SIRT1 regulates hepatic vldlr levels.

BACKGROUND: Endoplasmic reticulum (ER) stress-mediated increases in the hepatic levels of the very low-density lipoprotein (VLDL) receptor (VLDLR) promote hepatic steatosis by increasing the delivery of triglyceride-rich lipoproteins to the liver. Here, we examined whether the NAD(+)-dependent deacetylase sirtuin 1 (SIRT1) regulates hepatic lipid accumulation by modulating VLDLR levels and the subsequent uptake of triglyceride-rich lipoproteins. METHODS: Rats fed with fructose in drinking water, Sirt1-/- mice, mice treated with the ER stressor tunicamycin with or without a SIRT1 activator, and human Huh-7 hepatoma cells transfected with siRNA or exposed to tunicamycin or different inhibitors were used. RESULTS: Hepatic SIRT1 protein levels were reduced, while those of VLDLR were upregulated in the rat model of metabolic dysfunction-associated steatotic liver disease (MASLD) induced by fructose-drinking water. Moreover, Sirt1-/- mice displayed increased hepatic VLDLR levels that were not associated with ER stress, but were accompanied by an increased expression of hypoxia-inducible factor 1α (HIF-1α)-target genes. The pharmacological inhibition or gene knockdown of SIRT1 upregulated VLDLR protein levels in the human Huh-7 hepatoma cell line, with this increase abolished by the pharmacological inhibition of HIF-1α. Finally, SIRT1 activation prevented the increase in hepatic VLDLR protein levels in mice treated with the ER stressor tunicamycin. CONCLUSIONS: Overall, these findings suggest that SIRT1 attenuates fatty liver development by modulating hepatic VLDLR levels.

COVID-19 Outcomes in Patients with Hematologic Malignancies in the Era of COVID-19 Vaccination and the Omicron Variant.

A greater understanding of clinical trends in COVID-19 outcomes among patients with hematologic malignancies (HM) over the course of the pandemic, particularly the Omicron era, is needed. This ongoing, observational, and registry-based study with prospective data collection evaluated COVID-19 clinical severity and mortality in 1818 adult HM patients diagnosed with COVID-19 between 27 February 2020 and 1 October 2022, at 31 centers in the Madrid region of Spain. Of these, 1281 (70.5%) and 537 (29.5%) were reported in the pre-Omicron and Omicron periods, respectively. Overall, patients aged ≥70 years (odds ratio 2.16, 95% CI 1.64-2.87), with >1 comorbidity (2.44, 1.85-3.21), or with an underlying HM of chronic lymphocytic leukemia (1.64, 1.19-2.27), had greater odds of severe/critical COVID-19; odds were lower during the Omicron BA.1/BA.2 (0.28, 0.2-0.37) or BA.4/BA.5 (0.13, 0.08-0.19) periods and among patients vaccinated with one or two (0.51, 0.34-0.75) or three or four (0.22, 0.16-0.29) doses. The hospitalization rate (75.3% [963/1279], 35.7% [191/535]), rate of intensive care admission (30.0% [289/963], 14.7% [28/191]), and mortality rate overall (31.9% [409/1281], 9.9% [53/536]) and in hospitalized patients (41.3% [398/963], 22.0% [42/191]) decreased from the pre-Omicron to Omicron period. Age ≥70 years was the only factor associated with higher mortality risk in both the pre-Omicron (hazard ratio 2.57, 95% CI 2.03-3.25) and Omicron (3.19, 95% CI 1.59-6.42) periods. Receipt of prior stem cell transplantation, COVID-19 vaccination(s), and treatment with nirmatrelvir/ritonavir or remdesivir were associated with greater survival rates. In conclusion, COVID-19 mortality in HM patients has decreased considerably in the Omicron period; however, mortality in hospitalized HM patients remains high. Specific studies should be undertaken to test new treatments and preventive interventions in HM patients.

A perspective on the role of physiological stresses in cancer, diabetes and cognitive disease as environmental diseases.

With rapid industrialization, urbanization, and climate change, the impact of environmental factors on human health is becoming increasingly evident and understanding the complex mechanisms involved is vital from a healthcare perspective. Nevertheless, the relationship between physiological stress resulting from environmental stressors and environmental disease is complex and not well understood. Chronic exposure to environmental stressors, such as air and water contaminants, pesticides, and toxic metals, has been recognized as a potent elicitor of physiological responses ranging from systemic inflammation to immune system dysregulation causing or progressing environmental diseases. Conversely, physiological stress can exacerbate susceptibility to environmental diseases. Stress-induced alterations in immune function and hormonal balance may impair the ability to detoxify harmful substances and combat pathogens. Additionally, prolonged stress can impact lifestyle choices, leading to harmful behaviors. Understanding the link between physiological stress and environmental disease requires a systematic, multidisciplinary approach. Addressing this complex relationship necessitates the establishment of a global research network. This perspective discusses the intricate interplay between physiological stress and environmental disease, focusing on common environmental diseases, cancer, diabetes, and cognitive degeneration. Furthermore, we highlight the intricate and reciprocal nature of the connection between physiological stress and these environmental diseases giving a perspective on the current state of knowledge as well as identifying where further information is necessary. Recognizing the role of physiological stress in environmental health outcomes will aid in the development of comprehensive strategies to safeguard public health and promote ecological balance.

COVID-19 Severity and Survival over Time in Patients with Hematologic Malignancies: A Population-Based Registry Study.

Mortality rates for COVID-19 have declined over time in the general population, but data in patients with hematologic malignancies are contradictory. We identified independent prognostic factors for COVID-19 severity and survival in unvaccinated patients with hematologic malignancies, compared mortality rates over time and versus non-cancer inpatients, and investigated post COVID-19 condition. Data were analyzed from 1166 consecutive, eligible patients with hematologic malignancies from the population-based HEMATO-MADRID registry, Spain, with COVID-19 prior to vaccination roll-out, stratified into early (February-June 2020; n = 769 (66%)) and later (July 2020-February 2021; n = 397 (34%)) cohorts. Propensity-score matched non-cancer patients were identified from the SEMI-COVID registry. A lower proportion of patients were hospitalized in the later waves (54.2%) compared to the earlier (88.6%), OR 0.15, 95%CI 0.11-0.20. The proportion of hospitalized patients admitted to the ICU was higher in the later cohort (103/215, 47.9%) compared with the early cohort (170/681, 25.0%, 2.77; 2.01-3.82). The reduced 30-day mortality between early and later cohorts of non-cancer inpatients (29.6% vs. 12.6%, OR 0.34; 0.22-0.53) was not paralleled in inpatients with hematologic malignancies (32.3% vs. 34.8%, OR 1.12; 0.81-1.5). Among evaluable patients, 27.3% had post COVID-19 condition. These findings will help inform evidence-based preventive and therapeutic strategies for patients with hematologic malignancies and COVID-19 diagnosis.

To be or not to be a fat burner, that is the question for cpt1c in cancer cells.

There is an urgent need to identify reliable genetic biomarkers for accurate diagnosis, prognosis, and treatment of different tumor types. Described as a prognostic marker for many tumors is the neuronal protein carnitine palmitoyltransferase 1 C (CPT1C). Several studies report that CPT1C is involved in cancer cell adaptation to nutrient depletion and hypoxia. However, the molecular role played by CPT1C in cancer cells is controversial. Most published studies assume that, like canonical CPT1 isoforms, CPT1C is a mediator of fatty acid transport to mitochondria for beta-oxidation, despite the fact that CPT1C has inefficient catalytic activity and is located in the endoplasmic reticulum. In this review, we collate existing evidence on CPT1C in neurons, showing that CPT1C is a sensor of nutrients that interacts with and regulates other proteins involved in lipid metabolism and transport, lysosome motility, and the secretory pathway. We argue, therefore, that CPT1C expression in cancer cells is not a direct regulator of fat burn, but rather is a regulator of lipid metabolic reprograming and cell adaptation to environmental stressors. We also review the clinical relevance of CPT1C as a prognostic indicator and its contribution to tumor growth, cancer invasiveness, and cell senescence. This new and integrated vision of CPT1C function can help better understand the metabolic plasticity of cancer cells and improve the design of therapeutic strategies.

Experiencias sobre la implementación del Expediente Clínico Electrónico / Experiences on the implementation of the Electronic Medical Record

Resumen Introducción. Un elemento de la e-salud que ha cobrado gran relevancia es el Expediente Clínico Electrónico (ECE) ya que es un medio para lograr mejores resultados en la práctica médica. Al momento, han sido pocas las investigaciones que se han centrado en analizar e identificar la situación de esta estrategia en el mundo. Por ello, el objetivo de esta investigación es analizar el panorama actual del ECE en diversos países considerando las ventajas, desventajas, desafíos y factores de éxito en su implementación. Metodología: Se realizó una revisión de la literatura existente sobre el ECE en base de datos especializadas. Para obtener estos estudios se utilizó la base de datos de scopus y sciencedirect , utilizando palabras de búsqueda como como registro electrónico de salud, registro médico electrónico o expediente clínico electrónico; se seleccionaron solamente aquellos estudios con un alto factor de impacto, mismo que se refiere al número de veces que se hayan citado los artículos consultados. Se seleccionaron y analizaron 64 estudios académicos. Resultados. Se encontró que aún existen importantes desafíos y desventajas en la implementación del ECE como la interoperabilidad semántica y el estrés laboral que genera en los usuarios este sistema. Conclusiones. Existen cuestiones importantes que aún quedan por resolver para una implementación eficaz del ECE. Es necesario integrar a todos los involucrados en el proceso de cambio, así como establecer las medidas de seguridad necesarias para garantizar la privacidad de la información.

Abstract Introduction. An element of e-health that has gained great relevance is the Electronic Medical Record (ECE) since it is a means to achieve better results in medical practice. At the moment, few investigations have focused on analyzing and identifying the situation of this strategy in the world. Therefore, the objective of this research is to analyze the current panorama of ECE in various countries considering the advantages, disadvantages, challenges and success factors in its implementation. Methodology. A review of the existing literature on ECE was carried out in specialized databases. To obtain these studies, the scopus and sciencedirect databases were used, using search words such as "electronic health record", "electronic medical record" or "electronic medical record"; Only those studies with a high impact factor were selected, which refers to the number of times the articles consulted have been cited. 64 academic studies were selected and analyzed. Results. It was found that there are still important challenges and disadvantages in the implementation of ECE such as semantic interoperability and the work stress that this system generates in users. Conclusions. There are important issues that remain to be resolved in the effective implementation of the ECE. It is necessary to integrate all those involved in the change process as well as to establish the necessary security measures to guarantee the privacy of the information.

Molecular Mechanisms Underlying the Effects of Olive Oil Triterpenic Acids in Obesity and Related Diseases.

Dietary components exert protective effects against obesity and related metabolic and cardiovascular disturbances by interfering with the molecular pathways leading to these pathologies. Dietary biomolecules are currently promising strategies to help in the management of obesity and metabolic syndrome, which are still unmet medical issues. Olive oil, a key component of the Mediterranean diet, provides an exceptional lipid matrix highly rich in bioactive molecules. Among them, the pentacyclic triterpenic acids (i.e., oleanolic acid) have gained clinical relevance in the last decade due to their wide range of biological actions, particularly in terms of vascular function, obesity and insulin resistance. Considering the promising effects of these triterpenic compounds as nutraceuticals and components of functional foods against obesity and associated complications, the aim of our review is to decipher and discuss the main molecular mechanisms underlying these effects driven by olive oil triterpenes, in particular by oleanolic acid. Special attention is paid to their signaling and targets related to glucose and insulin homeostasis, lipid metabolism, adiposity and cardiovascular dysfunction in obesity. Our study is aimed at providing a better understanding of the impact of dietary components of olive oil in the long-term management of obesity and metabolic syndrome in humans.

Comparison of antibody response to SARS-CoV-2 after two doses of inactivated virus and BNT162b2 mRNA vaccines in kidney transplant.

BACKGROUND: Antibody response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) after mRNA or adenoviral vector-based vaccines is weak in kidney transplant (KT) patients. However, few studies have focused on humoral response after inactivated virus-based vaccines in KT. Here, we compare antibody response following vaccination with inactivated virus (CoronaVac®) and BNT162b2 mRNA. METHODS: A national multicentre cross-sectional study was conducted. The study group was composed of patients from all KT centres in Uruguay, vaccinated between 1 and 31 May 2021 (CoronaVac®, n = 245 and BNT162b2, n = 39). The control group was constituted of 82 healthy individuals. Participants had no prior confirmed coronavirus disease 2019 (COVID-19) test. Blood samples were collected between 30 and 40 days after the second dose. Serum-specific immunoglobulin G (IgG) antibodies against the receptor-binding domain (RBD) of SARS-CoV-2 Spike protein were determined using the COVID-19 IgG QUANT ELISA Kit. RESULTS: Only 29% of KT recipients showed seroconversion (36.5% BNT162b2, 27.8% inactivated virus, P = 0.248) in comparison with 100% in healthy control with either vaccine. Antibody levels against RBD were higher with BNT162b mRNA than with inactivated virus [median (interquartile range) 173 (73-554) and 29 (11-70) binding antibody units (BAU)/mL, P < 0.034] in KT and 10 times lower than healthy control [inactivated virus: 308 (209-335) and BNT162b2: 2638 (2608-3808) BAU/mL, P < 0.034]. In multivariate analysis, variables associated with negative humoral response were age, triple immunosuppression, estimated glomerular filtration rate and time post-KT. CONCLUSION: Seroconversion was low in KT patients after vaccination with both platforms. Antibody levels against SARS-CoV-2 were lower with inactivated virus than BNT162b mRNA. These findings support the need for strategies to improve immunogenicity in KT recipients after two doses of either vaccine.

Polyphosphate degradation by Nudt3-Zn2+ mediates oxidative stress response.

Polyphosphate (polyP) is a polymer of hundreds of phosphate residues present in all organisms. In mammals, polyP is involved in crucial physiological processes, including coagulation, inflammation, and stress response. However, after decades of research, the metabolic enzymes are still unknown. Here, we purify and identify Nudt3, a NUDIX family member, as the enzyme responsible for polyP phosphatase activity in mammalian cells. We show that Nudt3 shifts its substrate specificity depending on the cation; specifically, Nudt3 is active on polyP when Zn2+ is present. Nudt3 has in vivo polyP phosphatase activity in human cells, and importantly, we show that cells with altered polyP levels by modifying Nudt3 protein amount present reduced viability upon oxidative stress and increased DNA damage, suggesting that polyP and Nudt3 play a role in oxidative stress protection. Finally, we show that Nudt3 is involved in the early stages of embryo development in zebrafish.

Poly-ion complex micelles effectively deliver CoA-conjugated CPT1A inhibitors to modulate lipid metabolism in brain cells.

Carnitine palmitoyltransferase 1A (CPT1A) is a central player in lipid metabolism, catalyzing the first step to fatty acid oxidation (FAO). Inhibiting CPT1A, especially in the brain, can have several pharmacological benefits, such as in treating obesity and brain cancer. C75-CoA is a strong competitive inhibitor of CPT1A. However, due to its negatively charged nature, it has low cellular permeability. Herein, we report the use of poly-ion complex (PIC) micelles to deliver the specific CPT1A inhibitors (±)-, (+)-, and (-)-C75-CoA into U87MG glioma cells and GT1-7 neurons. PIC micelles were formed through charge-neutralization of the cargo with the cationic side chain of PEG-poly{N-[N'-(2-aminoethyl)-2-aminoethyl]aspartamide} (PEG-PAsp(DET)), forming particles with 55 to 65 nm diameter. Upon short-term incubation with cells, the micelle-encapsulated CPT1A inhibitors resulted in up to 5-fold reduction of ATP synthesis compared to the free drug, without an apparent decline in cell viability. Micelle treatment showed a discernible decrease in 14C-palmitate oxidation into CO2 and acid-soluble metabolites, confirming that the substantial lowering of ATP production has resulted from FAO inhibition. Micelle treatment also diminished IC50 by 2 to 4-fold over the free drug-treated U87MG after long-term incubation. To measure the cellular uptake of these CoA-adduct loaded PIC micelles, we synthesized a fluorescent CoA derivative and prepared Fluor-CoA micelles which showed efficient internalization in the cell lines, both in 2D and 3D culture models, especially in neurons where uptake reached up to 3-fold over the free dye. Our results starkly demonstrate that the PIC micelles are a promising delivery platform for anionic inhibitors of CPT1A in glioma cells and neurons, laying the groundwork for future research or clinical applications.

Hábitos de vida y rendimiento académico en periodo evaluativo en estudiantes de enfermería / Life Habits and Academic Performance during the Examination Period in Nursing Students

Introducción: Los hábitos de vida de los estudiantes universitarios, con poco tiempo para su realización debido al estrés académico, prácticas, horario de clase y estudio, suelen ser poco saludables, por tanto, pueden influir negativamente en el rendimiento académico. Objetivo: Analizar los hábitos de vida en periodo evaluativo y su influencia en el rendimiento académico en estudiantes universitarios del grado en enfermería. Métodos: Estudio observacional descriptivo de tipo transversal realizado en el momento del examen a 488 estudiantes de los cuatro cursos del grado en enfermería de una universidad al sur de España, en el curso académico 2018. Los instrumentos empleados fueron: un cuestionario con datos sociodemográficos y otro cuestionario de hábitos de estilo de vida. El análisis de la información se realizó través de estadísticos descriptivos, pruebas paramétricas y no paramétricas y correlación lineal. Se respetaron las consideraciones éticas para estudios con humanos. Resultados: El 53,30 por ciento de la muestra realizaba ejercicio físico de forma regular, siendo similar en los cuatro cursos evaluados para los hombres mientras que en las mujeres aumentó de 31,11 por ciento en 1º a 61,26 por ciento en 4º curso. No diferencias relevantes en el rendimiento académico según variables de estilo de vida excepto sueño. Conclusiones: Las horas de sueño dormidas, sobre todo la semana previa al examen se relacionan con mayor rendimiento académico. Nuestros resultados sugieren que los estilos de vida menos saludables conllevan a peor rendimiento académico(AU)

Introduction: The life habits of university students, with little time to carry them out due to academic stress, practices, class and study hours, are usually unhealthy; therefore, they can influence academic performance negatively. Objective: To analyze life habits in the evaluation period and their influence on academic performance in university students of the Nursing degree. Methods: Descriptive, cross-sectional and observational study carried out, in the academic year 2018, at the time of examination with 488 students from the four courses of the Nursing degree from a university in southern Spain. The instruments used were a questionnaire with sociodemographic data and another lifestyle habits quiz. Information analysis was carried out through descriptive statistics, parametric and nonparametric tests, and linear correlation. Ethical considerations for human studies were respected. Results: 53.30 percent of the sample did physical exercise on a regular basis, being similar for men in the four courses assessed, while for women it increased from 31.11 percent in first academic year to 61.26 percent in the fourth academic year. There were no relevant differences in academic performance according to lifestyle variables except sleep. Conclusions: The hours of sleep per se, especially during the week before the exam, are related to higher academic performance. Our results suggest that less healthy lifestyles lead to poorer academic performance(AU)

SIRT3 deficiency exacerbates fatty liver by attenuating the HIF1α-LIPIN 1 pathway and increasing CD36 through Nrf2.

BACKGROUND: Deficiency of mitochondrial sirtuin 3 (SIRT3), a NAD+-dependent protein deacetylase that maintains redox status and lipid homeostasis, contributes to hepatic steatosis. In this study, we investigated additional mechanisms that might play a role in aggravating hepatic steatosis in Sirt3-deficient mice fed a high-fat diet (HFD). METHODS: Studies were conducted in wild-type (WT) and Sirt3-/- mice fed a standard diet or a HFD and in SIRT3-knockdown human Huh-7 hepatoma cells. RESULTS: Sirt3-/- mice fed a HFD presented exacerbated hepatic steatosis that was accompanied by decreased expression and DNA-binding activity of peroxisome proliferator-activated receptor (PPAR) α and of several of its target genes involved in fatty acid oxidation, compared to WT mice fed the HFD. Interestingly, Sirt3 deficiency in liver and its knockdown in Huh-7 cells resulted in upregulation of the nuclear levels of LIPIN1, a PPARα co-activator, and of the protein that controls its levels and localization, hypoxia-inducible factor 1α (HIF-1α). These changes were prevented by lipid exposure through a mechanism that might involve a decrease in succinate levels. Finally, Sirt3-/- mice fed the HFD showed increased levels of some proteins involved in lipid uptake, such as CD36 and the VLDL receptor. The upregulation in CD36 was confirmed in Huh-7 cells treated with a SIRT3 inhibitor or transfected with SIRT3 siRNA and incubated with palmitate, an effect that was prevented by the Nrf2 inhibitor ML385. CONCLUSION: These findings demonstrate new mechanisms by which Sirt3 deficiency contributes to hepatic steatosis. Video abstract.

Drug uptake-based chemoresistance in breast cancer treatment.

Breast cancer is the most prevalent type of tumor and the second leading cause of death due to cancer among women. Although screening methods, diagnosis and therapeutic options have improved in the last decade, chemoresistance remains an important challenge. There is evidence relating breast cancer resistance with signaling pathways involving hormone and growth receptors, survival, apoptosis and the activation of efflux pumps. However, the resistance mechanisms linked to drug uptake are poorly understood, despite it often being observed that the drug content is lower in resistant cancer cells and that the entry of the drug into these cells is a limiting process for the subsequent therapeutic effect.In this review, we provide an overview of drug uptake-based resistance mechanisms developed by cancer cells in the four main types of chemotherapy used in breast cancer: anthracyclines, taxanes, oxazaphosphorines and platinum-based drugs. The contribution of tumor microenvironment to reduced drug-uptake and multidrug resistance is also analyzed. As a developing field, nanomedicine-based approaches provide promising opportunities to improve drug specific targeting, cell interaction and uptake into cancer cells. The endocytic-mediated pathways attributed to the different types of nanoformulations as well as the contribution of nanotherapeutics to overcoming chemoresistance affecting drug uptake in breast cancer will be described. New approaches focusing on drug uptake mechanisms could improve breast cancer chemotherapy, obtaining better dose-response outcomes and reducing toxic side effects.

Hypothalamic Regulation of Liver and Muscle Nutrient Partitioning by Brain-Specific Carnitine Palmitoyltransferase 1C in Male Mice.

Carnitine palmitoyltransferase (CPT) 1C, a brain-specific protein localized in the endoplasmic reticulum of neurons, is expressed in almost all brain regions. Based on global knockout (KO) models, CPT1C has demonstrated relevance in hippocampus-dependent spatial learning and in hypothalamic regulation of energy balance. Specifically, it has been shown that CPT1C is protective against high-fat diet-induced obesity (DIO), and that CPT1C KO mice show reduced peripheral fatty acid oxidation (FAO) during both fasting and DIO. However, the mechanisms mediating CPT1C-dependent regulation of energy homeostasis remain unclear. Here, we focus on the mechanistic understanding of hypothalamic CPT1C on the regulation of fuel selection in liver and muscle of male mice during energy deprivation situations, such as fasting. In CPT1C-deficient mice, modulation of the main hypothalamic energy sensors (5' adenosine monophosphate-activated protein kinase, Sirtuin 1, and mammalian target of rapamycin) was impaired and plasma catecholamine levels were decreased. Consequently, CPT1C-deficient mice presented defective fasting-induced FAO in liver, leading to higher triacylglycerol accumulation and lower glycogen levels. Moreover, muscle pyruvate dehydrogenase activity was increased, which was indicative of glycolysis enhancement. The respiratory quotient did not decrease in CPT1C KO mice after 48 hours of fasting, confirming a defective switch on fuel substrate selection under hypoglycemia. Phenotype reversion studies identified the mediobasal hypothalamus (MBH) as the main area mediating CPT1C effects on fuel selection. Overall, our data demonstrate that CPT1C in the MBH is necessary for proper hypothalamic sensing of a negative energy balance and fuel partitioning in liver and muscle.

Rice bran prevents high-fat diet-induced inflammation and macrophage content in adipose tissue.

BACKGROUND: The inflammatory process associated with obesity mainly arises from white adipose tissue (WAT) alterations. In the last few years, nutritional-based strategies have been positioned as promising alternatives to pharmacological approaches against these pathologies. Our aim was to determine the potential of a rice bran enzymatic extract (RBEE)-supplemented diet in the prevention of metabolic, biochemical and functional adipose tissue and macrophage changes associated with a diet-induced obesity (DIO) in mice. METHODS: C57BL/6J mice were fed high-fat diet (HF), 1 and 5 % RBEE-supplemented high-fat diet (HF1 % and HF5 %, respectively) and standard diet as control. Serum cardiometabolic parameters, adipocytes size and mRNA expression of pro-inflammatory biomarkers and macrophage polarization-related genes from WAT and liver were evaluated. RESULTS: RBEE administration significantly decreased insulin resistance in obese mice. Serum triglycerides, total cholesterol, glucose, insulin, adiponectin and nitrites from treated mice were partially restored, mainly by 1 % RBEE-enriched diet. The incremented adipocytes size observed in HF group was reduced by RBEE treatment, being 1 % more effective than 5 % RBEE. Pro-inflammatory biomarkers in WAT such as IL-6 and IL-1ß were significantly decreased in RBEE-treated mice. Adiponectin, PPARγ, TNF-α, Emr1 or M1/M2 levels were significantly restored in WAT from HF1 % compared to HF mice. CONCLUSIONS: RBEE-supplemented diet attenuated insulin resistance, dyslipidemia and morphological and functional alterations of adipose tissue in DIO mice. These benefits were accompanied by a modulating effect in adipocytes secretion and some biomarkers associated with macrophage polarization. Therefore, RBEE may be considered an alternative nutritional complement over metabolic syndrome and its complications.

Carnitine palmitoyltransferase 1C: From cognition to cancer.

Carnitine palmitoyltransferase 1 (CPT1) C was the last member of the CPT1 family of genes to be discovered. CPT1A and CPT1B were identified as the gate-keeper enzymes for the entry of long-chain fatty acids (as carnitine esters) into mitochondria and their further oxidation, and they show differences in their kinetics and tissue expression. Although CPT1C exhibits high sequence similarity to CPT1A and CPT1B, it is specifically expressed in neurons (a cell-type that does not use fatty acids as fuel to any major extent), it is localized in the endoplasmic reticulum of cells, and it has minimal CPT1 catalytic activity with l-carnitine and acyl-CoA esters. The lack of an easily measurable biological activity has hampered attempts to elucidate the cellular and physiological role of CPT1C but has not diminished the interest of the biomedical research community in this CPT1 isoform. The observations that CPT1C binds malonyl-CoA and long-chain acyl-CoA suggest that it is a sensor of lipid metabolism in neurons, where it appears to impact ceramide and triacylglycerol (TAG) metabolism. CPT1C global knock-out mice show a wide range of brain disorders, including impaired cognition and spatial learning, motor deficits, and a deregulation in food intake and energy homeostasis. The first disease-causing CPT1C mutation was recently described in humans, with Cpt1c being identified as the gene causing hereditary spastic paraplegia. The putative role of CPT1C in the regulation of complex-lipid metabolism is supported by the observation that it is highly expressed in certain virulent tumor cells, conferring them resistance to glucose- and oxygen-deprivation. Therefore, CPT1C may be a promising target in the treatment of cancer. Here we review the molecular, biochemical, and structural properties of CPT1C and discuss its potential roles in brain function, and cancer.

An Enzymatically Active ß-1,3-Glucanase from Ash Pollen with Allergenic Properties: A Particular Member in the Oleaceae Family.

Endo-ß-1,3-glucanases are widespread enzymes with glycosyl hydrolitic activity involved in carbohydrate remodelling during the germination and pollen tube growth. Although members of this protein family with allergenic activity have been reported, their effective contribution to allergy is little known. In this work, we identified Fra e 9 as a novel allergenic ß-1,3-glucanase from ash pollen. We produced the catalytic and carbohydrate-binding domains as two independent recombinant proteins and characterized them from structural, biochemical and immunological point of view in comparison to their counterparts from olive pollen. We showed that despite having significant differences in biochemical activity Fra e 9 and Ole e 9 display similar IgE-binding capacity, suggesting that ß-1,3-glucanases represent an heterogeneous family that could display intrinsic allergenic capacity. Specific cDNA encoding Fra e 9 was cloned and sequenced. The full-length cDNA encoded a polypeptide chain of 461 amino acids containing a signal peptide of 29 residues, leading to a mature protein of 47760.2 Da and a pI of 8.66. An N-terminal catalytic domain and a C-terminal carbohydrate-binding module are the components of this enzyme. Despite the phylogenetic proximity to the olive pollen ß-1,3-glucanase, Ole e 9, there is only a 39% identity between both sequences. The N- and C-terminal domains have been produced as independent recombinant proteins in Escherichia coli and Pichia pastoris, respectively. Although a low or null enzymatic activity has been associated to long ß-1,3-glucanases, the recombinant N-terminal domain has 200-fold higher hydrolytic activity on laminarin than reported for Ole e 9. The C-terminal domain of Fra e 9, a cysteine-rich compact structure, is able to bind laminarin. Both molecules retain comparable IgE-binding capacity when assayed with allergic sera. In summary, the structural and functional comparison between these two closely phylogenetic related enzymes provides novel insights into the complexity of ß-1,3-glucanases, representing a heterogeneous protein family with intrinsic allergenic capacity.

Structural, mechanical and myogenic properties of small mesenteric arteries from ApoE KO mice: characterization and effects of virgin olive oil diets.

OBJECTIVE: We analyzed the structural, mechanical, myogenic and functional properties of resistance arteries of ApoE KO compared to wild type (WT) mice. We also determined the influence of saturated fat in comparison to virgin olive oil-enriched diets in vascular wall abnormalities. METHODS: Male ApoE KO (ApoE) and WT mice (8-weeks-old) were assigned to the groups: standard chow diet (SD), high fat diet (HFD), virgin olive oil (VOO) and high polyphenol-VOO-enriched diet (Oleaster(®)) (OT) (15% w/w). After 20 weeks, structural, mechanical and myogenic properties of isolated small mesenteric arteries (SMA) were analyzed by pressure myography. For functional studies, vasodilatation to acetylcholine was assessed. Arterial superoxide anion production was measured by ethidium fluorescence. RESULTS: Hypertrophic remodeling and distensibility in ApoE KO SMA was lower compared to WT mice, suggesting an alteration in the autoregulation mechanisms aimed to compensate disease progression. However, ApoE deficiency resulted in a lower impairment in myogenic tone in response to intraluminal pressure, in addition to an improved endothelium-dependent hyperpolarizing vasodilatation. Also, we evidenced the beneficial effects of VOO in contrast to a saturated fat-enriched diet on SMA wall disorders. Only the endothelial function improvement induced by olive oil was dependent on polyphenols content. CONCLUSION: Resistance arteries structure, mechanic, myogenic and functional responses from ApoE KO mice significantly differ from WT mice, evidencing the influence of the type of diet on these disorders. These results are particularly useful to determine the contribution of resistance arteries during the atherosclerotic process and to provide novel insights into the Mediterranean dietary pattern to reduce the burden of atherosclerotic disease.

Oleanolic acid and related triterpenoids from olives on vascular function: molecular mechanisms and therapeutic perspectives.

Oleanolic acid and related triterpenoids from olives modulate different signaling pathways, showing a wide range of pharmacological activities against inflammation, cancer or cardiovascular diseases. In particular, emerging evidences reveal the potential of oleanolic acid to restore vascular disorders associated to cardiovascular risk factors, i.e. hypertension, obesity and diabetes, and atherosclerosis. During the previous years, in vitro and in vivo studies with these triterpenoids have positioned them as being mainly responsible for cardiovascular risk protection traditionally associated to olive oil. This review updates recent investigations in olive oil triterpenoids function related to cardiovascular diseases, as well as the underlying mechanisms and structural implications. Important aspects of olive oil triterpenoids such as bioavailability and clinical perspectives on cardiovascular disorder are also extensively analyzed. All these investigations evidence the potential of triterpenoids from olive oil as a promising therapeutic strategy against vascular function, thus efficiently preventing the progression of cardiovascular diseases.

Rice bran enzymatic extract-supplemented diets modulate adipose tissue inflammation markers in Zucker rats.

OBJECTIVE: Chronic low-grade inflammation in obesity is characterized by macrophage accumulation in white adipose tissue and adipokine production deregulation. Obesity also is characterized by oxidative stress related to inflammatory signaling. The aim of this study was to analyze whether dietary supplementation with a rice bran enzymatic extract (RBEE), rich in bioactive compounds with antioxidant and hypocholesterolemic properties, would ameliorate the inflammatory state existing in visceral adipose tissue of obese Zucker rats. METHODS: Obese Zucker rats and their littermate controls, lean Zucker rats ages 8 wk, were daily fed an enriched diet with either 1% or 5% RBEE supplementation over 20 wk. Measurement of adipocyte size and mRNA expression of proinflammatory molecules from visceral abdominal/epididymal tissue was performed. RESULTS: An RBEE-supplemented diet decreased the overproduction of tumor necrosis factor-α, interleukin (IL)-6, IL-1 ß, and inducible nitric oxide synthase (iNOS), as well as the overproduction of IL-6 and iNOs in visceral abdominal adipose tissue and visceral epididymal adipose tissue, respectively. An RBEE-supplemented diet modified the adipocyte-size distribution pattern in both abdominal and epididymal adipose tissue, shifting it toward smaller cell sizes. CONCLUSIONS: Chronic administration of a novel water-soluble RBEE, rich in polyphenols, tocotrienols and γ-oryzanol, could be a suitable treatment to ameliorate the obesity-associated proinflammatory response.