Explore the vast range of titles available.

The function of the immune system declines during aging, compromising its response against pathogens, a phenomenon termed as “immunosenescence.” Alterations of the immune system undergone by aged individuals include thymic involution, defective memory T cells, impaired activation of naïve T cells, and weak memory response. Age-linked alterations of the innate immunity comprise perturbed chemotactic, phagocytic, and natural killing functions, as well as impaired antigen presentation. Overall, these alterations result in chronic low-grade inflammation (inflammaging) that negatively impacts health of elderly people. In this review, we address the most relevant molecules and mechanisms that regulate the relationship between immunosenescence and inflammaging and provide an updated description of the therapeutic strategies aimed to improve immunity in aged individuals.

The functional diversity of β-dystroglycan is attributable to its dual distribution, the plasma membrane, and the nucleus. In the plasma membrane, β-DG is a component of the dystrophin-associated protein complex. In the nucleus, β-DG assembles with the nuclear lamina and emerin. Recent findings indicate a role for β-DG in senescence, as its knockout in C2C12 myoblasts induces genomic instability and promotes the senescent state. This study analyzed the behavior of β-DG in three distinct models of senescence: chronologically aged fibroblasts, sodium butyrate (NaBu)-induced senescent fibroblasts, and fibroblasts from a Hutchinson–Gilford progeria syndrome (HGPS) patient. β-DG was found mainly in the nucleus in all the senescent cell types, with a certain mislocalization to the cytoplasm in HGPS and NaBu-treated fibroblasts. Furthermore, the full-length β-DG (43 kDa) and the cleaved intracellular domain (ICD; ~26 kDa) were identified. The ICD level increased in aged fibroblasts, but its yield was poor or virtually nonexistent in NaBU-induced and HGPS fibroblasts, respectively. Remarkably, β-DG was sequestered by progerin in HGPS cells, hindering its interaction with lamin A. In summary, the observed alterations in β-DG may be associated with the senescent state, and such findings will serve for future studies aimed at elucidating its role in senescence.

Spinocerebellar ataxias (SCAs) comprise a heterogeneous group of autosomal dominant disorders. The relative frequency of the different SCA subtypes varies broadly among different geographical and ethnic groups as result of genetic drifts. This review aims to provide an update regarding SCA founders in the American continents and the Caribbean as well as to discuss characteristics of these populations. Clusters of SCAs were detected in Eastern regions of Cuba for SCA2, in South Brazil for SCA3/MJD, and in Southeast regions of Mexico for SCA7. Prevalence rates were obtained and reached 154 (municipality of Báguano, Cuba), 166 (General Câmara, Brazil), and 423 (Tlaltetela, Mexico) patients/100,000 for SCA2, SCA3/MJD, and SCA7, respectively. In contrast, the scattered families with spinocerebellar ataxia type 10 (SCA10) reported all over North and South Americas have been associated to a common Native American ancestry that may have risen in East Asia and migrated to Americas 10,000 to 20,000 years ago. The comprehensive review showed that for each of these SCAs corresponded at least the development of one study group with a large production of scientific evidence often generalizable to all carriers of these conditions. Clusters of SCA populations in the American continents and the Caribbean provide unusual opportunity to gain insights into clinical and genetic characteristics of these disorders. Furthermore, the presence of large populations of patients living close to study centers can favor the development of meaningful clinical trials, which will impact on therapies and on quality of life of SCA carriers worldwide.

Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disease characterized by cerebellar ataxia and retinal degeneration, caused by an abnormal expansion of CAG repeats at the ATXN7 gene. Disease onset and progression vary among patients, underscoring the need for novel tools to improve disease monitoring. Circulating miRNAs represent a promising prognostic tool, due to their minimally invasive sampling and high stability. The aim of this study was to assess the expression of twelve circulating miRNAs associated with neurodegeneration in plasma samples from SCA7 patients and in an inducible SCA7 glial cell model. A comparison of SCA7 patients and controls revealed that nine miRNAs exhibited significantly higher expression. Furthermore, comparison of patients with different SCA7 phenotypes to controls revealed that most miRNAs were overexpressed in plasma from early-onset patients corresponding to the clinically more severe phenotype. Regarding the cell model, we identified three miRNAs that were dysregulated; however, only hsa-miR-342-5p displayed a pattern consistent with that observed in the plasma of patient. Our findings indicate that hsa-miR-342-5p is differentially expressed in the plasma of patients and the SCA7 cellular model, implying that it can serve as a biomarker and facilitate the identification of novel processes involved in SCA7.

Safety and effectiveness are the cornerstone objectives of nanomedicine in developing nanotherapies. It is crucial to understand the biological interactions between nanoparticles and immune cells. This study focuses on the manufacture by the microfluidic technique of N-trimethyl chitosan/protein nanocarriers and their interaction with J774 cells to elucidate the cellular processes involved in absorption and their impact on the immune system, mainly through endocytosis, activation of lysosomes and intracellular degradation. TEM of the manufactured nanoparticles showed spherical morphology with an average diameter ranging from 36 ± 16 nm to 179 ± 92 nm, depending on the concentration of the cargo protein (0, 12, 55 μg/mL). FTIR showed the crosslinking between N-trimethyl chitosan and the sodium tripolyphosphate and the α-helix binding loss of BSA. TGA revealed an increase in the thermal stability of N-trimethyl chitosan/protein nanoparticles compared with the powder. The encapsulation of the cargo protein used was demonstrated using XPS. Their potential to improve cell permeability and use as nanocarriers in future vaccine formulations was demonstrated. The toxicity of the nanoparticles in HaCaT and J774 cells was studied, as well as the importance of evaluating the differentiation status of J774 cells. Thus, possible endocytosis pathways and their impact on the immune response were discussed. This allowed us to conclude that N-trimethyl chitosan nanoparticles show potential as carriers for the immune system. Still, more studies are required to understand their effectiveness and possible use in therapies.

Dystrophin Dp71 is expressed in all tissues, with the exception of skeletal muscle, and is the main Duchenne muscular dystrophy (DMD) gene product in brain. As full-length dystrophin does in skeletal muscle, Dp71 associates with dystroglycans, sarcoglycans, dystrobrevins, syntrophins, and accessory proteins to form the dystrophin-associated protein complex (DAPC) in non-muscle tissues. Although it has been nearly 20 years since the discovery of Dp71, its study has become relevant only recently due to its direct involvement with the two main DMD non-muscular phenotypes: cognitive impairment and abnormal retinal physiology. In this review, we describe the historical background of Dp71 and the experimental models developed for its study. Additionally, we present and discuss the experimental evidence supporting the participation of Dp71 in different cellular processes, including cell adhesion, water homeostasis, cell division, and nuclear architecture. The functional diversity of Dp71 is attributed to the formation of Dp71-containing DAPC in numerous cell types and different subcellular compartments, including in plasma membrane and nucleus, as well as to the capability of Dp71-containing DAPC to work as the scaffold for proper clustering and anchoring of structural and signaling proteins to the plasma membrane and of nuclear envelope proteins to the inner nuclear membrane.

Background/Objectives: Myotonic dystrophy type 1 (DM1) is a rare, multisystemic disorder caused by an expanded (CTG)n repeat in the DMPK gene. Although DM1 has been studied in several populations, access to molecular diagnosis and comprehensive care remains limited in many low- and middle-income countries. This study provides an updated overview of DM1 in Mexico, from diagnostic implementation to patient management, describing key clinical and genetic findings. Methods: We conducted a nationwide, 15-year prospective study at Mexico’s National Reference Center for neuromuscular diseases. A total of 853 individuals at risk were subjected to clinical and molecular evaluation using PCR, TP-PCR, and SP-PCR, encompassing symptomatic, pre-symptomatic, prenatal, and preimplantation genetic diagnosis. Socioeconomic, clinical, and molecular variables were analyzed. Results: A total of 488 individuals were confirmed as DM1 carriers, with the most prevalent phenotypes being classic (36.5%) and juvenile (28.5%). Genomic analysis revealed a correlation between CTG tract sizes and phenotypes. Intriguingly, interrupted CTG repeat tracts were identified in 2.8% of DM1 carriers, who exhibited milder clinical phenotypes and a reduced degree of somatic and intergenerational instability. Survival analysis revealed a reduction in symptom-free survival in patients with larger expansions, while interrupted CTG tracts were associated with delayed onset. Conclusions: The centralization of diagnostic services in Mexico resulted in regional disparities, impacting early diagnosis and family planning. This study highlights the clinical and molecular diversity of DM1 in a Latin American population and underscores the urgent need for decentralized diagnostic services, integrated care models, and tailored prognostic tools in underserved settings.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder caused by the expression of progerin, a mutant variant of Lamin A. Recently, HGPS studies have gained relevance because unraveling its underlying mechanism would help to understand physiological aging. We previously reported that the CRM1-mediated nuclear protein export pathway is exacerbated in HGPS cells, provoking the mislocalization of numerous protein targets of CRM1. We showed that normalization of this mechanism by pharmacologically inhibiting CRM1 with LMB (specific CRM1 inhibitor), mitigates the senescent phenotype of HGPS cells. Since mitochondrial dysfunction is a hallmark of HGPS, in this study we analyze the effect of LMB on mitochondrial function. Remarkably, LMB treatment induced the recovery of mitochondrial function in HGPS cells, as shown by the improvement in mitochondrial morphology, mitochondrial membrane potential, and ATP levels, which consequently impeded the accumulation of ROS but not mitochondrial superoxide. We provide evidence that the beneficial effect of LMB is mechanistically based on a combinatory effect on mitochondrial biogenesis via upregulation of PGC-1α expression (master transcription cofactor of mitochondrial genes), and mitophagy through the recovery of lysosomal content. The use of exportin CRM1 inhibitors constitutes a promising strategy to treat HGPS and other diseases characterized by mitochondrial impairment.

The function of dystrophin Dp71 in neuronal cells remains to be established. Previously, we revealed the involvement of this protein in both nerve growth factor (NGF)-induced neuronal differentiation and cell adhesion by isolation and characterization of PC12 neuronal cells with depleted levels of Dp71. In this work, a novel phenotype of Dp71-knockdown cells was characterized, which is their delayed growth rate. Cell cycle analyses revealed an altered behavior of Dp71-depleted cells, which consists of a delay in G0/G1 transition and an increase in apoptosis during nocodazole-induced mitotic arrest. Dp71 associates with lamin B1 and β-dystroglycan, proteins involved in aspects of the cell division cycle; therefore, we compared the distribution of Dp71 with that of lamin B1 and β-dystroglycan in PC12 cells at mitosis and cytokinesis by means of immunofluorescence and confocal microscopy analysis. All of these three proteins exhibited a similar immunostaining pattern, localized at mitotic spindle, cleavage furrow, and midbody. It is noteworthy that a drastic decreased staining in mitotic spindle, cleavage furrow, and midbody was observed for both lamin B1 and β-dystroglycan in Dp71-depleted cells. Furthermore, we demonstrated the interaction of Dp71 with lamin B1 in PC12 cells by immunoprecipitation and pull-down assays, and importantly, we revealed that knockdown of Dp71 expression caused a marked reduction in lamin B1 levels and altered localization of the nuclear envelope protein emerin. Our data indicate that Dp71 is a component of the mitotic spindle and cytokinesis multi-protein apparatuses that might modulate the cell division cycle by affecting lamin B1 and β-dystroglycan levels.

Cancer progression relies on cellular transition states accompanied by changes in the functionality of adhesion molecules. The gene for adhesion G protein-coupled receptor latrophilin-3 (aGPCR Lphn3 or ADGRL3) is targeted by tumor-specific somatic mutations predominantly affecting the conserved GAIN domain where most aGPCRs are cleaved. However, it is unclear how these GAIN domain-altering mutations impact Lphn3 function. Here, we studied Lphn3 cancer-related mutations as a proxy for revealing unknown GAIN domain functions. We found that while intra-GAIN cleavage efficiency was unaltered, most mutations produced a ligand-specific impairment of Lphn3 intercellular adhesion profile paralleled by an increase in cell-matrix actin-dependent contact structures for cells expressing the select S810L mutation. Aberrant remodeling of the intermediate filament vimentin, which was found to coincide with Lphn3-induced modification of nuclear morphology, had less impact on the nuclei of S810L expressing cells. Notoriously, receptor signaling through G13 protein was deficient for all variants bearing non-homologous amino acid substitutions, including the S810L variant. Analysis of cell migration paradigms revealed a non-cell-autonomous impairment in collective cell migration indistinctly of Lphn3 or its cancer-related variants expression, while cell-autonomous motility was potentiated in the presence of Lphn3, but this effect was abolished in S810L GAIN mutant-expressing cells. These data identify the GAIN domain as an important regulator of Lphn3-dependent cell motility, thus furthering our understanding of cellular and molecular events linking Lphn3 genetic somatic mutations to cancer-relevant pathogenesis mechanisms.