Yeray Brito-Casillas

The demand for refined anaesthetic protocols in ovine experimental surgery has increased due to ethical considerations and the need to improve perioperative stability. This study evaluated the analgesic efficacy of ultrasound-guided combined sciatic and saphenous nerve blocks using two different local anaesthetics in Hair Canarian Sheep undergoing invasive orthopaedic hindlimb surgery. Fifteen clinically healthy sheep were randomly assigned to one of three groups: lidocaine (2%), bupivacaine (0.5%), or control (general anaesthesia alone). Intraoperative physiological parameters, including heart rate, respiratory rate, and arterial blood pressure, were recorded, and postoperative pain was assessed using a modified Melbourne Pain Scale. Sheep receiving locoregional anaesthesia showed significantly lower postoperative pain scores compared with control animals. Intraoperatively, a significant difference between groups was observed only for respiratory rate, with lower values in the bupivacaine group. The bupivacaine group exhibited lower and more stable respiratory rates, with a trend towards lower heart rates during surgery, as well as consistently lower pain scores during the early postoperative period. Lidocaine provided limited intraoperative and postoperative effects compared with the control group. Respiratory rate appeared to be more closely associated with pain scores than other physiological parameters. In conclusion, ultrasound-guided sciatic and saphenous nerve blocks were associated with improved perioperative analgesia in sheep undergoing orthopaedic surgery. The use of bupivacaine was associated with lower respiratory rates intraoperatively and reduced postoperative pain scores, suggesting a potential benefit in perioperative analgesia.

The demand for refined anaesthetic protocols in ovine experimental surgery has increased due to ethical considerations and the need to improve perioperative stability. This study evaluated the analgesic efficacy of ultrasound-guided combined sciatic and saphenous nerve blocks using two different local anaesthetics in Hair Canarian Sheep undergoing invasive orthopaedic hindlimb surgery. Fifteen clinically healthy sheep were randomly assigned to one of three groups: lidocaine (2%), bupivacaine (0.5%), or control (general anaesthesia alone). Intraoperative physiological parameters, including heart rate, res-piratory rate, and arterial blood pressure, were recorded, and postoperative pain was assessed using a modified Melbourne Pain Scale. Sheep receiving locoregional anaes-thesia showed improved intraoperative physiological stability and significantly lower postoperative pain scores compared with control animals. The bupivacaine group ex-hibited the lowest and most stable heart and respiratory rates during surgery, as well as consistently lower pain scores during the early postoperative period. Lidocaine provided adequate intraoperative analgesia but showed a reduction in postoperative efficacy over time. Respiratory rate correlated more strongly with pain scores than other physiological parameters. In conclusion, ultrasound-guided sciatic and saphenous nerve blocks sig-nificantly enhance perioperative analgesia in sheep undergoing orthopaedic surgery. The use of bupivacaine resulted in superior and longer-lasting analgesia compared to lidocaine, supporting its inclusion in multimodal anaesthetic protocols to improve animal welfare and refinement in ovine experimental models.

During pregnancy, the maternal body adapts in several ways to create an optimal environment for embryonic growth. These changes include endocrine and metabolic shifts that can lead to insulin resistance and gestational diabetes mellitus (GDM), impacting both the mother and fetus in the short and long term. Fetal macrosomia, a condition where the fetus is significantly larger than average, is a primary concern associated with GDM. Although the underlying mechanism remains unclear, a pregnancy-induced proinflammatory state, combined with altered glucose homeostasis, plays a critical role. Several cytokines and hormones, such as interleukin 6 (IL-6), insulin growth factor 1 (IGF-1), prolactin (PRL), or progesterone, are essential for fetal growth, the control of the inflammatory response, and the regulation of lipid and carbohydrate metabolism to meet energy demands during pregnancy. However, although the role of these cytokines in metabolism and body growth during adulthood has been extensively studied, their implication in the pathophysiology of GDM and macrosomia is not well understood. Here, we review this pathophysiology and pose the hypothesis that an aberrant response to cytokine receptor activation, particularly involving the suppressor of cytokine signaling 2 (SOCS2), contributes to GDM and fetal macrosomia. This novel perspective suggests an unexplored mechanism by which SOCS2 dysregulation could impact pregnancy outcomes.

For thousands of years, Vachellia nilotica has been widely used as an herbal medicine to treat some diseases and symptoms, including respiratory, gastrointestinal and urogenital ailments. The present study was adapted to document and assemble existing information about V. nilotica and its evidence-based ethnopharmacological activities, with brief reviews on the description, geographical distribution, ecology, medical uses and phytochemistry. A literature review and information up to 2024 was performed in various scientific databases, including PubMed, Science Direct and Google Scholar. The keywords were “Acacia nilotica”, “Botany”, “ecology”, “Traditional uses”, “Phytochemistry”, “Polyphenols”, “Molecular docking”, “Ethnopharmacological activities” and “toxicity”, among others. V. nilotica has a wide range of uses, with low toxicity, reported in different countries. It can be infused into oils or tea or incorporated into paste, poultice and biscuits, used as an emollient, antidiarrheal, astringent and as an antidote for bite poisons. Glucose and lipid-lowering, anti-inflammatory, analgesic, antipyretic, antioxidant, antihypertensive, antibacterial, antifungal, antiviral and anthelmintic activities are the most prominent. Over 150 chemical components have been identified from V. nilotica that could be associated with its potential actions. Quercetin, rutin, kaempferol, naringenin, catechin, epicatechin, gallic acid, ellagic acid, lupeol and niloticane are its main active constituents. From the research data, and despite the fact that human clinical trials and detailed methodological studies are scarce, V. nilotica has shown wide-ranging activities, though the most robust evidence is related to the treatment of microbial infections, diarrhea, wound and ulcer healing and for topical application. More pharmacological and toxicological studies are required to further elucidate the mechanisms of action, potential side effects, and optimal dosages for these treatments. Additionally, more clinical trials are needed to validate these traditional uses in human populations and to ensure the safety and efficacy of V. nilotica for these applications. This article offers an overview of therapeutic applications by utilizing traditional uses and recent findings on phytochemical studies, and clinical and pharmacological research.

The p.(Tyr400_Phe402del) mutation in the LDL receptor (LDLR) gene is the most frequent cause of familial hypercholesterolaemia (FH) in Gran Canaria. The aim of this study was to determine the age and origin of this prevalent founder mutation and to explore its functional consequences. For this purpose, we obtained the haplotypic information of 14 microsatellite loci surrounding the mutation in one homozygous individual and 11 unrelated heterozygous family trios. Eight different mutation carrier haplotypes were identified, which were estimated to originate from a common ancestral haplotype 387 (110–1572) years ago. This estimation suggests that this mutation happened after the Spanish colonisation of the Canary Islands, which took place during the fifteenth century. Comprehensive functional studies of this mutation showed that the expressed LDL receptor was retained in the endoplasmic reticulum, preventing its migration to the cell surface, thus allowing us to classify this LDLR mutation as a class 2a, defective, pathogenic variant.

Tamoxifen improves the overall survival rate in hormone receptor-positive breast cancer patients. However, despite the fact that it exerts antagonistic effects on the ERα, it can act as a partial agonist, resulting in tumor growth in estrogen-sensitive tissues. In this study, highly functionalized 5-hydroxy-2H-pyrrol-2-ones were synthesized and evaluated by using ERα- and phenotype-based screening assays. Compounds 32 and 35 inhibited 17β-estradiol (E2)-stimulated ERα-mediated transcription of the luciferase reporter gene in breast cancer cells without inhibition of the transcriptional activity mediated by androgen or glucocorticoid receptors. Compound 32 regulated E2-stimulated ERα-mediated transcription by partial antagonism, whereas compound 35 caused rapid and non-competitive inhibition. Monitoring of 2D and 3D cell growth confirmed potent antitumoral effects of both compounds on ER-positive breast cancer cells. Furthermore, compounds 32 and 35 caused apoptosis and blocked the cell cycle of ER-positive breast cancer cells in the sub-G1 and G0/G1 phases. Interestingly, compound 35 suppressed the functional activity of ERα in the uterus, as demonstrated by the inhibition of E2-stimulated transcription of estrogen and progesterone receptors and alkaline phosphatase enzymatic activity. Compound 35 showed a relatively low binding affinity with ERα. However, its antiestrogenic effect was associated with an increased polyubiquitination and a reduced protein expression of ERα. Clinically relevant, a possible combinatory therapy with compound 35 may enhance the antitumoral efficacy of 4-hydroxy-tamoxifen in ER-positive breast cancer cells. In silico ADME predictions indicated that these compounds exhibit good drug-likeness, which, together with their potential antitumoral effects and their lack of estrogenic activity, offers a pharmacological opportunity to deepen the study of ER-positive breast cancer treatment.

Aims/hypothesis Delayed maternal age, obesity and diabetes are associated with reduced fertility. We investigated how age and obesity/metabolic syndrome impact fertility and hypothesized that its decrease is due to defects in preimplantation embryo development. Methods Three groups of female C57Bl6 mice (12 weeks, 9 months and 1 year old) were fed either a high fat diet for 8 weeks, to induce obesity and the metabolic syndrome, or a control chow diet. Body weight and composition, glucose tolerance and insulin resistance were assessed. Fecundity was evaluated by mating and pregnancy rates, as well as number of embryos. Embryo quality was assessed morphologically, and cell fate composition was analysed in preimplantation embryos by state-of-the-art single cell quantitative confocal image analysis. Results The high fat diet was associated with increased adiposity, glucose intolerance and insulin resistance, especially in the older mice. Fecundity was affected by age, more than by the diet. Both age and high fat diet were associated with reduced cell fate allocation, indicating a delay in preimplantation embryo development, and with increased expression of GATA3, an inhibitor of placentation. Conclusion/Interpretation These results support that age and the metabolic syndrome reduce fertility through mechanisms which are present at conception very early in pregnancy. What is already known about this subject? Lifestyle changes in modern societies have led to an increase in obesity and type 2 diabetes, and women tend to become pregnant later than ever. These factors have a negative influence on female fecundity. In mice, diet induced obesity is associated with poor quality oocytes that affect overall embryonic development. What is the key question? Do age and high fat diet influence cell fate differentiation during preimplantation embryo development? What are the new findings? Body composition and glucose metabolism are altered due to high fat diet even when weight is not affected in young animals. Although there are no differences in mating and fertilization rates, embryo quality is lower with high fat diet. Cells not fully committed to a cell fate (epiblast or primitive endoderm) are increased in embryos from mature dams or fed a high fat diet, indicating a delay in preimplantation embryo development. How might this impact on clinical practice in the foreseeable future? Our findings show a delay in early embryo development associated to obesity and maternal age. This delay could be responsible for the low fertility observed in women with type 2 diabetes and obesity.

Based on molecular docking studies on the ERα, a series of lignan derivatives (3–16) were designed and semisynthesized from the natural dibenzylbutyrolactones bursehernin (1) and matairesinol dimethyl ether (2). To examine their estrogenic and antiestrogenic potencies, the effects of these compounds on estrogen receptor element (ERE)-driven reporter gene expression and viability in human ER+ breast cancer cells were evaluated. Lignan compounds induced ERE-driven reporter gene expression with very low potency as compared with the pure agonist E2. However, coincubation of 5 μM of lignan derivatives 1, 3, 4, 7, 8, 9, 11, 13, and 14 with increasing concentrations of E2 (from 0.01 pM to 1 nM) reduced both the potency and efficacy of pure agonists. The binding to the rhERα-LBD was validated by TR-FRET competitive binding assay and lignans bound to the rhERα with IC₅₀ values from 0.16 μM (compound 14) to 6 μM (compound 4). Induced fit docking (IFD) and molecular dynamics (MD) simulations for compound 14 were carried out to further investigate the binding mode interactions. Finally, the in silico ADME predictions indicated that the most potent lignan derivatives exhibited good drug-likeness.

Parkinson’s disease (PD) is the second most common neurodegenerative disease. Diabetes mellitus (DM) is a metabolic disease characterized by high levels of glucose in blood. Recent epidemiological studies are highlighting the link between both diseases; it is even considered that DM might be a risk factor for PD. To further investigate the likely relation of these diseases, we have used a Drosophila PD model based on inactivation of the DJ-1β gene (ortholog of human DJ-1 ), and diet-induced Drosophila and mouse T2DM models, together with human neuron-like cells. T2DM models were obtained by feeding flies with a high sugar containing medium, and mice with a high fat diet. Our results showed that both fly models exhibit common phenotypes such as alterations in carbohydrate homeostasis, mitochondrial dysfunction or motor defects, among others. In addition, we demonstrated that T2DM might be a risk factor of developing PD since our diet-induced fly and mouse T2DM models present DA neurodegeneration, a hallmark of PD. We have also confirmed that neurodegeneration is caused by increased glucose levels, which has detrimental effects in human neuron-like cells by triggering apoptosis and leading to cell death. Besides, the observed phenotypes were exacerbated in DJ-1β mutants cultured in the high sugared medium, indicating that DJ-1 might have a role in carbohydrate homeostasis. Finally, we have confirmed that metformin, an antidiabetic drug, is a potential candidate for PD treatment and that it could prevent PD onset in T2DM model flies. This result supports antidiabetic drugs as promising PD therapeutics.