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1.
Int J Mol Sci ; 25(7)2024 Mar 29.
Artículo en Inglés | MEDLINE | ID: mdl-38612616

RESUMEN

Niemann-Pick Type C (NPC) represents an autosomal recessive disorder with an incidence rate of 1 in 150,000 live births, classified within lysosomal storage diseases (LSDs). The abnormal accumulation of unesterified cholesterol characterizes the pathophysiology of NPC. This phenomenon is not unique to NPC, as analogous accumulations have also been observed in Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders. Interestingly, disturbances in the folding of the mutant protein NPC1 I1061T are accompanied by the aggregation of proteins such as hyperphosphorylated tau, α-synuclein, TDP-43, and ß-amyloid peptide. These accumulations suggest potential disruptions in proteostasis, a regulatory process encompassing four principal mechanisms: synthesis, folding, maintenance of folding, and protein degradation. The dysregulation of these processes leads to excessive accumulation of abnormal proteins that impair cell function and trigger cytotoxicity. This comprehensive review delineates reported alterations across proteostasis mechanisms in NPC, encompassing changes in processes from synthesis to degradation. Additionally, it discusses therapeutic interventions targeting pharmacological facets of proteostasis in NPC. Noteworthy among these interventions is valproic acid, a histone deacetylase inhibitor (HDACi) that modulates acetylation during NPC1 synthesis. In addition, various therapeutic options addressing protein folding modulation, such as abiraterone acetate, DHBP, calnexin, and arimoclomol, are examined. Additionally, treatments impeding NPC1 degradation, exemplified by bortezomib and MG132, are explored as potential strategies. This review consolidates current knowledge on proteostasis dysregulation in NPC and underscores the therapeutic landscape targeting diverse facets of this intricate process.


Asunto(s)
Enfermedades por Almacenamiento Lisosomal , Enfermedad de Niemann-Pick Tipo C , Humanos , Proteostasis , Enfermedad de Niemann-Pick Tipo C/tratamiento farmacológico , Pliegue de Proteína , Proteolisis
2.
Int J Mol Sci ; 24(10)2023 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-37240421

RESUMEN

Multiple sclerosis (MS) is a chronic disease affecting the central nervous system (CNS) due to an autoimmune attack on axonal myelin sheaths. Epigenetics is an open research topic on MS, which has been investigated in search of biomarkers and treatment targets for this heterogeneous disease. In this study, we quantified global levels of epigenetic marks using an ELISA-like approach in Peripheral Blood Mononuclear Cells (PBMCs) from 52 patients with MS, treated with Interferon beta (IFN-ß) and Glatiramer Acetate (GA) or untreated, and 30 healthy controls. We performed media comparisons and correlation analyses of these epigenetic markers with clinical variables in subgroups of patients and controls. We observed that DNA methylation (5-mC) decreased in treated patients compared with untreated and healthy controls. Moreover, 5-mC and hydroxymethylation (5-hmC) correlated with clinical variables. In contrast, histone H3 and H4 acetylation did not correlate with the disease variables considered. Globally quantified epigenetic DNA marks 5-mC and 5-hmC correlate with disease and were altered with treatment. However, to date, no biomarker has been identified that can predict the potential response to therapy before treatment initiation.


Asunto(s)
Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Humanos , Acetato de Glatiramer/uso terapéutico , Interferón beta/uso terapéutico , Leucocitos Mononucleares , Metilación de ADN , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico
3.
Int J Mol Sci ; 22(7)2021 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-33810307

RESUMEN

Niemann-Pick type C (NPC) disease is a rare autosomal recessive inherited childhood neurodegenerative disease characterized by the accumulation of cholesterol and glycosphingolipids, involving the autophagy-lysosome system. Inhibition of soluble epoxide hydrolase (sEH), an enzyme that metabolizes epoxy fatty acids (EpFAs) to 12-diols, exerts beneficial effects in modulating inflammation and autophagy, critical features of the NPC disease. This study aims to evaluate the effects of UB-EV-52, an sEH inhibitor (sEHi), in an NPC mouse model (Npc) by administering it for 4 weeks (5 mg/kg/day). Behavioral and cognitive tests (open-field test (OF)), elevated plus maze (EPM), novel object recognition test (NORT) and object location test (OLT) demonstrated that the treatment produced an improvement in short- and long-term memory as well as in spatial memory. Furthermore, UB-EV-52 treatment increased body weight and lifespan by 25% and reduced gene expression of the inflammatory markers (i.e., Il-1ß and Mcp1) and enhanced oxidative stress (OS) markers (iNOS and Hmox1) in the treated Npc mice group. As for autophagic markers, surprisingly, we found significantly reduced levels of LC3B-II/LC3B-I ratio and significantly reduced brain protein levels of lysosomal-associated membrane protein-1 (LAMP-1) in treated Npc mice group compared to untreated ones in hippocampal tissue. Lipid profile analysis showed a significant reduction of lipid storage in the liver and some slight changes in homogenated brain tissue in the treated NPC mice compared to the untreated groups. Therefore, our results suggest that pharmacological inhibition of sEH ameliorates most of the characteristic features of NPC mice, demonstrating that sEH can be considered a potential therapeutic target for this disease.


Asunto(s)
Antiinflamatorios/uso terapéutico , Antioxidantes/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Epóxido Hidrolasas/antagonistas & inhibidores , Enfermedad de Niemann-Pick Tipo C/tratamiento farmacológico , Animales , Autofagia , Cognición , Femenino , Masculino , Memoria , Ratones , Ratones Endogámicos C57BL , Fenotipo
4.
Exp Appl Acarol ; 79(2): 255-266, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31659545

RESUMEN

Rhipicephalus microplus is a hematophagous ectoparasite that significantly affects parasitized cattle. As a one-host tick its entire life cycle consists of free-living and parasitic forms. Its extraordinary ability to survive during prolonged off-host periods has been related to the process of cytoplasmic degradation called autophagy. In order to deepen our understanding of this process during R. microplus non-parasitic stages, we determined the expression dynamics of a set of five autophagy-related genes (ATG genes) during embryonic development and over an increasing larval starvation period of 50 days. We found two apparent successive waves of ATG genes transcriptional activation, which paralleled key embryonic changes such as cellularization and organogenesis, as well as nutrient utilization. Moreover, during increasing larval starvation, ATG genes were up-regulated cyclically every 10-15 days. Taken together, our results suggest that autophagy is playing a major role in embryo development and energy metabolism during starvation in R. microplus.


Asunto(s)
Proteínas de Artrópodos/genética , Autofagia/genética , Expresión Génica , Rhipicephalus/genética , Animales , Proteínas de Artrópodos/metabolismo , Bovinos/parasitología , Desarrollo Embrionario/genética , Larva/genética , México , Rhipicephalus/embriología , Rhipicephalus/crecimiento & desarrollo
5.
Mediators Inflamm ; 2018: 9734845, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29785173

RESUMEN

Gut microbiota (GM) plays several crucial roles in host physiology and influences several relevant functions. In more than one respect, it can be said that you "feed your microbiota and are fed by it." GM diversity is affected by diet and influences metabolic and immune functions of the host's physiology. Consequently, an imbalance of GM, or dysbiosis, may be the cause or at least may lead to the progression of various pathologies such as infectious diseases, gastrointestinal cancers, inflammatory bowel disease, and even obesity and diabetes. Therefore, GM is an appropriate target for nutritional interventions to improve health. For this reason, phytochemicals that can influence GM have recently been studied as adjuvants for the treatment of obesity and inflammatory diseases. Phytochemicals include prebiotics and probiotics, as well as several chemical compounds such as polyphenols and derivatives, carotenoids, and thiosulfates. The largest group of these comprises polyphenols, which can be subclassified into four main groups: flavonoids (including eight subgroups), phenolic acids (such as curcumin), stilbenoids (such as resveratrol), and lignans. Consequently, in this review, we will present, organize, and discuss the most recent evidence indicating a relationship between the effects of different phytochemicals on GM that affect obesity and/or inflammation, focusing on the effect of approximately 40 different phytochemical compounds that have been chemically identified and that constitute some natural reservoir, such as potential prophylactics, as candidates for the treatment of obesity and inflammatory diseases.


Asunto(s)
Microbioma Gastrointestinal/fisiología , Inflamación/metabolismo , Obesidad/metabolismo , Obesidad/microbiología , Animales , Humanos , Inflamación/inmunología , Polifenoles/metabolismo
6.
Int J Mol Sci ; 19(12)2018 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-30513674

RESUMEN

Obesity is a noncommunicable disease that affects a considerable part of humanity. Recently, it has been recognized that gut microbiota constitutes a fundamental factor in the triggering and development of a large number of pathologies, among which obesity is one of the most related to the processes of dysbiosis. In this review, different animal model approaches, methodologies, and genome scale metabolic databases were revisited to study the gut microbiota and its relationship with metabolic disease. As a data source, PubMed for English-language published material from 1 January 2013, to 22 August 2018, were screened. Some previous studies were included if they were considered classics or highly relevant. Studies that included innovative technical approaches or different in vivo or in vitro models for the study of the relationship between gut microbiota and obesity were selected after a 16-different-keyword exhaustive search. A clear panorama of the current available options for the study of microbiota's influence on obesity, both for animal model election and technical approaches, is presented to the researcher. All the knowledge generated from the study of the microbiota opens the possibility of considering fecal transplantation as a relevant therapeutic alternative for obesity and other metabolic disease treatment.


Asunto(s)
Microbiota/fisiología , Obesidad/microbiología , Animales , Microbioma Gastrointestinal/fisiología , Humanos , Inflamación/inmunología , Inflamación/microbiología , Obesidad/inmunología
7.
Mol Cell Neurosci ; 75: 113-21, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-27468976

RESUMEN

Pleiotrophin (PTN) is a secreted growth factor recently proposed to act as a neuromodulatory peptide in the Central Nervous System. PTN appears to be involved in neurodegenerative diseases and neural disorders, and it has also been implicated in learning and memory. Specifically, PTN-deficient mice exhibit a lower threshold for LTP induction in the hippocampus, which is attenuated in mice overexpressing PTN. However, there is little information about the signaling systems recruited by PTN to modulate neural activity. To address this issue, the gene expression profile in hippocampus of mice lacking PTN was analyzed using microarrays of 22,000 genes. In addition, we corroborated the effect of the absence of PTN on the expression of these genes by silencing this growth factor in primary neuronal cultures in vitro. The microarray analysis identified 102 genes that are differentially expressed (z-score>3.0) in PTN null mice, and the expression of eight of those modified in the hippocampus of KO mice was also modified in vitro after silencing PTN in cultured neurons with siRNAs. The data obtained indicate that the absence of PTN affects AKT pathway response and modulates the expression of genes related with neuroprotection (Mgst3 and Estrogen receptor 1, Ers 1) and cell differentiation (Caspase 6, Nestin, and Odz4), both in vivo and in vitro.


Asunto(s)
Proteínas Portadoras/metabolismo , Cerebelo/metabolismo , Citocinas/metabolismo , Hipocampo/metabolismo , Neuronas/metabolismo , Transcriptoma , Animales , Proteínas Portadoras/genética , Caspasa 6/genética , Caspasa 6/metabolismo , Células Cultivadas , Cerebelo/citología , Citocinas/deficiencia , Citocinas/genética , Hipocampo/citología , Proteínas Quinasas JNK Activadas por Mitógenos/genética , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Ribosómico 18S/genética , ARN Ribosómico 18S/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Sinaptofisina/genética , Sinaptofisina/metabolismo
8.
Neuroimmunomodulation ; 23(1): 8-17, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26599431

RESUMEN

OBJECTIVE: The present study was specifically designed to discern the possible existence of subgroups of patients with the relapsing-remitting form of multiple sclerosis (RRMS) depending on their gender, age, disease stage (relapsing or remitting), time of disease evolution and response to different treatments. METHODS: We analyzed samples from patients with RRMS (50 females and 32 males) and healthy individuals (25 matched for age and gender) and determined serum concentrations of IFN-γ, IL-10 and IL-17A. We stratified patients by gender, age, treatment and disease evolution time, and subsequently correlated these independent variables with the concentrations of the previously mentioned cytokines. RESULTS: We provided initial evidence that treatment exerted possible differential effects depending on the time of disease duration. Results evidence the existence of different subgroups of patients with MS, who can be classified as follows: (a) male or female under or over 40 years of age; (b) disease duration according to treatment (under or over 8 years of disease); (c) classification according to fluctuating levels of IFN-γ, IL-10 and IL-17A in the following three stages of disease evolution: <5 years, between 5 and 10 years, and >10 years. CONCLUSION: These subgroups must be taken into account for the clinical follow-up of patients with MS in order to provide them with a better and more personalized treatment, and also for a deep and detailed analysis of progressive disease, in an attempt to comprehend fluctuations and clinical variability by means of a better understanding of intrinsically physiological variables of the disease.


Asunto(s)
Envejecimiento/fisiología , Interleucina-17/sangre , Esclerosis Múltiple Recurrente-Remitente , Adulto , Análisis de Varianza , Evaluación de la Discapacidad , Progresión de la Enfermedad , Femenino , Humanos , Interferón gamma/sangre , Interleucina-10/sangre , Masculino , Esclerosis Múltiple Recurrente-Remitente/sangre , Esclerosis Múltiple Recurrente-Remitente/fisiopatología , Esclerosis Múltiple Recurrente-Remitente/terapia , Índice de Severidad de la Enfermedad , Factores Sexuales , Factores de Tiempo , Adulto Joven
9.
Parasitology ; 143(13): 1802-1809, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27609093

RESUMEN

The cattle tick Rhipicephalus (Boophilus) microplus is a hematophagous ectoparasite of major importance for the livestock industry. It shows a remarkable ability to survive over long periods without feeding. However, the mechanisms used to endure long-term starvation are poorly understood. It is believed that autophagy, a process of intracellular protein degradation, may play a significant role to confront adverse environmental conditions. To advance our understanding of autophagy in R. microplus, in the present study we report the molecular characterization of three autophagy-related (ATG) genes, namely, RmATG3, RmATG4 and RmATG6, as well as their expression profiles in different developmental stages and organs of the parasite. The deduced amino acid sequences derived from the characterized gene sequences were subjected to Basic Local Alignment Search Tool analysis. The testing produced significant alignments with respective ATG proteins from Haemaphysalis longicornis and Ixodes scapularis ticks. Real-time polymerase chain reaction assays revealed that RmATG4 and RmATG6 transcripts were elevated in egg and ovary tissue, when compared with larva and midgut samples, while RmATG3 expression in midgut was 2-fold higher than in egg, larva and ovary samples.


Asunto(s)
Proteínas Relacionadas con la Autofagia/genética , Perfilación de la Expresión Génica , Rhipicephalus/embriología , Rhipicephalus/genética , Animales , Larva/genética , Larva/crecimiento & desarrollo , Reacción en Cadena en Tiempo Real de la Polimerasa , Cigoto/crecimiento & desarrollo
10.
Exp Parasitol ; 170: 227-235, 2016 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-27729251

RESUMEN

Rhipicephalus (Boophilus) microplus ticks are obligatory hematophagous ectoparasites of cattle and act as vectors for disease-causing microorganisms. Conventional tick control is based on the use of chemical acaricides; however, their uncontrolled use has increased tSresistant tick populations, as well as food and environmental contamination. Alternative immunological tick control has shown to be partially effective. The only anti-tick vaccine commercially available at present in the world is based on intestinal Bm86 protein, and shows a variable effectiveness depending on tick strains or geographic isolates. Therefore, there is a need to characterize new antigens in order to improve immunological protection. The aim of this work was to identify immunogenic proteins from ovarian tissue extracts of R. microplus, after cattle immunization. Results showed that ovarian proteins complexed with the adjuvant Montanide ISA 50 V generated a strong humoral response on vaccinated cattle. IgG levels peaked at fourth post-immunization week and remained high until the end of the experiment. 1D and 2D SDS-PAGE-Western blot assays with sera from immunized cattle recognized several ovarian proteins. Reactive bands were cut and analyzed by LC-MS/MS. They were identified as Vitellogenin, Vitellogenin-2 precursor and Yolk Cathepsin. Our findings along with bioinformatic analysis indicate that R. microplus has several Vitellogenin members, which are proteolytically processed to generate multiple polypeptide fragments. This apparent complexity of vitellogenic tick molecular targets gives the opportunity to explore their potential usefulness as vaccine candidates but, at the same time, imposes a challenge on the selection of the appropriate set of antigens.


Asunto(s)
Vectores Arácnidos/inmunología , Proteínas de Artrópodos/inmunología , Rhipicephalus/inmunología , Control de Ácaros y Garrapatas/métodos , Animales , Western Blotting , Bovinos , Enfermedades de los Bovinos/prevención & control , ADN Complementario/biosíntesis , Electroforesis/métodos , Desarrollo Embrionario/inmunología , Ensayo de Inmunoadsorción Enzimática , Femenino , Inmunoglobulina G/sangre , Larva/inmunología , Oogénesis/inmunología , Ovario/inmunología , Reacción en Cadena de la Polimerasa , Proteómica/métodos , ARN/genética , ARN/aislamiento & purificación , Reproducción/inmunología , Espectrometría de Masas en Tándem , Infestaciones por Garrapatas/prevención & control , Infestaciones por Garrapatas/veterinaria , Vacunas , Vitelogeninas/biosíntesis , Vitelogeninas/inmunología
11.
Mediators Inflamm ; 2016: 4036232, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27721574

RESUMEN

Multiple Sclerosis (MS) is an autoimmune disorder of the Central Nervous System that has been associated with several environmental factors, such as diet and obesity. The possible link between MS and obesity has become more interesting in recent years since the discovery of the remarkable properties of adipose tissue. Once MS is initiated, obesity can contribute to increased disease severity by negatively influencing disease progress and treatment response, but, also, obesity in early life is highly relevant as a susceptibility factor and causally related risk for late MS development. The aim of this review was to discuss recent evidence about the link between obesity, as a chronic inflammatory state, and the pathogenesis of MS as a chronic autoimmune and inflammatory disease. First, we describe the main cells involved in MS pathogenesis, both from neural tissue and from the immune system, and including a new participant, the adipocyte, focusing on their roles in MS. Second, we concentrate on the role of several adipokines that are able to participate in the mediation of the immune response in MS and on the possible cross talk between the latter. Finally, we explore recent therapy that involves the transplantation of adipocyte precursor cells for the treatment of MS.


Asunto(s)
Adipoquinas/metabolismo , Enfermedades Autoinmunes/complicaciones , Esclerosis Múltiple/complicaciones , Obesidad/complicaciones , Adipocitos/citología , Adiponectina/metabolismo , Tejido Adiposo/patología , Animales , Astrocitos/citología , Enfermedades Autoinmunes/metabolismo , Linfocitos T CD8-positivos/citología , Factor D del Complemento/metabolismo , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/metabolismo , Humanos , Sistema Inmunológico , Inflamación , Interleucina-17/metabolismo , Leptina/metabolismo , Células Madre Mesenquimatosas/citología , Ratones , Microglía/patología , Esclerosis Múltiple/metabolismo , Nicotinamida Fosforribosiltransferasa/metabolismo , Obesidad/metabolismo , Oligodendroglía/citología , Prevalencia , Resistina/metabolismo , Riesgo , Células TH1/citología , Células Th2/citología
12.
Artículo en Inglés | MEDLINE | ID: mdl-39238379

RESUMEN

BACKGROUND: Parkinson's Disease (PD) is frequently associated with a spectrum of sleep-related disorders, including insomnia, Excessive Daytime Sleepiness (EDS), REM sleep Behaviour Disorder (RBD), Restless Legs Syndrome (RLS), and Sleep-related Breathing Disorders (SBDs). These disorders significantly impact PD patients' Quality of Life (QoL) and present unique diagnostic and therapeutic challenges. METHODS: This review has explored the intricate relationship between PD and sleep-related disorders, emphasizing their distinctive features and underlying neurobiological mechanisms. It aimed to consolidate current knowledge to optimize clinical management and improve patient care. The profound impact of these disorders on QoL has been evaluated, along with precise diagnostic methodologies. Additionally, various therapeutic strategies, including pharmacological treatments, nonpharmacological interventions, and device-aided therapies, have been examined. RESULTS: Sleep-related disorders are prevalent among PD patients. Specifically, RBD exhibits a prevalence of 40-50%, often preceding the onset of motor symptoms, indicating its potential as an early marker of PD. Despite their significant impact on QoL, these non-motor symptoms are frequently under-recognized and inadequately managed in clinical practice. Pharmacological treatments, along with nonpharmacological interventions, like cognitive-behavioral therapy for insomnia and lifestyle modifications, have shown varied efficacy. Device-aided therapies have also demonstrated the potential to improve sleep-related disorders and overall non-motor symptom burden. CONCLUSION: Effective management of sleep-related disorders in PD calls for personalized, comprehensive, and multimodal therapeutic approaches. This requires the collaborative efforts of neurologists, sleep specialists, psychiatrists, and other healthcare professionals. Future research should focus on the intricate relationship between PD and sleep disorders, aiming to develop innovative treatments and significantly improve patient outcomes.

13.
Pharmaceuticals (Basel) ; 17(7)2024 Jun 27.
Artículo en Inglés | MEDLINE | ID: mdl-39065692

RESUMEN

Major depressive disorder (MDD) is a mood disorder that has become a global health emergency according to the World Health Organization (WHO). It affects 280 million people worldwide and is a leading cause of disability and financial loss. Patients with MDD present immunoendocrine alterations like cortisol resistance and inflammation, which are associated with alterations in neurotransmitter metabolism. There are currently numerous therapeutic options for patients with MDD; however, some studies suggest a high rate of therapeutic failure. There are multiple hypotheses explaining the pathophysiological mechanisms of MDD, in which several systems are involved, including the neuroendocrine and immune systems. In recent years, inflammation has become an important target for the development of new therapeutic options. Extracellular monomeric ubiquitin (emUb) is a molecule that has been shown to have immunomodulatory properties through several mechanisms including cholinergic modulation and the generation of regulatory T cells. In this perspective article, we highlight the influence of the inflammatory response in MDD. In addition, we review and discuss the evidence for the use of emUb contained in Transferon as a concomitant treatment with selective serotonin reuptake inhibitors (SSRIs).

14.
Aging Dis ; 15(1): 311-337, 2024 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-37307824

RESUMEN

Epigenetic alterations are a fundamental pathological hallmark of Alzheimer's disease (AD). Herein, we show the upregulation of G9a and H3K9me2 in the brains of AD patients. Interestingly, treatment with a G9a inhibitor (G9ai) in SAMP8 mice reversed the high levels of H3K9me2 and rescued cognitive decline. A transcriptional profile analysis after G9ai treatment revealed increased gene expression of glia maturation factor ß (GMFB) in SAMP8 mice. Besides, a H3K9me2 ChIP-seq analysis after G9a inhibition treatment showed the enrichment of gene promoters associated with neural functions. We observed the induction of neuronal plasticity and a reduction of neuroinflammation after G9ai treatment, and more strikingly, these neuroprotective effects were reverted by the pharmacological inhibition of GMFB in mice and cell cultures; this was also validated by the RNAi approach generating the knockdown of GMFB/Y507A.10 in Caenorhabditis elegans. Importantly, we present evidence that GMFB activity is controlled by G9a-mediated lysine methylation as well as we identified that G9a directly bound GMFB and catalyzed the methylation at lysine (K) 20 and K25 in vitro. Furthermore, we found that the neurodegenerative role of G9a as a GMFB suppressor would mainly rely on methylation of the K25 position of GMFB, and thus G9a pharmacological inhibition removes this methylation promoting neuroprotective effects. Then, our findings confirm an undescribed mechanism by which G9a inhibition acts at two levels, increasing GMFB and regulating its function to promote neuroprotective effects in age-related cognitive decline.


Asunto(s)
Enfermedad de Alzheimer , Fármacos Neuroprotectores , Humanos , Ratones , Animales , Enfermedad de Alzheimer/tratamiento farmacológico , Factor de Maduración de la Glia/genética , Neuroprotección , Fármacos Neuroprotectores/farmacología , Lisina
15.
Oncol Lett ; 27(3): 114, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38304177

RESUMEN

Patients with acute promyelocytic leukemia (APL) exhibit the t(15;17)(q24.1;q21.2) translocation that produces the promyelocytic leukemia (PML)/retinoic acid receptor α (RARA) fusion gene. Different PML breakpoints yield three alternative molecular transcripts, bcr1, bcr2 and bcr3. The present study reports the simultaneous presence of three PML/RARA transcripts in a pediatric female patient diagnosed with APL, according to the clinical characteristics, immunophenotype and karyotype of the patient. The simultaneous presence of the PML/RARA transcripts were detected using reverse transcription-quantitative PCR (RT-qPCR). This was confirmed with HemaVision-28N Multiplex RT-qPCR, HemaVision-28Q qualitative RT-qPCR and the AmpliSeq RNA Myeloid Panel. To the best of our knowledge, the pediatric patient described in the present study is the first case found to exhibit all three PML/RARA transcripts (bcr1, bcr2 and bcr3). Additionally, a microarray analysis was performed to determine the expression profile, potential predictive biomarkers and the implications of this uncommon finding. According to the information obtained from molecular monitoring, the results reported in the present study were associated with a good patient prognosis. In addition, upregulated genes that are rare in acute myeloid leukemia were identified, and these genes may be promising diagnostic biomarkers for further study. For example, CCL-1 is present in leukemic stem cells, causing treatment failure and relapse, and α- and ß-defensins have been reported exclusively in chronic myeloid leukemia. However, the results of the present study confirmed that they may also be present in APL. Thus, these findings suggested a possible signaling pathway that involves the PML/RARA oncoprotein in APL.

16.
Mediators Inflamm ; 2013: 381815, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24453416

RESUMEN

Garlic (Allium sativum L.) has been used to alleviate a variety of health problems due to its high content of organosulfur compounds and antioxidant activity. The main active component is alliin (S-allyl cysteine sulfoxide), a potent antioxidant with cardioprotective and neuroprotective actions. In addition, it helps to decrease serum levels of glucose, insulin, triglycerides, and uric acid, as well as insulin resistance, and reduces cytokine levels. However its potential anti-inflammatory effect is unknown. We examined the effects of alliin in lipopolysaccharide- (LPS-) stimulated 3T3-L1 adipocytes by RT-PCR, Western blot, and microarrays analysis of 22,000 genes. Incubation of cells for 24 h with 100 µmol/L alliin prevented the increase in the expression of proinflammatory genes, IL-6, MCP-1, and Egr-1 in 3T3-L1 adipocytes exposed to 100 ng/mL LPS for 1 h. Interestingly, the phosphorylation of ERK1/2, which is involved in LPS-induced inflammation in adipocytes, was decreased following alliin treatment. Furthermore, the gene expression profile by microarrays evidentiate an upregulation of genes involved in immune response and downregulation of genes related with cancer. The present results have shown that alliin is able to suppress the LPS inflammatory signals by generating an anti-inflammatory gene expression profile and by modifying adipocyte metabolic profile.


Asunto(s)
Adipocitos/efectos de los fármacos , Antiinflamatorios/farmacología , Cisteína/análogos & derivados , Lipopolisacáridos/farmacología , Células 3T3-L1 , Adipocitos/fisiología , Animales , Quimiocina CCL2/análisis , Quimiocina CCL2/antagonistas & inhibidores , Quimiocina CCL2/genética , Cisteína/farmacología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Interleucina-6/análisis , Interleucina-6/antagonistas & inhibidores , Interleucina-6/genética , Ratones , FN-kappa B/fisiología , Fosforilación , Transcriptoma
17.
J Clin Med ; 12(9)2023 May 04.
Artículo en Inglés | MEDLINE | ID: mdl-37176711

RESUMEN

Autoimmune rheumatic diseases are a cluster of heterogeneous disorders that share some clinical symptoms such as pain, tissue damage, immune deregulation, and the presence of inflammatory mediators. Biologic disease-modifying antirheumatic drugs are some of the most effective treatments for rheumatic diseases. However, their molecular and pharmacological complexity makes them potentially immunogenic and capable of inducing the development of anti-drug antibodies. TNF inhibitors appear to be the main contributors to immunogenicity because they are widely used, especially in rheumatoid arthritis. Immunogenicity response on these treatments is crucial since the appearance of ADAs has consequences in terms of safety and efficacy. Therefore, this review proposes an overview of the immunogenicity of biological agents used in autoimmune rheumatic diseases highlighting the prevalence of anti-drug antibodies.

18.
Front Immunol ; 14: 1212736, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37359537

RESUMEN

The close interaction between fetal and maternal cells during pregnancy requires multiple immune-endocrine mechanisms to provide the fetus with a tolerogenic environment and protection against any infectious challenge. The fetal membranes and placenta create a hyperprolactinemic milieu in which prolactin (PRL) synthesized by the maternal decidua is transported through the amnion-chorion and accumulated into the amniotic cavity, where the fetus is bedded in high concentrations during pregnancy. PRL is a pleiotropic immune-neuroendocrine hormone with multiple immunomodulatory functions mainly related to reproduction. However, the biological role of PRL at the maternal-fetal interface has yet to be fully elucidated. In this review, we have summarized the current information on the multiple effects of PRL, focusing on its immunological effects and biological significance for the immune privilege of the maternal-fetal interface.


Asunto(s)
Decidua , Prolactina , Embarazo , Femenino , Humanos , Placenta , Membranas Extraembrionarias , Líquido Amniótico
19.
Cells ; 12(13)2023 06 27.
Artículo en Inglés | MEDLINE | ID: mdl-37443767

RESUMEN

During embryonic and fetal development, the cerebellum undergoes several histological changes that require a specific microenvironment. Pleiotrophin (PTN) has been related to cerebral and cerebellar cortex ontogenesis in different species. PTN signaling includes PTPRZ1, ALK, and NRP-1 receptors, which are implicated in cell differentiation, migration, and proliferation. However, its involvement in human cerebellar development has not been described so far. Therefore, we investigated whether PTN and its receptors were expressed in the human cerebellar cortex during fetal and early neonatal development. The expression profile of PTN and its receptors was analyzed using an immunohistochemical method. PTN, PTPRZ1, and NRP-1 were expressed from week 17 to the postnatal stage, with variable expression among granule cell precursors, glial cells, and Purkinje cells. ALK was only expressed during week 31. These results suggest that, in the fetal and neonatal human cerebellum, PTN is involved in cell communication through granule cell precursors, Bergmann glia, and Purkinje cells via PTPRZ1, NRP-1, and ALK signaling. This communication could be involved in cell proliferation and cellular migration. Overall, the present study represents the first characterization of PTN, PTPRZ1, ALK, and NRP-1 expression in human tissues, suggesting their involvement in cerebellar cortex development.


Asunto(s)
Corteza Cerebelosa , Citocinas , Recién Nacido , Humanos , Corteza Cerebelosa/metabolismo , Citocinas/metabolismo , Proteínas Portadoras/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Proteínas Tirosina Fosfatasas Clase 5 Similares a Receptores/metabolismo
20.
Hippocampus ; 22(2): 128-40, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-20928830

RESUMEN

Multiple factors are involved in the glutamate-induced excitotoxicity phenomenon, such as overload of ionotropic and metabotropic receptors, excess Ca(2+) influx, nitric oxide synthase activation, oxidative damage due to increase in free radicals, and release of endogenous polyamine, among others. In order to attempt a more integrated approach to address this issue, we established, by microarray analysis, the hippocampus gene expression profiles under glutamate-induced excitotoxicity conditions. Increased gene expression is mainly related to excitotoxicity (CaMKII, glypican 2, GFAP, NCX3, IL-2, and Gmeb2) or with cell damage response (dynactin and Ecel1). Several genes that augmented their expression are related to glutamatergic system modulation, in particular with NMDA receptor modulation and calcium homeostasis (IL-2, CaMKII, acrosin, Gmeb2, hAChE, Slc83a, and SP1 factor). Conversely, among genes that diminished their expression, we found the Syngap 1, which is downregulated by CaMKII, and the MHC II, which is downregulated by glutamate. Changes observed in gene expression induced by monosodium glutamate (MSG) neonatal treatment in the hippocampus are consistent with the activation of the mechanisms that modulate NMDA receptor function as well as with the implementation of plastic response to cell damage and intracellular calcium homeostasis. Regarding this aspect, we report here that NCX3/Slc8a3, a Na(+)/Ca(2+) membrane exchanger, is highly expressed in astrocytes, both in vitro and in vivo, in response to glutamate-induced excitotoxicity. Hence, the results of this analysis present a broad view of the expression profile elicited by MSG neonatal treatment, and lead us to suggest the possible molecular pathways of action and reaction involved under this experimental model of excitotoxicity.


Asunto(s)
Aminoácidos Excitadores/farmacología , Perfilación de la Expresión Génica , Hipocampo/metabolismo , Neuroglía/metabolismo , Intercambiador de Sodio-Calcio/biosíntesis , Animales , Western Blotting , Ácido Glutámico/farmacología , Hipocampo/efectos de los fármacos , Inmunohistoquímica , Análisis de Secuencia por Matrices de Oligonucleótidos , Ratas , Ratas Wistar
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