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1.
Biomedicines ; 12(5)2024 May 07.
Article in English | MEDLINE | ID: mdl-38790984

ABSTRACT

Forkhead box protein 3 (FoxP3) is a key transcription factor responsible for the development, maturation, and function of regulatory T cells (Tregs). The FoxP3 pre-mRNA is subject to alternative splicing, resulting in the translation of multiple splice variants. We have shown that Tregs from patients with amyotrophic lateral sclerosis (ALS) have reduced expression of full-length (FL) FoxP3, while other truncated splice variants are expressed predominantly. A correlation was observed between the reduced number of Tregs in the peripheral blood of ALS patients, reduced total FoxP3 mRNA, and reduced mRNA of its FL splice variant. Induction of FL FoxP3 was achieved using splice-switching oligonucleotides capable of base pairing with FoxP3 pre-mRNA and selectively modulating the inclusion of exons 2 and 7 in the mature mRNA. Selective expression of FL FoxP3 resulted in the induction of CD127low, CD152, and Helios-positive cells, while the cell markers CD4 and CD25 were not altered. Such Tregs had an increased proliferative activity and a higher frequency of cell divisions per day. The increased suppressive activity of Tregs with the induced FL FoxP3 splice variant was associated with the increased synthesis of the pro-apoptotic granzymes A and B, and perforin, IL-10, and IL-35, which are responsible for contact-independent suppression, and with the increased ability to suppress telomerase in target cells. The upregulation of Treg suppressive and proliferative activity using splice-switching oligonucleotides to induce the predominant expression of the FoxP3 FL variant is a promising approach for regenerative cell therapy in Treg-associated diseases.

2.
Cells ; 13(1)2023 12 29.
Article in English | MEDLINE | ID: mdl-38201281

ABSTRACT

The maturation, development, and function of regulatory T cells (Tregs) are under the control of the crucial transcription factor Forkhead Box Protein 3 (FoxP3). Through alternative splicing, the human FoxP3 gene produces four different splice variants: a full-length variant (FL) and truncated variants with deletions of each of exons 2 (∆2 variant) or 7 (∆7 variant) or a deletion of both exons (∆2∆7 variant). Their involvement in the biology of Tregs as well as their association with autoimmune diseases remains to be clarified. The aim of this work was to induce a single FoxP3 splice variant in human Tregs by splice switching oligonucleotides and to monitor their phenotype and proliferative and suppressive activity. We demonstrated that Tregs from peripheral blood from patients with multiple sclerosis preferentially expressed truncated splice variants, while the FL variant was the major variant in healthy donors. Tregs with induced expression of truncated FoxP3 splice variants demonstrated lower suppressive activity than those expressing FL variants. Reduced suppression was associated with the decreased expression of Treg-associated suppressive surface molecules and the production of cytokines. The deletion of exons 2 and/or 7 also reduced the cell proliferation rate. The results of this study show an association between FoxP3 splice variants and Treg function and proliferation. The modulation of Treg suppressive activity by the induction of the FoxP3 FL variant can become a promising strategy for regenerative immunotherapy.


Subject(s)
RNA Precursors , T-Lymphocytes, Regulatory , Humans , Cell Proliferation , Forkhead Transcription Factors/genetics , Oligonucleotides , RNA Precursors/genetics
3.
Consort Psychiatr ; 4(2): 65-77, 2023 Jul 10.
Article in English | MEDLINE | ID: mdl-38250646

ABSTRACT

BACKGROUND: Eating disorders (EDs) are associated with a risk of premature death, as well as suicidal and self-injurious behavior. A low or high body mass index (BMI) and weight control behavior can also have an impact on self-injurious and suicidal behavior. While some studies show that interpersonal sensitivity is a risk factor for EDs, affective disorders, and self-injurious behavior, in-depth studies of these issues have not been done. AIM: The present study investigates how self-injurious and suicidal behavior relate to weight control behavior, BMI, and interpersonal sensitivity in adolescent girls from a clinical population with diagnosed EDs compared with adolescent girls from the general population. METHODS: The main group was comprised of 31 girls with a diagnosis of ED (as the main diagnosis or co-occurring with affective disorders, M=151.13 years), being treated in in the Eating Disorder Clinic of the Scientific and Practical Center for Mental Health of Children and Adolescents named after G.E. Sukhareva. The comparison group consisted of 27 adolescent girls recruited from Proton Educational Center (M=15.511.09 years). The measures included a qualitative survey that yielded data on weight control behavior, and self-injurious behavior, a Blitz questionnaire probing the suicide risk (used only in the main group), and the Interpersonal Sensitivity Measure. Height and weight data were also recorded for BMI calculation. RESULTS: The qualitative analysis of weight control behavior yielded the following results: purging behavior, restrictive behavior, and corrective behavior. Participants in the main group used purging and restrictive behavior more often, whereas participants in the comparison group used strategies associated with a healthy lifestyle. The main group and participants who practiced purging and restrictive weight control in the overall sample had the smallest BMI. Self-injurious behavior was approximately evenly distributed both amongst the main and comparison groups. Self-cutting was the most prevalent type of self-injury. In the main group, self-injury was associated with a smaller BMI, while in the comparison group it was associated with an increase in the fear of rejection and overall interpersonal sensitivity. Based on the assessment of the suicide risk, six participants in the main group were deemed high-risk; they also displayed increased fear of rejection, dependence on the assessments of others, and overall interpersonal sensitivity. All girls in the suicide risk subgroup had non-suicidal self-injuries. CONCLUSION: The results of our study broaden our understanding of the risk factors of suicidal and self-injurious behavior in adolescent girls with EDs and reveal the characteristics of the type of weight control behavior used by this group in comparison with adolescent girls in the general population. Girls with EDs who were considered at the risk of committing suicide demonstrated high interpersonal sensitivity, which provides a rationale for further studying the general interpersonal mechanisms that underlie the pathogenesis of EDs, as well as that of self-injurious and suicidal behavior.

4.
Neural Regen Res ; 17(1): 65-73, 2022 Jan.
Article in English | MEDLINE | ID: mdl-34100429

ABSTRACT

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by progressive muscle wasting, breathing and swallowing difficulties resulting in patient's death in two to five years after disease onset. In amyotrophic lateral sclerosis, both upper and lower motor neurons of the corticospinal tracts are involved in the process of neurodegeneration, accounting for great clinical heterogeneity of the disease. Clinical phenotype has great impact on the pattern and rate of amyotrophic lateral sclerosis progression and overall survival prognosis. Creating more homogenous patient groups in order to study the effects of drug agents on specific manifestations of the disease is a challenging issue in amyotrophic lateral sclerosis clinical trials. Since amyotrophic lateral sclerosis has low incidence rates, conduction of multicenter trials requires certain standardized approaches to disease diagnosis and staging. This review focuses on the current approaches in amyotrophic lateral sclerosis classification and staging system based on clinical examination and additional instrumental methods, highlighting the role of upper and lower motor neuron involvement in different phenotypes of the disease. We demonstrate that both clinical and instrumental findings can be useful in evaluating severity of upper motor neuron and lower motor neuron involvement and predicting the following course of the disease. Addressing disease heterogeneity in amyotrophic lateral sclerosis clinical trials could lead to study designs that will assess drug efficacy in specific patient groups, based on the disease pathophysiology and spatiotemporal pattern. Although clinical evaluation can be a sufficient screening method for dividing amyotrophic lateral sclerosis patients into clinical subgroups, we provide proof that instrumental studies could provide valuable insights in the disease pathology.

5.
Sleep Sci ; 14(Spec 1): 97-100, 2021.
Article in English | MEDLINE | ID: mdl-34917281

ABSTRACT

Both non-epileptic sleep disturbances and epilepsy are common in patients with mucopolysaccharidoses (MPS), so diagnosis of sleep-related hypermotor epilepsy in these patients is a tackling issue. We present a case of an adult patient with MPS IIIB (Sanfilippo syndrome), who presented with numerous nocturnal events of sudden awakening and hypermotor behavior, which had been previously regarded as parasomnias. Overnight video-EEG captured numerous stereotypical seizures with ictal pattern in the frontal regions, which led the diagnosis of SHE. The patient was started with carbamazepine, which resulted in a substantial reduction in the number of seizures. Our report provides further support for use of overnight video-EEG in the differential diagnosis of sleep-related disorders in MPS, yet true incidence of SHE in MPS patients remains unknown.

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