First Report of Two Gymnodimines and Two Tetrodotoxin Analogues in Invertebrates from the North Atlantic Coast of Spain.

Gymnodimine D (GYM D), 16-desmethyl gymnodimine D (16-desmethyl GYM D), and two tetrodotoxin analogues have been found in invertebrates obtained from the north Atlantic coast of Spain from May 2021 to October 2022. It is the first report of GYMD and 16-desmethyl GYM D in invertebrates worldwide and of the tetrodotoxin analogues, 5,6,11 trideoxy tetrodotoxin (5,6,11 trideoxy TTX) and its isomer (referred to as 5,6,11 trideoxy-epi-TTX), in the north Atlantic Coast of Spain. In this study, we also report for the first time the detection of tetrodotoxin (TTX) in three species (the cnidaria Calliactis parasitica, an unidentified species, and the bivalve Tellina donacina). The prevalence was medium for GYM D and 16-desmethyl GYM D and low for TTXs overall. The concentrations recorded were variable, with maximum values of GYM D in the bivalve Cerastoderma edule (8.8 µg GYM A equivalents kg-1), of 16-desmethyl GYM D in the bivalve Magellana gigas (10 µg GYM A equivalents kg-1) and of TTX and 5,6,11 trideoxy TTX in the cnidaria C. parasitica (49.7 and 233 µg TTX equivalents kg-1, respectively). There is very scarce information about these compounds. Therefore, the reporting of these new detections will increase the knowledge on the current incidence of marine toxins in Europe that the European Food Safety Authority (EFSA), in particular, and the scientific community, in general, have. This study also highlights the importance of analyzing toxin analogues and metabolites for effective monitoring programs and adequate health protection.

Exploiting the Features of Short Peptides to Recognize Specific Cell Surface Markers.

Antibodies are the macromolecules of choice to ensure specific recognition of biomarkers in biological assays. However, they present a range of shortfalls including a relatively high production cost and limited tissue penetration. Peptides are relatively small molecules able to reproduce sequences of highly specific paratopes and, although they have less biospecificity than antibodies, they offer advantages like ease of synthesis, modifications of their amino acid sequences and tagging with fluorophores and other molecules required for detection. This work presents a strategy to design peptide sequences able to recognize the CD44 hyaluronic acid receptor present in the plasmalemma of a range of cells including human bone marrow stromal mesenchymal cells. The protocol of identification of the optimal amino acid sequence was based on the combination of rational design and in silico methodologies. This protocol led to the identification of two peptide sequences which were synthesized and tested on human bone marrow mesenchymal stromal cells (hBM-MSCs) for their ability to ensure specific binding to the CD44 receptor. Of the two peptides, one binds CD44 with sensitivity and selectivity, thus proving its potential to be used as a suitable alternative to this antibody in conventional immunostaining. In the context of regenerative medicine, the availability of this peptide could be harnessed to functionalize tissue engineering scaffolds to anchor stem cells as well as to be integrated into systems such as cell sorters to efficiently isolate MSCs from biological samples including various cell subpopulations. The data here reported can represent a model for developing peptide sequences able to recognize hBM-MSCs and other types of cells and for their integration in a range of biomedical applications.

Prenatal and Early Postnatal Cerebral d-Aspartate Depletion Influences l-Amino Acid Pathways, Bioenergetic processes, and Developmental Brain Metabolism.

d-Amino acids were believed to occur only in bacteria and invertebrates. Today, it is well known that d-amino acids are also present in mammalian tissues in a considerable amount. In particular, high levels of free d-serine (d-Ser) and d-aspartate (d-Asp) are found in the brain. While the functions of d-Ser are well known, many questions remain unanswered regarding the role of d-Asp in the central nervous system. d-Asp is very abundant at the embryonic stage, while it strongly decreases after birth because of the expression of d-aspartate oxidase (Ddo) enzyme, which catalyzes the oxidation of this d-amino acid into oxaloacetate, ammonium, and hydrogen peroxide. Pharmacologically, d-Asp acts as an endogenous agonist of N-methyl d-aspartate and mGlu5 receptors, which are known to control fundamental brain processes, including brain development, synaptic plasticity, and cognition. In this work, we studied a recently generated knockin mouse model (R26ddo/ddo), which was designed to express DDO beginning at the zygotic stage. This strategy enables d-Asp to be almost eliminated in both prenatal and postnatal lives. To understand which biochemical pathways are affected by depletion of d-Asp, in this study, we carried out a metabolomic and lipidomic study of ddo knockin brains at different stages of embryonic and postnatal development, combining nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS) techniques. Our study shows that d-Asp deficiency in the brain influences amino acid pathways such as threonine, glycine, alanine, valine, and glutamate. Interestingly, d-Asp is also correlated with metabolites involved in brain development and functions such as choline, creatine, phosphocholine (PCho), glycerophosphocholine (GPCho), sphingolipids, and glycerophospholipids, as well as metabolites involved in brain energy metabolism, such as GPCho, glucose, and lactate.

Effect of Very-Low-Calorie Ketogenic Diet on Psoriasis Patients: A Nuclear Magnetic Resonance-Based Metabolomic Study.

Psoriasis is an inflammatory disease of the epidermis based on an immunological mechanism involving Langerhans cells and T lymphocytes that produce pro-inflammatory cytokines. Genetic factors, environmental factors, and improper nutrition are considered triggers of the disease. Numerous studies have reported that in a high number of patients, psoriasis is associated with obesity. Excess adipose tissue, typical of obesity, causes a systemic inflammatory status coming from the inflammatory active adipose tissue; therefore, weight reduction is a strategy to fight this pro-inflammatory state. This study aimed to evaluate how a nutritional regimen based on a ketogenic diet influenced the clinical parameters, metabolic profile, and inflammatory state of psoriasis patients. To this end, 30 psoriasis patients were subjected to a ketogenic nutritional regimen and monitored for 4 weeks by evaluating the clinical data, biochemical and clinical parameters, NMR metabolomic profile, and IL-2, IL-1ß, TNF-α, IFN-γ, and IL-4 concentrations before and after the nutritional regimen. Our data show that a low-calorie ketogenic diet can be considered a successful strategy and therapeutic option to gain an improvement in psoriasis-related dysmetabolism, with significant correction of the full metabolic and inflammatory status.

Development of a Fast Liquid Chromatography Coupled to Mass Spectrometry Method (LC-MS/MS) to Determine Fourteen Lipophilic Shellfish Toxins Based on Fused-Core Technology: In-House Validation.

Prevalence and incidence of the marine toxins (paralytic, amnesic, and lipophilic toxins) including the so-called emerging toxins (these are, gymnodimines, pinnatoxins, or spirolides among others) have increased in recent years all over the world. Climate change, which is affecting the distribution of their producing phytoplankton species, is probably one of the main causes. Early detection of the toxins present in a particular area, and linking the toxins to their causative phytoplankton species are key tools to minimize the risk they pose for human consumers. The development of both types of studies requires fast and highly sensitive analytical methods. In the present work, we have developed a highly sensitive liquid chromatography-mass spectrometry methodology (LC-MS/MS), using a column with fused-core particle technology, for the determination of fourteen lipophilic toxins in a single run of 3.6 min. The performance of the method was evaluated for specificity, linearity, precision (repeatability and reproducibility) and accuracy by analysing spiked and naturally contaminated samples. The in-house validation was successful, and the limit of detection (LOD) and quantification (LOQ) for all the toxins were far below their regulatory action limits. The method is suitable to be considered in monitoring systems of bivalves for food control.

[Transformations in the health system in Cuba and current strategies for its consolidation and sustainabilityTransformações no sistema de saúde em Cuba e estratégias atuais para sua consolidação e sustentabilidade]. / Transformaciones en el sistema de salud en Cuba y estrategias actuales para su consolidación y sostenibilidad.

In Cuba, universal access and health coverage rest on three key principles: health as a human right, equity and solidarity. Although many of the Cuban health indicators are among the best in the Region of the Americas, in 2011 it was decided to reorganize health services, in line with the process of updating the Cuban economic and social model that occurred in all sectors. For this purpose, an action-research project was designed, including a situation diagnosis, implementation of changes and evaluation of the results, in several stages. As a result, human resources were rationalized with a reduction of more than 150 000 posts not directly linked to patient care, management structures were reduced in 57 municipalities, 46 polyclinics were compacted, the Family Physician and Nurse Program was optimized with 20 specialties for the community care, teaching was reorganized, and the international medical cooperation programs were revisited. These changes have contributed to improving the sustaina-bility of the National Health System and its performance: increase in the number of consultations at the primary level (19.3%) and oral care visits (56.6%), reduction in the number of visits to emergency rooms (16.1%), increase in the number of patients surgically treated (12.1%), increase in the number of research projects (300%) and increase in the number of medical students (55.7%), among others. In Cuba, transformations in health is an ongoing project.

Em Cuba, o acesso universal e a cobertura de saúde dependem de três princípios fundamentais: a saúde como direito humano, equidade e solidariedade. Embora muitos dos indicadores de saúde cubanos estejam entre os melhores da Região das Americas, em 2011 foi decidido reorganizar os serviços de saúde, de acordo com o processo de atualização do modelo econômico e social cubano ocorrido em todos os setores do país. Para o efeito, foi elaborado um projeto de pesquisa-ação, que incluiu o diagnóstico da situação, a implementação das mudanças e a avaliação dos resultados, em várias etapas. Como resultado, os recursos humanos foram racionalizados com uma redução de mais de 150 000 postos não diretamente ligados ao atendimento ao paciente, as estruturas de manejo foram reduzidas em 57 municípios, 46 policlínicas foram compactadas, o Programa Médico e Enfermeiro da Familia foi otimizado com a projeção para a comunidade de 20 especialidades, o ensino foi reorganizado, e os programas internacionais de cooperação médica foram reordenados. Essas mudanças contribuíram para melhorar a sustentabilidade do Sistema Nacional de Saúde e seu desempenho: aumento do número de consultas no nível primário (19,3%) e odontologia (56,6%), redução do número de consultas na emergência (16,1%), aumento do número de pacientes tratados cirurgicamente (12,1%), aumento do número de projetos de pesquisa (300%) e crescimento do número de estudantes de medicina (55,7%), entre outros. O projeto de transformação em saúde realizado em Cuba continua.

Efficacy of cognitive rehabilitation of attention, executive functions, and working memory in psychotic disorders: A systematic review.

dies have postulated that it is the basis of the disease as evidenced by its independent and persistent quality and its relation to prognosis. Research on cognitive deficits in psychotic disorders has led to the development of intervention strategies for the cognitive rehabilitation of these patients. Attention, working memory, and executive functions are among the most widely affected functions and are closely related to the functionality of these patients. This work aims to study the effectiveness of cognitive rehabilitation targeting attention, executive functions, and working memory in people diagnosed with a psychotic disorder (mostly schizophrenia). An exhaustive search in PubMed and PsycINFO was conducted up to January 2016. All research papers that were included studied a therapeutic technique to improve one or more of the aforementioned functions in patients over age 16 years diagnosed with psychotic disorder. Studies with methodological diversity were included, which were afterwards organized by levels of evidence. Thirty-four papers were studied, from which we can conclude that cognitive rehabilitation of the aforementioned cognitive functions brings about improvements in cognition. As a result of the influence of cognitive rehabilitation on other variables such as social functioning and symptoms of the disease, the results are promising.

Peptides as modulators of FPPS enzyme: A multifaceted evaluation from the design to the mechanism of action.

Bone diseases are medical conditions caused by the loss of bone homeostasis consecutive to increased osteoclast activity and diminished osteoblast activity. The mevalonate pathway (MVA) is crucial for maintaining this balance since it drives the post-translational prenylation of small guanosine triphosphatases (GTPases) proteins. Farnesyl pyrophosphate synthase (FPPS) plays a crucial role in the MVA pathway. Consequently, in the treatment of bone-related diseases, FPPS is the target of FDA-approved nitrogen-containing bisphosphonates (N-BPs), which have tropism mainly for bone tissue due to their poor penetration in soft tissues. The development of inhibitors targeting the FPPS enzyme has garnered significant interest in recent decades due to FPPS's role in the biosynthesis of cholesterol and other isoprenoids, which are implicated in cancer, bone diseases, and other conditions. In this study, we describe a multidisciplinary approach to designing novel FPPS inhibitors, combining computational modeling, biochemical assays, and biophysical techniques. A series of peptides and phosphopeptides were designed, synthesized, and evaluated for their ability to inhibit FPPS activity. Molecular docking was employed to predict the binding modes of these compounds to FPPS, while Surface Plasmon Resonance (SPR) and Nuclear Magnetic Resonance (NMR) spectroscopy experiments - based on Saturation Transfer Difference (STD) and an enzymatic NMR assay - were used to measure their binding affinities and kinetics. The biological activity of the most promising compounds was further assessed in cellular assays using murine colorectal cancer (CRC) cells. Additionally, genomics and metabolomics profiling allowed to unravel the possible mechanisms underlying the activity of the peptides, confirming their involvement in the modulation of the MVA pathway. Our findings demonstrate that the designed peptides and phosphopeptides exhibit significant inhibitory activity against FPPS and possess antiproliferative effects on CRC cells, suggesting their potential as therapeutic agents for cancer.

Investigating the Effectiveness of a Carb-Free Oloproteic Diet in Fibromyalgia Treatment.

Fibromyalgia (FM), a chronic disease with a high incidence in women, poses a significant challenge for diagnosis and treatment, especially due to the absence of specific biomarkers and the multifaceted nature of its symptoms, which range from neuromuscular pain to mood disorders and intestinal dysbiosis. While diagnosis currently relies on rheumatological clinical evaluations and treatment options mainly focus on symptom management, FM seems to have possible links with systemic metabolic dysfunctions with a common inflammatory root. In this context, a new therapeutic avenue emerges: could a therapeutic nutritional approach be the missing piece of the puzzle? Indeed, diet therapies employed particularly for metabolic syndromes proved recently to be efficacious for correcting systemic dysmetabolism and a high number of chronic inflammation conditions. In particular, the very-low-calorie ketogenic diet (VLCKD) demonstrated therapeutic benefits in many disorders. In the present study, we aimed to investigate the specific effects of two dietary interventions, namely the oloproteic VLCKD and the low-glycemic insulinemic (LOGI) diet, on two groups of female FM patients (FM1 and FM2) over a 45-day period. Utilizing clinical and laboratory tests, as well as non-invasive NMR metabolomic analysis of serum, urine, and saliva samples, we sought to uncover how these dietary regimens impact the metabolic dysfunctions associated with FM.

Lipophilic Shellfish Poisoning Toxins in Marine Invertebrates from the Galician Coast.

For the purpose of assessing human health exposure, it is necessary to characterize the toxins present in a given area and their potential impact on commercial species. The goal of this research study was: (1) to screen the prevalence and concentrations of lipophilic toxins in nine groups of marine invertebrates in the northwest Iberian Peninsula; (2) to evaluate the validity of wild mussels (Mytilus galloprovincialis) as sentinel organisms for the toxicity in non-bivalve invertebrates from the same area. The screening of multiple lipophilic toxins in 1150 samples has allowed reporting for the first time the presence of 13-desmethyl spirolide C, pinnatoxin G, okadaic acid, and dinophysistoxins 2 in a variety of non-traditional vectors. In general, these two emerging toxins showed the highest prevalence (12.5-75%) in most of the groups studied. Maximum levels for 13-desmethyl spirolide C and pinnatoxin G were found in the bivalves Magallana gigas (21 µg kg-1) and Tellina donacina (63 µg kg-1), respectively. However, mean concentrations for the bivalve group were shallow (2-6 µg kg-1). Okadaic acid and dinophysistoxin 2 with lower prevalence (1.6-44.4%) showed, on the contrary, very high concentration values in specific species of crustaceans and polychaetes (334 and 235 µg kg--1, respectively), to which special attention should be paid. Statistical data analyses showed that mussels could be considered good biological indicators for the toxicities of certain groups in a particular area, with correlations between 0.710 (for echinoderms) and 0.838 (for crustaceans). Polychaetes could be an exception, but further extensive surveys would be needed to draw definitive conclusions.

SMN deficiency perturbs monoamine neurotransmitter metabolism in spinal muscular atrophy.

Beyond motor neuron degeneration, homozygous mutations in the survival motor neuron 1 (SMN1) gene cause multiorgan and metabolic defects in patients with spinal muscular atrophy (SMA). However, the precise biochemical features of these alterations and the age of onset in the brain and peripheral organs remain unclear. Using untargeted NMR-based metabolomics in SMA mice, we identify cerebral and hepatic abnormalities related to energy homeostasis pathways and amino acid metabolism, emerging already at postnatal day 3 (P3) in the liver. Through HPLC, we find that SMN deficiency induces a drop in cerebral norepinephrine levels in overt symptomatic SMA mice at P11, affecting the mRNA and protein expression of key genes regulating monoamine metabolism, including aromatic L-amino acid decarboxylase (AADC), dopamine beta-hydroxylase (DßH) and monoamine oxidase A (MAO-A). In support of the translational value of our preclinical observations, we also discovered that SMN upregulation increases cerebrospinal fluid norepinephrine concentration in Nusinersen-treated SMA1 patients. Our findings highlight a previously unrecognized harmful influence of low SMN levels on the expression of critical enzymes involved in monoamine metabolism, suggesting that SMN-inducing therapies may modulate catecholamine neurotransmission. These results may also be relevant for setting therapeutic approaches to counteract peripheral metabolic defects in SMA.

Supplementing Low-Sodium Bicarbonate-Calcic (Lete)® Water: Effects in Women on Bone and Systemic Metabolism.

Calcium (Ca) represents about 40% of the total mineral mass, mainly in the bone, providing mechanical strength to the skeleton and teeth. An adequate Ca intake is necessary for bone growth and development in children and adolescents and for maintaining bone mineral loss in elderly age. Ca deficiency predisposes to osteopenia and osteoporosis. Healthy nutrition, including an adequate intake of Ca-rich food, is paramount to prevent and cure osteoporosis. Recently, several clinical studies have demonstrated that, in conditions of Ca dysmetabolism, Ca-rich mineral water is beneficial as a valuable source of Ca to be used as an alternative to caloric Ca-rich dairy products. Although promising, these data have been collected from small groups of participants. Moreover, they mainly regard the effect of Ca-rich mineral water on bone metabolism. In contrast, an investigation of the effect of Ca supplementation on systemic metabolism is needed to address the spreading of systemic metabolic dysfunction often associated with Ca dysmetabolism. In the present study, we analyzed urine and blood sera of 120 women in perimenopausal condition who were subjected for six months to 2l daily consumption of bicarbonate-calcium mineral water marketed under ®Lete. Remarkably, this water, in addition to being rich in calcium and bicarbonate, is also low in sodium. A complete set of laboratory tests was carried out to investigate whether the specific water composition was such to confirm the known therapeutic effects on bone metabolism. Second, but not least, urine and blood sera were analyzed using NMR-based metabolomic procedures to investigate, other than the action on Ca metabolism, potential system-wide metabolic effects. Our data show that Lete water is a valid supplement for compensating for Ca dysmetabolism and preserving bone health and integrity.

Okadaic Acid Depuration from the Cockle Cerastoderma edule.

The cockle Cerastoderma edule is a commercially important species in many European Countries. It can accumulate okadaic acid (OA) and other toxins in its group, which makes it unsuitable for human consumption, producing harvesting bans to avoid intoxications. The duration of those bans depends in part on the depuration kinetics of the toxin in this species. In this work, this kinetics was studied by means of fitting different models to depuration data experimentally obtained, using naturally contaminated cockles. Cockles depurated OA faster than most other bivalve species studied. Models that include Michaelis-Menten kinetics describe the depuration better than those using a first order exponential decrease to describe the first (or the only) compartment. One-compartment models were not able to describe the final part of the depuration curve, in which OA was depurated very slowly. Therefore, two-compartment models were needed. Esters were depurated at a much faster rate than the free form of the toxin; however, no significant esterification was detected during the process. The slow depuration rate suggests that other bivalve species could be used as sentinels to monitor cockle populations, but caution should be taken when toxin concentrations are very high.

Enzymatic Biotransformation of 13-desmethyl Spirolide C by Two Infaunal Mollusk Species: The Limpet Patella vulgata and the Cockle Cerastoderma edule.

The presence of a 13-desmethyl Spirolide C isomer (Iso-13-desm SPX C) is very common in some infaunal mollusks in Galicia contaminated with this toxin. Its possible origin by biological transformation was investigated by incubating homogenates of the soft tissues of limpets and cockles spiked with 13-desmethyl Spirolide C (13-desm SPX C). The involvement of an enzymatic process was also tested using a raw and boiled cockle matrix. The enzymatic biotransformation of the parent compound into its isomer was observed in the two species studied, but with different velocities. The structural similarity between 13-desm SPX C and its isomer suggests that epimerization is the most likely chemical process involved. Detoxification of marine toxins in mollusks usually implies the enzymatic biotransformation of original compounds, such as hydroxylation, demethylation, or esterification; however, this is the first time that this kind of transformation between spirolides in mollusks has been demonstrated.

The Metabolomic Profile in Amyotrophic Lateral Sclerosis Changes According to the Progression of the Disease: An Exploratory Study.

Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative pathology of the upper or lower motor neuron. Evaluation of ALS progression is based on clinical outcomes considering the impairment of body sites. ALS has been extensively investigated in the pathogenetic mechanisms and the clinical profile; however, no molecular biomarkers are used as diagnostic criteria to establish the ALS pathological staging. Using the source-reconstructed magnetoencephalography (MEG) approach, we demonstrated that global brain hyperconnectivity is associated with early and advanced clinical ALS stages. Using nuclear magnetic resonance (1H-NMR) and high resolution mass spectrometry (HRMS) spectroscopy, here we studied the metabolomic profile of ALS patients' sera characterized by different stages of disease progression-namely early and advanced. Multivariate statistical analysis of the data integrated with the network analysis indicates that metabolites related to energy deficit, abnormal concentrations of neurotoxic metabolites and metabolites related to neurotransmitter production are pathognomonic of ALS in the advanced stage. Furthermore, analysis of the lipidomic profile indicates that advanced ALS patients report significant alteration of phosphocholine (PCs), lysophosphatidylcholine (LPCs), and sphingomyelin (SMs) metabolism, consistent with the exigency of lipid remodeling to repair advanced neuronal degeneration and inflammation.

Nusinersen Induces Disease-Severity-Specific Neurometabolic Effects in Spinal Muscular Atrophy.

Intrathecal delivery of Nusinersen-an antisense oligonucleotide that promotes survival motor neuron (SMN) protein induction-is an approved therapy for spinal muscular atrophy (SMA). Here, we employed nuclear magnetic resonance (NMR) spectroscopy to longitudinally characterize the unknown metabolic effects of Nusinersen in the cerebrospinal fluid (CSF) of SMA patients across disease severity. Modulation of amino acid metabolism is a common denominator of biochemical changes induced by Nusinersen, with distinct downstream metabolic effects according to disease severity. In severe SMA1 patients, Nusinersen stimulates energy-related glucose metabolism. In intermediate SMA2 patients, Nusinersen effects are also related to energy homeostasis but involve ketone body and fatty acid biosynthesis. In milder SMA3 patients, Nusinersen mainly modulates amino acid metabolism. Moreover, Nusinersen modifies the CSF metabolome of a more severe clinical group towards the profile of untreated SMA patients with milder disease. These findings reveal disease severity-specific neurometabolic signatures of Nusinersen treatment, suggesting a selective modulation of peripheral organ metabolism by this CNS-directed therapy in severe SMA patients.

Abdominal obesity modifies the risk of hypertriglyceridemia for all-cause and cardiovascular mortality in hemodialysis patients.

Hypertriglyceridemia is the most prevalent lipid alteration in end-stage renal disease, and we studied the relationship between serum triglycerides and all-cause and cardiovascular death in these patients. Since abdominal fat modifies the effect of lipids on atherosclerosis, we analyzed the interaction between serum lipids and waist circumference (WC) as a metric of abdominal obesity. In a cohort of 537 hemodialysis patients, 182 died, 113 from cardiovascular causes, over an average follow-up of 29 months. In Cox models that included traditional and nontraditional risk factors, there were significant strong interactions between triglycerides and WC to both all-cause and cardiovascular death. A fixed (50 mg/dl) excess in triglycerides was associated with a progressive lower risk of all-cause and cardiovascular mortality in patients with threshold WC <95 cm but with a progressive increased risk in those above this threshold. A significant interaction between cholesterol and WC with all-cause and cardiovascular death emerged only in models excluding the triglycerides-WC interaction. Neither high-density lipoprotein (HDL) nor non-HDL cholesterol or their interaction terms with WC were associated with study outcomes. Thus, the predictive value of triglycerides and cholesterol for survival and atherosclerotic complications in hemodialysis patients is critically dependent on WC. Hence, intervention studies in end-stage renal disease should specifically target patients with abdominal obesity and hyperlipidemia.

Characterization of the Domoic Acid Uptake Mechanism of the Mussel (Mytilus galloprovincialis) Digestive Gland.

Cultures of the mussel Mytilus galloprovincialis are frequently affected by accumulation of the amnesic shellfish poisoning toxin domoic acid (DA). This species is characterized by a fast uptake and release of the toxin. In this work, the main characteristics of the uptake mechanism have been studied by incubation of digestive gland thin slices in media with different composition and DA concentration. DA uptake seems to follow Michaelis-Menten kinetics, with a very high estimated KM (1722 µg DA mL-1) and a Vmax of 71.9 µg DA g-1 h-1, which is similar to those found for other amino acids in invertebrates. Replacement of NaCl from the incubation media by Cl-choline (Na+-free medium) did not significantly reduce the uptake, but replacement by sorbitol (Na+-free and Cl--depleted medium) did. A new experiment replacing all chlorides with their equivalent gluconates (Na+- and Cl--free medium) showed an important reduction in the uptake that should be attributed to the absence of chloride, pointing to a Na+-independent, Cl- (or anion-) dependent transporter. In media with Na+ and Cl-, neither decreasing the pH nor adding cyanide (a metabolic inhibitor) had significant effect on DA uptake, suggesting that the transport mechanism is not H+- or ATP-dependent. In a chloride depleted medium, lowering pH or adding CN increased the uptake, suggesting that other anions could, at least partially, substitute chloride.

Fibromyalgia and Depression in Women: An 1H-NMR Metabolomic Study.

Fibromyalgia is a chronic and systemic syndrome characterized by muscle, bone, and joint pain. It is a gender-specific condition with a 9:1 incidence ratio between women and men. Fibromyalgia is frequently associated with psychic disorders affecting the cognitive and emotional spheres. In the reported work, we compared 31 female fibromyalgia patients to 31 female healthy controls. They were analyzed for biochemical clinical parameters, for autoimmune markers, and were subjected to 1H-NMR metabolomics analysis. To identify a correlation between the metabolomic profile and the psychic condition, a subset of 19 fibromyalgia patients was subjected to HAM-A and HAM-D Hamilton depression tests. Multivariate statistical analysis showed the dysmetabolism of several metabolites involved in energy balance that are associated with systemic inflammatory conditions. The severity of depression worsens dysmetabolic conditions; conversely, glycine and glutamate, known for their critical role as neuromodulators, appear to be potential biomarkers of fibromyalgia and are associated with different severity depression conditions.

NMR-based metabolomic profile of hypercholesterolemic human sera: Relationship with in vitro gene expression?

Hypercholesterolaemia is considered an important cause of atherosclerotic cardiovascular disease. In a previous investigation, we demonstrated that cultured hepatoma cells treated with hypercholesterolaemic sera compared with cells treated with normocholesterolaemic sera show overexpression of mRNAs related to mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase (HMGCS2). In the present work, using an NMR metabolomic analysis, we demonstrate that the hypercholesterolaemic blood sera previously used to treat cultured hepatoma cells are characterized by a metabolomic profile that is significantly different from the normocholesterolaemic sera. Acetate, acetone, 2-hydroxybutyrate, cysteine, valine, and glutamine are the metabolites distinguishing the two groups. Abnormalities in the concentrations of these metabolites reflect alterations in energy-related pathways, such as pantothenate and CoA biosynthesis, pyruvate, glycolysis/gluconeogenesis, the citrate cycle, and ketone bodies. Regarding ketone bodies, the pathway is regulated by HMGCS2; therefore, serum samples previously found to be able to increase HMGCS2 mRNA levels in cultured cells also contain higher amounts of the metabolites of its encoded enzyme protein product.