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1.
Mol Biol Rep ; 51(1): 729, 2024 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-38862809

RESUMEN

BACKGROUND: Preclinical and clinical studies over the past several decades have indicated the potential value of metformin, a widely utilized treatment for Type 2 diabetes, in prostate cancer therapy. Notably, these studies demonstrated metformin's pleiotropic effects on several molecular and metabolic pathways, such as androgen signaling, cell cycle, and cellular bioenergetics. In this study we investigated the role of metformin in regulating intracellular redox status and cell survival in LNCaP prostate cancer cells. METHODS AND RESULTS: The cytotoxic effects of metformin with or without the presence of SBI0206965 (AMPK inhibitor) on LNCaP cells were determined using MTT and trypan blue exclusion assays. Seahorse XP extracellular analysis, Liquid Chromatography/ Mass Spectrophotometry (LC/MS), and 2,7- and Dichlorofluoresin diacetate (DCFDA) assay were used to assess the effects of metformin on cellular bioenergetics, redox status, and redox-related metabolites. mRNA expression and protein concentration of redox-related enzymes were measured using Real Time-qPCR and ELISA assay, respectively. Independently of AMP-activated protein kinase, metformin exhibited a dose- and time-dependent inhibition of LNCaP cell survival, a response mitigated by glutathione or N-acetylcysteine (ROS scavengers) treatment. Notably, these findings were concomitant with a decline in ATP levels and the inhibition of oxidative phosphorylation. The results further indicated metformin's induction of reactive oxygen species, which significantly decreased glutathione levels and the ratio of reduced to oxidized glutathione, as well as the transsulfuration metabolite, cystathionine. Consistent with an induction of oxidative stress condition, metformin increased mRNA levels of the master redox transcription factor Nrf-2 (nuclear factor erythroid-derived 2-like), as well as transsulfuration enzymes cystathionine beta-synthase and cystathionase and GSH synthesis enzymes γ-glutamylcysteine synthetase and glutathione synthetase. CONCLUSION: Our findings highlight multiple mechanisms by which metformin-induced formation of reactive oxygen species may contribute to its efficacy in prostate cancer treatment, including promotion of oxidative stress, Nrf2 activation, and modulation of redox-related pathways, leading to its anti-survival action.


Asunto(s)
Supervivencia Celular , Metformina , Estrés Oxidativo , Neoplasias de la Próstata , Especies Reactivas de Oxígeno , Metformina/farmacología , Humanos , Masculino , Estrés Oxidativo/efectos de los fármacos , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Supervivencia Celular/efectos de los fármacos , Línea Celular Tumoral , Especies Reactivas de Oxígeno/metabolismo , Oxidación-Reducción/efectos de los fármacos , Glutatión/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Metabolismo Energético/efectos de los fármacos
2.
Int J Mol Sci ; 24(20)2023 Oct 18.
Artículo en Inglés | MEDLINE | ID: mdl-37894968

RESUMEN

Network oscillations are essential for all cognitive functions. Oscillatory deficits are well established in psychiatric diseases and are recapitulated in animal models. They are significantly and specifically affected by pharmacological interventions using psychoactive compounds. Dopamine D4 receptor (D4R) activation was shown to enhance gamma rhythm in freely moving rats and to specifically affect slow delta and theta oscillations in the urethane-anesthetized rat model. The goal of this study was to test the effect of D4R activation on slow network oscillations at delta and theta frequencies during wake states, potentially supporting enhanced functional connectivity during dopamine-induced attention and cognitive processing. Network activity was recorded in the prefrontal cortex (PFC), hippocampus (HC) and nucleus reuniens (RE) in control conditions and after injecting the D4R agonist A-412997 (3 and 5 mg/kg; systemic administration). We found that A-412997 elicited a lasting (~40 min) wake state and drastically enhanced narrow-band delta oscillations in the PFC and RE in a dose-dependent manner. It also preferentially enhanced delta synchrony over theta coupling within the PFC-RE-HC circuit, strongly strengthening PFC-RE coupling. Thus, our findings indicate that the D4R may contribute to cognitive processes, at least in part, through acting on wake delta oscillations and that the RE, providing an essential link between the PFC and HC, plays a prominent role in this mechanism.


Asunto(s)
Agonistas de Dopamina , Receptores de Dopamina D4 , Animales , Ratas , Agonistas de Dopamina/farmacología , Hipocampo/metabolismo , Núcleos Talámicos de la Línea Media/metabolismo , Corteza Prefrontal/metabolismo
3.
FASEB J ; 33(2): 2460-2471, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30277817

RESUMEN

Iron deficiency is closely associated with altered GABA metabolism and affective behavior. While mutation in the hemochromatosis ( HFE) gene disrupts iron homeostasis and promotes oxidative stress that increases the risk of neurodegeneration, it is largely unknown whether HFE mutation modifies GABAergic homeostasis and emotional behavior. The goal of our study was to investigate the impact of HFE on GABAergic neurochemistry and redox-epigenetic regulation in the brain using H67D HFE-mutant mice that recapitulates the H63D-HFE mutation in humans. H67D mice displayed elevated redox-active iron levels in the brain by 32% compared to age-matched wild-type mice. Moreover, the H67D brain had increased isoprostane and decreased glutathione, indicating elevated oxidative stress. Additionally, the H67D brain had decreased global methylation and attenuated DNA methyltransferase (DNMT) activity. Direct addition of iron to purified DNMT in vitro decreased enzyme activity in a concentration-dependent manner. Last, H67D mice exhibited decreased anxiety-like behavior, which was associated with increased expression of the GABAA receptor α2 subunits by 93%, and these changes were also observed in H67D mice fed a low-iron diet. Taken together, our results suggest a putative role of HFE in regulating labile iron status in the brain, and mutation in H67D perturbs redox-methylation status, contributing to GABAergic dysfunction.-Ye, Q., Trivedi, M., Zhang, Y., Böhlke, M., Alsulimani, H., Chang, J., Maher, T., Deth, R., Kim, J. Brain iron loading impairs DNA methylation and alters GABAergic function in mice.


Asunto(s)
Encéfalo/metabolismo , Encéfalo/patología , Metilación de ADN , Proteína de la Hemocromatosis/fisiología , Hierro/metabolismo , Mutación , Receptores de GABA-A/metabolismo , Animales , Epigénesis Genética , Regulación de la Expresión Génica , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Estrés Oxidativo , Subunidades de Proteína , Receptores de GABA-A/genética
4.
Nutr Cancer ; 71(1): 100-110, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30372163

RESUMEN

Folate and vitamin B12 deficiency is associated with depletion of the major intracellular antioxidant glutathione, and oxidative stress is emerging as an etiological mechanism for colon cancer. Azoxymethane (AOM), a potent carcinogen, induces colon cancer in rats by causing pathophysiological changes and oxidative stress. We investigated the synergistic effect of folate and vitamin B12 supplementation against AOM-induced carcinogenesis and oxidative stress in rat colon. Adult male rats were distributed into four groups: 1) Basal diet only; 2) AOM injection (15 mg/kg once per week in weeks 5 and 6); 3) Folate and vitamin B12 supplemented diet; 4) Folate and B12 diet with AOM injection. After 16 weeks, rats were sacrificed, colon tissue dissected, indicators of oxidative stress were measured, and immunohistochemical and ultrastructural changes were evaluated. AOM-injected rats showed oxidative stress, evident by glutathione depletion, oxidation of cellular proteins, and DNA oxidative damage. AOM increased mucosal levels of antiapoptotic and proapoptotic proteins Bcl2 and Bax and caused ultrastructure changes in colonic cell organelles. Folate and vitamin B12 supplementation decreased the level of oxidative stress and ameliorated the cytotoxic effects of AOM. In this in vivo experimental model of colon cancer, folate and vitamin B12 supplementation combats carcinogen-induced oxidative stress.


Asunto(s)
Azoximetano/toxicidad , Neoplasias del Colon/prevención & control , Ácido Fólico/administración & dosificación , Estrés Oxidativo/efectos de los fármacos , Vitamina B 12/administración & dosificación , Animales , Carcinogénesis/efectos de los fármacos , Suplementos Dietéticos , Modelos Animales de Enfermedad , Glutatión/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley
5.
Sci Eng Ethics ; 23(6): 1691-1718, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-29119411

RESUMEN

Historically, entities with a vested interest in a product that critics have suggested is harmful have consistently used research to back their claims that the product is safe. Prominent examples are: tobacco, lead, bisphenol A, and atrazine. Research literature indicates that about 80-90% of studies with industry affiliation found no harm from the product, while only about 10-20% of studies without industry affiliation found no harm. In parallel to other historical debates, recent studies examining a possible relationship between mercury (Hg) exposure and autism spectrum disorder (ASD) show a similar dichotomy. Studies sponsored and supported by industry or entities with an apparent conflict of interest have most often shown no evidence of harm or no "consistent" evidence of harm, while studies without such affiliations report positive evidence of a Hg/autism association. The potentially causal relationship between Hg exposure and ASD differs from other toxic products since there is a broad coalition of entities for whom a conflict of interest arises. These include influential governmental public health entities, the pharmaceutical industry, and even the coal burning industry. This review includes a systematic literature search of original studies on the potential relationship between Hg and ASD from 1999 to August 2015, finding that of the studies with public health and/or industry affiliation, 86% reported no relationship between Hg and ASD. However, among studies without public health and/or industry affiliation, only 21% find no relationship between Hg and ASD. The discrepancy in these results suggests a bias indicative of a conflict of interest.


Asunto(s)
Trastorno del Espectro Autista/etiología , Investigación Biomédica/ética , Conflicto de Intereses , Exposición a Riesgos Ambientales/efectos adversos , Industrias/ética , Mercurio/efectos adversos , Trastorno Autístico/etiología , Carbón Mineral , Industria Farmacéutica , Ética en los Negocios , Ética en Investigación , Humanos , Salud Pública
6.
Nutr J ; 15(1): 82, 2016 Sep 29.
Artículo en Inglés | MEDLINE | ID: mdl-27680716

RESUMEN

This study reports the plasma glutathione concentrations in a double-blind, randomized, controlled, 2 × 2 cross-over study in which healthy participants consumed conventional milk (2 × 250 mL per day) containing both A1 and A2 types of ß-casein, or milk containing only A2 type ß-casein. Beta-casomorphin-7 (BCM-7), a peptide uniquely derived from the A1 type of ß-casein, was previously reported to downregulate glutathione expression in human gut epithelial and neuronal cell lines by limiting cysteine uptake. The current human study demonstrates that consumption of milk containing only A2 ß-casein was associated with a greater increase in plasma glutathione concentrations compared with the consumption of milk containing both ß-casein types, and did not increase plasma BCM-7 concentrations compared with the washout diet in the study participants. Thus, milk containing only A2 ß-casein and not A1 ß-casein has the potential to promote the production of the antioxidant glutathione in humans. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; identifier: NCT02406469.

7.
Molecules ; 21(9)2016 Sep 08.
Artículo en Inglés | MEDLINE | ID: mdl-27617989

RESUMEN

Elevated blood concentrations of homocysteine have been well established as a risk factor for cardiovascular diseases and neuropsychiatric diseases, yet the etiologic relationship of homocysteine to these disorders remains poorly understood. Protein N-homocysteinylation has been hypothesized as a contributing factor; however, it has not been examined globally owing to the lack of suitable detection methods. We recently developed a selective chemical method to label N-homocysteinylated proteins with a biotin-aldehyde tag followed by Western blotting analysis, which was further optimized in this study. We then investigated the variation of protein N-homocysteinylation in plasma from rats on a vitamin B12 deficient diet. Elevated "total homocysteine" concentrations were determined in rats with a vitamin B12 deficient diet. Correspondingly, overall levels of plasma protein N-homocysteinylation displayed an increased trend, and furthermore, more pronounced and statistically significant changes (e.g., 1.8-fold, p-value: 0.03) were observed for some individual protein bands. Our results suggest that, as expected, a general metabolic correlation exists between "total homocysteine" and N-homocysteinylation, although other factors are involved in homocysteine/homocysteine thiolactone metabolism, such as the transsulfuration of homocysteine by cystathionine ß-synthase or the hydrolysis of homocysteine thiolactone by paraoxonase 1 (PON1), may play more significant or direct roles in determining the level of N-homocysteinylation.


Asunto(s)
Proteínas Sanguíneas/metabolismo , Homocisteína/sangre , Hiperhomocisteinemia/sangre , Plasma/metabolismo , Procesamiento Proteico-Postraduccional , Deficiencia de Vitamina B 12/sangre , Animales , Ratas
8.
Mol Pharmacol ; 85(5): 747-57, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24569088

RESUMEN

Canonically, opioids influence cells by binding to a G protein-coupled opioid receptor, initiating intracellular signaling cascades, such as protein kinase, phosphatidylinositol 3-kinase, and extracellular receptor kinase pathways. This results in several downstream effects, including decreased levels of the reduced form of glutathione (GSH) and elevated oxidative stress, as well as epigenetic changes, especially in retrotransposons and heterochromatin, although the mechanism and consequences of these actions are unclear. We characterized the acute and long-term influence of morphine on redox and methylation status (including DNA methylation levels) in cultured neuronal SH-SY5Y cells. Acting via µ-opioid receptors, morphine inhibits excitatory amino acid transporter type 3-mediated cysteine uptake via multiple signaling pathways, involving different G proteins and protein kinases in a temporal manner. Decreased cysteine uptake was associated with decreases in both the redox and methylation status of neuronal cells, as defined by the ratios of GSH to oxidized forms of glutathione and S-adenosylmethionine to S-adenosylhomocysteine levels, respectively. Further, morphine induced global DNA methylation changes, including CpG sites in long interspersed nuclear elements (LINE-1) retrotransposons, resulting in increased LINE-1 mRNA. Together, these findings illuminate the mechanism by which morphine, and potentially other opioids, can influence neuronal-cell redox and methylation status including DNA methylation. Since epigenetic changes are implicated in drug addiction and tolerance phenomenon, this study could potentially extrapolate to elucidate a novel mechanism of action for other drugs of abuse.


Asunto(s)
Cisteína/antagonistas & inhibidores , Metilación de ADN/efectos de los fármacos , Transportador 3 de Aminoácidos Excitadores/antagonistas & inhibidores , Morfina/farmacología , Retroelementos/efectos de los fármacos , Transcripción Genética/efectos de los fármacos , Línea Celular Tumoral , Cisteína/metabolismo , Metilación de ADN/fisiología , Transportador 3 de Aminoácidos Excitadores/fisiología , Humanos , Oxidación-Reducción/efectos de los fármacos , Retroelementos/fisiología , Transcripción Genética/fisiología
9.
Nutr Rev ; 2024 Jul 18.
Artículo en Inglés | MEDLINE | ID: mdl-39024213

RESUMEN

The gut and brain communicate through bidirectional neural, endocrine, and immune signals to coordinate central nervous system activity with gastrointestinal function. Dysregulated inflammation can promote immune cell activation and increase entero-endocrine signaling and intestinal permeability; hence, a functional gut-brain axis is necessary for a healthy digestive system. The consumption of milk products can lead to gut discomfort via effects on gastrointestinal tract function and the inflammatory state, which, in turn, affect the brain. A1 ß-casein and A2 ß-casein are major components of bovine-milk protein, and their digestion may result in different physiological effects following the consumption of milk products. Peptides derived from A1 ß-casein, such as ß-casomorphins, may increase gut dysfunction and inflammation, thereby modulating the availability of bioactive metabolites in the bloodstream and contribute to changes in cognitive function. This narrative review examines the functional interrelationships between the consumption of cow-milk-derived ß-caseins and their effect on the brain, immune system, and the gut, which together comprise the gut-brain axis.

10.
Cells ; 13(13)2024 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-38994948

RESUMEN

Excessive inflammatory reactions and oxidative stress are well-recognized molecular findings in autism and these processes can affect or be affected by the epigenetic landscape. Nonetheless, adequate therapeutics are unavailable, as patient-specific brain molecular markers for individualized therapies remain challenging. METHODS: We used iPSC-derived neurons and astrocytes of patients with autism vs. controls (5/group) to examine whether they replicate the postmortem brain expression/epigenetic alterations of autism. Additionally, DNA methylation of 10 postmortem brain samples (5/group) was analyzed for genes affected in PSC-derived cells. RESULTS: We found hyperexpression of TGFB1, TGFB2, IL6 and IFI16 and decreased expression of HAP1, SIRT1, NURR1, RELN, GPX1, EN2, SLC1A2 and SLC1A3 in the astrocytes of patients with autism, along with DNA hypomethylation of TGFB2, IL6, TNFA and EN2 gene promoters and a decrease in HAP1 promoter 5-hydroxymethylation in the astrocytes of patients with autism. In neurons, HAP1 and IL6 expression trended alike. While HAP1 promoter was hypermethylated in neurons, IFI16 and SLC1A3 promoters were hypomethylated and TGFB2 exhibited increased promoter 5-hydroxymethlation. We also found a reduction in neuronal arborization, spine size, growth rate, and migration, but increased astrocyte size and a reduced growth rate in autism. In postmortem brain samples, we found DNA hypomethylation of TGFB2 and IFI16 promoter regions, but DNA hypermethylation of HAP1 and SLC1A2 promoters in autism. CONCLUSION: Autism-associated expression/epigenetic alterations in iPSC-derived cells replicated those reported in the literature, making them appropriate surrogates to study disease pathogenesis or patient-specific therapeutics.


Asunto(s)
Astrocitos , Trastorno Autístico , Encéfalo , Metilación de ADN , Epigénesis Genética , Células Madre Pluripotentes Inducidas , Neuronas , Humanos , Astrocitos/metabolismo , Astrocitos/patología , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/patología , Trastorno Autístico/genética , Trastorno Autístico/patología , Trastorno Autístico/metabolismo , Neuronas/metabolismo , Neuronas/patología , Metilación de ADN/genética , Encéfalo/patología , Encéfalo/metabolismo , Masculino , Femenino , Regiones Promotoras Genéticas/genética , Forma de la Célula , Niño , Regulación de la Expresión Génica , Proteína Reelina
11.
Cells ; 12(18)2023 09 13.
Artículo en Inglés | MEDLINE | ID: mdl-37759491

RESUMEN

Cardiac injury, such as myocardial infarction and heart failure, remains a significant global health burden. The limited regenerative capacity of the adult heart poses a challenge for restoring its function after injury. Mesenchymal stem cells (MSCs) have emerged as promising candidates for cardiac regeneration due to their ability to differentiate into various cell types and secrete bioactive molecules. In recent years, attention has been given to noncoding RNAs derived from MSCs, particularly long noncoding RNAs (lncRNAs), and their potential role in cardiac injury and repair. LncRNAs are RNA molecules that do not encode proteins but play critical roles in gene regulation and cellular responses including cardiac repair and regeneration. This review focused on MSC-derived lncRNAs and their implications in cardiac regeneration, including their effects on cardiac function, myocardial remodeling, cardiomyocyte injury, and angiogenesis. Understanding the molecular mechanisms of MSC-derived lncRNAs in cardiac injury and repair may contribute to the development of novel therapeutic strategies for treating cardiovascular diseases. However, further research is needed to fully elucidate the potential of MSC-derived lncRNAs and address the challenges in this field.


Asunto(s)
Lesiones Cardíacas , Células Madre Mesenquimatosas , Infarto del Miocardio , ARN Largo no Codificante , Adulto , Humanos , ARN Largo no Codificante/genética , Infarto del Miocardio/genética , Infarto del Miocardio/terapia , Miocitos Cardíacos
12.
World J Clin Pediatr ; 12(2): 25-37, 2023 Mar 09.
Artículo en Inglés | MEDLINE | ID: mdl-37034430

RESUMEN

In the United States, schools offer special education services to children who are diagnosed with a learning or neurodevelopmental disorder and have difficulty meeting their learning goals. Pediatricians may play a key role in helping children access special education services. The number of children ages 6-21 in the United States receiving special education services increased 10.4% from 2006 to 2021. Children receiving special education services under the autism category increased 242% during the same period. The demand for special education services for children under the developmental delay and other health impaired categories increased by 184% and 83% respectively. Although student enrollment in American schools has remained stable since 2006, the percentage distribution of children receiving special education services nearly tripled for the autism category and quadrupled for the developmental delay category by 2021. Allowable heavy metal residues remain persistent in the American food supply due to food ingredient manufacturing processes. Numerous clinical trial data indicate heavy metal exposures and poor diet are the primary epigenetic factors responsible for the autism and attention deficit hyperactivity disorder epidemics. Dietary heavy metal exposures, especially inorganic mercury and lead may impact gene behavior across generations. In 2021, the United States Congress found heavy metal residues problematic in the American food supply but took no legislative action. Mandatory health warning labels on select foods may be the only way to reduce dietary heavy metal exposures and improve child learning across generations.

13.
Aging Cell ; 22(5): e13806, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36967480

RESUMEN

Accumulation of senescent cells (SNCs) with a senescence-associated secretory phenotype (SASP) has been implicated as a major source of chronic sterile inflammation leading to many age-related pathologies. Herein, we provide evidence that a bifunctional immunotherapeutic, HCW9218, with capabilities of neutralizing TGF-ß and stimulating immune cells, can be safely administered systemically to reduce SNCs and alleviate SASP in mice. In the diabetic db/db mouse model, subcutaneous administration of HCW9218 reduced senescent islet ß cells and SASP resulting in improved glucose tolerance, insulin resistance, and aging index. In naturally aged mice, subcutaneous administration of HCW9218 durably reduced the level of SNCs and SASP, leading to lower expression of pro-inflammatory genes in peripheral organs. HCW9218 treatment also reverted the pattern of key regulatory circadian gene expression in aged mice to levels observed in young mice and impacted genes associated with metabolism and fibrosis in the liver. Single-nucleus RNA Sequencing analysis further revealed that HCW9218 treatment differentially changed the transcriptomic landscape of hepatocyte subtypes involving metabolic, signaling, cell-cycle, and senescence-associated pathways in naturally aged mice. Long-term survival studies also showed that HCW9218 treatment improved physical performance without compromising the health span of naturally aged mice. Thus, HCW9218 represents a novel immunotherapeutic approach and a clinically promising new class of senotherapeutic agents targeting cellular senescence-associated diseases.


Asunto(s)
Senescencia Celular , Fenotipo Secretor Asociado a la Senescencia , Ratones , Animales , Senescencia Celular/genética , Envejecimiento , Inflamación , Inmunoterapia , Fenotipo
15.
Biochimie ; 192: 1-12, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-34517051

RESUMEN

Nuclear factor erythroid 2-related factor 2 (Nrf2) promotes expression of a large number of antioxidant genes and multiple studies have described oxidative stress and impaired methylation in autism spectrum disorder (ASD), including decreased brain levels of methylcobalamin(III) (MeCbl). Here we report decreased expression of the Nrf2 gene (NFE2L2) in frontal cortex of ASD subjects, as well as differences in other genes involved in redox homeostasis. In pooled control and ASD correlation analyses, hydroxocobalamin(III) (OHCbl) was inversely correlated with NFE2L2 expression, while MeCbl and total cobalamin abundance were positively correlated with NFE2L2 expression. Levels of methionine, S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH) and cystathionine were positively correlated with NFE2L2 expression, while homocysteine (HCY) was negatively correlated. The relationship between Nrf2 activity and cobalamin was further supported by a bioinformatics-based comparison of cobalamin levels in different tissues with expression of a panel of 40 Nrf2-regulated genes, which yielded a strong correlation. Lastly, Nrf2-regulated gene expression was also correlated with expression of intracellular cobalamin trafficking and processing genes, such as MMADHC and MTRR. These findings highlight a previously unrecognized relationship between the antioxidant-promoting role of Nrf2 and cobalamin status, which is dysfunctional in ASD.


Asunto(s)
Trastorno Autístico/metabolismo , Lóbulo Frontal/metabolismo , Regulación de la Expresión Génica , Factor 2 Relacionado con NF-E2/metabolismo , Vitamina B 12/metabolismo , Trastorno Autístico/genética , Humanos , Factor 2 Relacionado con NF-E2/genética , Vitamina B 12/genética
16.
Alcohol Clin Exp Res ; 35(2): 277-83, 2011 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-21121936

RESUMEN

BACKGROUND: Methionine synthase (MS) is a ubiquitous enzyme that requires vitamin B12 (cobalamin) and 5-methyl-tetrahydrofolate for the methylation of homocysteine to methionine. Previous studies have shown that acute or chronic ethanol (ETOH) administration results in the inhibition of MS and depletion of glutathione (GSH), and it has been proposed that GSH is required for the synthesis of methylcobalamin (MeCbl). METHODS: We measured GSH levels and investigated the ability of different cobalamin cofactors [cyano- (CNCbl), glutathionyl- (GSCbl), hydroxo- (OHCbl), and MeCbl] to support MS activity in liver and brain cortex from control and ETOH-treated rats. RESULTS: In control animals, MS activity was higher in liver than in cortex for all cobalamins and MeCbl-based activity was higher than for other cofactors. S-adenosylmethionine (SAM) was required for OHCbl, CNCbl, and GSCbl-based activity, but not for MeCbl. Feeding an ETOH-containing diet for four weeks caused a significant decrease in liver MS activity, in a cobalamin-dependent manner (OHCbl ≥ CNCbl > GSCbl > MeCbl). In brain cortex, OHCbl, CNCbl, and GSCbl-based activity was reduced by ETOH treatment, but MeCbl-based activity was unaffected. GSH levels were reduced by ETOH treatment in both liver and cortex homogenates, and addition of GSH restored OHCbl-based MS activity to control levels. Betaine administration had no significant effect on GSH levels or MS activity in either control or ETOH-fed groups. CONCLUSIONS: The ETOH-induced decrease in OHCbl-based MS activity is secondary to decreased GSH levels and a decreased ability to synthesize MeCbl. The ability of MeCbl to completely offset ETOH inhibition in brain cortex, but not liver, suggests tissue-specific differences in the GSH-dependent regulation of MS activity.


Asunto(s)
5-Metiltetrahidrofolato-Homocisteína S-Metiltransferasa/antagonistas & inhibidores , Encéfalo/metabolismo , Etanol/administración & dosificación , Glutatión/metabolismo , Hígado/metabolismo , Vitamina B 12/metabolismo , 5-Metiltetrahidrofolato-Homocisteína S-Metiltransferasa/metabolismo , Animales , Betaína/administración & dosificación , Masculino , Ratas , Ratas Wistar
17.
Trends Mol Med ; 27(10): 931-934, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-34312076

RESUMEN

Vitamin B12 is a redox-active compound containing a cobalt atom that cycles between oxidation states. Superoxide scavenging induces its oxidation, disabling activation of the enzymes methionine synthase and methylmalonyl-CoA mutase, disrupting gene expression and energy production. High-dosed vitamin B12 may be clinically used to reduce oxidative stress and preserve cofactor functions.


Asunto(s)
Metilmalonil-CoA Mutasa , Vitamina B 12 , Cobalto , Humanos , Metilmalonil-CoA Mutasa/genética , Metilmalonil-CoA Mutasa/metabolismo , Oxidación-Reducción , Vitamina B 12/metabolismo , Vitamina B 12/farmacología , Vitaminas
19.
Front Immunol ; 11: 591571, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33329577

RESUMEN

Background: Among different types of sphingolipids produced by human cells, the possible engagement of ceramide species in the pathogenesis of Alzheimer's disease (AD) has attracted recent attention. While ceramides are primarily generated by de novo synthesis in mammalian cells, only a limited number of bacterial species, produce ceramides, including phosphoglycerol dihydroceramide (PGDHC) that is produced by the key periodontal pathogen Porphyromonas gingivalis. Emerging evidence indicates that virulence factors produced by P. gingivalis, such as lipopolysaccharide and gingipain, may be engaged in the initiation and/or progression of AD. However, the potential role of PGDHC in the pathogenesis of AD remains unknown. Therefore, the aim of this study was to evaluate the influence of PGDHC on hallmark findings in AD. Material and Methods: CHO-7WD10 and SH-SY-5Y cells were exposed to PGDHC and lipopolysaccharide (LPS) isolated from P. gingivalis. Soluble Aß42 peptide, amyloid precursor protein (APP), phosphorylated tau and senescence-associated secretory phenotype (SASP) factors were quantified using ELISA and Western blot assays. Results: Our results indicate that P. gingivalis (Pg)-derived PGDHC, but not Pg-LPS, upregulated secretion of soluble Aß42 peptide and expression of APP in CHO-7WD10 cells. Furthermore, hyperphosphorylation of tau protein was observed in SH-SY-5Y cells in response to PGDHC lipid. In contrast, Pg-LPS had little, or no significant effect on the tau phosphorylation induced in SH-SY-5Y cells. However, both PGDHC and Pg-LPS contributed to the senescence of SH-SY5Y cells as indicated by the production of senescence-associated secretory phenotype (SASP) markers, including beta-galactosidase, cathepsin B (CtsB), and pro-inflammatory cytokines TNF-α, and IL-6. Additionally, PGDHC diminished expression of the senescence-protection marker sirtuin-1 in SH-SY-5Y cells. Conclusions: Altogether, our results indicate that P. gingivalis-derived PGDHC ceramide promotes amyloidogenesis and hyperphosphorylation, as well as the production of SASP factors. Thus, PGDHC may represent a novel class of bacterial-derived virulence factors for AD associated with periodontitis.


Asunto(s)
Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/metabolismo , Ceramidas/biosíntesis , Susceptibilidad a Enfermedades , Periodontitis/complicaciones , Periodontitis/microbiología , Porphyromonas gingivalis/metabolismo , Enfermedad de Alzheimer/patología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Ácido Aspártico Endopeptidasas/metabolismo , Línea Celular , Humanos , Fosforilación , Proteínas tau/metabolismo
20.
Nutr Rev ; 78(7): 515-531, 2020 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-31876938

RESUMEN

Autism spectrum disorder (ASD) is an increasingly prevalent neurodevelopmental disorder with considerable clinical heterogeneity. With no cure for the disorder, treatments commonly center around speech and behavioral therapies to improve the characteristic social, behavioral, and communicative symptoms of ASD. Gastrointestinal disturbances are commonly encountered comorbidities that are thought to be not only another symptom of ASD but to also play an active role in modulating the expression of social and behavioral symptoms. Therefore, nutritional interventions are used by a majority of those with ASD both with and without clinical supervision to alleviate gastrointestinal and behavioral symptoms. Despite a considerable interest in dietary interventions, no consensus exists regarding optimal nutritional therapy. Thus, patients and physicians are left to choose from a myriad of dietary protocols. This review, summarizes the state of the current clinical and experimental literature on nutritional interventions for ASD, including gluten-free and casein-free, ketogenic, and specific carbohydrate diets, as well as probiotics, polyunsaturated fatty acids, and dietary supplements (vitamins A, C, B6, and B12; magnesium and folate).


Asunto(s)
Trastorno del Espectro Autista/dietoterapia , Animales , Dieta , Suplementos Dietéticos , Ácidos Grasos Omega-3/uso terapéutico , Humanos , Probióticos/uso terapéutico , Vitaminas/uso terapéutico
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