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1.
Arch Pathol Lab Med ; 2024 May 27.
Artículo en Inglés | MEDLINE | ID: mdl-38797516

RESUMEN

CONTEXT.­: Leptomeningeal disease (LMD) is a clinical sequela of central nervous system metastasis involving the cerebrospinal fluid (CSF), often seen in late-stage solid tumors. It has a grave prognosis without urgent treatment. Standard of care methodologies to diagnose LMD include CSF cytology, magnetic resonance imaging, and clinical evaluation. These methods offer limited sensitivity and specificity for the evaluation of LMD. Here, we describe the analytic performance characteristics of a microfluidic-based tumor cell enrichment and detection assay optimized to detect epithelial cells in CSF using both contrived samples as well as CSF from patients having suspected or confirmed LMD from carcinomas. OBJECTIVE.­: To demonstrate the feasibility of using a microfluidic, multi-antibody cell capture assay to identify and quantify tumor cells in CSF. DESIGN.­: An artificial CSF solution was spiked with 34 different human carcinoma cell lines at different concentrations and assayed for the ability to detect tumor cells to assess analytic accuracy. Two cell lines were selected to assess linearity, intra-assay precision, interinstrument precision, and sample stability. Clinical verification was performed on 65 CSF specimens from patients. Parameters assessed included the number of tumor cells, coefficient of variation percentage, and percentage of tumor cell capture (TCC). RESULTS.­: Among contrived samples, average tumor cell capture ranged from 50% to 82% (261 of 522; 436 of 531), and coefficients of variation ranged from 7% to 67%. The cell capture assay demonstrated a sensitivity of 92% and a specificity of 95% among clinical samples. CONCLUSIONS.­: This assay demonstrated the ability to detect and enumerate epithelial cells in contrived and clinical specimens in an accurate and reproducible fashion. The use of cell capture assays in CSF may be useful as a sensitive test for the diagnosis and longitudinal monitoring of LMD from solid tumors.

2.
Addict Biol ; 29(3): e13388, 2024 03.
Artículo en Inglés | MEDLINE | ID: mdl-38497285

RESUMEN

Protein kinase C epsilon (PKCε) regulates behavioural responses to ethanol and plays a role in anxiety-like behaviour, but knowledge is limited on downstream substrates of PKCε that contribute to these behaviours. We recently identified brain-specific serine/threonine-protein kinase 1 (BRSK1) as a substrate of PKCε. Here, we test the hypothesis that BRSK1 mediates responses to ethanol and anxiety-like behaviours that are also PKCε dependent. We used in vitro kinase assays to further validate BRSK1 as a substrate of PKCε and used Brsk1-/- mice to assess the role of BRSK1 in ethanol- and anxiety-related behaviours and in physiological responses to ethanol. We found that BRSK1 is phosphorylated by PKCε at a residue identified in a chemical genetic screen of PKCε substrates in mouse brain. Like Prkce-/- mice, male and female Brsk1-/- mice were more sensitive than wild-type to the acute sedative-hypnotic effect of alcohol. Unlike Prkce-/- mice, Brsk1-/- mice responded like wild-type to ataxic doses of ethanol. Although in Prkce-/- mice ethanol consumption and reward are reduced in both sexes, they were reduced only in female Brsk1-/- mice. Ex vivo slice electrophysiology revealed that ethanol-induced facilitation of GABA release in the central amygdala was absent in male Brsk1-/- mice similar to findings in male Prkce-/- mice. Collectively, these results indicate that BRSK1 is a target of PKCε that mediates some PKCε-dependent responses to ethanol in a sex-specific manner and plays a role distinct from PKCε in anxiety-like behaviour.


Asunto(s)
Etanol , Proteína Quinasa C-epsilon , Animales , Femenino , Masculino , Ratones , Ansiedad , Encéfalo/metabolismo , Etanol/farmacología , Ratones Endogámicos C57BL , Fenotipo , Proteína Quinasa C-epsilon/genética , Proteína Quinasa C-epsilon/metabolismo , Serina , Treonina/genética
3.
Mol Cell Proteomics ; 22(4): 100522, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36863607

RESUMEN

PKC epsilon (PKCε) plays important roles in behavioral responses to alcohol and in anxiety-like behavior in rodents, making it a potential drug target for reducing alcohol consumption and anxiety. Identifying signals downstream of PKCε could reveal additional targets and strategies for interfering with PKCε signaling. We used a chemical genetic screen combined with mass spectrometry to identify direct substrates of PKCε in mouse brain and validated findings for 39 of them using peptide arrays and in vitro kinase assays. Prioritizing substrates with several public databases such as LINCS-L1000, STRING, GeneFriends, and GeneMAINA predicted interactions between these putative substrates and PKCε and identified substrates associated with alcohol-related behaviors, actions of benzodiazepines, and chronic stress. The 39 substrates could be broadly classified in three functional categories: cytoskeletal regulation, morphogenesis, and synaptic function. These results provide a list of brain PKCε substrates, many of which are novel, for future investigation to determine the role of PKCε signaling in alcohol responses, anxiety, responses to stress, and other related behaviors.


Asunto(s)
Proteína Quinasa C-epsilon , Transducción de Señal , Ratones , Animales , Proteína Quinasa C-epsilon/genética , Proteína Quinasa C-epsilon/metabolismo , Etanol , Consumo de Bebidas Alcohólicas/genética , Encéfalo/metabolismo
4.
Meat Sci ; 194: 108987, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36182687
5.
Foods ; 11(4)2022 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-35205994

RESUMEN

This study used 1076 crossbred steers to evaluate the effects of calf-fed and yearling-fed beef production systems, implant strategies (with and without implants), and their interactions on the primal tissue composition (lean and fat components) of individual primal cuts using complete carcass dissection data. The results indicate that production system × implant interactions affected loin and rib primal weight percentages as well as marbling (p < 0.05) but did not affect the dissectible lean and fat contents of the individual primal cut (p > 0.05). Implants increased lean and decreased fat tissue contents of primal cut; however, the production system only affected lean content in the loin (p < 0.05) and fat content in the loin, round, and rib (p < 0.05). Redundancy analysis revealed a strong association between Angus breed percentage and marbling, as well as between Simmental breed percentage and multiple primal lean traits. Response surface regression models explained less variability in the tissue composition traits in calf-fed compared with yearling-fed animals, suggesting the need for further exploration using genomic studies.

6.
Lipids ; 56(6): 539-562, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34608647

RESUMEN

Trans (t) fatty acids (TFA) from partially hydrogenated vegetable oils (i.e., industrial trans) have been phased out of foods in many countries due to their promotion of cardiovascular disease. This leaves ruminant-derived foods as the main source of TFA. Unlike industrial TFA where catalytic hydrogenation yields a broad distribution of isomers, ruminant TFA are enzymatically derived and can result in enrichment of specific isomers. Comparisons between industrial and ruminant TFA have often exonerated ruminant TFA due to their lack or at times positive effects on health. At extremes, however, ruminant-sourced foods can have either high levels of t10- or t11-18:1, and when considering enriched sources, t10-18:1 has properties similar to industrial TFA, whereas t11-18:1 can be converted to an isomer of conjugated linoleic acid (cis(c)9,t11-conjugated linoleic acid), both of which have potential positive health effects. Increased t10-18:1 in meat-producing ruminants has not been associated with negative effects on live animal production or meat quality. As such, reducing t10-18:1 has not been of immediate concern to ruminant meat producers, as there have been no economic consequences for its enrichment; nevertheless at high levels, it can compromise the nutritional quality of beef and lamb. In anticipation that regulations regarding TFA may focus more on t10-18:1 in beef and lamb, the present review will cover its production, analysis, biological effects, strategies for manipulation, and regulatory policy.


Asunto(s)
Enfermedades Cardiovasculares , Ácidos Grasos trans , Animales , Bovinos , Hidrogenación , Carne/análisis , Rumiantes , Ovinos
7.
PLoS One ; 16(5): e0251868, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34033656

RESUMEN

Evaluating RNA quality and transcriptomic profile of beef muscle over time post-mortem may provide insight into RNA degradation and underlying biological and functional mechanisms that accompany biochemical changes occurring post-mortem during transformation of muscle to meat. RNA was extracted from longissimus thoracis (LT) sampled from British Continental crossbred heifer carcasses (n = 7) stored at 4°C in an abattoir drip cooler at 5 time points post-mortem, i.e., 45 min (0 h), 6 h, 24 h, 48 h, and 72 h. Following RNA-Sequencing, processed reads were aligned to the ARS-UCD1.2 bovine genome assembly. Subsequent differential expression (DE) analysis identified from 51 to 1434 upregulated and 27 to 2256 downregulated DE genes at individual time points compared to time 0 h, showing a trend for increasing counts of both upregulated and downregulated genes over time. Gene ontology and biological pathway term enrichment analyses on sets of DE genes revealed several processes and their timelines of activation/deactivation that accompanied or were involved with muscle transformation to meat. Although the quality of RNA in refrigerated LT remained high for several days post-mortem, the expression levels of several known biomarker genes for meat quality began to change from 24 h onwards. Therefore, to ensure accuracy of predictions on meat quality traits based on the expression levels of those biomarker genes in refrigerated beef muscle tissue, it is crucial that those expression measurements be made on RNA sampled within 24 h post-mortem. The present study also highlighted the need for more research on the roles of mitochondrial genes and non-coding genes in orchestrating muscle tissue processes after death, and how pre-mortem immune status might influence post-mortem meat quality.


Asunto(s)
Carne/análisis , Músculos Paraespinales/química , ARN/genética , Transcriptoma/genética , Animales , Bovinos , Músculo Esquelético/química , Cambios Post Mortem , ARN/química
8.
Meat Sci ; 178: 108526, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-33945979

RESUMEN

Pemmican is a meat product principally comprised of dried meat and fat that has served as a source of sustenance in cold, harsh climates and/or a means of preservation of meat for some Indigenous peoples, fur traders, polar explorers, military and police. Pemmican is acclaimed for its high nutrient density and long shelf life. However, for a meat product that has historically played a significant role and is often cited as the ultimate endurance food, there is a surprising paucity of scientific literature. The present study aims to review the literature to document the history of pemmican, its preparation, nutritional evaluation and additional use in the diet of animals. In view of food security and crisis situations in the world today, meat science may have a role to play in reviving, reformulating and potentially developing new processing strategies for a product like pemmican as a culturally appropriate food, with extended use as emergency provisions or for endurance athletes.


Asunto(s)
Manipulación de Alimentos/métodos , Conservación de Alimentos/métodos , Productos de la Carne/historia , Animales , Almacenamiento de Alimentos , Historia del Siglo XVI , Historia del Siglo XVII , Historia del Siglo XVIII , Historia del Siglo XIX , Historia del Siglo XX , Humanos , Productos de la Carne/análisis , Valor Nutritivo
9.
Foods ; 10(5)2021 Apr 29.
Artículo en Inglés | MEDLINE | ID: mdl-33946945

RESUMEN

This study evaluated the relationship among palatability attributes, volatile compounds, and fatty acid (FA) profiles in meat from barley, corn, and blended (50:50, barley and corn) grain-fed steers. Multiple correspondence analysis with three dimensions (Dim) explained 62.2% of the total variability among samples. The Dim 1 and 2 (53.3%) separated pure from blended grain-fed beef samples. Blended grain beef was linked to a number of volatiles including (E,E)-2,4-decadienal, hexanal, 1-octen-3-ol, and 2,3-octanedione. In addition, blended grain-fed beef was linked to fat-like and rancid flavors, stale-cardboard, metallic, cruciferous, and fat-like aroma descriptors, and negative categories for flavor intensity (FI), off-flavor, and tenderness. A possible combination of linoleic and linolenic acids in the blended diet, lower rumen pH, and incomplete biohydrogenation of blended grain-fed polyunsaturates could have increased (p ≤ 0.05) long-chain n-6 fatty acids (LCFA) in blended grain-fed beef, leading to more accumulation of FA oxidation products in the blended than in barley and corn grain-fed meat samples. The Dim 3 (8.9%) allowed corn separation from barley grain beef. Barley grain-fed beef was mainly linked to alkanes and beef positive FI, whereas corn grain-fed beef was associated with pyrazines, in addition to aldehydes related to n-6 LCFA oxidation.

10.
Circ Heart Fail ; 14(5): e008100, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-34003690

RESUMEN

BACKGROUND: Iron deficiency (ID) has a prevalence of ≈40% to 50% among patients in heart failure (HF) with reduced ejection fraction and is associated with worse prognosis. Several trials demonstrated that intravenous ferric carboxymaltose leads to early and sustained improvement in patient-reported outcomes and functional capacity in patients with HF with reduced ejection fraction with ID, yet morbidity and mortality data are limited. METHODS: The objective of the HEART-FID trial (Ferric Carboxymaltose in Heart Failure With Iron Deficiency) is to assess efficacy and safety of ferric carboxymaltose compared with placebo as treatment for symptomatic HF with reduced ejection fraction with ID. HEART-FID is a multicenter, randomized, double-blind, placebo-controlled trial enrolling ≈3014 patients at ≈300 international centers. Eligible patients are aged ≥18 years in stable chronic HF with New York Heart Association functional class II to IV symptoms, ejection fraction ≤40%, ID (ferritin <100 ng/mL or ferritin 100-300 ng/mL with a transferrin saturation <20%), and documented HF hospitalization or elevated N-terminal pro-brain natriuretic peptide. Consented patients are assigned to ferric carboxymaltose or placebo at baseline, with repeated visits/assessments every 6 months for additional study drug based on hemoglobin and iron indices for the trial duration. The primary end point is a hierarchical composite of death and HF hospitalization at 12 months and change from baseline to 6 months in the 6-minute walk test distance. CONCLUSIONS: The HEART-FID trial will inform clinical practice by clarifying the role of long-term treatment with intravenous ferric carboxymaltose, added to usual care, in ambulatory patients with symptomatic HF with reduced ejection fraction with ID. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03037931.


Asunto(s)
Anemia Ferropénica/tratamiento farmacológico , Compuestos Férricos/farmacología , Insuficiencia Cardíaca/tratamiento farmacológico , Maltosa/análogos & derivados , Disfunción Ventricular Izquierda/tratamiento farmacológico , Adolescente , Adulto , Anciano , Femenino , Ferritinas/metabolismo , Ferritinas/farmacología , Insuficiencia Cardíaca/fisiopatología , Humanos , Masculino , Maltosa/farmacología , Persona de Mediana Edad , Volumen Sistólico/efectos de los fármacos , Resultado del Tratamiento
11.
Foods ; 10(4)2021 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-33923499

RESUMEN

Consumption of red meat contributes to the intake of many essential nutrients in the human diet including protein, essential fatty acids, and several vitamins and trace minerals, with high iron content, particularly in meats with high myoglobin content. Demand for red meat continues to increase worldwide, particularly in developing countries where food nutrient density is a concern. Dietary and genetic manipulation of livestock can influence the nutritional value of meat products, providing opportunities to enhance the nutritional value of meat. Studies have demonstrated that changes in livestock nutrition and breeding strategies can alter the nutritional value of red meat. Traditional breeding strategies, such as genetic selection, have influenced multiple carcass and meat quality attributes relevant to the nutritional value of meat including muscle and fat deposition. However, limited studies have combined both genetic and nutritional approaches. Future studies aiming to manipulate the composition of fresh meat should aim to balance potential impacts on product quality and consumer perception. Furthermore, the rapidly emerging fields of phenomics, nutrigenomics, and integrative approaches, such as livestock precision farming and systems biology, may help better understand the opportunities to improve the nutritional value of meat under both experimental and commercial conditions.

12.
Appl Environ Microbiol ; 87(9)2021 04 13.
Artículo en Inglés | MEDLINE | ID: mdl-33608290

RESUMEN

Listeria monocytogenes is a deadly intracellular pathogen mostly associated with consumption of ready-to-eat foods. This study investigated the effectiveness of total beef fat (BF-T) from flaxseed-fed cattle and its fractions enriched with monounsaturated fatty acids (BF-MUFA) and polyunsaturated fatty acids (BF-PUFA), along with commercially available long-chain fatty acids (LC-FA), as natural antimicrobials against L. monocytogenes BF-T was ineffective at concentrations up to 6 mg/ml, while L. monocytogenes was susceptible to BF-MUFA and BF-PUFA, with MICs at pH 7 of 0.33 ± 0.21 mg/ml and 0.06 ± 0.03 mg/ml, respectively. The MIC of C14:0 was significantly lower than those of C16:0 and C18:0 (P < 0.05). Fatty acids c9-C16:1, C18:2n-6, and C18:3n-3 showed stronger inhibitory activity than c9-C18:1 and conjugated C18:2, with MICs of <1 mg/ml. Furthermore, global transcriptional analysis by transcriptome sequencing (RNA-seq) was performed to characterize the response of L. monocytogenes to selected fatty acids. Functional analysis indicated that antimicrobial LC-UFA repressed the expression of genes associated with nutrient transmembrane transport, energy generation, and oxidative stress resistance. On the other hand, upregulation of ribosome assembly and translation process is possibly associated with adaptive and repair mechanisms activated in response to LC-UFA. Virulence genes and genes involved in bile, acid, and osmotic stresses were largely downregulated, and more so for c9-C16:1, C18:2n-6, and C18:3n-3, likely through interaction with the master virulence regulator PrfA and the alternative sigma factor σBIMPORTANCEListeria monocytogenes is a bacterial pathogen known for its ability to survive and thrive under adverse environments and, as such, its control poses a significant challenge, especially with the trend of minimally processed and ready-to-eat foods. This work investigated the effectiveness of fatty acids from various sources as natural antimicrobials against L. monocytogenes and evaluated their potential role in L. monocytogenes pathogenicity modulation, using the strain ATCC 19111. The findings show that long-chain unsaturated fatty acids (LC-UFA), including unsaturated beef fat fractions from flaxseed-fed cattle, could have the potential to be used as effective antimicrobials for L. monocytogenes through controlling growth as well as virulence attenuation. This not only advances our understanding of the mode of action of LC-UFA against L. monocytogenes but also suggests the potential for use of beef fat or its fractions as natural antimicrobials for controlling foodborne pathogens.


Asunto(s)
Grasas/farmacología , Ácidos Grasos/farmacología , Listeria monocytogenes/efectos de los fármacos , Carne Roja , Animales , Antibacterianos/farmacología , Bovinos , Perfilación de la Expresión Génica , Regulación Bacteriana de la Expresión Génica/efectos de los fármacos , Listeria monocytogenes/genética , Listeria monocytogenes/crecimiento & desarrollo
13.
Food Res Int ; 139: 109923, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33509490

RESUMEN

The present study compared the effects of feeding dried grape pomace (DGP) or citrus pulp (DCP) at 150 g/kg dry matter compared to a control diet on major polyunsaturated fatty acids (PUFA), volatile and sensory profiles of beef. Feeding DGP or DCP diets to Angus steers for 90 d increased the proportions of C18:2n-6, C20:4n-6, C18:3n-3, total conjugated linoleic acid (CLA), n-3 and n-6 PUFA in muscle. Control-fed beef had greater concentrations of C18:1n-9, total aldehydes, ketones, and alcohols compared to DCP and DGP. Feeding DGP and DCP diets produced less tender beef than control. Overall, finishing steers on diets containing DGP or DCP compared to control increased proportions of total CLA, n-3 and n-6 PUFA, and reduced concentrations of aldehydes, ketones, and alcohols, but did not affect beef sensory attributes except for a slight reduction in tenderness.


Asunto(s)
Citrus , Vitis , Alimentación Animal/análisis , Animales , Bovinos , Dieta , Músculo Esquelético
14.
Animal ; 15(1): 100020, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33516014

RESUMEN

Feedlot beef production in tropics and subtropics is being limited by shortage of feed ingredients due to prolonged droughts resulting in high prices of cereal grains and reduced profitability. To alleviate feed shortages and increase profitability for the feedlot industry, it is important to explore underutilized non-conventional resources such as fruit by-products. The current study compared the nutrient intake, digestibility and utilization effects of feeding either 150 g/kg of dried citrus pulp (DCP) or grape pomace (DGP) as alternative dietary fibre sources to 7 months-old Angus steers (281 ±â€¯15.7 kg) under feedlot conditions. Twenty-four steers were assigned to three dietary treatments (8 steers/treatment) in a completely randomised design. Each steer was treated as an experimental unit. Steers were adapted to diets for 21 d followed by 7 d of sample collection during which nutrient intake, digestibility, rumen fermentation parameters, nitrogen retention and microbial N supply were determined. All the data were analysed using the GLIMMIX procedures. Overall, steers fed DGP had the greatest dry matter intake (DM), organic matter (OM) crude protein (CP), ash free neutral detergent fibre (aNDFom), ether extract (EE) and starch intake followed by DCP and control (CON) diets (P ≤ .05). Apparent digestibilities of DM, OM and aNDFom were higher (P ≤ .05) for DCP diet compared to DGP and CON diets. Feeding DCP and DGP diets increased ruminal concentrations of total volatile fatty acids, acetate and isovalerate, and acetate to propionate ratio, and reduced propionate concentrations compared to the CON diet (P ≤ .05). The steers fed the CON diet had the greatest urinary excretions of allantoin, uric acid and total purine derivatives followed by those fed the DCP and DGP diets (P ≤ .05). Nitrogen intake, faecal nitrogen (N), N retention and N efficiency utilization were in the order of DGP > DCP > CON diets (P ≤ .05). Overall, feeding DGP as alternative fibre source to wheat bran improved nutrient intake, retention and efficiency of N utilization but reduced apparent nutrient digestibility compared to DCP. Current finding suggests that DGP may be a better fibre substitute for wheat bran in beef diets than DCP.


Asunto(s)
Citrus , Vitis , Alimentación Animal/análisis , Animales , Bovinos , Dieta/veterinaria , Digestión , Fermentación , Nutrientes , Rumen/metabolismo
15.
RNA Biol ; 18(6): 854-862, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-32931715

RESUMEN

Increasing the healthy/unhealthy fatty acid (FA) ratio in meat is one of the urgent tasks required to address consumer concerns. However, the regulatory mechanisms ultimately resulting in FA profiles vary among animals and remain largely unknown. In this study, using ~1.2 Tb high-quality RNA-Seq-based transcriptomic data of 188 samples from four key metabolic tissues (rumen, liver, muscle, and backfat) together with the contents of 49 FAs in backfat, the molecular regulatory mechanisms of these tissues contributing to FA formation in cattle were explored. Using this large dataset, the alternative splicing (AS) events, one of the transcriptional regulatory mechanisms in four tissues were identified. The highly conserved and absent AS events were detected in rumen tissue, which may contribute to its functional differences compared with the other three tissues. In addition, the healthy/unhealthy FA ratio related AS events, differential expressed (DE) genes, co-expressed genes, and their functions in four tissues were analysed. Eight key genes were identified from the integrated analysis of DE, co-expressed, and AS genes between animals with high and low healthy/unhealthy FA ratios. This study provides an applicable pipeline for AS events based on comprehensive RNA-Seq analysis and improves our understanding of the regulatory mechanism of FAs in beef cattle.


Asunto(s)
Empalme Alternativo , Bovinos/genética , Ácidos Grasos/metabolismo , Perfilación de la Expresión Génica/métodos , Redes Reguladoras de Genes , Transducción de Señal/genética , Animales , Bovinos/metabolismo , Proteoglicanos de Heparán Sulfato/genética , Proteoglicanos de Heparán Sulfato/metabolismo , Hígado/metabolismo , Masculino , Músculos/metabolismo , Protoporfirinógeno-Oxidasa/genética , Protoporfirinógeno-Oxidasa/metabolismo , Rumen/metabolismo , Grasa Subcutánea/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
16.
Neuropharmacology ; 178: 108220, 2020 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-32736086

RESUMEN

Phosphodiesterase type 4 (PDE4) inhibitors prevent hydrolysis of cyclic adenosine monophosphate and increase protein kinase A (PKA)-mediated phosphorylation. PDE4 inhibitors also regulate responses to ethanol and GABAergic drugs. We investigated mechanisms by which the PDE4 inhibitor, apremilast, regulates acute effects of ethanol and GABAergic drugs in male and female mice. Apremilast prolonged the sedative-hypnotic effects of gaboxadol, zolpidem, and propofol but did not alter etomidate effects, and unexpectedly shortened the sedative-hypnotic effects of diazepam. Apremilast prolonged rotarod ataxia induced by zolpidem, propofol, and loreclezole, shortened recovery from diazepam, but had no effect on ataxia induced by gaboxadol or etomidate. The PKA inhibitor H-89 blocked apremilast's ability to prolong the sedative-hypnotic effects of ethanol, gaboxadol, and propofol and to prolong ethanol- and propofol-induced ataxia. H-89 also blocked apremilast's ability to shorten the sedative-hypnotic and ataxic effects of diazepam. The ß1-specific antagonist, salicylidene salicylhydrazide (SCS), produced faster recovery from ethanol- and diazepam-induced ataxia, but did not alter propofol- or etomidate-induced ataxia. SCS shortened the sedative-hypnotic effects of ethanol and diazepam but not of propofol. In Xenopus oocytes, a phosphomimetic (aspartate) mutation at the PKA phosphorylation site in ß1 subunits decreased the maximal GABA current in receptors containing α1 or α3, but not α2 subunits. In contrast, phosphomimetic mutations at PKA sites in ß3 subunits increased the maximal GABA current in receptors containing α1 or α2, but not α3 subunits. The GABA potency and allosteric modulation by ethanol, propofol, etomidate, zolpidem, flunitrazepam, or diazepam were not altered by these mutations. We propose a model whereby apremilast increases PKA-mediated phosphorylation of ß1-and ß3-containing GABAA receptors and selectively alters acute tolerance to ethanol and GABAergic drugs.


Asunto(s)
Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Etanol/administración & dosificación , Moduladores del GABA/administración & dosificación , Reflejo de Enderezamiento/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Talidomida/análogos & derivados , Animales , Relación Dosis-Respuesta a Droga , Femenino , Agonistas del GABA/administración & dosificación , Masculino , Ratones , Ratones Endogámicos C57BL , Inhibidores de Fosfodiesterasa 4/administración & dosificación , Receptores de GABA-A/fisiología , Reflejo de Enderezamiento/fisiología , Transducción de Señal/fisiología , Talidomida/administración & dosificación , Xenopus laevis
17.
Leuk Lymphoma ; 61(8): 1965-1973, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32432489

RESUMEN

Gemtuzumab ozogamicin (GO) remained available to US clinicians through an open-label expanded-access protocol (NCT02312037) until GO was reapproved. Patients were aged ≥3 months with relapsed/refractory (R/R) acute myeloid leukemia (AML), high-risk myelodysplastic syndrome, or acute promyelocytic leukemia (APL), and had exhausted other treatment options. Three hundred and thirty one patients received GO as monotherapy for R/R AML (n = 139), combination therapy for R/R AML (n = 183), or treatment for R/R APL (n = 9). Corresponding treatment discontinuations occurred in 68, 39, and 33% of patients. All-causality grade 5 AEs occurred in 52, 22, and 22% of patients in the monotherapy, combination, and APL groups, respectively. Corresponding grades 3 and 4 treatment-related AEs were reported in 60, 55 and 78% of patients. Hepatotoxicity occurred in five patients: veno-occlusive disease (n = 4) and drug-induced liver injury (n = 1). GO was generally well tolerated in patients with R/R AML or APL. Most frequent treatment-related grade ≥3 AEs were hematologic AEs.Clinicaltrials.gov identifier: NCT02312037.


Asunto(s)
Aminoglicósidos , Leucemia Mieloide Aguda , Aminoglicósidos/efectos adversos , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Gemtuzumab , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico
18.
Meat Sci ; 165: 108114, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-32272342

RESUMEN

Ruminant meat (RM) is an excellent source of high-quality protein, B vitamins and trace minerals and plays an important role in global food and nutrition security. However, nutritional guidelines commonly recommend reduced intake of RM mainly because of its high saturated fatty acid (SFA) content, and more recently because of its perceived negative environmental impacts. RM is, however, rich in heart healthy cis-monounsaturated fatty acids and can be an important source of long-chain omega-3 (n-3) fatty acids in populations with low fish consumption. In addition, RM is a source of bioactive phospholipids, as well as rumen-derived bioactive fatty acids including branched-chain, vaccenic and rumenic acids, which have been associated with several health benefits. However, the role of bioactive RM lipids in maintaining and improving consumers' health have been generally ignored in nutritional guidelines. The present review examines RM lipids in relation to human health, and evaluates the effectiveness of different feeding strategies and possibilities for future profile and content improvement.


Asunto(s)
Lípidos/análisis , Valor Nutritivo , Carne Roja/análisis , Animales , Ácidos Grasos/análisis , Humanos , Rumiantes
19.
J Anim Sci ; 98(4)2020 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-32277699

RESUMEN

Leptin genotypes can be identified as homozygous normal (CC), homozygous mutant (TT), and heterozygous (CT) based on a single-nucleotide polymorphism in exon 2 of the leptin gene, which has been associated with feed intake and fat deposition in cattle. The experiment was designed as 2 × 2 × 2 factorial with three main factors: (1) genotype (CT or TT) and diets fed 2) with or without triticale dried distiller's grains with solubles (DDG), and 3) with either flaxseed (FS) or high-oleate sunflower seed (SS). Evaluations included growth performance, subcutaneous fat deposition, adipocyte cellularity, meat quality, and fatty acid (FA) profile of various depots. Beef steers (n = 40, 459 ± 31 kg) of either CT or TT genotypes were housed in individual pens with ad libitum access to one of the four diets: 75% steam-rolled barley + 10% barley silage with 10% FS or SS (non-DDG diets, NDG) and 46.5% barley + 10% barley silage + 30% DDG, with 8.5% FS or SS, all on a dry matter basis. Growth performance, ultrasound subcutaneous fat thickness, rib eye area (REA), and plasma FA were measured prior to and during the finishing period. At slaughter, samples of subcutaneous fat, perirenal fat, and Longissimus thoracis (LT) muscle were collected for FA analysis and carcass and meat quality were measured. Compared with CT cattle, TT tended to have less (P = 0.06) C18:2-c9,t11 (rumenic acid) in plasma and subcutaneous fat and a greater proportion (P < 0.05) of C18:0 in subcutaneous, perirenal, and LT fat. Cattle with TT genotype also tended (P < 0.1) to have more total saturated and less unsaturated (USFA) and monounsaturated fats (MUFA) and had less (P = 0.04) linoleic acid in LT. Ultrasound fat thickness, REA, and average diameter of adipocytes in subcutaneous fat at 12 wk were not affected (P > 0.39) by genotype. Generally, carcass and meat quality were similar (P > 0.1) among diets, although adding FS tended to increase (P = 0.06) total USFA of subcutaneous fat including omega-3 FA (P < 0.001). For the high-fat diets evaluated, CT cattle would have more potential to produce beef with enhanced health benefits than would TT cattle.


Asunto(s)
Alimentación Animal/análisis , Bovinos/fisiología , Ácidos Grasos/análisis , Leptina/genética , Carne Roja/normas , Adipocitos/metabolismo , Animales , Bovinos/genética , Bovinos/crecimiento & desarrollo , Dieta/veterinaria , Lino , Genotipo , Helianthus , Hordeum , Masculino , Ácido Oléico/análisis , Semillas , Ensilaje/análisis , Grasa Subcutánea/química , Triticale
20.
Meat Sci ; 162: 108029, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-31837542

RESUMEN

The shelf-life of beef was compared from 7-months old Angus steers (281 ± 15.4 kg initial body weight) fed 150 g/kg DM dried citrus pulp (DCP) or grape pomace (DGP) for 90 days. The antioxidant activity, bacterial load, and lipid and protein oxidation were evaluated on the longissimus lumborum subjected to air-permeable packaging at days 1, 3, 5, 7 and 9 post-slaughter. Beef antioxidant activity was DGP > DCP > control (P ≤ 0.05). Beef from steers fed DGP or DCP had higher L* values (P ≤ 0.05) and fewer (P ≤ 0.05) coliform counts than steers fed the control diet. Beef antioxidant activity was DGP > DCP > control (P ≤ 0.05). Beef TBARS and carbonyl contents were DGP < DCP < control (P ≤ 0.05). Overall, antioxidant activity decreased (P ≤ 0.05), while bacterial loads, TBARS and carbonyl contents increased (P ≤ 0.05) during retail display for all diets. Current findings indicate that DGP could be a better natural preservative than DCP when included in beef cattle finishing diets.


Asunto(s)
Citrus , Carne Roja/análisis , Carne Roja/microbiología , Vitis , Alimentación Animal , Animales , Antioxidantes/análisis , Bovinos , Dieta/veterinaria , Enterobacteriaceae , Almacenamiento de Alimentos , Masculino , Músculo Esquelético/química , Oxidación-Reducción , Sustancias Reactivas al Ácido Tiobarbitúrico/análisis
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