Summary
Objective
Both glucagon‐like peptide‐1 (GLP‐1) and peptide YY (PYY) are gut hormones involved in energy homoeostasis. Obesity, insulin resistance and hyperglycaemia are significant ...confounders when GLP‐1 and PYY secretion is assessed. Thus, we evaluated GLP‐1 and PYY response after fat load in morbidly obese patients with different degrees of insulin resistance and glycemic status.
Design
We studied 40 morbidly obese subjects (mean age, 40·6 ± 1·3 years; mean BMI, 53·1 ± 1·2 kg/m2) divided into groups according to their glycemic status: normal fasting glucose (NFG) group, impaired fasting glucose (IFG) group and type 2 diabetes mellitus (T2D) group. NFG patients were additionally subclassified, according to the homoeostasis model assessment of insulin resistance (HOMAIR), into a low insulin‐resistance (LIR) group (HOMAIR <3·9) or a high insulin‐resistance (HIR) group (HOMAIR ≥3·9).
Measurements
Lipid emulsion was administered orally and measurements made at baseline and 180 min postprandially of levels of GLP‐1, PYY, insulin, glucose, free fatty acids, triglycerides and leptin.
Results
At the 180‐minute postprandial reading, GLP‐1 and PYY had increased in LIR‐NFG subjects (41·84%, P = 0·01; 35·7%, P = 0·05; respectively), whereas no changes were observed in HIR‐NFG, IFG or T2D subjects.
Conclusions
These results suggest that in morbidly obese subjects, both insulin resistance and abnormal glucose metabolism (IFG or T2D) impair the GLP‐1 and PYY response to fat load. The implications of this attenuated enteroendocrine response should be elucidated by further studies.
Mesenchymal stromal cells (MSCs) currently constitute the most frequently used cell type in advanced therapies with different purposes, most of which are related with inflammatory processes. Although ...the therapeutic efficacy of these cells has been clearly demonstrated in different disease animal models and in numerous human phase I/II clinical trials, only very few phase III trials using MSCs have demonstrated the expected potential therapeutic benefit. On the other hand, diverse controversial issues on the biology and clinical applications of MSCs, including their specific phenotype, the requirement of an inflammatory environment to induce immunosuppression, the relevance of the cell dose and their administration schedule, the cell delivery route (intravascular/systemic vs. local cell delivery), and the selected cell product (i.e., use of autologous vs. allogeneic MSCs, freshly cultured vs. frozen and thawed MSCs, MSCs vs. MSC-derived extracellular vesicles, etc.) persist. In the current review article, we have addressed these issues with special emphasis in the new approaches to improve the properties and functional capabilities of MSCs after distinct cell bioengineering strategies.
Prader⁻Willi syndrome (PWS) is a complex genetic disorder that, besides cognitive impairments, is characterized by hyperphagia, obesity, hypogonadism, and growth impairment. Proprotein convertase ...subtilisin/kexin type 1 (
) deficiency, a rare recessive congenital disorder, partially overlaps phenotypically with PWS, but both genetic disorders show clear dissimilarities as well. The recent observation that
is downregulated in a model of human PWS suggests that overlapping pathways are affected. In this review we will not only discuss the mechanisms by which PWS and
deficiency could lead to hyperphagia but also the therapeutic interventions to treat obesity in both genetic disorders.
Studies have proposed that mesenchymal stem cells (MSCs) improve the hematopoietic engraftment in allogeneic or xenogeneic transplants and this is probably due to the MSCs' immunosuppressive ...properties. Our study aimed to discern, for the first time, whether MSC infusion could facilitate the engraftment of hematopoietic stem cells (HSCs) in autologous transplantations models, where no immune rejection of donor HSCs is expected.
Recipient mice (CD45.2) mice, conditioned with moderate doses of radiation (5-7 Gy), were transplanted with low numbers of HSCs (CD45.1/CD45.2) either as a sole population or co-infused with increasing numbers of adipose-derived-MSCs (Ad-MSCs). The influence of Ad-MSC infusion on the short-term and long-term engraftment of donor HSCs was investigated. Additionally, homing assays and studies related with the administration route and with the Ad-MSC/HSC interaction were conducted.
Our data show that the co-infusion of Ad-MSCs with low numbers of purified HSCs significantly improves the short-term and long-term hematopoietic reconstitution of recipients conditioned with moderate irradiation doses. This effect was Ad-MSC dose-dependent and associated with an increased homing of transplanted HSCs in recipients' bone marrow. In vivo and in vitro experiments also indicate that the Ad-MSC effects observed in this autologous transplant model are not due to paracrine effects but rather are related to Ad-MSC and HSC interactions, allowing us to propose that Ad-MSCs may act as HSC carriers, facilitating the migration and homing of the HSCs to recipient bone marrow niches.
Our results demonstrate that Ad-MSCs facilitate the engraftment of purified HSCs in an autologous mouse transplantation model, opening new perspectives in the application of Ad-MSCs in autologous transplants, including HSC gene therapy.
Many food items included in the Mediterranean diet (MedDiet) are rich in polyamines, small aliphatic amines with potential cardioprotective effects. The consumption of a MedDiet could increase ...polyamine concentrations. Based on experimental models, polyamine concentrations may be also influenced by physical activity (PA).
We aimed to evaluate whether an intervention based on an energy-restricted MedDiet (er-MedDiet) and PA promotion, in comparison with an energy-unrestricted MedDiet and traditional health care, influences the serum pattern of polyamines and related metabolites in subjects at high risk of cardiovascular disease (CVD).
This was a substudy from the PREDIMED-Plus trial, an ongoing randomized clinical trial including 6874 participants allocated either to an intensive weight-loss lifestyle intervention based on er-MedDiet, PA promotion, and behavioral support (er-MedDiet + PA group), or to an energy-unrestricted MedDiet and traditional health care group (MedDiet group). A total of 75 patients (n = 38, er-MedDiet + PA group; n = 37, MedDiet group) were included in this study. Serum concentrations of arginine, ornithine, polyamines, and acetyl polyamines at baseline and 26 wk of intervention were measured by an ultra-high-performance LC–tandem MS platform.
At week 26, study groups had similar adherence to the MedDiet but patients randomly assigned to the er-MedDiet + PA group showed significantly lower mean energy intake (−340.3 kcal/d; 95% CI: −567.3, −113.4 kcal/d; P = 0.004), higher mean PA (1290.6; 95% CI: 39.9, 2541.3 metabolic equivalent tasks · min/d; P = 0.043), and higher mean decrease in BMI (in kg/m2) (−1.3; 95% CI: −1.8, −0.6; P < 0.001) than the MedDiet group. However, no significant differences in serum polyamines or related metabolites were found between study groups after 26 wk of intervention and no significant between-group differences were found in glycated hemoglobin, HDL-cholesterol, or triglyceride concentrations.
In individuals at high CVD risk, an er-MedDiet with increased PA did not result in significant changes of serum concentrations of polyamines or related metabolites in comparison with an energy-unrestricted MedDiet and no increase in PA. This trial was registered at isrctn.com as ISRCTN89898870.
The Mediterranean diet is a healthy dietary pattern that emphasizes the consumption of vegetables, fruits, whole grains, fish, and unsaturated fats such olive oil and nuts, and aims to limit the consumption of saturated fats found in butter and read meats, and sweets. Multiple studies have reported evidence for an inverse relationship between adherence to Mediterranean diet and risk of cardiovascular disease-related mortality associated to the metabolic syndrome. Previous studies on nutritional metabolomics have shown that a higher adherence to the Mediterranean diet is associated to an increase in specific metabolites in the circulation. Remarkably, many food items included in the Mediterranean diet such as fruits, vegetables, legumes, whole grains, fish and nuts are rich in polyamines such as spermidine and spermine, small molecules with potent anti-aging and cardioprotective effects. In this work we have evaluated whether an intervention based on an energy-restricted MedDiet and physical promotion, in comparison with an energy-unrestricted MedDiet and traditional health care, influences the serum pattern of polyamines and related metabolites in subjects at high cardiovascular risk.
Background
Monoamine oxidase (MAO) activity has been traditionally implicated in blood pressure through its effects on biogenic amine levels such as catecholamines, serotonin, and dopamine. Nowadays, ...this role is considered relegated to side‐effects such as orthostatic hypotension and/or hypertensive crisis derived from MAO‐inhibitory treatments in patients with psychiatric disease.
Methods
In the present work we have found an association between a polymorphic variant of MAOB gene and arterial hypertension in obese hypogonadic patients. The study cases comprised a series of 219 nondiabetic males with a body mass index ≥30 kg/m2 and aged <45 years. Hypogonadism was defined as subnormal testosterone concentrations, when free testosterone values ranged <65 pg/ml.
Results
MAOB rs3027452‐A allele carriers were significantly over‐represented among hypertensive (HT) patients (25.49%) in comparison to either the non‐HT patients (10%, OR = 3.079 CI95 1.364–6.952, p = .005, Chi‐square test) and the control population series of nonobese nor hypogonadic males (also 10%, p = .003 Chi‐square test). Upon adjusted, an independent association was shown with the hypogonadic group with hypertension when compared with nonhypertensive hypogonadics (Beta = 3.653, p = .005). When quantitative analysis was performed, hypertensive patients harboring rs3027452‐A allele showed higher systolic blood pressure values (p = .038, Mann–Whitney U‐test) as well as an increased Systolic‐Diastolic range despite following HT treatment (∆mmHg 54 vs. 48 for rs3027452‐A and rs3027452‐G respectively, p‐value .019, Mann–Whitney U‐test). Previous studies on MAOB revealed that rs3027452‐A allele has been correlated to a lower activity of the enzyme, what gives a functional evidence over our observation.
Conclusion
If this result could be extrapolated to other hypertensive patient groups, it would implicate a review of the markers and therapeutic targets on human hypertension.
Male hypogonadism is a disorder in which the testes are not functional or there is a genetic inability of the hypothalamus to secrete normal amounts of GnRH. The masculine sexual characteristics are not developed and can bring a wide range of clinical manifestations. We have found an association between a polymorphic variant of MAOB gene and arterial hypertension in obese hypogonadic patients.
New human β‐glucocerebrosidase (GCase) ligands with rigid 1,6‐anhydro‐β‐L‐idonojirimycin cores have been designed with the aid of molecular modeling. Efficient pharmacological chaperones for the ...L444P (trafficking‐incompetent) mutant GCase enzyme associated with type 2 and 3 Gaucher disease (GD) were identified.
CYLD is a deubiquitinating enzyme known for its role as a tumor suppressor whose mutation leads to skin appendages tumors and other cancers. In this manuscript we report that the tumor suppressor ...CYLD, similarly to other renowned tumor suppressor genes, protects from premature aging and cancer. We have generated transgenic mice expressing the mutant CYLD
protein, lacking its deubiquitinase function, under the control of the keratin 5 promoter, the K5-CYLD
mice. These mice express the transgene in different organs, including those considered to be more susceptible to aging, such as skin and thymus. Our results show that K5-CYLD
mice exhibit epidermal, hair follicle, and sebaceous gland alterations; and, importantly, they show signs of premature aging from an early age. Typically, 3-month-old K5-CYLD
mice exhibit a phenotype characterized by alopecia and kyphosis, and, the histological examination reveals that transgenic mice show signs of accelerated aging in numerous organs such as skin, thymus, pancreas, liver and lung. Additionally, they spontaneously develop tumors of diverse origin. Over-activation of the NF-κB pathway, along with hyperactivation of Akt, JNK and c-Myc, and chronic inflammation, appear as the mechanisms responsible for the premature aging of the K5-CYLD
mice.
La constatación empírica, así como la argumentación teórica, de que la violencia contra las mujeres se sustenta en factores de tipo psicológico y social, nos lleva a explorar variables como la ...estima, el estilo de apego y el sexismo en jóvenes universitarios, cuyo futuro desarrollo profesional está ligado a la educación infantil. Nos planteamos un diseño de investigación ex pos facto con una muestra de 124 estudiantes del Grado en Educación Infantil. Esperamos que los resultados revelen, el posible valor predictivo del estilo de apego y la estima en manifestaciones sexistas, así como estrategias de intervención, eficaces y concretas en el ámbito de la formación del profesorado.
Owing to its roles in human health and disease, the modification of nuclear, cytoplasmic, and mitochondrial proteins with O-linked N-acetylglucosamine residues (O-GlcNAc) has emerged as a topic of ...great interest. Despite the presence of O-GlcNAc on hundreds of proteins within cells, only two enzymes regulate this modification. One of these enzymes is O-GlcNAcase (OGA), a dimeric glycoside hydrolase that has a deep active site cleft in which diverse substrates are accommodated. Chemical tools to control OGA are emerging as essential resources for helping to decode the biochemical and cellular functions of the O-GlcNAc pathway. Here we describe rationally designed bicyclic thiazolidine inhibitors that exhibit superb selectivity and picomolar inhibition of human OGA. Structures of these inhibitors in complex with human OGA reveal the basis for their exceptional potency and show that they extend out of the enzyme active site cleft. Leveraging this structure, we create a high affinity chemoproteomic probe that enables simple one-step purification of endogenous OGA from brain and targeted proteomic mapping of its post-translational modifications. These data uncover a range of new modifications, including some that are less-known, such as O-ubiquitination and N-formylation. We expect that these inhibitors and chemoproteomics probes will prove useful as fundamental tools to decipher the mechanisms by which OGA is regulated and directed to its diverse cellular substrates. Moreover, the inhibitors and structures described here lay out a blueprint that will enable the creation of chemical probes and tools to interrogate OGA and other carbohydrate active enzymes.
PDF
