Ethyl pyruvate (EP) has potent influence on redox processes, cellular metabolism, and inflammation. It has been intensively studied in numerous animal models of systemic and organ-specific disorders ...whose pathogenesis involves a strong immune component. Here, basic chemical and biological properties of EP are discussed, with an emphasis on its redox and metabolic activity. Further, its influence on myeloid and T cells is considered, as well as on intracellular signaling beyond its effect on immune cells. Also, the effects of EP on animal models of chronic inflammatory and autoimmune disorders are presented. Finally, a possibility to apply EP as a treatment for such diseases in humans is discussed. Scientific papers cited in this review were identified using the PubMed search engine that relies on the MEDLINE database. The reference list covers the most important findings in the field in the past twenty years.
Gut immune cells have been increasingly appreciated as important players in the central nervous system (CNS) autoimmunity in animal models of multiple sclerosis (MS). Among the gut immune cells, ...innate lymphoid cell type 3 (ILC3) is of special interest in MS research, as they represent the innate cell counterpart of the major pathogenic cell population in MS,
T helper (Th)17 cells. Importantly, these cells have been shown to stimulate regulatory T cells (Treg) and to counteract pathogenic Th17 cells in animal models of autoimmune diseases. Besides, they are also well known for their ability to stabilize the intestinal barrier and to shape the immune response to the gut microbiota. Thus, proper maintenance of the intestinal barrier and the establishment of the regulatory milieu in the gut performed by ILC3 may prevent activation of CNS antigen-specific Th17 cells by the molecular mimicry. Recent findings on the role of ILC3 in the gut-CNS axis and their relevance for MS pathogenesis will be discussed in this paper. Possibilities of ILC3 functional modulation for the benefit of MS patients will be addressed, as well.
The Amsterdam instrumental activities of daily living questionnaire (A-IADL-Q) was developed as a sensitive tool in detecting a functional decline in early dementia. The aim of our study was to ...analyze the validity and reliability of the Serbian translation of the short version of A-IADL-Q in a population of memory clinic patients.
We have included 160 subjects with Alzhemier's disease (AD) dementia, mild cognitive impairment (MCI), or normal cognition (NC). All patients were examined by a neurologist, screened for cognitive impairment (MMSE) and depression, and referred to laboratory testing, neuroimaging examination, and neuropsychological assessment. Informants (close friends or relatives) completed Serbian language versions of the A-IADL-Q –Short version and the Lawton-Brody Instrumental Activities of Daily Living (LB-IADL) scale. Reliability analysis was performed by assessing internal consistency and reproducibility (test-retest reliability). Construct validity was assessed as the impact of gender, аgе, education, diagnosis, cognitive and functional measures on A-IADL-Q scores.
The internal consistency of the Serbian version of A-IADL-Q was acceptable (Cronbach's alpha 0.82), Test-retest reliability of the A-IADL-Q was excellent (ICC=0.92, 95% CI 0.84–0.98, p < 0.001). There was no statistically significant difference in A-IADL-Q scores between male and female subjects (t = 1.183; p = 0.241), while the difference was registered between subjects with different education levels (F=12.955; p < 0.001) and diagnosis (F=209.433; p < 0.001). There was a strong and statistically significant correlation between A-IADL-Q and MMSE scores (tau-b= 0.638; p < 0.001) and IADL-Q and LB-ADL scores (tau-b=0.714; p < 0.001). A significant multiple regression model was found (F(4, 155) = 103.692;p < 0.001), which explained 72.1% of the A-IADL-Q score variance with MMSE score and age as significant predictors.
The Serbian adaptation of the A-IADL-Q-short version is a reliable and valid measure of instrumental activities of daily living in patients with dementia and mild cognitive impairment. This easy-to-administer instrument is useful for the early diagnostics of dementia syndrome in a memory clinic population.
•Amsterdam IADL questionary (A-IADL-Q) detects a functional decline in early dementia.•We have developed a Serbian adaptation of the A-IADL-Q- short version.•Serbian adaptation of the A-IADL-Q is shown to be a valid and reliable instrument.
In the present study, the in vitro biocompatibility and cell response to two commonly used orthodontic bonding materials of different types, one self-curing and one light-curing, were examined and ...compared in indirect and direct cell culture systems. The study was conducted on fibroblasts and macrophages as in vitro models to study the biocompatibility of dental materials. Differences were found between the light- and self-curing material in cytotoxicity and effects on fibroblasts' proliferation in indirect cell culture systems as well as in macrophages response in vitro in both direct and indirect cell culture systems. Based on the obtained results, we can conclude that the self-curing material is generally more cytotoxic for fibroblasts compared to the light-curing, while macrophages' response to these materials was dependent on the macrophages' state and differed between the examined materials. This indicates that more attention should be paid when choosing and applying these materials in practice due to their toxicity to cells. Prior to their use, all aspects should be considered regarding the patient's conditions, associated problems, microenvironment in the oral cavity, etc. Further studies on in vivo models should be conducted to fully understand the potential long-term effects of the use of mentioned materials in orthodontics.
Gut-associated lymphoid tissue (GALT) is crucial for the maintenance of the intestinal homeostasis, but it is also the potential site of the activation of autoreactive cells and ...initiation/propagation of autoimmune diseases in the gut and in the distant organs. Type 3 innate lymphoid cells (ILC3) residing in the GALT integrate signals from food ingredients and gut microbiota metabolites in order to control local immunoreactivity. Notably, ILC3 secrete IL-17 and GM-CSF that activate immune cells in combating potentially pathogenic microorganisms. ILC3 also produce IL-22 that potentiates the strength and integrity of epithelial tight junctions, production of mucus and antimicrobial peptides thus enabling the proper function of the intestinal barrier. The newly discovered function of small intestine ILC3 is the secretion of IL-2 and the promotion of regulatory T cell (Treg) generation and function. Since the intestinal barrier dysfunction, together with the reduction in small intestine ILC3 and Treg numbers are associated with the pathogenesis of type 1 diabetes (T1D), the focus of this article is intestinal ILC3 modulation for the therapy of T1D. Of particular interest is free fatty acids receptor 2 (FFAR2), predominantly expressed on intestinal ILC3, that can be stimulated by available selective synthetic agonists. Thus, we propose that FFAR2-based interventions by boosting ILC3 beneficial functions may attenuate autoimmune response against pancreatic β cells during T1D. Also, it is our opinion that treatments based on ILC3 stimulation by functional foods can be used as prophylaxis in individuals that are genetically predisposed to develop T1D.
Type 1 diabetes (T1D) is an autoimmune disease in which a strong inflammatory response causes the death of insulin-producing pancreatic β-cells, while inefficient regulatory mechanisms allow that ...response to become chronic. Ethyl pyruvate (EP), a stable pyruvate derivate and certified inhibitor of an alarmin-high mobility group box 1 (HMGB1), exerts anti-oxidant and anti-inflammatory properties in animal models of rheumatoid arthritis and encephalomyelitis. To test its therapeutic potential in T1D, EP was administered intraperitoneally to C57BL/6 mice with multiple low-dose streptozotocin (MLDS)-induced T1D. EP treatment decreased T1D incidence, reduced the infiltration of cells into the pancreatic islets and preserved β-cell function. Apart from reducing HMGB1 expression, EP treatment successfully interfered with the inflammatory response within the local pancreatic lymph nodes and in the pancreas. Its effect was restricted to boosting the regulatory arm of the immune response through up-regulation of tolerogenic dendritic cells (CD11c
CD11b
CD103
) within the pancreatic infiltrates and through the enhancement of regulatory T cell (Treg) levels (CD4
CD25
FoxP3
). These EP-stimulated Treg displayed enhanced suppressive capacity reflected in increased levels of CTLA-4, secreted TGF-β, and IL-10 and in the more efficient inhibition of effector T cell proliferation compared to Treg from diabetic animals. Higher levels of Treg were a result of increased differentiation and proliferation (Ki67
cells), but also of the heightened potency for migration due to increased expression of adhesion molecules (CD11a and CD62L) and CXCR3 chemokine receptor. Treg isolated from EP-treated mice had the activated phenotype and T-bet expression more frequently, suggesting that they readily suppressed IFN-γ-producing cells. The effect of EP on Treg was also reproduced
. Overall, our results show that EP treatment reduced T1D incidence in C57BL/6 mice predominantly by enhancing Treg differentiation, proliferation, their suppressive capacity, and recruitment into the pancreas.
ILC3: a case of conflicted identity Koprivica, Ivan; Stanisavljević, Suzana; Mićanović, Dragica ...
Frontiers in immunology,
10/2023, Letnik:
14
Journal Article
Recenzirano
Odprti dostop
Innate lymphoid cells type 3 (ILC3s) are the first line sentinels at the mucous tissues, where they contribute to the homeostatic immune response in a major way. Also, they have been increasingly ...appreciated as important modulators of chronic inflammatory and autoimmune responses, both locally and systemically. The proper identification of ILC3 is of utmost importance for meaningful studies on their role in immunity. Flow cytometry is the method of choice for the detection and characterization of ILC3. However, the analysis of ILC3-related papers shows inconsistency in ILC3 phenotypic definition, as different inclusion and exclusion markers are used for their identification. Here, we present these discrepancies in the phenotypic characterization of human and mouse ILC3s. We discuss the pros and cons of using various markers for ILC3 identification. Furthermore, we consider the possibilities for the efficient isolation and propagation of ILC3 from different organs and tissues for
in-vitro
and
in-vivo
studies. This paper calls upon uniformity in ILC3 definition, isolation, and propagation for the increased possibility of confluent interpretation of ILC3’s role in immunity.
Mesenchymal stem cells (MSCs) are known for their immunosuppressive properties. Based on the demonstrated anti-inflammatory effect of mouse MSCs from hair follicles (moMSCORS) in a murine wound ...closure model, this study evaluates their potential for preventing type 1 diabetes (T1D) in C57BL/6 mice. T1D was induced in C57BL/6 mice by repeated low doses of streptozotocin. moMSCORS were injected intravenously on weekly basis. moMSCORS reduced T1D incidence, the insulitis stage, and preserved insulin production in treated animals. moMSCORS primarily exerted immunomodulatory effects by inhibiting CD4+ T cell proliferation and activation. Ex vivo analysis indicated that moMSCORS modified the cellular immune profile within pancreatic lymph nodes and pancreatic infiltrates by reducing the numbers of M1 pro-inflammatory macrophages and T helper 17 cells and upscaling the immunosuppressive T regulatory cells. The proportion of pathogenic insulin-specific CD4+ T cells was down-scaled in the lymph nodes, likely via soluble factors. The moMSCORS detected in the pancreatic infiltrates of treated mice presumably exerted the observed suppressive effect on CD4+ through direct contact. moMSCORS alleviated T1D symptoms in the mouse, qualifying as a candidate for therapeutic products by multiple advantages: non-invasive sampling by epilation, easy access, permanent availability, scalability, and benefits of auto-transplantation.
Recent data indicate the link between the number and function of T regulatory cells (Treg) in the gut immune tissue and initiation and development of autoimmunity associated with type 1 diabetes ...(T1D). Since type 3 innate lymphoid cells (ILC3) in the small intestine are essential for maintaining FoxP3
Treg and there are no data about the possible role of ILC3 in T1D pathogenesis, the aim of this study was to explore ILC3-Treg link during the development of T1D. Mature diabetic NOD mice had lower frequencies of IL-2-producing ILC3 and Treg in small intestine lamina propria (SILP) compared to prediabetic NOD mice. Similarly, in multiple low doses of streptozotocin (MLDS)-induced T1D in C57BL/6 mice, hyperglycemic mice exhibited lower numbers of ILC3, IL-2
ILC3 and Treg in SILP compared to healthy controls. To boost T1D severity, mice were treated with broad-spectrum antibiotics (ABX) for 14 days prior to T1D induction by MLDS. The higher incidence of T1D in ABX-treated mice was associated with significantly lower frequencies of IL-2
ILC3 and FoxP3
Treg in SILP compared with mice without ABX treatment. The obtained findings show that the lower proportions of IL-2-expressing ILC3 and FoxP3
Treg in SILP coincided with diabetes progression and severity.
While the effects of chronic exposure to microplastic particles (MPs) are extensively studied, the outcomes of a single treatment have received relatively less attention. To investigate MPs' ...potential acute toxicity, including their impact on general health status (victual consumption, sensorimotor deficits, and clinical toxicity signs) and serum biochemical parameters (markers of organ/tissue function and oxidative stress indicators), we administered thoroughly characterized MPs (1.4, 35, or 125 mg/kg), generated from polyethylene terephthalate (PET) bottles, to adult male Wistar rats via oral gavage. The MPs' short-term effects were assessed with well-established tests and methods. The results point to the absence of sensorimotor deficits and clinical toxicity signs, while levels of markers of liver, heart, and kidney function were altered in all MP groups. Decreased victual consumption and increased levels of oxidative stress indicators were evident following treatment with the two higher MP doses. Presented data indicate that examined MPs are able to initiate the development of local changes in tissues and organs within a short time frame, potentially leading to their damage and dysfunction. This study may increase the awareness of the detrimental effects of plastic contamination, as even a single exposure to MPs may provoke adverse health outcomes.
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