The Role of B Cell and T Cell Glycosylation in Systemic Lupus Erythematosus.

Glycosylation is a post-translational modification that affects the stability, structure, antigenicity and charge of proteins. In the immune system, glycosylation is involved in the regulation of ligand-receptor interactions, such as in B-cell and T-cell activating receptors. Alterations in glycosylation have been described in several autoimmune diseases, such as systemic lupus erythematosus (SLE), in which alterations have been found mainly in the glycosylation of B lymphocytes, T lymphocytes and immunoglobulins. In immunoglobulin G of lupus patients, a decrease in galactosylation, sialylation, and nucleotide fucose, as well as an increase in the N-acetylglucosamine bisector, are observed. These changes in glycoisolation affect the interactions of immunoglobulins with Fc receptors and are associated with pericarditis, proteinuria, nephritis, and the presence of antinuclear antibodies. In T cells, alterations have been described in the glycosylation of receptors involved in activation, such as the T cell receptor; these changes affect the affinity with their ligands and modulate the binding to endogenous lectins such as galectins. In T cells from lupus patients, a decrease in galectin 1 binding is observed, which could favor activation and reduce apoptosis. Furthermore, these alterations in glycosylation correlate with disease activity and clinical manifestations, and thus have potential use as biomarkers. In this review, we summarize findings on glycosylation alterations in SLE and how they relate to immune system defects and their clinical manifestations.

Heparan Sulfate and Sialic Acid in Viral Attachment: Two Sides of the Same Coin?

Sialic acids and heparan sulfates make up the outermost part of the cell membrane and the extracellular matrix. Both structures are characterized by being negatively charged, serving as receptors for various pathogens, and are highly expressed in the respiratory and digestive tracts. Numerous viruses use heparan sulfates as receptors to infect cells; in this group are HSV, HPV, and SARS-CoV-2. Other viruses require the cell to express sialic acids, as is the case in influenza A viruses and adenoviruses. This review aims to present, in a general way, the participation of glycoconjugates in viral entry, and therapeutic strategies focused on inhibiting the interaction between the virus and the glycoconjugates. Interestingly, there are few studies that suggest the participation of both glycoconjugates in the viruses addressed here. Considering the biological redundancy that exists between heparan sulfates and sialic acids, we propose that it is important to jointly evaluate and design strategies that contemplate inhibiting the interactions of both glycoconjugates. This approach will allow identifying new receptors and lead to a deeper understanding of interspecies transmission.

Role of the Cholinergic Anti-Inflammatory Reflex in Central Nervous System Diseases.

In several central nervous system diseases, it has been reported that inflammation may be related to the etiologic process, therefore, therapeutic strategies are being implemented to control inflammation. As the nervous system and the immune system maintain close bidirectional communication in physiological and pathological conditions, the modulation of inflammation through the cholinergic anti-inflammatory reflex has been proposed. In this review, we summarized the evidence supporting chemical stimulation with cholinergic agonists and vagus nerve stimulation as therapeutic strategies in the treatment of various central nervous system pathologies, and their effect on inflammation.

Neuroprotection mediated by prolactin against streptozotocin injury in brain rat areas.

Prolactin has been recognized as neuroprotective hormone against various types of neuronal damage. This study was aimed to determine if prolactin protects against streptozotocin injury. A series of experiments were performed to determine neuronal survival by counting total neurons in medial hippocampus cortex and cerebellum. Astrogliosis was determined by immunofluorescence assays using GFAP, and behavioral improvement by prolactin after neuronal damage was determined by open-field and light-dark box tests. Results demonstrated that prolactin induced significant neuronal survival in both the hippocampus and cortex, but not in the cerebellum. No increase in astrogliosis was identified, but a significant reduction in anxiety levels was observed. Overall data indicate that prolactin may protect against a complex form of cell damage including oxidant stress and metabolic disruption by streptozotocin. Prolactin may be helpful strategy in the treatment of neuronal damage in neurological diseases.

Modulatory role of prolactin in type 1 diabetes.

OBJECTIVES: Patients with type 1 diabetes mellitus have been reported to have elevated prolactin levels and a possible relationship between prolactin levels and the development of the disease has been proposed. However, some studies show that prolactin mediates beneficial functions in beta cells. Therefore, we review information on the roles of prolactin in type 1 diabetes mellitus. CONTENT: Here we summarize the functions of prolactin in the immune system and in pancreatic beta cells, in addition, we describe studies related to PRL levels, its regulation and alterations of secretion in patients with type 1 diabetes mellitus. SUMMARY: Studies in murine models have shown that prolactin protects beta cells from apoptosis, stimulates their proliferation and promotes pancreatic islet revascularization. In addition, some studies in patients with type 1 diabetes mellitus have shown that elevated prolactin levels correlate with better disease control. OUTLOOK: Prolactin treatment appears to be a promising strategy to improve beta-cell vascularization and proliferation in transplantation and immunotherapies.

Effect of Dexamethasone on the Expression of the α2,3 and α2,6 Sialic Acids in Epithelial Cell Lines.

N-acetylneuraminic acid linked to galactose by α2,6 and α2,3 linkages (Siaα2,6 and Siaα2,3) is expressed on glycoconjugates of animal tissues, where it performs multiple biological functions. In addition, these types of sialic acid residues are the main targets for the binding and entry of influenza viruses. Here we used fluorochrome-conjugated Sambuccus nigra, Maackia amurensis, and peanut lectins for the simultaneous detection of Siaα2,3 and Siaα2,6 and galactosyl residues by two-color flow cytometry on A549 cells, a human pneumocyte cell line used for in vitro studies of the infection by influenza viruses, as well as on Vero and MDCK cell lines. The dexamethasone (DEX) glucocorticoid (GC), a widely used anti-inflammatory compound, completely abrogated the expression of Siaα2,3 in A549 cells and decreased its expression in Vero and MDCK cells; in contrast, the expression of Siaα2,6 was increased in the three cell lines. These observations indicate that DEX can be used for the study of the mechanism of sialylation of cell membrane molecules. Importantly, DEX may change the tropism of avian and human/pig influenza viruses and other infectious agents to animal and human epithelial cells.

Association between Galectin Levels and Neurodegenerative Diseases: Systematic Review and Meta-Analysis.

Galectins are a family of proteins with an affinity for ß-galactosides that have roles in neuroprotection and neuroinflammation. Several studies indicate that patients with neurodegenerative diseases have alterations in the concentration of galectins in their blood and brain. However, the results of the studies are contradictory; hence, a meta-analysis is performed to clarify whether patients with neurodegenerative diseases have elevated galectin levels compared to healthy individuals. Related publications are obtained from the databases: PubMed, Central-Conchrane, Web of Science database, OVID-EMBASE, Scope, and EBSCO host until February 2022. A pooled standard mean difference (SMD) with a 95% confidence interval (CI) is calculated by fixed-effect or random-effect model analysis. In total, 17 articles are included in the meta-analysis with a total of 905 patients. Patients with neurodegenerative diseases present a higher level of galectin expression compared to healthy individuals (MDS = 0.70, 95% CI 0.28-1.13, p = 0.001). In the subgroup analysis by galectin type, a higher galectin-3 expression is observed in patients with neurodegenerative diseases. Patients with Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALD), and Parkinson's disease (PD) expressed higher levels of galectin-3. Patients with multiple sclerosis (MS) have higher levels of galectin-9. In conclusion, our meta-analysis shows that patients with neurovegetative diseases have higher galectin levels compared to healthy individuals. Galectin levels are associated with the type of disease, sample, detection technique, and region of origin of the patients.

Prognostic Value of Galectin Expression in Patients with Breast Cancer: Systematic Review and Meta-Analysis.

Galectins are a family of proteins with affinity for ß-galactosides and their expression correlates with overall survival (OS) in several cancers. However, in breast cancer their prognostic potential is unclear. In this study we performed a meta-analysis to clarify the prognostic value of galectin expression in breast cancer and to identify sources of heterogeneity. For this purpose, we performed a search of related publications in PubMed, Central-Conchrane, Web of Science database, OVID-EMBASE, Scope and EBSCOhost until November 2021.Thirteen articles were included with a total of 2700 patients. High galectin expression was found not to correlate with OS in breast cancer (HR = 1.11, 95% CI 0.93-1.31). In the case of galectin-3, correlation with OS was observed when performing subgroup analysis by cellular localization (HR = 0.59, 95% CI 0.36-0.94 for cytoplasmic and HR = 1.82, 95% CI 1.00-3.29 for cytoplasmic plus nuclear). Galectin-7 correlates with DFS/PFS/DSS (HR = 2.43; 95% CI 1.36-4.31). Finally, galectin-3 correlates with some clinicopathological features such as lymph node metastasis, estrogen receptor expression and age. In conclusion, galectin-3 correlates with OS in breast cancer when cellular localization is considered while galectin-7 correlates with DFS/PFS/DSS. The cellular localization of galectins should be as fundamental aspect to be determined in future studies.

The role of prolactin in central nervous system inflammation.

Prolactin has been shown to favor both the activation and suppression of the microglia and astrocytes, as well as the release of inflammatory and anti-inflammatory cytokines. Prolactin has also been associated with neuronal damage in diseases such as multiple sclerosis, epilepsy, and in experimental models of these diseases. However, studies show that prolactin has neuroprotective effects in conditions of neuronal damage and inflammation and may be used as neuroprotector factor. In this review, we first discuss general information about prolactin, then we summarize recent findings of prolactin function in inflammatory and anti-inflammatory processes and factors involved in the possible dual role of prolactin are described. Finally, we review the function of prolactin specifically in the central nervous system and how it promotes a neuroprotective effect, or that of neuronal damage, particularly in experimental autoimmune encephalomyelitis and during excitotoxicity. The overall studies indicated that prolactin may be a promising molecule for the treatment of some neurological diseases.

Abnormal N-Glycosylation of Human Lens Epithelial Cells in Type-2 Diabetes May Contribute to Cataract Progression.

PURPOSE: In order to better understand cataract development, we analyzed the glycosylation profile of human lens epithelial cells (HLECs) from anterior lens capsules of type 2 diabetes mellitus (T2DM) and non-diabetic (ND) patients undergoing routine cataract surgery. SETTING: Research Department of the Asociación para Evitar la Ceguera, Hospital "Dr. Luis Sánchez Bulnes", Mexico. DESIGN: Experimental study. METHODS: Evaluation of anterior lens capsules from T2DM and ND patients undergoing phacoemulsification and free from other ocular diseases. RESULTS: Hematoxylin-eosin staining revealed HLECs alterations in T2DM samples. From lectins with different sugar specificities used, concanavalin A showed significant differences, labeling homogeneously both in the cytoplasm and in cell membranes in ND capsules, while in T2DM capsules, in addition to membrane and cytoplasm labeling, there were perinuclear vesicles with high concanavalin A labeling. Two-dimensional gel electrophoresis showed that T2DM patients have a ~65-kDa spot with an isoelectric point of 5.5 with a higher density compared to ND capsules, and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis showed 62% homology with type-1 cytokeratin. Immunohistochemistry using anti-pan cytokeratin antibody revealed co-localization with concanavalin A, and a lectin blot revealed with concanavalin A showed a band of ~65 kDa, a molecular weight that corresponds to human type 1 cytokeratin. CONCLUSION: These results suggest that over-expression of N-glycosidically linked human type 1 cytokeratin may induce capsule disruption and affect selective permeability, allowing the entry of different molecules to the lens that facilitate cataract progression.

Multiple Origins of Extracellular DNA Traps.

Extracellular DNA traps (ETs) are evolutionarily conserved antimicrobial mechanisms present in protozoa, plants, and animals. In this review, we compare their similarities in species of different taxa, and put forward the hypothesis that ETs have multiple origins. Our results are consistent with a process of evolutionary convergence in multicellular organisms through the application of a congruency test. Furthermore, we discuss why multicellularity is related to the presence of a mechanism initiating the formation of ETs.

Interplay between Oxidative Stress, Inflammation, and Amyloidosis in the Anterior Segment of the Eye; Its Pathological Implications.

There are different pathologies associated with amyloidogenic processes caused by the increase of reactive oxygen species (ROS) and the overactivation of inflammatory responses. These alterations are present in different regions of the anterior segment of the eye, and they have been associated with the development and progression of ocular pathologies, such as glaucoma, dry eye syndrome, keratitis, and cataracts among other pathologies. Aim. To discuss briefly the anatomical characteristics of the anterior segment of the eye and describe the interaction between oxidative stress (OS) and inflammatory responses, emphasizing the misfolding of several proteins leading to amyloidogenic processes occurring in the anterior segment and their implications in the development of ocular diseases. We performed a search on PubMed, CINAHL, and Embase using the MeSH terms "eye," "anterior segment", "inflammation", "oxidative stress", and "amyloidosis". The search encompassed manuscripts published up to April 2019. A hundred forty-four published studies met the inclusion criteria. We present the current knowledge regarding the interaction between OS and the activation of inflammatory processes and how both can cause conformational changes in several peptides and proteins in each compartment of the anterior segment. However, we found that there is no consensus about which factor is the first to cause amyloidosis. Our conclusions suggest that there is an interplay among these factors forming a vicious cycle that leads to the loss of protein structure in ocular pathologies, and multifactorial therapies should be developed to avoid protein misfolding and to stop the progression of ocular pathologies.

Neuroinflammation induced by amyloid ß25-35 modifies mucin-type O-glycosylation in the rat's hippocampus.

Amyloid-ß (Aß) plays a relevant role in the neurodegenerative process of Alzheimer's disease (AD). The 25-35 peptide of amyloid-ß (Aß25-35) induces the inflammatory response in brain experimental models. Mucin-type O-glycosylation has been associated with inflammation of brain tissues in AD, thus in this work, we aimed at identifying changes in the glycosylation profile generated by the injection of Aß25-35 into the CA1 of the hippocampus of rats, using histochemistry with lectins. Our results indicate that 100µM Aß25-35 induce increased recognition of the Amaranthus leucocarpus lectin (ALL) (specific for Galß1,3-GalNAcα1,0-Ser/Thr); whereas concanavalin A (Con A) (specific for α-Man) showed no differences among treated and control groups of rats. Jacalin and peanut agglutinin (Galß1,3GalNAcα1,0-Ser/Thr) showed no recognition of brain cells of control or treated rats. After 6-h treatment of the tissue with trypsin or with 200mM GalNAc, the interaction with ALL was inhibited. Immunohistochemistry showed positive anti-NeuN and ALL-recognition of neurons; however, anti-GFAP and anti-CD11b showed no co-localization with ALL. The ALL+ neurons revealed the presence of cytochrome C in the cytosol and active caspase 3 in the cytosol and nucleus. Administration of the interleukin-1 receptor antagonist (IL-1RA) to Aß25-35-treated rats diminished neuroinflammation and ALL recognition. These results suggest a close relationship among over-expression of mucin-type O-glycosylation, the neuroinflammatory process, and neuronal death.

Effect of amyloid-Β (25-35) in hyperglycemic and hyperinsulinemic rats, effects on phosphorylation and O-GlcNAcylation of tau protein.

Aggregation of the amyloid beta (Aß) peptide and hyperphosphorylation of tau protein, which are markers of Alzheimer's disease (AD), have been reported also in diabetes mellitus (DM). One regulator of tau phosphorylation is O-GlcNAcylation, whereas for hyperphosphorylation it could be GSK3beta, which is activated in hyperglycemic conditions. With this in mind, both O-GlcNAcylation and phosphorylation of tau protein were evaluated in the brain of rats with streptozotocin (STZ)-induced hyperglycemia and hyperinsulinemia and treated with the Aß25-35 peptide in the hippocampal region CA1. Weight, glycated hemoglobin, glucose, and insulin were determined. Male Wistar rats were divided in groups (N=20): a) control, b) treated only with the Aß25-35 peptide, c) treated with Aß25-35 and STZ, and d) treated only with STZ. Results showed statistically significant differences in the mean weight, glucose levels, insulin concentration, and HbA1c percentage, between C- and D-treated groups and not STZ-treated A and B (P<0.05). Interestingly, our results showed diminution of O-GlcNAcylation and increase in P-tau-Ser-396 in the hippocampal area of the Aß25-35- and STZ-treated groups; moreover, enhanced expression of GSK3beta was observed in this last group. Our results suggest that hyperinsulinemia-Aß25-35-hyperglycemia is relevant for the down regulation of O-GlcNAcylation and up-regulation of the glycogen synthase kinase-3 beta (GSK3beta), favoring Aß25-35-induced neurotoxicity in the brain of rats.