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Context: Type 2 diabetes has been described to be associated with hypothyroidism but we recently found that a decrease in pituitary sensitivity to thyroid hormone is associated with diabetes, obesity, and metabolic syndrome., Objective: We aimed to assess the longitudinal nature of this association in the population-based Study of Health in Pomerania (SHIP) in Germany., Methods: Among a population-based sample of 4308 participants aged 20 to 79 years, 77% were followed for a period of 5 years. We studied 2542 participants without diabetes or thyroid medication at baseline and complete data in the variables of interest. Data of baseline free thyroxine (fT4) and thyrotropin (TSH) were used to calculate the Parametric Thyroid Feedback Quantile-based Index (PTFQI), which measures whether TSH remains elevated despite fT4 being high. It uses the average population response as reference. PTFQI association with incidence of type 2 diabetes over 5 years was estimated with Poisson regression models adjusted for age, sex, and body mass index (BMI)., Results: Compared with the first PTFQI quartile, incidence rate ratios for diabetes were 1.54 (95% CI, 0.97-2.46), 1.55 (0.94-2.57), and 1.97 (1.27-3.10) for the upper quartiles (P trend = .004) after adjusting for age and sex. The association remained statistically significant after additionally adjusting for BMI: 1.64 (1.05-2.59) for the fourth vs the first quartile (P trend = .043)., Conclusion: An elevation of the pituitary TSH-inhibition threshold is associated with incident type 2 diabetes independently of BMI. The PTFQI might have clinical potential for prognosis and metabolic status monitoring., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Recently, the development of nonalcoholic steatohepatitis (NASH) in common strains of pigs has been achieved using a diet high in saturated fat, fructose, cholesterol, and cholate and deficient in choline and methionine. The aim of the present work was to characterize the hepatic and plasma lipidomic changes that accompany the progression of NASH and its reversal by switching pigs back to a chow diet. One month of this extreme steatotic diet was sufficient to induce porcine NASH. The lipidomic platform using liquid chromatography-mass spectrometry analyzed 467 lipid species. Seven hepatic phospholipids [PC(30:0), PC(32:0), PC(33:0), PC(33:1), PC(34:0), PC(34:3) and PC(36:2)] significantly discriminated the time of dietary exposure, and PC(30:0), PC(33:0), PC(33:1) and PC(34:0) showed rapid adaptation in the reversion period. Three transcripts ( CS , MAT1A , and SPP1 ) showed significant changes associated with hepatic triglycerides and PC(33:0). Plasma lipidomics revealed that these species [FA 16:0, FA 18:0, LPC(17:1), PA(40:5), PC(37:1), TG(45:0), TG(47:2) and TG(51:0)] were able to discriminate the time of dietary exposure. Among them, FA 16:0, FA 18:0, LPC(17:1) and PA(40:5) changed the trend in the reversion phase. Plasma LDL-cholesterol and IL12P40 were good parameters to study the progression of NASH, but their capacity was surpassed by hepatic [PC(33:0), PC(33:1), and PC(34:0)] or plasma lipid [FA 16:0, FA 18:0, and LPC(17:1)] species. Taken together, these lipid species can be used as biomarkers of metabolic changes in the progression and regression of NASH in this model. The lipid changes suggest that the development of NASH also affects peripheral lipid metabolism. NEW & NOTEWORTHY A NASH stage was obtained in crossbred pigs. Hepatic [PC(33:0), PC(33:1) and PC(34:0)] or plasma [FA 16:0, FA 18:0 and LPC(17:1)] species were sensitive parameters to detect subtle changes in development and regression of nonalcoholic steatohepatitis (NASH). These findings may delineate the liquid biopsy to detect subtle changes in progression or in treatments. Furthermore, phospholipid changes according to the insult-inducing NASH may play an important role in accepting or rejecting fatty livers in transplantation.

Introduction: Atrial fibrillation is associated with hyperthyroidism. Within the euthyroid range, it is also associated with high thyroxine (fT4), but not with thyrotropin (TSH). We aim to describe differences in thyroid regulation, measured by the Parametric Thyroid Feedback Quantile-Based Index (PTFQI), between patients with atrial fibrillation and the general population., Materials and Methods: Thyroid parameters (PTFQI, TSH, and fT4) of a sample of 84 euthyroid subjects with atrial fibrillation (cases) were compared to a reference sample of euthyroid healthcare patients (controls). We calculated age and sex adjusted ORs for atrial fibrillation across tertiles of these parameters. Also, within cases, we studied thyroid parameters association with clinical characteristics of the atrial fibrillation., Results: After adjusting for age and sex, fT4 and PTFQI were higher in subjects with atrial fibrillation when compared to the general sample (p<0.01 and p=0.01, respectively). Atrial fibrillation ORs of the third versus the first PTFQI tertile was 1.88(95%CI 1.07,3.42), and there was a gradient across tertiles (p trend=0.02). Among atrial fibrillation patients, we observed that higher PTFQI was associated with sleep apnea/hypopnea syndrome (OSAS) (p=0.03), higher fT4 was associated with the presence of an arrhythmogenic trigger (p=0.02) and with heart failure (p<0.01), and higher TSH was also associated with OSAS (p<0.01)., Conclusions: Euthyroid subjects with atrial fibrillation have an elevation of the pituitary TSH-inhibition threshold, measured by PTFQI, with respect to the general population. Within atrial fibrillation patients, high PTFQI was associated with OSAS, and high fT4 with heart failure. These results hint of the existence of a relationship between thyroid regulation and atrial fibrillation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Alonso-Ventura, Campos-Magallon, Moreno-Franco, Calmarza, Calvo-Gracia, Lou-Bonafonte, de Diego-Garcia, Casasnovas, Marco-Benedi, Civeira and Laclaustra.)

Squalene is a key minor component of virgin olive oil, the main source of fat in the Mediterranean diet, and had shown to improve the liver metabolism in rabbits and mice. The present research was carried out to find out whether this effect was conserved in a porcine model of hepatic steatohepatitis and to search for the lipidomic changes involved. The current study revealed that a 0.5% squalene supplementation to a steatotic diet for a month led to hepatic accumulation of squalene and decreased triglyceride content as well as area of hepatic lipid droplets without influencing cholesterol content or fiber areas. However, ballooning score was increased and associated with the hepatic squalene content. Of forty hepatic transcripts related to lipid metabolism and hepatic steatosis, only citrate synthase and a non-coding RNA showed decreased expressions. The hepatic lipidome, assessed by liquid chromatography-mass spectrometry in a platform able to analyze 467 lipids, revealed that squalene supplementation increased ceramide, Cer(36:2), and phosphatidylcholine (PC[32:0], PC[33:0] and PC[34:0]) species and decreased cardiolipin, CL(69:5), and triglyceride (TG[54:2], TG[55:0] and TG[55:2]) species. Plasma levels of interleukin 12p40 increased in pigs receiving the squalene diet. The latter also modified plasma lipidome by increasing TG(58:12) and decreasing non-esterified fatty acid (FA 14:0, FA 16:1 and FA 18:0) species without changes in total NEFA levels. Together this shows that squalene-induced changes in hepatic and plasma lipidomic profiles, non-coding RNA and anti-inflammatory interleukin are suggestive of an alleviation of the disease despite the increase in the ballooning score., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The usual inverse correlation between thyrotropin (TSH) and thyroid hormone disappears in syndromes of central resistance to thyroid hormone, where both are high. TSH and thyroid hormone are also simultaneously high when there is an elevation of the set point of the thyroid regulation axis. This can be estimated with indices, such as the Parametric Thyroid Feedback Quantile-based Index (PTFQI), which was designed for the general population. The PTFQI is positively associated with diabetes prevalence, but association with other pathologies has not been yet explored. The aim of this project was to explore the potential relationship of the PTFQI with metabolic and cardiovascular disease in a sample of ambulatory adult patients from Spain. Methods: A cross-sectional study was carried out among the patients who underwent thyroid hormones measurement (6434 measurements from September to November 2018 in a central laboratory in Spain). We retrospectively reviewed clinical records of a subgroup of adults aged >18 years with normal TSH and free thyroxine (fT4) belonging to groups that represent extreme PTFQI ( n  = 661). Individuals with known conditions interfering the thyroid axis were excluded (remaining n  = 296). Logistic and linear regression models adjusted for age and sex were used to calculate odds ratio (OR) of diseases and differences of clinical parameters, and 95% confidence intervals [CI]. Results: Across levels with higher PTFQI, there was an increase in the prevalence of type 2 diabetes (High vs. Low PTFQI OR: 2.88 [CI: 1.14-7.86], p -Trend = 0.02), ischemic heart disease (16.4% vs. 0%, unadjusted Haldane-Anscombe corrected OR: 23.90 [CI: 1.36-21.48], adjusted p -Trend = 0.04), atrial fibrillation (OR: 8.13 [CI: 1.33-158.20], p -Trend = 0.05), and hypertension (OR: 3.19 [CI: 1.14-9.94], p -Trend = 0.05). While the prevalence of type 2 diabetes was similarly associated with TSH and fT4, ischemic heart disease, atrial fibrillation, and hypertension were more strongly associated with the differences in fT4 values. Conclusions: Type 2 diabetes, ischemic heart disease, atrial fibrillation, and hypertension may be associated with a higher central regulation set point for thyroid hormone. These findings should be confirmed in other populations.

Non-alcoholic fatty liver disease (NAFLD) is currently a growing epidemic disease that can lead to cirrhosis and hepatic cancer when it evolves into non-alcoholic steatohepatitis (NASH), a gap not well understood. To characterize this disease, pigs, considered to be one of the most similar to human experimental animal models, were used. To date, all swine-based settings have been carried out using rare predisposed breeds or long-term experiments. Herein, we fully describe a new experimental swine model for initial and reversible NASH using cross-bred animals fed on a high saturated fat, fructose, cholesterol, cholate, choline and methionine-deficient diet. To gain insight into the hepatic transcriptome that undergoes steatosis and steatohepatitis, we used RNA sequencing. This process significantly up-regulated 976 and down-regulated 209 genes mainly involved in cellular processes. Gene expression changes of 22 selected transcripts were verified by RT-qPCR. Lipid droplet area was positively associated with CD68, GPNMB, LGALS3, SLC51B and SPP1, and negatively with SQLE expressions. When these genes were tested in a second experiment of NASH reversion, LGALS3, SLC51B and SPP1 significantly decreased their expression. However, only LGALS3 was associated with lipid droplet areas. Our results suggest a role for LGALS3 in the transition of NAFLD to NASH., (© 2022. The Author(s).)

Purpose: Compaction of particulated grafts is done manually; thus, the effect of compression force on bone regeneration remains unclear. The aim of this study was to evaluate the impact of two different compression forces on the consolidation of particulated bovine hydroxyapatite., Materials and Methods: Two titanium cylinders were fixed on the calvarium of eight New Zealand rabbits. Both defects were filled with particulated bovine hydroxyapatite subjected to a compression force of 0.7 kg/cm 2 or 1.6 kg/cm 2 before being covered with a resorbable collagen membrane. A handheld device that uses a spring to control the compression force applied by the plugger was used. At 6 weeks, histomorphometry of the area immediately adjacent to the calvaria bone and to the collagen membrane was performed., Results: It was shown that next to the calvaria, the bone volume per tissue volume (BV/TV) was 29.0% ± 8.8% and 27.6% ± 8.2% at low and high compression force, respectively; the bone-to-biomaterial contact (BBC) was 58.2% ± 25.0% and 69.3% ± 22.9%, respectively (P > .05). In the corresponding area next to the collagen membrane, BV/TV was 4.9% ± 5.1% and 5.7% ± 4.7%, and the BBC was 18.3% ± 20.8% and 20.1% ± 15.9%, respectively (P > .05). In addition, the number and area of blood vessels were not significantly affected by compression force., Conclusion: Both compression forces applied resulted in similar consolidation of bovine hydroxyapatite expressed by new bone formation and vascularization based on a rabbit calvaria augmentation model.

Soria, M, Ansón, M, Lou-Bonafonte, JM, Andrés-Otero, MJ, Puente, JJ, and Escanero, J. Fat oxidation rate as a function of plasma lipid and hormone response in endurance athletes. J Strength Cond Res 34(1): 104-113, 2020-Plasma lipid changes during incremental exercise are not well known. The aim of this study was to investigate the relationship among fat oxidation rate, plasma lipids, and hormone concentrations in well-trained athletes. Twenty-six trained triathletes completed a graded cycle ergometer test to exhaustion increasing by 0.5 W·kg every 10 minutes. Fat oxidation rates were determined using indirect calorimetry. For each individual, maximal fat oxidation (MFO), the intensity at which MFO occurred (Fatmax), and the intensity at which fat oxidation became negligible (Fatmin) were determined. Blood samples for lipids and hormones analysis were collected at the end of each stage of the graded exercise test. All variables studied except insulin showed an increase at the end of incremental protocol with respect to basal levels. Free fatty acid reached significant increase at 60%VO2max and maximal levels at 70%VO2max. Low-density lipoprotein (LDL) and triglycerides (TG) decreased and showed lowest levels at 60%VO2max and reaching significant increases after 80%VO2max. High-density lipoprotein reached significant increase at 60%VO2max. Adrenaline and noradrenaline increased until the end of the incremental exercise, and significant differences were from 50%VO2max. These results suggest that exercise intensities are related to plasma lipids levels. In the zone when lipids oxidation is maximal, plasma LDL and TG variation differs from other lipids. These results may have application for the more adequate exercise intensity prescription to maximize the beneficial effects of exercise.

Objective: Diabetes prevalence and incidence increase among individuals with hypothyroidism but also among those with hyperthyroxinemia, which seems contradictory. Both high free thyroxine (fT4) and high thyroid-stimulating hormone (TSH) are present in the resistance to thyroid hormone syndrome. A mild acquired resistance to thyroid hormone might occur in the general population and be associated with diabetes. We aimed to analyze the association of resistance to thyroid hormone indices (the Thyroid Feedback Quantile-based Index [TFQI], proposed in this work, and the previously used Thyrotroph T4 Resistance Index and TSH Index) with diabetes., Research Design and Methods: We calculated the aforementioned resistance to thyroid hormone indices based on a U.S. representative sample of 5,129 individuals ≥20 years of age participating in the 2007-2008 National Health and Nutrition Examination Survey (NHANES). Also, to approximate TFQI, a U.S.-referenced Parametric TFQI (PTFQI) can be calculated with the spreadsheet formula =NORM.DIST(fT4&#95;cell&#95;in&#95;pmol&#95;per&#95;L,10.075,2.155,TRUE)+NORM.DIST(LN(TSH&#95;cell&#95;in&#95;mIU&#95;per&#95;L),0.4654,0.7744,TRUE)-1. Outcomes of interest were glycohemoglobin ≥6.5%, diabetes medication, diabetes-related deaths (diabetes as contributing cause of death), and additionally, in a fasting subsample, diabetes and metabolic syndrome. Logistic and Poisson regressions were adjusted for sex, age, and race/ethnicity., Results: Odd ratios for the fourth versus the first quartile of TFQI were 1.73 (95% CI 1.32, 2.27) ( P trend = 0.002) for positive glycohemoglobin and 1.66 (95% CI 1.31, 2.10) ( P trend = 0.001) for medication. Diabetes-related death rate ratio for TFQI being above versus below the median was 4.81 (95% CI 1.01, 22.94) ( P trend = 0.015). Further adjustment for BMI and restriction to normothyroid individuals yielded similar results. Per 1 SD in TFQI, odds increased 1.13 (95% CI 1.02, 1.25) for diabetes and 1.16 (95% CI 1.02, 1.31) for metabolic syndrome. The other resistance to thyroid hormone indices showed similar associations for diabetes-related deaths and metabolic syndrome., Conclusions: Higher values in resistance to thyroid hormone indices are associated with obesity, metabolic syndrome, diabetes, and diabetes-related mortality. Resistance to thyroid hormone may reflect energy balance problems driving type 2 diabetes. These indices may facilitate monitoring treatments focused on energy balance., (© 2018 by the American Diabetes Association.)

Squalene is a triterpenic compound found in a large number of plants and other sources with a long tradition of research since it was first reported in 1926. Herein a systematic review of studies concerning squalene published in the last 8 years is presented. These studies have provided further support for its antioxidant, anti-inflammatory, and anti-atherosclerotic properties in vivo and in vitro. Moreover, an antineoplastic effect in nutrigenetic-type treatments, which depends on the failing metabolic pathway of tumors, has also been reported. The bioavailability of squalene in cell cultures, animal models, and in humans has been well established, and further progress has been made in regard to the intracellular transport of this lipophilic molecule. Squalene accumulates in the liver and decreases hepatic cholesterol and triglycerides, with these actions being exerted via a complex network of changes in gene expression at both transcriptional and post-transcriptional levels. Its presence in different biological fluids has also been studied. The combination of squalene with other bioactive compounds has been shown to enhance its pleiotropic properties and might lead to the formulation of functional foods and nutraceuticals to control oxidative stress and, therefore, numerous age-related diseases in human and veterinary medicine., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Elevated levels of low density lipoproteins (LDLs) cause atherosclerotic disease, and proteomic analyses have found that these lipoproteins are endowed with prenylcysteine lyase. This systematic review summarizes current understanding of this enzyme, now known as prenylcysteine oxidase 1 (PCYOX1), which hydrolyzes the thioether bond of prenylcysteines in the final step in the degradation of prenylated proteins, releasing hydrogen peroxide, cysteine and the isoprenoid aldehyde. Despite the high variability of the PCYOX1 gene, no polymorphism has yet been associated with any disease. The liver, which is responsible for vehiculization of the enzyme in lipoproteins, is one of the main organs responsible for its expression, together with the gastrointestinal tract, kidney, male reproductive tissue and muscle. Moreover, although hepatic mRNA expression is sensitive to diet and hormones, the repercussion of these changes in LDLs containing PCYOX1 has not been addressed. One consequence of its elevated activity could be an increase in hydrogen peroxide, which might help to propagate the oxidative burden of LDLs, thus making PCYOX1 a potential pharmacological target and a new biomarker in cardiovascular disease.

The Mediterranean diet has been proven to be highly effective in the prevention of cardiovascular diseases and cancer and in decreasing overall mortality. Nowadays, transcriptomics is gaining particular relevance due to the existence of non-coding RNAs capable of regulating many biological processes. The present work describes a systematic review of current evidence supporting the influence of the Mediterranean diet on transcriptomes of different tissues in various experimental models. While information on regulatory RNA is very limited, they seem to contribute to the effect. Special attention has been given to the oily matrix of virgin olive oil. In this regard, monounsaturated fatty acid-rich diets prevented the expression of inflammatory genes in different tissues, an action also observed after the administration of olive oil phenolic compounds. Among these, tyrosol, hydroxytyrosol, and secoiridoids have been found to be particularly effective in cell cycle expression. Less explored terpenes, such as oleanolic acid, are important modulators of circadian clock genes. The wide range of studied tissues and organisms indicate that response to these compounds is universal and poses an important level of complexity considering the different genes expressed in each tissue and the number of different tissues in an organism.

Low levels of paraoxonase 1 (PON1) have been associated with the development of several pathological conditions, whereas high levels have been shown to be anti-atherosclerotic in mouse models. These findings suggest that PON1 could be a good surrogate biomarker. The other members of the family, namely PON2 and PON3, the role of which has been much less studied, deserve more attention. This paper provides a systematic review of current evidence concerning dietary supplements in that regard. Preliminary studies indicate that the response to dietary supplements may have a nutrigenetic aspect that will need to be considered in large population studies or in clinical trials. A wide range of plant preparations have been found to have a positive action, with pomegranate and some of its components being the best characterized and Aronia melanocarpa one of the most active. Flavonoids are found in the composition of all active extracts, with catechins and genistein being the most promising agents for increasing PON1 activity. However, some caveats regarding the dose, length of treatment, bioavailability, and stability of these compounds in formulations still need to be addressed. Once these issues have been resolved, these compounds could be included as nutraceuticals and functional foods capable of increasing PON1 activity, thereby helping with the long-term prevention of atherosclerosis and other chronic ailments.

Background: The aim of this study was to compare fourteen non-invasive indexes/scores: AAR, APRI, Fibroindex, MODEL3, Forns index, FIB4, GUCI, FI, FCI, Pohl score, AP index, CDS, HGM-1 and HGM-2, in order to diagnose the hepatic fibrosis stage in a survey of patients with chronic hepatitis C., Methods: 84 patients with chronic hepatitis C were studied. Liver fibrosis was staged according to the Scheuer scoring system. The diagnostic accuracy of these indexes/scores was evaluated by AUROC, contingency tables and logistic regression analysis., Results: The best AUROCs (>0.9) to discriminate cirrhosis (F=4), were observed for CDS, FI, AAR, MODEL3, FIB4, HGM-2 and FCI. To discriminate at least advance fibrosis (F≥3), the best AUROCs (>0.89) were for CDS, FI, FIB4, HGM2-2, MODEL3 and FCI. To discriminate at least significant fibrosis (F≥2), the best AUROCs (>0.8) were for FIB4, GUCI, APRI, FI, Forns index, HGM-2 and FCI. Contingency tables and logistic regression analysis supported the results obtained by AUROC., Conclusions: This study compares the diagnostic performance of fourteen indexes for the diagnosis of liver fibrosis stage in the same group of CHC patients. These results allow the selection of the best indexes for further studies in larger populations, in order to build diagnostic algorithms as an alternative to liver biopsy for fibrosis staging in patients with chronic HCV infection. These algorithms would allow to take therapeutical decisions and the continuous follow-up of hepatic fibrosis in these patients., (Copyright © 2016. Published by Elsevier Inc.)

The Mediterranean diet has been proven to be highly effective in the prevention of cardiovascular diseases. Paraoxonase 1 (PON1) has been implicated in the development of those conditions, especially atherosclerosis. The present work describes a systematic review of current evidence supporting the influence of Mediterranean diet and its constituents on this enzyme. Despite the differential response of some genetic polymorphisms, the Mediterranean diet has been shown to exert a protective action on this enzyme. Extra virgin olive oil, the main source of fat, has been particularly effective in increasing PON1 activity, an action that could be due to low saturated fatty acid intake, oleic acid enrichment of phospholipids present in high-density lipoproteins that favor the activity, and increasing hepatic PON1 mRNA and protein expressions induced by minor components present in this oil. Other Mediterranean diet constituents, such as nuts, fruits and vegetables, have been effective in modulating the activity of the enzyme, pomegranate and its compounds being the best characterized items. Ongoing research on compounds isolated from all these natural products, mainly phenolic compounds and carotenoids, indicates that some of them are particularly effective, and this may enhance the use of nutraceuticals and functional foods capable of potentiating PON1 activity.

High-density lipoprotein (HDL) levels are an inverse risk factor for cardiovascular diseases, and sphingomyelin (SM) is the second most abundant phospholipid component and the major sphingolipid in HDL. Considering the marked presence of SM, the present review has focused on the current knowledge about this phospholipid by addressing its variable distribution among HDL lipoparticles, how they acquire this phospholipid, and the important role that SM plays in regulating their fluidity and cholesterol efflux from different cells. In addition, plasma enzymes involved in HDL metabolism such as lecithin-cholesterol acyltransferase or phospholipid transfer protein are inhibited by HDL SM content. Likewise, HDL SM levels are influenced by dietary maneuvers (source of protein or fat), drugs (statins or diuretics) and modified in diseases such as diabetes, renal failure or Niemann-Pick disease. Furthermore, increased levels of HDL SM have been shown to be an inverse risk factor for coronary heart disease. The complexity of SM species, described using new lipidomic methodologies, and their distribution in different HDL particles under many experimental conditions are promising avenues for further research in the future.

Hyperhomocysteinemia has been reported in human reproduction as a risk factor for early pregnancy loss, preeclampsia, and congenital birth defects like spina bifida. Female infertility was also observed in cystathionine beta synthase-deficient mice (Cbs-KO) as an animal model for severe hyperhomocysteinemia. The aim for the present research was to elucidate the time-point of pregnancy loss and to pinpoint gene and cellular changes involved in the underlying pathological mechanism. By mating 90-day-old wild-type and Cbs-KO female mice with their homologous male partners, we found that pregnancy loss in Cbs-KO occurred between the 8th and 12th gestation day during placenta formation. DNA microarrays were carried out on uterus from implantation and interimplantation samples obtained on day 8. The results allowed us to select genes potentially involved in embryo death; these were individually confirmed by RT-qPCR, and their expressions were also followed throughout pregnancy. We found that changes in expression of Calb1, Ttr, Expi, Inmt, Spink3, Rpgrip1, Krt15, Mt-4, Gzmc, Gzmb, Tdo2, and Afp were important for pregnancy success, since a different regulation in Cbs-KO mice was found. Also, differences in relationships among selected genes were observed, indicating a dysregulation of these genes in Cbs-KO females. In conclusion, our data provide more information on the gene expression cascade and its timely regulated process required for a successful pregnancy. In addition, we unveil new potential avenues to explore further investigations in pregnancy loss.

As olive oil is the main source of calories in the Mediterranean diet, a great deal of research has been devoted to characterizing its role in atherosclerosis. Virgin olive oil is an oily matrix that contains hydrocarbons, mainly squalene; triterpenes such as uvaol, erythrodiol, oleanolic, and maslinic acid; phytosterols; and a wide range of phenolic compounds comprising simple phenols, flavonoids, secoiridoids, and lignans. In this review, we analyze the studies dealing with atherosclerosis and olive oil in several species. A protective role of virgin olive oil against atherosclerosis has been shown in ApoE-deficient mice and hamsters. In the former animal, sex, dose, and dietary cholesterol are modulators of the outcome. Contradictory findings have been reported for rabbits, a circumstance that could be due to the profusion of experimental designs, differing in terms of doses and animal strains, as well as sources of olive oils. This role has yet to be fully validated in humans. Minor components of olive oil have been shown to be involved in atherosclerosis protection. Nevertheless, evidence of the potential of isolated compounds or the right combination of them to achieve the antiatherosclerotic effect of virgin olive oil is inconclusive and will undoubtedly require further experimental support., (© 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The low incidence of cardiovascular disease in countries bordering the Mediterranean basin, where olive oil is the main source of dietary fat, and the negative association between this disease with high density lipoproteins has stimulated interest. This review summarizes the current knowledge gathered from human and animal studies regarding olive oil and high density lipoproteins. Cumulative evidence suggests that high density lipoprotein (HDL) cholesterol, and its main apolipoprotein A1, may be increased by consuming olive oil when compared with carbohydrate and low fat diets in humans. Conflicting results have been found in many studies when olive oil diets were compared with other sources of fat. The role of virgin olive oil minor components on its protective effect has been demonstrated by a growing number of studies although its exact mechanism remains to be elucidated. Dietary amount of olive oil, use of virgin olive oil, cholesterol intake, and physiopathological states such as genetic background, sex, age, obesity or fatty liver are variables that may offset those effects. Further studies in this field in humans and in animal models are warranted due to the complexity of HDL particles.

Purpose of Review: To summarize currently available information about the mechanisms involved in liver fat accumulation., Recent Findings: The contribution of functional genomics approaches, such as those represented by high-throughput analysis and genetically modified mice, may envision a complex network involving fatty acid, triglyceride and phospholipid metabolisms and lipid droplet dynamics. Likewise, it may pose an exquisite regulation exerted through insulin, glucocorticoids, thyroid hormones, transcription factors and microRNAs, orchestrated with sexual differences and able to respond to environmental factors such as nutritional or viral influences among others., Summary: The information gathered will facilitate further research to complete gaps of interacting pieces among regulators and new contributing agents emerging from high-throughput analyses. With this new paradigm, new biomarkers able to discriminate the progression of hepatic steatosis into human steatohepatitis will eventually emerge, and hopefully new therapeutic approaches will be developed.

Objective: Genetic and dietary hyperhomocysteinemia has been found to decrease high density lipoproteins (HDL) and their apolipoprotein A1 (APOA1). To test the hypothesis that the presence of cysteine could normalize HDL levels in hyperhomocysteinemic cystathionine beta-synthase (Cbs)-deficient mice and that the inclusion of glycine would block this effect., Methods: Lipids and HDL cholesterol were studied in Cbs-deficient mice and wild-type animals fed a low-methionine diet supplemented with cysteine and glycine and in Cbs-deficient mice on the same diet supplemented only with cysteine., Results: Triglyceride and homocysteine levels were significantly decreased and increased, respectively in Cbs-deficient mice irrespective of treatment. However, plasma cholesterol, glucose and APOA1 were significantly decreased in homozygous Cbs-deficient mice when they received the cysteine and glycine-enriched beverage. This group of mice also showed decreased mRNA levels and increased hepatic content of APOA1 protein, the latter increase was observed in endothelial cells. A significant, inverse relationship was observed between plasma and hepatic APOA1 concentrations while a positive one was found between plasma levels of cysteine and APOA1., Conclusion: These data suggest an altered hepatic management of APOA1 and that cysteine may be involved in the control of this apolipoprotein at this level. Overall these findings represent a new aspect of dietary regulation of HDL at the hepatic transendothelial transport., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

The low incidence of cardiovascular disease in countries bordering the Mediterranean basin, where olive oil is the main source of dietary fat, has stimulated interest in the chemical composition of olive oil and in the production of other oils enriched with its minor components. This review summarizes what has been learned about the effects of different olive oil preparations on the development of atherosclerosis and about the prognostic value of associated plasma variables in the disease from experiments on genetically modified mice that spontaneously develop atherosclerosis. The limitations of this animal model associated with its morphological and physiological differences with humans are minimized by the similarity of the two genomes and by the potential for increased understanding attainable, given that the dietary interventions reported here would have taken 400 years to achieve in humans. As observed in traditional Mediterranean populations, it has been confirmed that extra virgin olive oil is beneficial when consumed judiciously and in a diet that is low in cholesterol due to the relative scarcity of animal products. Furthermore, the use of genomic techniques has led to the identification of new markers of response to olive oil. In conclusion, multidisciplinary research into extra virgin olive oil is expanding our knowledge of the substance's biological properties.

Cisplatin accumulates in mitochondria, which are a major target for this drug in cancer cells. Thus alterations in mitochondrial function have been implicated in cancer cell resistance to chemotherapeutic agents. Moreover, cisplatin toxic side effects seem to be associated with mitochondrial injury in vivo and in vitro. In order to clarify the potential effect of cisplatin in mtDNA (mitochondrial DNA) maintenance and expression, we have analysed rat liver mtDNA and mtRNA (mitochondrial RNA) synthesis as well as their stability under the influence of in vivo treatment or in vitro exposure to cisplatin. We show that cisplatin causes a direct and significant impairment of mtDNA and mtRNA synthesis and decreases steady-state levels of mtRNAs in isolated mitochondria. Furthermore, in vivo treatment of the animals with cisplatin exerts a protective effect from the impairment of mtRNA metabolism caused by in vitro exposure to the drug, by means of increased mitochondrial GSH levels after in vivo cisplatin treatment.