Moderate glomerular mass reduction is emerging as a critical factor that exacerbates susceptibility to blood pressure (BP) elevation. In this way, it accounts for 40%-50% of all hypertension cases. Coenzyme Q10 (CoQ10) has antioxidative properties and anti-inflammatory response that could prevent blood pressure elevation and preserve renal functional reserve supporting the pressure natriuresis mechanism. Wistar rats underwent uninephrectomy (UNX) and were divided into four groups: G1 normal-sodium diet (NNaD); G2 high-sodium diet (HNaD4%); G3 HNaD4% with CoQ10 supplementation (200 mg/kg/day) (HNaD4%+CoQ10); and G4 NNaD with CoQ10 supplementation (CoQ10). Physiological, histological, and biochemical parameters were measured. After 45 days on a high-salt diet, G2 elevated BP while G3 did not (G2: 128±2.8 vs. G3: 119.2±3.7 mmHg, P < .05). CoQ10 effect in G3 was associated with decreased proteinuria. Creatinine clearance increased in all groups, but G3 did not. CoQ10 prevented pressure natriuresis deterioration, resulting in lower BP increases in G3 and G4. CoQ10 prevented the increase in reactive oxygen species (ROS) and systemic lipid peroxides induced by HNaD4%. In the renal cortex, it prevented mitochondrial glutathione (GSH) depletion and normalized superoxide dismutase (SOD) activity. CoQ10 improved renal morphology and ultrastructure in HNaD4%. These findings suggest a potential therapeutic role for CoQ10 in preventing the development of hypertension by protecting the pressure natriuresis mechanism and renal complications.

Pancreatic cancer is a devastating malignancy in great need of new and more effective treatment approaches. In recent years, studies have indicated that nutritional interventions, particularly nutraceuticals, may provide novel avenues to modulate cancer progression. Here, our study characterizes the impact of ω-3 polyunsaturated fatty acids, eicosapentaenoic acid, and docosahexaenoic acid, as a nutraceutical intervention in pancreatic cancer using a genetically engineered mouse model driven by KrasG12D and Trp53R172H. This model closely resembles human pancreatic carcinogenesis, offering a disease relevant platform for translational research. Our findings showed that ω-3 polyunsaturated fatty acids intervention (using a diet supplemented with 6% cod liver oil) significantly reduced tumor volume as well as lung and liver metastasis and a trend toward improved survival rate compared with control treated mice. This antitumoral effect was accompanied by distinct changes in tumor membrane fatty acid profile and eicosanoids release. Furthermore, the eicosapentaenoic acid and docosahexaenoic acid intervention also reduced malignant histological parameters and induced apoptosis without affecting cell proliferation. Of note is the significant reduction in tumor fibrosis that was associated with decreased levels of Sonic Hedgehog, a major ligand controlling this cellular compartment in pancreatic cancer. All together our results demonstrate the impact of eicosapentaenoic acid and docosahexaenoic acid as antitumor regulators in pancreatic cancer, suggesting potential for ω-3 polyunsaturated fatty acids as a possible antitumoral dietary intervention. This research opens new avenues for integrating nutraceutical strategies in pancreatic cancer management.

OBJECTIVE:This work aimed to evaluate the modulating effect of polyunsaturated fatty acids omega-3 and omega-6 on the expression of TP53 and specific primiRNAs 34 b/c in the development of premalignant characteristics in tongue epithelial dysplasias in-vivo experimental models DESIGN: BALB/c mice were divided into two diet groups: fish oil rich in omega-3 and corn oil rich in omega-6. Tongue dysplasia was generated by applying a 0.5 % solution of 7,12-dimethylbenzantracene (DMBA) in acetone. After sacrificing, the animals were assessed for omega-6 and omega-3, TP53/Ki67 immunostaining, Trp53R270H mutations, and primiRNA 34 b/c expression. RESULTS:Mice fed omega-6 showed higher dysplasias and Ki67 immunostaining percentages than those fed omega-3-rich oils. Furthermore, mice fed with corn oil rich in omega-6 showed significantly high average arachidonic-acid values, while the group fed cod oil rich in omega-3 showed substantially higher average values of Ecosapentanoic acid and Docosahexanoic acid in tongue tissue cell membranes. The primiRNA-34 b/c was upregulated in animals fed corn oil, enriched-omega-6 at 90 days. CONCLUSIONS:Our findings suggest that dietary lipids influence the development of DMBA-induced premalignant features on the tongue of mice; therefore, a low intake of omega-6-rich oils and a higher intake of omega-3 could be recommended for preventing features similar to mucosal dysplasia, which could be an important preventive strategy.

Today, consumption of diets rich in saturated fat and fructose, associated with a variety of metabolic deregulations, has increased. The aim of this study was to evaluate the effect of dietary supplementation with a residue of defatted chia seed on a diet with low nutritional quality. To do this, C57BL/6 male mice were fed with the Control (C), Low-Nutritional-Quality (LNQ), or supplemented-with-chia-defatted-flour (LNQ+C) diets. After 12 weeks, the glucose and lactate levels were determined in the serum, liver, and kidney, along with reactive oxygen species (ROS) levels, antioxidant enzyme activity, reduced glutathione (GSH), and protein oxidation (AOPP). The LNQ diet increased the glucose and lactate levels (+25% and +50% approx. in the liver, with respect to the control group) and generated oxidative stress by modifying the levels of ROS and the activity of antioxidant enzymes, causing oxidative damage to proteins (+12% in the liver, with respect to the control). Chia supplementation helped to restore the glucose to control levels and modulate the endogenous antioxidant system, resulting in a decrease in protein oxidation products with no differences compared to the control group. In conclusion, supplementation with chia showed beneficial effects on the general health of mice, even when fed a low-nutritional-quality diet.

The aim of this study was to evaluate the effect of dietary supplementation with defatted sesame seeds on a diet with low nutritional quality (high-fructose and high proportion of saturated fatty acids), in terms of the redox state and carbohydrate metabolism. C57BL/6 male mice were fed for 12 weeks with Control (C), Low Nutritional Quality (LNQ), or supplemented with sesame defatted flour (LNQ + S) diets. Levels of glucose, lactate, reactive oxygen species, antioxidant enzyme activity, reduced glutathione, and protein oxidation (AOPP) were determined. Overall, LNQ increased liver glucose (+ 20

Background: Cardiovascular risk is modifiable by changes in lifestyle and pharmacological management, with hypertension being a common pathology worldwide. Its treatment must address multiple metabolic targets. Based on the hypothesis that certain antihypertensive medications, such as the commonly used enalapril and losartan, and dietary habits improve hypertension-related changes in carotid structure and cardiometabolic variables, this work aimed to associate these drugs, as well as the Mediterranean diet adherence and non -modifiable biological factors, with changes in carotid intima-media thickness [cIMT] and blood lipids.Methods: Sociodemographic, clinical, biochemical and lifestyle data were collected in a cross-sectional study of 313 subjects under survey due to cardiovascular risk factors, aged 34-83 years (Cordoba, Argentina). Generalised structural equation models were used for analysis.Results: A higher cIMT with age and male sex was confirmed. Women had lower triacylglycerols and saturated fatty acids in serum but higher circulating levels of LDL-C, HDL-C and total cholesterol than men. Also, a higher adherence to the Mediterranean diet was associated with lower triacylglycerols, but higher levels of HDL-C cholesterol and omega-3 polyunsaturated fatty acids (omega-3 PUFAs) in serum. A greater adherence to the Mediterra-nean diet did not affect cIMT. Enalapril was associated with increased serum omega-3 PUFAs levels, but it did not affect other lipid fractions. Moreover, enalapril may control cIMT, whereas losartan may not.Conclusions: Our data demonstrate that the Mediterranean diet and enalapril are associated with a car-dioprotective circulating lipid profile in hypertension. Concerning this, enalapril potentially promotes serum omega-3 PUFAs levels beyond its classical antihypertensive effect, which encourages future clinical studies to confirm it.

Background: An important aspect of oral carcinogenesis is individual genetic susceptibility. The two Single Nucleotide Polymorphisms (SNPs) were selected because they are related to different cancers including oral squamous cell carcinoma. Aim: The aim of this work was to evaluate the relationship between the daily intake of saturated, mono-unsaturated, and polyunsaturated fatty acids in people with/without cancer or precancer lesions, and its possible relationship with the TP53 -R72P and pri-miR 34b/c- rs4938723. Subjects and methods: A retrospective study was carried out. The groups of patients were control (n = 27), potentially malignant oral lesions (PPOL) (n = 24), and OSCC (n = 29). Daily dietary data was collected by quantitative-food-frequency questionnaire, and genotyping of SNP was performed using allele-specific PCR or RFLP techniques. The Mann-Whitney-U and logistic regression were applied; setting p < 0.05 for statistical significance. Results: Patients carrying the GC TP53 rs 1,042,522 were 4 times more likely to develop OSCC in comparison with controls (OR = 4.32; 95% CI [1.23-15.18]; p = 0.0331). Patients with OSCC carried the GC + CC in relation to the GG genotype (OR = 3.84, 95%CI [1.17-12.59]; p = 0.0415) and carrying on the allele T of Pri-miR 34b/c rs4938723 (mutation variant) GC were 3 times more likely to develop OSCC in comparison with subjects with allele C (OR = 3.14, 95% CI [1.08-9.18]; p = 0.0374) (Table 2A). Similar, PPOL patients who have allele T were 8 times more likely to develop the premalignant lesions (OR = 8.22, 95% CI [3.17-21.31]; p = 0.0001). Significant high average values were observed in the intake of saturated (palmitic-stearic-arachidic), monounsaturated (palmitoleic-oleic), and polyunsaturated fatty acids (linoleic-alpha linoleic) mg/day in cases compared to controls. Furthermore, the omega-6/ omega 3 ratio was higher in cases compared to controls. Conclusion: High-fat dietary intake and the presence of mutant alleles of TP53 and micro34b/c were associated with a high risk of OSCC and PPOL.

The aim of this study was to investigate the in vivo and in vitro effects of dietary ω-6 and ω-3 polyunsaturated fatty acids (PUFAs) and their derivatives on the expression of TP53 and their relationship with cellular proliferation and death in a murine mammary adenocarcinoma model. BALB/c mice were divided in three diet groups: chia oil (ChO) rich in ω-3, corn oil (CO) rich in ω-6/ω-3 and safflower oil (SO) rich in ω-6 and subcutaneously inoculated with LMM3 mammary tumor cell line. Results demonstrated that diets with higher concentration of omega-6 PUFAs induced an increment of linoleic and arachidonic acid on tumor cell membranes increasing ROS liberation, 12(S)-HHT generation, TP53, Ki67 expression and cell proliferation. However, diets enriched with high content in omega-3 PUFAs induced higher tumor cell apoptosis and tumor infiltration of CD3+ lymphocytes, lowest cell viability and proliferation. Dietary omega-3 PUFAs nutritional intervention can be used as a potential preventative strategy to inhibit the molecular signaling pathways involved in the mammary tumor growth process as the TP53.

Having demonstrated the ability of monosialoganglioside GM1 micelles as oncology drug transporter, this work focuses on evaluating its application in an in vivo system, studying the toxicity and antitumoral effect of GM1-Ptx micellar formulation. The maximum tolerated dose (MTD) obtained after intravenous administration of GM1-Ptx in mice was 55mg/kg and the 50% lethal dose (LD50) was 70mg/kg. This value is higher than those described for the commercial formulations TAXOL and ABRAXANE, with LD50 of 30 and 45mg/kg respectively. The antitumor activity, mortality and incidence of metastasis were studied on a murine model of mammary gland cancer. The GM1-Ptx formulation was administered i.v. at different doses for 9 weeks using empty GM1 micelles and saline as treatment controls. Once the treatments were completed, biochemical markers were quantified and histological tissue tests were performed. The most promising results were obtained with the treatment at a dose of 15mg/kg/twice a week, condition in which a longer survival and significant reduction in the incidence of animals with metastasis, since only one 25% of the mice showed presence of pulmonary micro metastases.

The aim of this study was to determine whether α-linolenic acid (ALA ω-3 fatty acid) enriched diet affects growth parameters when applied to a syngeneic model of mammary carcinoma.

The aim of this work was: to assess the impact of diets enriched in polyunsaturated fatty acids ω-3 and ω-6 families on the lipid profile of cell membrane and their effect on cycle regulation and apoptosis, evaluated by TP53 and Ki-67 expression in 9,10-dimethyl-1,2-benzanthracene (DMBA) induced tumor development in submandibular glands (SMG) in murine models. To generate tumorigenic changes, SMG mice in the experimental group were injected with 50μl of 0.5% of DMBA. Both control (no DMBA) and experimental groups of BALB/c mice were fed with: chia oil (ChO), rich in ω-3 fatty acid; corn oil (CO), rich in ω-6/ω-3 fatty acid; and safflower (SO) oil, rich in ω-6fatty acid. Results demonstrate novel differential effects of ω-3 and ω-6 PUFAs on the regulation of early tumorigenesis events in murine SMG injected with DMBA. This knowledge may help to develop chemoprotective treatments, therapeutic agents and health promotion and prevention activities in humans.

Background and Aims. Evidence suggests that quantity and quality of dietary polyunsaturated fatty acids (PUFAs) play a role in the development of cancer. However, the mechanisms involved in this interaction(s) are not clear. Endocannabinoids are lipid metabolites known to have growth modulatory actions. We studied the effect of supplementation with PUFAs omega-6 and omega-3 (essential fatty acids, EFAs), saturated and monoun-saturated fatty acids (non-EFAs) on the growth of tumor cells and modifications in their endocannabinoid content.Methods. Cell cultures of human glioblastoma (T98G) and breast cancer (MCF7) were supplemented with 50 or 100 mmol EFAs and non-EFAs for 72 h. Cell proliferation was then determined by MTT, anandamide (AEA) levels by HPLC, total fatty acids profiles by GLC, CB1 receptor expression by WB and FAAH activity by spectrophotometric method.Results. Fatty acids profile reflected the incorporation of the lipids supplemented in each assay. Arachidonic acid (EFA omega-6) supplementation increased AEA levels and inhibited the growth of T98G, whereas palmitic acid (non-EFA) enhanced their proliferation. In breast cancer (MCF7) cells, eicosapentaenoic acid (EFA omega-3) reduced and oleic acid (non-EFA) enhanced their proliferation. CB1 expression was higher in T98G and no differences were observed in FAAH activity.Conclusions. The growth of tumor cells can be differentially modulated by fatty acids and, at least in part, can be attributed to their ability to act on the components of the endocannabinoid system. (c) 2017 IMSS. Published by Elsevier Inc.

Numerous reports have demonstrated a tumor inhibitory effect of polyunsaturated fatty acids (PUFAs). However, the molecular mechanisms modulating this phenomenon are in part poorly understood. Here, we provide evidence of a novel antitumoral mechanism of the PUFA arachidonic acid (AA). In vivo and in vitro experiments showed that AA treatment decreased tumor growth and metastasis and increased apoptosis. Molecular analysis of this effect showed significantly reduced expression of a subset of antiapoptotic proteins, including BCL2, BFL1/A1, and 4-1BB, in AA-treated cells. We demonstrated that down-regulation of the transcription factor glioma-associated protein 1 (GLI1) in AA-treated cells is the underlying mechanism controlling BCL2, BFL1/A1, and 4-1BB expression. Using luciferase reporters, chromatin immunoprecipitation, and expression studies, we found that GLI1 binds to the promoter of these antiapoptotic molecules and regulates their expression and promoter activity. We provide evidence that AA-induced apoptosis and down-regulation of antiapoptotic genes can be inhibited by overexpressing GLI1 in AA-sensitive cells. Conversely, inhibition of GLI1 mimics AA treatments, leading to decreased tumor growth, cell viability, and expression of antiapoptotic molecules. Further characterization showed that AA represses GLI1 expression by stimulating nuclear translocation of NFATc1, which then binds the GLI1 promoter and represses its transcription. AA was shown to increase reactive oxygen species. Treatment with antioxidants impaired the AA-induced apoptosis and down-regulation of GLI1 and NFATc1 activation, indicating that NFATc1 activation and GLI1 repression require the generation of reactive oxygen species. Collectively, these results define a novel mechanism underlying AA antitumoral functions that may serve as a foundation for future PUFA-based therapeutic approaches.

Objective: The aim of this study was to determine the effects of some polyunsaturated fatty acids plus phytomelatonin from walnuts in the development of mammary gland adenocarcinoma.Methods: BALB/c mice were fed a semisynthetic diet supplemented with either 6% walnut oil and 8% walnut flour containing phytomelatonin (walnut diet: WD); or 6% corn oil plus commercial melatonin (melatonin diet: MD), or the control group (CD), which received only 6% of corn oil. Membrane fatty acids of tumor cells (TCs) were analyzed by gas liquid chromatography, cyclooxygenase (COX) and lipoxygenase (LOX) derivatives, and plasma melatonin by high-performance liquid chromatography; apoptosis and tumor-infiltrating lymphocytes by flow cytometry.Results: TCs from the MD and WD mice showed significant decreases in linoleic acid compared with the CD group (P < 0.05). Significantly lower levels of LOX-[13(S)-HODE] were found in TCs from the MD and WD group than in CD (P < 0.0001). COX-[12(S)-HHT] was lower and 12 LOX-[12(S)-HETE] was higher in TCs from the MD group than form the WD and CD arms (P < 0.05). Plasma melatonin, apoptosis, tumor infiltration, and survival time were significantly lower in CD mice than in MD and WD mice (P < 0.05).Conclusions: This study shows that melatonin, along with polyunsaturated fatty acids, exerts a selective inhibition of some COX and LOX activities and has a synergistic anti-tumor effect on a mammary gland adenocarcinoma model. Published by Elsevier Inc.

OBJECTIVE:Oxidative stress and inflammation seem to mediate the cardiovascular risks associated with salt sensitivity. Because hydroxymethyl glutaryl coenzyme A reductase inhibitors decrease oxidation and increase nitric oxide (NO) synthesis, we examined the effects of atorvastatin (ator) on tissue injury in rats with a reduced renal mass produced by 5/6 nephrectomy. This salt-sensitive hypertension model causes kidney and cardiovascular injuries.METHODS:After undergoing 5/6 nephrectomy or sham surgery, male Sprague-Dawley rats were randomized into five groups: sham, reduced renal mass and a normal salt diet (NNaD), NNaD+ator (50 mg · kg(-1) · d(-1)), reduced renal mass and a high salt diet (HNaD), and HNaD+ator. After assessing the sodium balance for 7 d, we measured blood pressure (BP), creatinemia, proteinuria, nitrites, and 12(S)-hydroxy 5,8,10-heptadecatrienoic acid, the renal cortical expression of endothelial NO synthase, and the ratio of left ventricular weight to body weight.RESULTS:In NNaD rats, creatinine, proteinuria, and 12(S)-hydroxy 5,8,10-heptadecatrienoic acid increased, renal NO indices decreased, but the Na(+) balance, BP, and the left ventricular weight/body weight ratio remained unchanged. In the NNaD group, atorvastatin normalized the NO indices and decreased BP and proteinuria, although the remaining parameters continued unchanged. In contrast, HNaD increased creatinemia, proteinuria, and 12(S)-hydroxy 5,8,10-heptadecatrienoic acid excretion rates and decreased renal endothelial NO synthase. Salt retention was accompanied by increased BP and ventricular weight. In this HNaD group, atorvastatin prevented a BP increase, partly decreased sodium retention, but failed to improve NO indices, proteinuria, oxidant stress, and the left ventricular weight/body weight ratio.CONCLUSION:Atorvastatin exerts beneficial effects on renal function, injury, and salt sensitivity in rats with a reduced renal mass on an NNaD. The HNaD hampers these beneficial effects.

This article reviews the current knowledge and experimental research about the mechanisms by which fatty acids and their derivatives control specific gene expression involved during carcinogenesis. Changes in dietary fatty acids, specifically the polyunsaturated fatty acids of the ω-3 and ω-6 families and some derived eicosanoids from lipoxygenases, cyclooxygenases, and cytochrome P-450, seem to control the activity of transcription factor families involved in cancer cell proliferation or cell death. Their regulation may be carried out either through direct binding to DNA as peroxisome proliferator-activated receptors or via modulation in an indirect manner of signaling pathway molecules (e.g., protein kinase C) and other transcription factors (nuclear factor kappa B and sterol regulatory element binding protein). Knowledge of the mechanisms by which fatty acids control specific gene expression may identify important risk factors for cancer and provide insight into the development of new therapeutic strategies for a better management of whole body lipid metabolism.