencing (19 known oncodrivers), immunohistochemistry (pERK, pVEGFR2, Ki67), fluorescence in situ hybridisation (VEGFA) and immunome. A gene signature capturing improved RFS in sorafenib-treated patients was generated. All 70 RFS events were recurrences, thus time to recurrence equalled RFS. Predictive and prognostic value was assessed using Cox regression models and interaction test. RESULTS: BIOSTORM recapitulates clinicopathological characteristics of STORM. None of the biomarkers tested (related to angiogenesis and proliferation) or previously proposed gene signatures, or mutations predicted sorafenib benefit or recurrence. A newly generated 146-gene signature identifying 30% of patients captured benefit to sorafenib in terms of RFS (p of interaction=0.04). These sorafenib RFS responders were significantly enriched in CD4+ T, B and cytolytic natural killer cells, and lacked activated adaptive immune components. Hepatocytic pERK (HR=2.41; p=0.012) and microvascular invasion (HR=2.09; p=0.017) were independent prognostic factors. CONCLUSION: In BIOSTORM, only hepatocytic pERK and microvascular invasion predicted poor RFS. No mutation, gene amplification or previously proposed gene signatures predicted sorafenib benefit. A newly generated multigene signature associated with improved RFS on sorafenib warrants further validation. TRIAL REGISTRATION NUMBER: NCT00692770.

Trace Elements and Paraoxonase-1 Activity in Lower Extremity Artery Disease.

Oxidative stress and inflammation are candidate mechanisms to explain the potential role of exposure to metals and reduced activity of paraoxonase-1 (PON1) in age-related diseases. Both may be risk factors contributing to atherosclerosis. In the present study, inductively coupled mass spectrometry was used to explore multiple trace elements, while in-house methods were employed to measure PON1-related variables in patients with lower extremity artery disease (LEAD). Healthy controls were matched for sex, age, body weight, and relevant genotype variants. Serum concentrations of As, Ba, Cu, and Sr were higher in patients than those in controls, with a strong predictive ability to discriminate between groups. Differences in serum Pb, Cd, and Zn were negligible. Serum Cu increased when the disease was more severe, but a negative trend was noted for serum As, B, Ba, and Zn. The only variable associated with ankle-brachial index was serum Zn. Serum PON1 activity was significantly lower in LEAD patients. When the ability of serum trace elements to modulate PON1 activity was explored, the analysis revealed a unique association with serum Zn. The current results strongly suggest that Zn may have a protective effect in non-coronary atherosclerosis and indicate that this element may exert its anti-inflammatory and antioxidant functions through interactions with PON1 activity. These findings deserve confirmation and further research. In particular, the periodic evaluation of serum trace elements and the prescription of Zn supplements are easy measures to implement and that can improve the treatment of patients with LEAD.

Nuclear IGF-1R predicts chemotherapy and targeted therapy resistance in metastatic colorectal cancer.

BACKGROUND: Although chemotherapy is the cornerstone treatment for patients with metastatic colorectal cancer (mCRC), acquired chemoresistance is common and constitutes the main reason for treatment failure. Monoclonal antibodies against insulin-like growth factor-1 receptor (IGF-1R) have been tested in pre-treated mCRC patients, but results have been largely deceiving. METHODS: We analysed time to progression, overall survival, and the mutational status of RAS, BRAF and nuclear p-IGF-1R expression by immunohistochemistry, in 470 metastatic CRC patients. The effect of IGF-1R activation and distribution was also assessed using cellular models of CRC and RNAi for functional validation. RESULTS: Nuclear IGF-1R increased in metastatic tumours compared to paired untreated primary tumours, and significantly correlated with poor overall survival in mCRC patients. In vitro, chemo-resistant cell lines presented significantly higher levels of IGF-1R expression within the nuclear compartment, and PIAS3, a protein implicated also in the sumoylation process of intranuclear proteins, contributed to IGF-1R nuclear sequestration, highlighting the essential role of PIAS3 in this process. Intriguingly, we observed that ganitumab, an IGF-1R blocking-antibody used in several clinical trials, and dasatinib, an SRC inhibitor, increased the nuclear localisation of IGF-1R. CONCLUSIONS: Our study demonstrates that IGF-1R nuclear location might lead to chemotherapy and targeted agent resistance.

The acute impact of polyphenols from Hibiscus sabdariffa in metabolic homeostasis: an approach combining metabolomics and gene-expression analyses.

We explored the acute multifunctional effects of polyphenols from Hibiscus sabdariffa in humans to assess possible consequences on the host's health. The expected dynamic response was studied using a combination of transcriptomics and metabolomics to integrate specific functional pathways through network-based methods and to generate hypotheses established by acute metabolic effects and/or modifications in the expression of relevant genes. Data were obtained from healthy male volunteers after 3 hours of ingestion of an aqueous Hibiscus sabdariffa extract. The data were compared with data obtained prior to the ingestion, and the overall findings suggest that these particular polyphenols had a simultaneous role in mitochondrial function, energy homeostasis and protection of the cardiovascular system. These findings suggest beneficial actions in inflammation, endothelial dysfunction, and oxidation, which are interrelated mechanisms. Among other effects, the activation of the heme oxygenase-biliverdin reductase axis, the systemic inhibition of the renin-angiotensin system, the inhibition of the angiotensin-converting enzyme, and several actions mirroring those of the peroxisome proliferator-activated receptor agonists further support this notion. We also found concordant findings in the serum of the participants, which include a decrease in cortisol levels and a significant increase in the active vasodilator metabolite of bradykinin (des-Arg(9)-bradykinin). Therefore, our data support the view that polyphenols from Hibiscus sabdariffa play a regulatory role in metabolic health and in the maintenance of blood pressure, thus implying a multi-faceted impact in metabolic and cardiovascular diseases.

Managing hypertension by polyphenols.

Some polyphenols, obtained from plants of broad use, induce a favorable endothelial response in hypertension and beneficial effects in the management of other metabolic cardiovascular risks. Previous studies in our laboratories using the calyces of Hibiscus sabdariffa as a source of polyphenols show that significant effects on hypertension are noticeable in humans only when provided in high amounts. Available data are suggestive in animal models and ex vivo experiments, but data in humans are difficult to acquire. Additionally, and despite the low bioavailability of polyphenols, intervention studies provide evidence for the protective effects of secondary plant metabolites. Assumptions on public health benefits are limited by the lack of scientific knowledge, robust data derived from large randomized clinical trials, and an accurate assessment of the bioactive components provided by common foodstuff. Because it is likely that clinical effects are the result of multiple interactions among different polyphenols rather than the isolated action of unique compounds, to provide polyphenol-rich botanical extracts as dietary supplements is a suggestive option. Unfortunately, the lack of patent perspectives for the pharmaceutical industries and the high cost of production and release for alimentary industries will hamper the performance of the necessary clinical trials. Here we briefly discuss whether and how such limitations may complicate the extensive use of plant-derived products in the management of hypertension and which steps are the necessary to deal with the predictable complexity in a possible clinical practice.

Stevia-derived compounds attenuate the toxic effects of ectopic lipid accumulation in the liver of obese mice: a transcriptomic and metabolomic study.

There is a close interaction between Type 2 Diabetes, obesity and liver disease. We have studied the effects of the two most abundant Stevia-derived steviol glycosides, stevioside and rebaudioside A, and their aglycol derivative steviol on liver steatosis and the hepatic effects of lipotoxicity using a mouse model of obesity and insulin resistance. We treated ob/ob and LDLR-double deficient mice with stevioside (10 mg⋅kg(-1)⋅day-1 p.o., n = 8), rebaudioside A (12 mg⋅kg(-1)⋅day-1 p.o., n = 8), or steviol (5 mg⋅kg(-1)⋅day(-1) p.o., n = 8). We determined their effects on liver steatosis and on the metabolic effects of lipotoxicity by histological analysis, and by combined gene-expression and metabolomic analyses. All compounds attenuated hepatic steatosis. This could be explained by improved glucose metabolism, fat catabolism, bile acid metabolism, and lipid storage and transport. We identified PPARs as important regulators and observed differences in effects on insulin resistance, inflammation and oxidative stress between Stevia-derived compounds. We conclude that Stevia-derived compounds reduce hepatic steatosis to a similar extent, despite differences in effects on glucose and lipid metabolism, and inflammation and oxidative stress. Thus our data show that liver toxicity can be reduced through several pathophysiological changes. Further identification of active metabolites and underlying mechanisms are warranted.

Hibiscus sabdariffa extract lowers blood pressure and improves endothelial function.

Polyphenols from Hibiscus sabdariffa calices were administered to patients with metabolic syndrome (125 mg/kg/day for 4 wk, n = 31) and spontaneously hypertensive rats (125 or 60 mg/kg in a single dose or daily for 1 wk, n = 8 for each experimental group). The H. sabdariffa extract improved metabolism, displayed potent anti-inflammatory and antioxidant activities, and significantly reduced blood pressure in both humans and rats. Diuresis and inhibition of the angiotensin I-converting enzyme were found to be less important mechanisms than those related to the antioxidant, anti-inflammatory, and endothelium-dependent effects to explain the beneficial actions. Notably, polyphenols induced a favorable endothelial response that should be considered in the management of metabolic cardiovascular risks.

Xenohormetic and anti-aging activity of secoiridoid polyphenols present in extra virgin olive oil: a new family of gerosuppressant agents.

Aging can be viewed as a quasi-programmed phenomenon driven by the overactivation of the nutrient-sensing mTOR gerogene. mTOR-driven aging can be triggered or accelerated by a decline or loss of responsiveness to activation of the energy-sensing protein AMPK, a critical gerosuppressor of mTOR. The occurrence of age-related diseases, therefore, reflects the synergistic interaction between our evolutionary path to sedentarism, which chronically increases a number of mTOR activating gero-promoters (e.g., food, growth factors, cytokines and insulin) and the "defective design" of central metabolic integrators such as mTOR and AMPK. Our laboratories at the Bioactive Food Component Platform in Spain have initiated a systematic approach to molecularly elucidate and clinically explore whether the "xenohormesis hypothesis," which states that stress-induced synthesis of plant polyphenols and many other phytochemicals provides an environmental chemical signature that upregulates stress-resistance pathways in plant consumers, can be explained in terms of the reactivity of the AMPK/mTOR-axis to so-called xenohormetins. Here, we explore the AMPK/mTOR-xenohormetic nature of complex polyphenols naturally present in extra virgin olive oil (EVOO), a pivotal component of the Mediterranean style diet that has been repeatedly associated with a reduction in age-related morbid conditions and longer life expectancy. Using crude EVOO phenolic extracts highly enriched in the secoiridoids oleuropein aglycon and decarboxymethyl oleuropein aglycon, we show for the first time that (1) the anticancer activity of EVOO secoiridoids is related to the activation of anti-aging/cellular stress-like gene signatures, including endoplasmic reticulum (ER) stress and the unfolded protein response, spermidine and polyamine metabolism, sirtuin-1 (SIRT1) and NRF2 signaling; (2) EVOO secoiridoids activate AMPK and suppress crucial genes involved in the Warburg effect and the self-renewal capacity of "immortal" cancer stem cells; (3) EVOO secoiridoids prevent age-related changes in the cell size, morphological heterogeneity, arrayed cell arrangement and senescence-associated ß-galactosidase staining of normal diploid human fibroblasts at the end of their proliferative lifespans. EVOO secoiridoids, which provide an effective defense against plant attack by herbivores and pathogens, are bona fide xenohormetins that are able to activate the gerosuppressor AMPK and trigger numerous resveratrol-like anti-aging transcriptomic signatures. As such, EVOO secoiridoids constitute a new family of plant-produced gerosuppressant agents that molecularly "repair" the aimless (and harmful) AMPK/mTOR-driven quasi-program that leads to aging and aging-related diseases, including cancer.

Moderately high folic acid supplementation exacerbates experimentally induced liver fibrosis in rats.

Under certain clinical circumstances, folic acid can have undesirable effects. We investigated the following: (i) the effects of moderately high folic acid supplementation on the course of liver impairment in CCl(4)-treated rats and (ii) the influence of folic acid supplements on the hepatic recovery following the interruption of the CCl(4)-induced toxic injury. Four experimental groups of rats were used: CCl(4)-treated rats (0.5 ml of CCl(4) twice a week i.p.) fed standard chow for up to 12 weeks (Group A); treated rats fed chow supplemented with 25 mg/kg folic acid from weeks 6 to 12 (Group B); treated rats fed a standard diet but with CCl(4) discontinued after 6 weeks to allow for tissue recovery over 4 weeks (Group C); rats as Group C but fed a diet supplemented with 25 mg/kg folic acid from weeks 6 to 10 (Group D). Liver and blood samples were obtained for biochemical, histological, and gene expression analyses. Animals that received the supplement had a higher content of collagen, activated stellate cells, and apoptotic parenchymal cells in biopsy tissue at weeks 8 and 10 of treatment and more extensive alterations in serum albumin and bilirubin concentrations (Group B vs. Group A). In some of the time periods analyzed, alterations were observed in the expression of genes related to apoptosis (B-cell leukemia/lymphoma 2, inhibitor of apoptosis 2) and to fibrosis (procollagen I, matrix metalloproteinase 7). In the recovery period (Groups C and D), folic acid administration was associated with increased hepatic inflammation and apoptosis and with a decrease in the tissue inhibitor of metalloproteinase-3 expression following 1 week of recovery. We conclude that folic acid administration aggravates the development of fibrosis in CCl(4)-treated rats. Follow-up studies are needed to determine whether folic acid treatment would be contraindicated in patients with chronic liver diseases.

Longitudinal changes in serum paraoxonase-1 activity throughout normal pregnancy.

The aim of this study was to investigate the longitudinal changes in serum paraoxonase-1 (PON1) activity from preconception throughout normal pregnancy and their relationships with maternal dietary vitamin C and E intake. The study was performed in 35 women (studied at preconception, at 8, 20 and 32 weeks of pregnancy, and at labour). PON1 activity decreased significantly from 145.8 (109.8-198.8) U/L at preconception to 111.1 (85.3-179.9) U/L (p<0.01) at 32 weeks and 100.4 (54.7-171.4) U/L (p<0.001) at labour. There was a direct association between vitamin C intake and PON1 at week 32 (p=0.018). We conclude that adequate vitamin C intake in pregnant women may merit consideration, since vitamin C supplementation has proved beneficial in the prevention of preeclampsia in women at increased risk of this condition.