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1.
Clin Nutr ; 43(11): 80-90, 2024 Sep 14.
Artículo en Inglés | MEDLINE | ID: mdl-39357086

RESUMEN

BACKGROUND & AIMS: Eggs contain nutrients which could help enrich the diets of postmenopausal women. Egg consumption and elevated body weight have been associated with elevated risk of serious chronic disease. It is possible that elevated body weight mediates between egg consumption and serious chronic disease. However, few studies exist on the link between egg consumption and body weight in post-menopausal women, and none of them accounted for genetic weight gain predispositions. Our objective was to examine associations between egg consumption, body weight, and genetic predisposition for an elevated Body Mass Index (BMI), in postmenopausal women. METHODS: We analyzed data from 4439 healthy Women's Health Initiative participants of European descent during a 6-year follow up using multivariable generalized linear mixed models to prospectively evaluate egg and egg-nutrient intake (measured by a food frequency questionnaire) against body weight and a BMI polygenic score (PGS-BMI) derived from GWAS meta-analysis effect-allele frequencies. RESULTS: We found a positive prospective association between change in egg intake and body weight during the 6-year follow up. For instance, at year 3, women whose intake had increased by 2.0 eggs/week had gained 0.70 kg (95%CI: 0.34, 1.07, p = 0.0002) more than women whose intake had decreased by 2.4 eggs/week, p-linear <0.0001. Cholesterol-intake and choline-intake, but not betaine-intake, showed similar significant associations. Exploratory analysis revealed that: 1) women only demonstrated these significant associations if they exhibited higher intakes of "Western-pattern" foods including processed and red meats, French fries, sweets and deserts, sugar-sweetened beverages, fried foods, and dietary fat, and dietary energy; and 2) there was a significant positive prospective association between PGS-BMI and body-weight change, but only in the top quintile of egg-intake change. CONCLUSIONS: We found significant positive prospective associations between weight change and changes in egg intake, cholesterol intake, and choline intake among healthy postmenopausal women of European ancestry in the Women's Health Initiative. Exploratory analyses revealed that: 1) these significant associations only obtained among women who ate large amounts of "Western-pattern" foods; and 2) women with a higher genetic susceptibility for an elevated BMI gained more weight only if they increased their egg intake considerably. Our results require confirmation.

2.
Acta Neuropsychiatr ; : 1-17, 2024 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-39351633

RESUMEN

OBJECTIVES: This study aims to assess the correlation between NAA (N-acetyl-l-aspartate), CHO (choline), and CRE (creatine) levels in the hippocampus regions of individuals suffering from obsessive-compulsive disorder (OCD) and defensive styles of the ego. METHODS: The study group was composed of twenty patients with OCD and twenty healthy controls. NAA, CHO, and CRE values in the hippocampal region using proton magnetic resonance spectroscopy (1H-MRS) were measured. Participants' defense styles were ascertained by administering the Defense Style Questionnaire-40. RESULTS: The patient group's NAA levels were considerably lower than the control group's on both sides of the hippocampus. The levels of CHO and CRE did not significantly differ between the two groups. The following statistically significant correlations were discovered: in the comparison group, there were negative correlations between the scores of mature defense styles and the right and left CHO levels, as well as between the immature defense mechanism scores and the right NAA levels in both the patient and control groups. In the patient group, there were also negative correlations between the left NAA values and the scores of mature defense styles. CONCLUSION: OCD patients have lower levels of NAA in the hippocampus. To validate and extend the current findings, more research involving a greater sample size is required.

3.
Clin Nutr ESPEN ; 64: 177-195, 2024 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-39357562

RESUMEN

BACKGROUND AND AIMS: Growing evidence suggests nutritional intervention may influence the development and progression of Alzheimer's Disease (AD). Choline, an essential dietary nutrient plays a critical role in neurological development and brain function, however, its effects on AD in humans is unclear. The research aims to investigate mechanistic links between dietary choline intake and cognitive functioning, focusing on the role of phosphatidylcholine (PC) in neuroplasticity and its interaction with amyloid beta (Aß) peptides in neuron membranes. Additionally, human evidence on the potential benefits of PC interventions on AD, cognition, and proposed mechanisms are evaluated. METHODS: A reproducible systematic literature search was performed using a three-tranche strategy, consisting of a review, mechanism, and intervention search. Using PubMed as the main database, 1254 titles and abstracts were screened, 149 papers were read in full and 65 peer-reviewed papers were accepted, critically appraised, and analysed in a narrative review. RESULTS: Predominantly preclinical evidence demonstrated that PC enhances neuroplasticity, a key biological substrate for cognition, by activating intracellular neuronal signalling pathways or through neuron membrane function. Molecular dynamic simulation methods provided a mechanistic understanding of the interconnection between neuronal PC content and the potential behaviour and trajectory of Aß peptide aggregation. The results indicate that the neuronal membrane composition of PC is critical to inhibiting Aß aggregation and neuronal damage, protecting the neuron from Aß toxicity. This might provide a foundation for optimising cellular PC which may prove beneficial in the treatment or prevention of neurodegenerative disease. Altered PC metabolism in AD was evidenced in observational studies; however, whether this relationship represents a cause or consequence of AD remains to be determined. Human intervention studies did not produce conclusive evidence supporting its effectiveness in enhancing cognitive function. This lack of consistency primarily stems from methodological constraints within the conducted studies. Human observational research provided the most compelling evidence linking a higher dietary PC intake to a reduced risk of dementia and significant improvements in cognitive testing. CONCLUSION: Despite the lack of randomised control trials (RCTs) assessing the efficacy of lecithin/PC to improve cognition in AD patients, there exists promising evidence supporting its neuroprotective and neurotrophic role. This review establishes an evidence-based framework through chains of mechanistic evidence, that may provide potential strategies for enhanced neuroprotection and reduced neurodegeneration caused by AD. Considering the escalating global burden of AD and the current shortcomings in effective treatments, this review together with the limitations and gaps identified in the existing research presents valuable insights that emphasise the urgency of more comprehensive research into the relationship between PC and AD.

4.
Mol Imaging Radionucl Ther ; 33(3): 185-188, 2024 Oct 07.
Artículo en Inglés | MEDLINE | ID: mdl-39373191

RESUMEN

Prostatic adenocarcinoma is characterized by elevated phosphatidylcholine metabolism. 18F-choline positron emission tomography/computed tomography (PET/CT) is widely used for patients with biochemical recurrence and a prostate-specific antigen threshold above 2 ng/mL. We report a case of a patient with high-risk prostatic adenocarcinoma undergoing 18F-choline PET/CT for biochemical recurrence. In addition to hypermetabolic abdominal lymph nodes, an unexpected right testicular hypermetabolism was observed. Such findings on 18F-choline PET/CT may suggest a primary tumor or testicular metastasis of prostate cancer. Bilateral orchiectomy revealed a vitelline tumor associated with known primary prostatic cancer. The incidental discovery of a testicular vitelline tumor during prostate cancer imaging is rare, highlighting the importance of thorough diagnostics. This case underscores the need for comprehensive care in managing complex and atypical cancer cases, emphasizing the potential for unrelated tumor discoveries during diagnostic workup. Further research is essential for a better understanding of these rare co-occurring cancers and their treatment implications.

5.
J Sci Food Agric ; 104(14): 8553-8560, 2024 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-39392653

RESUMEN

BACKGROUND: The nutritional intake of formula-fed newborns is often limited to a single source, so it must be supplemented with essential nutrients for the growth and proper development of infants. Taurine, l-carnitine, and choline are considered conditionally essential nutrients especially in newborns and infants. RESULTS: In this work, a simple routine hydrophilic interaction liquid chromatography-electrospray ionization-tandem mass spectrometry (HILIC-ESI-MS/MS) method was developed and validated for the simultaneous determination of these semi-essential nutrients in infant and adult/pediatric milk formulas. The extraction recoveries were between 90% and 114%. Precision of the method offered relative standard deviation below 5% and 7% for intra-day and inter-day precision, respectively. The proposed method was successfully applied to quantification of taurine, l-carnitine, and choline in milk formula. The contents found were in good agreement with those provided on the product label for almost all samples. CONCLUSION: In view of these results, it can be concluded that the developed method can be a useful approach for the simultaneous determination of taurine, l-carnitine and choline in powdered milk samples, so it can be useful in the routine quality control of this kind of samples. © 2024 The Author(s). Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.


Asunto(s)
Carnitina , Colina , Interacciones Hidrofóbicas e Hidrofílicas , Fórmulas Infantiles , Espectrometría de Masa por Ionización de Electrospray , Espectrometría de Masas en Tándem , Taurina , Colina/análisis , Carnitina/análisis , Taurina/análisis , Espectrometría de Masas en Tándem/métodos , Fórmulas Infantiles/química , Humanos , Espectrometría de Masa por Ionización de Electrospray/métodos , Animales , Lactante , Cromatografía Liquida/métodos , Adulto
6.
Adv Exp Med Biol ; 1463: 9-14, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39400792

RESUMEN

Building on an extensive history of physiological and systems-oriented modelling, my group and others have recently used molecular simulation studies to understand oxygen (O2) transport and localisation. Molecular simulations enable biophysical insight into processes difficult to study with experiments alone and are sometimes described as a "computational microscope." Our work has emphasised lipid membrane contributions to oxygen diffusion and uptake, suggesting that lipid-based pathways along membranes and lipid deposits are likely to accelerate diffusive transport through cells and tissues. Moreover, the lipid and fluid fractions of the tissue are expected to be primary determinants of the local oxygen partial pressure (pO2) as well as the oxygen permeability. Measurements using molecular probes can be influenced by the local molecular environment, due to differential solubility of both the probe and the oxygen molecules in various components of the cell's complex solvent system. The biomolecular simulation work complements experimental studies, which enable evaluation of the models' accuracy and their applicability to real biological systems. Further work is needed to assess fully the possible influence of nanoscale crowders and obstacles (especially protein molecules) on tissue-level diffusive transport of oxygen. Likewise, water-rich carbohydrate layers, such as the glycocalyx, should be evaluated as potential barriers to oxygen transport. Insights gained through biophysical modelling studies could be broadly relevant to clinical phenomena affected by tissue oxygenation, such as tumour radiotherapy, ischaemia, neuropathy, and wound healing.


Asunto(s)
Oxígeno , Oxígeno/metabolismo , Difusión , Humanos , Animales , Modelos Biológicos , Simulación de Dinámica Molecular , Transporte Biológico
7.
J Dairy Res ; : 1-9, 2024 Oct 14.
Artículo en Inglés | MEDLINE | ID: mdl-39397767

RESUMEN

Minerals are supplemented routinely to dairy cows during the dry period to prevent metabolic issues postpartum. However, limited information exists on the impacts of mineral supplementation on colostrum carotenoids. This study aimed to determine the effects of prepartum supplementation with three micro-nutrients; inorganic selenium (INORG), organic selenium (ORG) or rumen-protected choline (RPC) on the carotenoid content of bovine colostrum and transition milk (TM) from pasture-based dairy cows. A total of 57 (12 primiparous and 45 multiparous) Holstein-Friesian (HF) and HF × Jersey (JEX) cows were supplemented daily for 49 ± 12.9 d before calving. Colostrum samples were collected from all cows immediately postpartum and TM one to five (TM1-TM5) were collected from a sub-set of 15 cows (five per treatment group) at each consecutive milking postpartum. Carotenoid concentration was determined using ultra-high performance liquid chromatography - diode array detection (UHPLC-DAD). With the use of transmittance, the colour index and colour parameters a*, b* and L* were used to determine colour variations over this period. Prepartum supplementation did not have a significant effect on colostrum ß-carotene concentration or colour. Positive correlations between ß-carotene and colour parameter b* (R2 = 0.671; P < 0.001) and ß-carotene and colour index (R2 = 0.560; P < 0.001) were observed. Concentrations of ß-carotene were highest in colostrum (1.34 µg/g) and decreased significantly with each milking postpartum (TM5 0.31 µg/g). Breed had a significant effect on colostrum colour with JEX animals producing a greater b* colostrum than HF animals (P = 0.030). Primiparous animals produced colostrum with the weakest colour compared to second or ≥third parity animals (P = 0.042). Despite statistical increases in the b* parameter in colostrum from JEX cows and multiparous cows, ß-carotene concentrations did not significantly increase suggesting that other factors may influence colostrum colour. The b* parameter may be used as an indicator for estimating carotenoid concentrations in colostrum and TM, particularly when assessed via transmittance spectroscopy.

8.
Cells ; 13(17)2024 Sep 02.
Artículo en Inglés | MEDLINE | ID: mdl-39273042

RESUMEN

Ischemic stroke is one of the leading causes of disability and death globally, with a rising incidence in younger age groups. It is well known that maternal diet during pregnancy and lactation is vital for the early neurodevelopment of offspring. One-carbon (1C) metabolism, including folic acid and choline, plays a vital role in closure of the neural tube in utero. However, the impact of maternal dietary deficiencies in 1C on offspring neurological function following ischemic stroke later in life remains undefined. The aim of this study was to investigate inflammation in the blood and brain tissue of offspring from mothers deficient in dietary folic acid or choline. Female mice were maintained on either a control or deficient diet prior to and during pregnancy and lactation. When offspring were 3 months of age, ischemic stroke was induced. One and a half months later, blood and brain tissue were collected. We measured levels of matrix metalloproteases (MMP)-2 and 9 in both plasma and brain tissue, and reported reduced levels of MMP-2 in ChDD male offspring in both tissue types. No changes were observed in MMP-9. This observation supports our working hypothesis that maternal dietary deficiencies in folic acid or choline during early neurodevelopment impact the levels of inflammation in offspring after ischemic stroke.


Asunto(s)
Encéfalo , Colina , Metaloproteinasa 2 de la Matriz , Animales , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 2 de la Matriz/sangre , Femenino , Encéfalo/metabolismo , Masculino , Ratones , Embarazo , Colina/metabolismo , Ratones Endogámicos C57BL , Dieta , Ácido Fólico/metabolismo , Ácido Fólico/sangre , Metaloproteinasa 9 de la Matriz/metabolismo , Deficiencia de Colina , Efectos Tardíos de la Exposición Prenatal/metabolismo , Efectos Tardíos de la Exposición Prenatal/sangre
9.
Genet Med ; : 101273, 2024 Sep 19.
Artículo en Inglés | MEDLINE | ID: mdl-39306721

RESUMEN

PURPOSE: FLVCR1 encodes a solute carrier (SLC) protein implicated in heme, choline, and ethanolamine transport. While Flvcr1-/- mice exhibit skeletal malformations and defective erythropoiesis reminiscent of Diamond-Blackfan anemia (DBA), biallelic FLVCR1 variants in humans have previously only been linked to childhood or adult-onset ataxia, sensory neuropathy, and retinitis pigmentosa. METHODS: We identified individuals with undiagnosed neurodevelopmental disorders and biallelic FLVCR1 variants through international data sharing and characterized the functional consequences of their FLVCR1 variants. RESULTS: We ascertained 30 patients from 23 unrelated families with biallelic FLVCR1 variants and characterized a novel FLVCR1-related phenotype: severe developmental disorders with profound developmental delay, microcephaly (Z-score -2.5 to -10.5), brain malformations, epilepsy, spasticity, and premature death. Brain malformations ranged from mild brain volume reduction to hydranencephaly. Severely affected patients share traits including macrocytic anemia and skeletal malformations with Flvcr1-/- mice and DBA. FLVCR1 variants significantly reduce choline and ethanolamine transport and/or disrupt mRNA splicing. CONCLUSION: These data demonstrate a broad FLVCR1-related phenotypic spectrum ranging from severe multiorgan developmental disorders resembling DBA to adult-onset neurodegeneration. Our study expands our understanding of Mendelian choline and ethanolamine disorders and illustrates the importance of anticipating a wide phenotypic spectrum for known disease genes and incorporating model organism data into genome analysis to maximize genetic testing yield.

10.
BMC Geriatr ; 24(1): 774, 2024 Sep 19.
Artículo en Inglés | MEDLINE | ID: mdl-39300341

RESUMEN

BACKGROUND: Effective interventions for overall healthy subjects with mild cognitive impairment are currently limited. Choline alphoscerate (alpha glyceryl phosphorylcholine, αGPC) is a choline-containing phospholipid used to treat cognitive function impairments in specific neurological conditions. This study aimed to investigate the efficacy and safety of αGPC in individuals diagnosed with mild cognitive impairment. METHODS: In this multicenter, randomized, placebo-controlled trial, 100 study subjects with mild cognitive impairment underwent a double-blind SHCog™ soft capsule (600 mg αGPC) or placebo treatment for 12 weeks. The primary efficacy outcome included changes from baseline on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog). Safety assessments included regular monitoring of adverse events, and clinical laboratory tests were conducted at baseline and the end of the trial. RESULTS: After 12 weeks of αGPC treatment, the ADAS-cog score decreased by 2.34 points, which was significantly greater than the change observed in the placebo group. No serious AEs were reported, and no study subjects discontinued the intervention because of AEs. There was no significant difference in incidence rate of AEs between the αGPC group and the placebo group. CONCLUSION: This study suggests that αGPC is a safe and effective intervention for improving cognitive function in study subjects with mild cognitive impairment. TRIAL REGISTRATION: Clinical Research Information Service; Osong (Chungcheongbuk-do): Korea Centers for Disease Control and Prevention, Ministry of Health and Welfare (Republic of Korea); KCT0008797; A 12-week, multicenter, randomized, double-blind, placebo-controlled human application study to evaluate the efficacy and safety of SH_CAPK08 on cognitive function improvement in mild cognitive decline.


Asunto(s)
Disfunción Cognitiva , Glicerilfosforilcolina , Humanos , Disfunción Cognitiva/tratamiento farmacológico , Método Doble Ciego , Masculino , Femenino , Anciano , Glicerilfosforilcolina/administración & dosificación , Glicerilfosforilcolina/uso terapéutico , Glicerilfosforilcolina/efectos adversos , Resultado del Tratamiento , Amnesia/tratamiento farmacológico , Persona de Mediana Edad , Anciano de 80 o más Años
11.
Int J Mol Sci ; 25(18)2024 Sep 14.
Artículo en Inglés | MEDLINE | ID: mdl-39337430

RESUMEN

The potassium-chloride cotransporter KCC2 is the main extruder of Cl- in neurons. It plays a fundamental role in the activity of the inhibitory neurotransmitters (GABA and glycine) since low levels of KCC2 promote intracellular Cl- accumulation, leading to the depolarizing activity of GABA and glycine. The downregulation of this cotransporter occurs in neurological disorders characterized by hyperexcitability, such as epilepsy, neuropathic pain, and spasticity. KCC2 is also downregulated after axotomy. If muscle reinnervation is allowed, the KCC2 levels recover in motoneurons. Therefore, we argued that target-derived neurotrophic factors might be involved in the regulation of KCC2 expression. For this purpose, we performed the axotomy of extraocular motoneurons via the monocular enucleation of adult rats, and a pellet containing either VEGF or BDNF was chronically implanted in the orbit. Double confocal immunofluorescence of choline acetyl-transferase (ChAT) and KCC2 was carried out in the brainstem sections. Axotomy led to a KCC2 decrease in the neuropil and somata of extraocular motoneurons, peaking at 15 days post-lesion, with the exception of the abducens motoneuron somata. VEGF administration prevented the axotomy-induced KCC2 downregulation. By contrast, BDNF either maintained or reduced the KCC2 levels following axotomy, suggesting that BDNF is involved in the axotomy-induced KCC2 downregulation in extraocular motoneurons. The finding that VEGF prevents KCC2 decrease opens up new possibilities for the treatment of neurological disorders coursing with neuronal hyperactivity due to KCC2 downregulation.


Asunto(s)
Axotomía , Factor Neurotrófico Derivado del Encéfalo , Cotransportadores de K Cl , Neuronas Motoras , Simportadores , Factor A de Crecimiento Endotelial Vascular , Animales , Masculino , Ratas , Factor Neurotrófico Derivado del Encéfalo/administración & dosificación , Regulación hacia Abajo , Neuronas Motoras/metabolismo , Ratas Wistar , Simportadores/metabolismo , Simportadores/genética , Factor A de Crecimiento Endotelial Vascular/administración & dosificación
12.
Eur J Neurosci ; 60(7): 5785-5811, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39230060

RESUMEN

Acetylcholine esterases (AChEs) are essential enzymes in cholinergic synapses, terminating neurotransmission by hydrolysing acetylcholine. While membrane bound AChEs at synaptic clefts efficiently perform this task, soluble AChEs are less stable and effective, but function over broader areas. In vertebrates, a single gene produces alternatively spliced forms of AChE, whereas invertebrates often have multiple genes, producing both enzyme types. Despite their significance as pesticide targets, the physiological roles of invertebrate AChEs remain unclear. Here, we characterized seven putative AChEs in the wandering spider, Cupiennius salei, a model species for neurophysiological studies. Sequence analyses and homology modeling predicted CsAChE7 as the sole stable, membrane-bound enzyme functioning at synaptic clefts, while the others are likely soluble enzymes. In situ hybridization of sections from the spider's nervous system revealed CsAChE7 transcripts co-localizing with choline acetyltransferase in cells that also exhibited AChE activity. CsAChE7 transcripts were also found in rapidly adapting mechanosensory neurons, suggesting a role in precise and transient activation of postsynaptic cells, contrasting with slowly adapting, also cholinergic, neurons expressing only soluble AChEs, which allow prolonged activation of postsynaptic cells. These findings suggest that cholinergic transmission is influenced not only by postsynaptic receptors but also by the enzymatic properties regulating acetylcholine clearance. We also show that acetylcholine is a crucial neurotransmitter in the spider's visual system and sensory and motor pathways, but absent in excitatory motor neurons at neuromuscular junctions, consistent with other arthropods. Our findings on sequence structures may have implications for the development of neurological drugs and pesticides.


Asunto(s)
Acetilcolinesterasa , Arañas , Animales , Acetilcolinesterasa/metabolismo , Acetilcolinesterasa/genética , Arañas/genética , Filogenia , Secuencia de Aminoácidos
13.
Int J Biol Macromol ; 280(Pt 2): 135787, 2024 Sep 18.
Artículo en Inglés | MEDLINE | ID: mdl-39304051

RESUMEN

This study explores an eco-friendly delignification technique for raw oil palm leaves (OPL), highlighting the optimized conditions of choline chloride-lactic acid deep eutectic solvent (DES)-mediated ball milling pretreatment to maximize the co-production yields of highly crystalline cellulose and lignin. Our five-level-four-factor Taguchi design identified the optimal reaction settings for cellulose production (85.83 % yield, 47.28 % crystallinity) as 90-minute milling, 1500 rpm, mill-ball size ratio of 30:10, ball-to-sample mass ratio of 20:1, DES-to-sample mass ratio of 3:1. Conversely, the maximal lignin extraction yield (35.23 %) occurred optimally at 120-minute milling, 600 rpm, mill-ball size ratio of 25:5, ball-to-sample mass ratio of 20:1 and DES-to-sample mass ratio of 9:1. Statistical results showed that milling frequency (p-value ≤ 0.0001) was highly significant in improving cellulose crystallinity and yield, while DES-to-sample mass ratio (p-value ≤ 0.0001) was the most impacting on lignin yield. The thermogravimetric method affirmed the elevated cellulose thermal stability, corroborating the enhanced cellulose content (40.14 % to 73.67 %) alongside elevated crystallinity and crystallite size (3.31 to 4.72 nm) shown by X-ray diffractograms. The increased surface roughness seen in micrographs mirrored the above-said post-treatment changes. In short, our optimized one-pot dual-action pretreatment effectively delignified the raw OPL to produce cellulose-rich material with enhanced crystallinity and lignin solidity.

14.
Neurosci Lett ; 842: 137971, 2024 Sep 07.
Artículo en Inglés | MEDLINE | ID: mdl-39251083

RESUMEN

The demand for pediatric anesthesia has risen in decades, raising concerns about the neurotoxic potential of anesthetics like remimazolam, which may impact neurodevelopment and later cognitive function. This study utilized a neonatal mouse model to assess remimazolam's neurodevelopmental effects. Results indicate that remimazolam-exposed mice displayed cognitive impairment and depressive behaviors in adulthood. Acute reductions in synaptic protein expression post-anesthesia were observed, along with long-term decreases in hippocampal choline acetyltransferase levels, reduced dendritic spine density in the CA1 region, and microglial proliferation. Collectively, these findings suggest that remimazolam can induce neurotoxicity and neuroinflammation, leading to synaptic dysfunction and associated cognitive and behavioral deficits.

15.
Cancer Lett ; 605: 217280, 2024 Sep 28.
Artículo en Inglés | MEDLINE | ID: mdl-39343354

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic malignancy for which there are currently no effective anti-metastatic therapies. Herein, we employed single-cell RNA sequencing and metabolomics analysis to demonstrate that metastatic cells highly express focal adhesion kinase (FAK), which promotes metastasis by remodeling choline kinase α (CHKα)-dependent choline metabolism. We designed a novel CHKα inhibitor, CHKI-03, and verified its efficacy in inhibiting metastasis in multiple preclinical models. Classical and newly synthesized small-molecule inhibitors have previously been used to assess the therapeutic potential of targeting mTOR and CHKα in various animal models. Mechanistically, FAK activated mTOR and its downstream HIF-1α, thereby elevating CHKα expression and promoting the proliferation, migration, and invasion of PDAC cells, as well as tumor growth and metastasis. Consistently, high expression levels of both FAK and CHKα are correlated with poor prognosis in patients with PDAC. Notably, CHK1-03 inhibited CHKα expression and also suppressed mTORC1 phosphorylation, disrupting the mTORC1-CHKα positive feedback loop. In addition, the combination of CHKI-03 and the mTORC1 inhibitor rapamycin synergistically inhibited tumor growth and metastasis in PDX models. The combination of CHKI-03 and rapamycin demonstrates considerable therapeutic efficacy in PDO models resistant to gemcitabine. Our findings reveal a pivotal mechanism underlying PDAC metastasis regulated by mTORC1-CHKα loop-dependent choline metabolism reprogramming, highlighting the therapeutic potential of this novel regimen for treating PDAC metastasis.

16.
Artículo en Inglés | MEDLINE | ID: mdl-39349175

RESUMEN

BACKGROUND AND OBJECTIVES: To assess the feasibility of performing selective parathyroidectomy without intraoperative parathyroid hormone (PTHio) determination when first-line preoperative localization tests (ultrasonography and [99mTc]Tc-MIBI) are negative and/or discordant, and second-line [18F]F-Colina PET-CT, is positive. MATERIALS AND METHODS: Retrospective cohort study, including patients with negative or discordant ultrasound and MIBI scans and positive [18F]F-Colina PET-CT, who underwent selective parathyroidectomy between 2019 and 2022. Groups were compared based on PTHio determination. Study variables were: gender, mean age, biochemical cure assessed by PTH value (pg/mL) and corrected calcium by albumin (mg/dL) at 6 months post-surgery follow-up, and histopathological analysis. RESULTS: The final sample included 42 patients. At 6 months post-surgery, in the PTHio group (20 patients), PTH values were 64.50 pg/mL and calcium 9.30 pg/mL, with 19 adenomas and 1 hyperplasia found. In the non-PTHio group (22 patients), PTH values were 61 pg/mL and calcium 9.37 pg/mL, with 22 adenomas found. No statistically significant differences were found between both groups. CONCLUSIONS: Based on the results obtained in our patient cohort, selective parathyroidectomy could be considered with negative or discordant first-line tests and positive [18F]F-Colina PET-CT, without intraoperative PTH determination.

17.
Nutr Res ; 130: 48-66, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39341000

RESUMEN

Evidence indicates that choline and betaine intakes are associated with mortality. Based on the available evidence, we hypothesized that dietary choline and betaine do not increase mortality risk. This meta-analysis was conducted to investigate the association of dietary choline and betaine with mortality from all causes, cardiovascular diseases, and stroke. Online databases including PubMed, Scopus, Web of Science, Embase, and Google Scholar were searched up to 9 March 2024. Six cohort studies comprising 482,778 total participants, 57,235 all-cause, 9351 cardiovascular disease, and 4,400 stroke deaths were included in this study. The linear dose-response analysis showed that each 100 mg/day increase in choline intake was significantly associated with 6% and 11% increases in risk of all-cause (RR = 1.06, 95% CI: 1.03, 1.10, I2 =83.7%, P < .001) and cardiovascular diseases mortality (RR = 1.11, 95% CI: 1.06, 1.16, I2 = 54.3%, P = .02) respectively. However, dietary betaine, was not associated with the risk of mortality. Furthermore, the result of the nonlinear dose-response analysis showed a significant relationship between betaine intake and stroke mortality at the dosages of 50 to 250 mg/day (Pnon-linearity= .0017). This study showed that each 100 mg/day increment in choline consumption was significantly associated with a 6% and 11% higher risk of all-cause and cardiovascular disease mortality respectively. In addition, a significant positive relationship between betaine intake and stroke mortality at doses of 50 to 250 mg/day was observed. Due to the small number of the included studies and heterogeneity among them more well-designed prospective observational studies considering potential confounding variables are required.


Asunto(s)
Betaína , Enfermedades Cardiovasculares , Colina , Dieta , Humanos , Colina/administración & dosificación , Betaína/administración & dosificación , Enfermedades Cardiovasculares/mortalidad , Estudios de Cohortes , Accidente Cerebrovascular/mortalidad , Causas de Muerte , Factores de Riesgo , Femenino , Masculino , Relación Dosis-Respuesta a Droga , Persona de Mediana Edad , Anciano , Adulto
18.
Int J Pharm ; 665: 124657, 2024 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-39226987

RESUMEN

Surfactants are crucial in formulating poorly soluble drugs but lead to serious side effects due to PEG chains. Novel supra-amphiphiles consisting of fatty acids and choline are developed, which spontaneously form ionic co-aggregates (ICAs) in water and exhibit strong solubilizing capacity. Paclitaxel (PTX) is adopted as a model drug here to evaluate the feasibility of choline oleate-based ICAs in the intravenous delivery of poorly soluble drugs by comparing the kinetics and distribution of payloads and nanocarriers. Choline oleate presents a maximum 10-fold enhancement in solubilizing capacity to PTX than Cremophor EL (CreEL), enabling a one-tenth use level in the formulation. Aggregation-caused quenching probes are utilized to evaluate the kinetics and biodistribution of ICAs or CreEL-based micelles (MCs). A huge gap is found between the pharmacokinetic and particokinetic curves of either nanocarrier, indicating fast leakage. ICAs lead to faster PTX leakage in blood circulation but higher PTX distribution to organs than MCs. MCs present a longer circulation in blood but a slower distribution to organs than ICAs. ICAs do not arise adverse reactions in rats following repeated injections, while MCs cause pathological changes in varying degrees. In conclusion, choline oleate-based ICAs provide an alternative to surfactants in formulating poorly soluble drugs.


Asunto(s)
Portadores de Fármacos , Nanopartículas , Paclitaxel , Animales , Distribución Tisular , Paclitaxel/administración & dosificación , Paclitaxel/farmacocinética , Paclitaxel/química , Portadores de Fármacos/química , Nanopartículas/química , Colina/farmacocinética , Colina/química , Colina/administración & dosificación , Solubilidad , Micelas , Masculino , Administración Intravenosa , Ratas , Ácido Oléico/química , Tensoactivos/química , Ratas Sprague-Dawley , Sistemas de Liberación de Medicamentos , Glicerol/química , Glicerol/análogos & derivados , Cinética
19.
Poult Sci ; 103(12): 104296, 2024 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-39305615

RESUMEN

The research aimed to examine the impact of coated cysteamine (CS) and choline chloride (CC) on relieving the pathological effects of fatty liver hemorrhagic syndrome (FLHS) in laying hens. FLHS was induced by a high-energy low-protein (HELP) diet. Ninety laying hens were equally divided into 5 treatments with 6 replicates per treatment (3 hens/replicate). The control treatment (Cont) was fed a basal diet, while the remaining treatments were fed a HELP diet. Under the HELP dietary plan, 4 treatments were set by a 2 × 2 factorial design. Two levels of CS (CS-: 0.00 mg/kg CS; CS+: 100 mg/kg diet) and 2 levels of choline (CC-: 1,182 mg/kg; CC+: 4,124 mg/kg) were set and named CS-CC- (HELP), CS+CC-, CS-CC+ and CS+CC+. The liver of the CS-CC- (HELP) group became yellowish-brown and greasy, with hemorrhages and bleeding spots. Elevated (P < 0.05) plasma and hepatic ALT and AST and hepatic MDA levels, combined with reduced (P < 0.05) plasma and hepatic SOD and GSH-Px activities in the CS-CC- (HELP) group proved that FLHS was successfully induced. Dietary supplementation of CS, CC, or both (CS+CC+) in HELP diets relieved the pathological changes, significantly (P < 0.05) reduced the AST and ALT levels, and strengthened the antioxidant potential in laying hens under FLHS. The highest (P < 0.001) plasma adiponectin concentration was observed in the CS+CC- and lowest in the CS-CC- (HELP) group. In addition, CS and CC supplementation lowers the elevated levels of hepatic T-CHO and TG by increasing the HDL-C and reducing LDL-C levels (P < 0.05) than CS-CC- (HELP) group. CS supplementation, either alone or with CC, helps laying hens restore their egg production. It could be stated that CS and CC supplements could ameliorate the adverse effects of FLHS by regulating antioxidant enzymes activities, modulating the hepatic lipid metabolism, and restoring the production performance in laying hens. Hence, adding CS and CC could be an effective way to reduce FLHS in laying hens.

20.
Nutrients ; 16(18)2024 Sep 18.
Artículo en Inglés | MEDLINE | ID: mdl-39339751

RESUMEN

BACKGROUND/OBJECTIVES: Choline and essential fatty acids (EFA) are vital for fetal brain development, supporting pregnancy, and maintaining hormonal balance. They also promote overall health. The childbearing years present a window of opportunity to increase the intake of these key nutrients and develop healthy dietary habits. The aims of this study were to evaluate the intake of choline and EFA in women of childbearing age (15-49 years old), identify their food sources and determine if supplements containing choline and EFA were available across the Estudio Latinoamericano de Nutrición y Salud (ELANS) countries. METHODS: Survey data were collected for the ELANS, including participants from Argentina, Brazil, Chile, Colombia, Costa Rica, Ecuador, Peru, and Venezuela (n = 9218; 15-65 years old). Women of childbearing age were extracted from the largest database (n = 3704). RESULTS: In general, choline intake was inadequate in all countries, while EFA intake was normal or above requirements. Chile had the lowest intake of choline, and Colombia had the highest. The results showed that some countries had more inadequate choline intake than others. Consuming a larger quantity of eggs helped reduce choline inadequacy, as did including eggs and fish in the diet. The intake of EFA, including ALA, EPA, and DHA, showed variability. The contributions of EPA and DHA were lower than that of ALA, and the results differed by age group. CONCLUSIONS: choline intake is inadequate, and EFA intake is variable among women of childbearing age in the ELANS study. More awareness and education are needed to achieve better intake of these nutrients.


Asunto(s)
Colina , Ácidos Grasos Esenciales , Humanos , Femenino , Adulto , Colina/administración & dosificación , Adolescente , Persona de Mediana Edad , Adulto Joven , Ácidos Grasos Esenciales/administración & dosificación , Embarazo , América Latina , Suplementos Dietéticos , Dieta/estadística & datos numéricos , Encuestas Nutricionales
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