Molecular Mechanisms Linking Genes and Vitamins of the Complex B Related to One-Carbon Metabolism in Breast Cancer: An In Silico Functional Database Study.

Carcinogenesis is closely related to the expression, maintenance, and stability of DNA. These processes are regulated by one-carbon metabolism (1CM), which involves several vitamins of the complex B (folate, B2, B6, and B12), whereas alcohol disrupts the cycle due to the inhibition of folate activity. The relationship between nutrients related to 1CM (all aforementioned vitamins and alcohol) in breast cancer has been reviewed. The interplay of genes related to 1CM was also analyzed. Single nucleotide polymorphisms located in those genes were selected by considering the minor allele frequency in the Caucasian population and the linkage disequilibrium. These genes were used to perform several in silico functional analyses (considering corrected p-values < 0.05 as statistically significant) using various tools (FUMA, ShinyGO, and REVIGO) and databases such as the Kyoto Encyclopedia of Genes and Genomes (KEGG) and GeneOntology (GO). The results of this study showed that intake of 1CM-related B-complex vitamins is key to preventing breast cancer development and survival. Also, the genes involved in 1CM are overexpressed in mammary breast tissue and participate in a wide variety of biological phenomena related to cancer. Moreover, these genes are involved in alterations that give rise to several types of neoplasms, including breast cancer. Thus, this study supports the role of one-carbon metabolism B-complex vitamins and genes in breast cancer; the interaction between both should be addressed in future studies.

Single Nucleotide Polymorphisms in the Vitamin D Metabolic Pathway as Survival Biomarkers in Colorectal Cancer.

Several studies have suggested that single nucleotide polymorphisms (SNPs) related to vitamin D metabolism may affect CRC carcinogenesis and survival. The aim of this study was to evaluate the influence of 13 SNPs involved in the vitamin D metabolic pathway on CRC survival. We conducted an observational retrospective cohort study, which included 127 Caucasian CRC patient from the south of Spain. SNPs in VDR, CYP27B1, CYP2R1, CYP24A1, and GC genes were analyzed by real-time polymerase chain reaction. Progression-free survival (PFS) and overall survival (OS) were assessed. Cox regression analysis adjusted for metastasis, age of diagnosis, stage (IIIB, IV or IVB), ECOG score (2-4), lymph node involvement, adjuvant chemotherapy, and no family history of CRC showed that the VDR ApaI (p = 0.036), CYP24A1 rs6068816 (p < 0.001), and GC rs7041 (p = 0.006) were associated with OS in patients diagnosed with CRC, and CYP24A1 rs6068816 (p < 0.001) was associated with PFS adjusted for metastasis, age of diagnosis, stage (IIIB, IV or IVB), ECOG score (2-4), lymph node involvement, adjuvant chemotherapy, and no primary tumor resection. The rest of the SNPs showed no association with CRC survival. Thus, the SNPs mentioned above may have a key role as prognostic biomarkers of CRC.

Polymorphisms in VDR, CYP27B1, CYP2R1, GC and CYP24A1 Genes as Biomarkers of Survival in Non-Small Cell Lung Cancer: A Systematic Review.

The objective of this systematic review was to provide a compilation of all the literature available on the association between single-nucleotide polymorphisms (SNPs) in the genes involved in the metabolic pathway of vitamin D and overall survival (OS) and progression-free survival (PFS) in patients with non-small cell lung cancer (NSCLC). This systematic review was conducted in accordance with the PRISMA guidelines. It included all the literature published up to 1 November 2022 and was carried out in four databases (Medline [PubMed], Scopus, Web of Science, and Embase), using the PICO strategy, with relevant keywords related to the objective. The quality of the studies included was evaluated with an assessment tool derived from the Strengthening the Reporting of Genetic Association Studies (STREGA) statement. Six studies were included in this systematic review. Our findings showed that the BsmI (rs1544410), Cdx-2 (rs11568820), FokI (rs2228570), ApaI (rs7975232), TaqI (rs731236), rs4646536, rs6068816, rs7041, and rs10741657 SNPs in the genes that play a part in vitamin D synthesis (CYP2R1, CYP27B1), transport (GC), and metabolism (CYP24A1), as well as in the vitamin D receptor (VDR), are associated with OS and/or PFS in patients with NSCLC. The SNPs in VDR have been the most extensively analyzed. This systematic review summed up the available evidence concerning the association between 13 SNPs in the main genes involved in the vitamin D metabolic pathway and prognosis in NSCLC. It revealed that SNPs in the VDR, CYP27B1, CYP24A1, GC, and CYP2R1 genes could have an impact on survival in this disease. These findings suggest the identification of prognostic biomarkers in NSCLC patients. However, evidence remains sparse for each of the polymorphisms examined, so these findings should be treated with caution.

Hypoxia-Inducible Factor-1 Alpha Expression Is Predictive of Pathological Complete Response in Patients with Breast Cancer Receiving Neoadjuvant Chemotherapy.

To demonstrate the value of hypoxia-inducible factor-1α (HIF-1α) in predicting response in patients with breast cancer receiving standard neoadjuvant chemotherapy (NAC). METHODS: Ninety-five women enrolled in two prospective studies underwent biopsies for the histopathological diagnosis of breast carcinoma before receiving NAC, based on anthracyclines and taxanes. For expression of HIF-1α, EGFR, pAKT and pMAPK, tumor samples were analyzed by immunohistochemistry in tissues microarrays. Standard statistical methods (Pearson chi-square test, Fisher exact test, Kruskal-Wallis test, Mann-Whitney test and Kaplan-Meier method) were used to study the association of HIF-1α with tumor response, survival and other clinicopathologic variables/biomarkers. RESULTS: HIF-1α expression was positive in 35 (39.7%) cases and was significantly associated to complete pathological response (pCR) (p = 0.014). HIF-1α expression was correlated positively with tumor grade (p = 0.015) and Ki-67 expression (p = 0.001) and negativity with progesterone receptors (PR) (p = 0.04) and luminal A phenotype expression (p = 0.005). No correlation was found between HIF-1α expression and EGFR, pAKT and pMAPK. In terms of survival, HIF-1α expression was associated with a significantly shorter disease-free survival (p = 0.013), being identified as an independent prognostic factor in multivariate analysis. CONCLUSIONS: Overexpression of HIF-1α is a predictor of pCR and shorter DFS; it would be valuable to confirm these results in prospective studies.

Longevity and Cause of Death in Male Wistar Rats Fed Lifelong Diets Based on Virgin Olive Oil, Sunflower Oil, or Fish Oil.

Extending life by delaying the aging process has been proven to be the most effective way to fight multiple chronic diseases in elderly adults. Evidence suggests that longevity is inversely related to unsaturation of membrane phospholipids. This study investigated how different unsaturated dietary fats affect life span and cause of death in male Wistar rats fed diets based on virgin olive oil (V), sunflower oil (S), or fish oil (F), which were supplemented or not with Coenzyme Q10 (CoQ10). Previous results suggest that individual longevity and survival probability at different ages may be modulated by an appropriate dietary fat treatment. Lifelong feeding with V or F diets would reduce death probability compared to feeding with S diet at certain ages, although the effects of V diet would be maintained for most of life. Furthermore, the addition of lower amounts of CoQ10 reduced mortality associated with S diet, but CoQ10 had no effect on survival when combined with virgin olive oil or fish oil. Supplementation with low doses of CoQ10 failed to increase the maximum life span potential of rats fed a V or F diet. No clear evidence showing that monounsaturated fatty acids, n-3 polyunsaturated fatty acids, or CoQ10 exerted the observed effects by modulating the rate of aging has been found.

Heart Histopathology and Mitochondrial Ultrastructure in Aged Rats Fed for 24 Months on Different Unsaturated Fats (Virgin Olive Oil, Sunflower Oil or Fish Oil) and Affected by Different Longevity.

Diet plays a decisive role in heart physiology, with lipids having especial importance in pathology prevention and development. This study aimed to investigate how dietary lipids varying in lipid profile (virgin olive oil, sunflower oil or fish oil) affected the heart of rats during aging. Heart histopathology, mitochondrial morphometry, and oxidative status were assessed. Typical histopathological features associated with aging, such as valvular lesions, endomyocardical hyperplasia, or papillary muscle calcification, were found at a low extent in all the experimental groups. The most relevant finding was that inflammation registered by fish oil group was lower compared to the other treatments. At the ultrastructural level, heart mitochondrial area, perimeter, and aspect ratio were higher in fish oil-fed rats than in those fed on sunflower oil. Concerning oxidative stress markers, there were differences only in coenzyme Q levels and catalase activity, lower in sunflower oil-fed animals compared with those fed on fish oil. In summary, dietary intake for a long period on dietary fats with different fatty acids profile led to differences in some aspects associated with the aging process at the heart. Fish oil seems to be the fat most protective of heart during aging.

Hydroxytyrosol Supplementation Modifies Plasma Levels of Tissue Inhibitor of Metallopeptidase 1 in Women with Breast Cancer.

The etiology of breast cancer can be very different. Most antineoplastic drugs are not selective against tumor cells and also affect normal cells, leading to a wide variety of adverse reactions such as the production of free radicals by altering the redox state of the organisms. Therefore, the objective of this study was to elucidate if hydroxytyrosol (HT) (an antioxidant present in extra virgin olive oil) has a chemomodulatory effect when combined with the chemotherapeutic drugs epirubicin and cyclophosphamide followed by taxanes in breast cancer patients. Changes in plasma levels of matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinases 1 (TIMP-1) throughout the chemotherapy treatment were studied. Both molecules are involved in cell proliferation, apoptosis, neoangiogenesis, and metastasis in breast cancer patients. Women with breast cancer were divided into two groups: a group of patients receiving a dietary supplement of HT and a control group of patients receiving placebo. The results showed that the plasma levels of TIMP-1 in the group of patients receiving HT were significantly lower than those levels found in the control group after the epirubicin-cyclophosphamide chemotherapy.

Modulation by hydroxytyrosol of oxidative stress and antitumor activities of paclitaxel in breast cancer.

PURPOSE: The main objective of this study was to test the therapeutic potential of hydroxytyrosol and its combination with paclitaxel in breast cancer on oxidative stress status. METHODS: Impact on proliferation rates of different chemotherapy administration patterns was assayed in MCF-7 and MDA-MB-231 breast cancer cell lines. Breast tumor-bearing rats were randomly assigned to Control, Hydroxytyrosol, Paclitaxel and Paclitaxel plus hydroxytyrosol groups, for 6 weeks. Tumor volume, cell proliferation and several systemic oxidative stress parameters were measured. Anti-proliferative activity in vitro experiments was correlated with in vivo experiments. RESULTS: Combination group did significantly reduce tumor volume when compared with paclitaxel alone. Additionally, the combination improved the antioxidant status without compromising the antitumor activity of standard chemotherapy. CONCLUSION: These findings reveal for the first time that hydroxytyrosol is an active partner in combined therapies with paclitaxel against breast cancer. Combination with hydroxytyrosol would also ensure a less oxidative impact of chemotherapeutic drugs that could potentially improve patient wellness.

Hydroxytyrosol: Bioavailability, toxicity, and clinical applications.

Many beneficial properties have been attributed to the Mediterranean diet. Over the years, researchers have attempted to learn which foods and which food components are responsible for good health. One of these components is hydroxytyrosol, an important phenolic compound present in olive oil. Hydroxytyrosol is a molecule of high interest to the pharmaceutical industry due to its anti-inflammatory and antimicrobial qualities its role against cardiovascular diseases and metabolic syndrome and for its neuroprotection, antitumour, and chemo modulation effects. The interest in this molecule has led to wide research on its biological activities, its beneficial effects in humans and how to synthetize new molecules from hydroxytyrosol. This review describes the vast range of information about hydroxytyrosol, focusing on its involvement in biological mechanisms and modulation effects on different pathologies. This review also serves to highlight the role of hydroxytyrosol as a nutraceutical and as a potential therapeutic agent.

Age-Related Loss in Bone Mineral Density of Rats Fed Lifelong on a Fish Oil-Based Diet Is Avoided by Coenzyme Q10 Addition.

During aging, bone mass declines increasing osteoporosis and fracture risks. Oxidative stress has been related to this bone loss, making dietary compounds with antioxidant properties a promising weapon. Male Wistar rats were maintained for 6 or 24 months on diets with fish oil as unique fat source, supplemented or not with coenzyme Q10 (CoQ10), to evaluate the potential of adding this molecule to the n-3 polyunsaturated fatty acid (n-3 PUFA)-based diet for bone mineral density (BMD) preservation. BMD was evaluated in the femur. Serum osteocalcin, osteopontin, receptor activator of nuclear factor-κB ligand, ostroprotegerin, parathyroid hormone, urinary F2-isoprostanes, and lymphocytes DNA strand breaks were also measured. BMD was lower in aged rats fed a diet without CoQ10 respect than their younger counterparts, whereas older animals receiving CoQ10 showed the highest BMD. F2-isoprostanes and DNA strand breaks showed that oxidative stress was higher during aging. Supplementation with CoQ10 prevented oxidative damage to lipid and DNA, in young and old animals, respectively. Reduced oxidative stress associated to CoQ10 supplementation of this n-3 PUFA-rich diet might explain the higher BMD found in aged rats in this group of animals.

The relationship between insulin resistance and periodontitis is not affected by Mediterranean diet in a Spanish population.

OBJETIVE: To examine the insulin resistance measured by surrogate indices in subjects with and without periodontitis and to find out any correlation among dietary intake with insulin resistance. DESIGN: Fifty-five patients were recruited to participate in this cross-sectional study. Insulin resistance measured by the homoeostasis model assessment (HOMA-IR) and the quantitative insulin sensitivity check index moreover glycaemia, creatinine, uric acid, high density lipoproteins, low density lipoproteins, very low density lipoproteins and triglycerides among others. True periodontal disease was elucidated through the examination of probing pocket depth, clinical attachment level, recession of the gingival margin and gingival bleeding. The statistical analyses used were the student's T-test for independent variables, Kolmogorov-Smirnov if variations were homogeneous; if not, the Mann-Whitney U Test was applied instead. Correlations between variables were assessed using Pearson's correlation coefficients. True periodontal disease was confirmed through the greater values of probing pocket depth, clinical attachment level, gingival margin and gingival bleeding in the periodontitis group in comparison with non-periodontitis group. RESULTS: Insulin resistance was evidenced by the greater values of HOMA-IR as well as by the lower quantitative insulin sensitivity check index values in the periodontitis group. Fasting insulin, glucose, uric acid, creatinine, low density lipoproteins, triglycerides and very low density lipoprotein levels were significant higher in periodontitis group. Pearson's correlations did not show any association among diet data and insulin resistance parameters in periodontitis patients. CONCLUSION: A putative systemic relationship between insulin resistance and periodontitis exists but it does not seem conceivable any effect of diet over such relationship.

Curcumin and Health.

Nowadays, there are some molecules that have shown over the years a high capacity to act against relevant pathologies such as cardiovascular disease, neurodegenerative disorders or cancer. This article provides a brief review about the origin, bioavailability and new research on curcumin and synthetized derivatives. It examines the beneficial effects on health, delving into aspects such as cancer, cardiovascular effects, metabolic syndrome, antioxidant capacity, anti-inflammatory properties, and neurological, liver and respiratory disorders. Thanks to all these activities, curcumin is positioned as an interesting nutraceutical. This is the reason why it has been subjected to several modifications in its structure and administration form that have permitted an increase in bioavailability and effectiveness against different diseases, decreasing the mortality and morbidity associated to these pathologies.

Hydroxytyrosol ameliorates oxidative stress and mitochondrial dysfunction in doxorubicin-induced cardiotoxicity in rats with breast cancer.

Oxidative stress is involved in several processes including cancer, aging and cardiovascular disease, and has been shown to potentiate the therapeutic effect of drugs such as doxorubicin. Doxorubicin causes significant cardiotoxicity characterized by marked increases in oxidative stress and mitochondrial dysfunction. Herein, we investigate whether doxorubicin-associated chronic cardiac toxicity can be ameliorated with the antioxidant hydroxytyrosol in rats with breast cancer. Thirty-six rats bearing breast tumors induced chemically were divided into 4 groups: control, hydroxytyrosol (0.5mg/kg, 5days/week), doxorubicin (1mg/kg/week), and doxorubicin plus hydroxytyrosol. Cardiac disturbances at the cellular and mitochondrial level, mitochondrial electron transport chain complexes I-IV and apoptosis-inducing factor, and oxidative stress markers have been analyzed. Hydroxytyrosol improved the cardiac disturbances enhanced by doxorubicin by significantly reducing the percentage of altered mitochondria and oxidative damage. These results suggest that hydroxytyrosol improve the mitochondrial electron transport chain. This study demonstrates that hydroxytyrosol protect rat heart damage provoked by doxorubicin decreasing oxidative damage and mitochondrial alterations.

Curcumin and liver disease.

Liver diseases pose a major medical problem worldwide and a wide variety of herbs have been studied for the management of liver-related diseases. In this respect, curcumin has long been used in traditional medicine, and in recent years it has been the object of increasing research interest. In combating liver diseases, it seems clear that curcumin exerts a hypolipidic effect, which prevents the fatty acid accumulation in the hepatocytes that may result from metabolic imbalances, and which may cause nonalcoholic steatohepatitis. Another crucial protective activity of curcumin, not only in the context of chronic liver diseases but also regarding carcinogenesis and other age-related processes, is its potent antioxidant activity, which affects multiple processes and signaling pathways. The effects of curcumin on NF-κß are crucial to our understanding of the potent hepatoprotective role of this herb-derived micronutrient. Because curcumin is a micronutrient that is closely related to cellular redox balance, its properties and activity give rise to a series of molecular reactions that in every case and biological situation affect the mitochondria.

Transcriptional shift identifies a set of genes driving breast cancer chemoresistance.

BACKGROUND: Distant recurrences after antineoplastic treatment remain a serious problem for breast cancer clinical management, which threats patients' life. Systemic therapy is administered to eradicate cancer cells from the organism, both at the site of the primary tumor and at any other potential location. Despite this intervention, a significant proportion of breast cancer patients relapse even many years after their primary tumor has been successfully treated according to current clinical standards, evidencing the existence of a chemoresistant cell subpopulation originating from the primary tumor. METHODS/FINDINGS: To identify key molecules and signaling pathways which drive breast cancer chemoresistance we performed gene expression analysis before and after anthracycline and taxane-based chemotherapy and compared the results between different histopathological response groups (good-, mid- and bad-response), established according to the Miller & Payne grading system. Two cohorts of 33 and 73 breast cancer patients receiving neoadjuvant chemotherapy were recruited for whole-genome expression analysis and validation assay, respectively. Identified genes were subjected to a bioinformatic analysis in order to ascertain the molecular function of the proteins they encode and the signaling in which they participate. High throughput technologies identified 65 gene sequences which were over-expressed in all groups (P ≤ 0·05 Bonferroni test). Notably we found that, after chemotherapy, a significant proportion of these genes were over-expressed in the good responders group, making their tumors indistinguishable from those of the bad responders in their expression profile (P ≤ 0.05 Benjamini-Hochgerg`s method). CONCLUSIONS: These data identify a set of key molecular pathways selectively up-regulated in post-chemotherapy cancer cells, which may become appropriate targets for the development of future directed therapies against breast cancer.

Long-term effects of systemic cancer treatment on DNA oxidative damage: the potential for targeted therapies.

The main pathological consequence of free radical exposure is DNA damage, which is known to induce cell transformation and to facilitate important mutations in cancer progression. It is a matter of intense discussion whether the drug-induced production of free radicals limits the therapeutic efficacy of chemotherapeutics and enhances their toxicity or whether they may be enhanced to provoke cancer cell apoptosis. This paper reviews essential molecular processes to better understand the controversial role of free radicals in cancer development and progression, and discusses some novel therapeutic strategies based on oxidative stress induction and prevention.

Gingival vascular damage in atherosclerotic rabbits: hydroxytyrosol and squalene benefits.

Cardiovascular alterations and periodontal disease have been associated, although cardiovascular disease treatments have not yet been tested against periodontal alterations. We investigated effects of squalene, hydroxytyrosol and coenzyme Q(10) on gingival tissues of rabbits fed on an atherosclerotic diet. Forty-eight rabbits were distributed in six groups. Control group was fed on standard chow for 80 days. The rest were fed with an atherogenic diet for 50 days. After that, a group was sacrificed and the rest were subjected for another extra 30 days on commercial chow alone or supplemented with coenzyme Q(10), squalene or hydroxytyrosol. Atherosclerotic rabbits had higher fibrosis and endothelial activation and lower cellularity in gingival mucosa than controls (P<0.05). Hydroxytyrosol reduced endothelial activation (P<0.05) and squalene additionally decreased fibrosis (P<0.05). Results suggest that gingival vascular changes after the atherosclerotic diet have been reversed by hydroxytyrosol and squalene, natural products from the minor fraction of virgin olive oil.