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PMC11277492_p0
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1. Introduction
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biomedical
Review
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Schizophrenia (SCZ) is a pervasive neuropsychiatric disorder characterized by a diverse range of mental symptoms, encompassing multifaceted manifestations of cognitive, emotional, and behavioral abnormalities, thereby rendering its trajectory intricate and heterogeneous . As a chronic condition, it can have detrimental effects on individuals and impose significant costs on families, society, and healthcare systems . The development and progression of SCZ are influenced by a complex interplay of genetic, environmental, and neurobiological factors . Genetic factors contribute significantly to an individual’s susceptibility to developing SCZ, with specific gene variations increasing the risk of the disorder . Environmental factors, such as prenatal stress, substance abuse, urban upbringing, and social adversity, can also have a profound impact on the onset and course of SCZ . The onset of SCZ has prompted the formulation of numerous theories regarding neurobiological factors, encompassing abnormalities in brain structure and function, imbalances in neurotransmitters (such as dysregulation of dopamine), inflammation, and dysregulation of the immune system. These factors play pivotal roles in the pathogenesis of SCZ. Dopamine, a neurotransmitter closely associated with emotional regulation, motivation, and cognitive function, is found to be abnormally elevated in individuals with SCZ, which correlates with symptoms such as auditory hallucinations, delusions, and cognitive impairments . Therefore, an imbalance in the dopamine system may constitute a key factor in the pathogenesis of SCZ. Recent studies have indicated that inflammatory responses significantly contribute to the development of SCZ . Aberrant release of inflammatory factors may lead to neuronal damage and brain dysfunction, thereby exacerbating disease progression . Furthermore, inflammatory responses may be associated with symptom severity in SCZ, necessitating regulation as a crucial strategy for treatment intervention against this disorder . The immune system serves not only as a defense mechanism against pathogens but also exerts significant influence on brain function and mental health . Abnormal activation of the immune system can result in inflammatory responses and autoimmune reactions affecting normal neuronal functioning . Thus, immune system abnormalities might be closely linked to SCZ pathogenesis. Therefore, gaining a more profound comprehension of the involvement of the dopamine system, inflammation, and immune response not only enhances understanding but also provides valuable guidance for future preventive treatment strategies. Simultaneously, the existing diagnostic approaches for SCZ depend on subjective assessments, lacking objective measures to precisely evaluate the patient’s condition . Culture also holds a crucial position in understanding the causes, diagnosis, and treatment of SCZ . Introducing an objective diagnostic method would facilitate the development of more targeted treatment plans for effective patient management in the future.
[ "Ke Li", "Lin Zhu", "Haibing Lv", "Yulong Bai", "Chuang Guo", "Kuanjun He" ]
https://doi.org/10.3390/ijms25147673
N/A
https://creativecommons.org/licenses/by/4.0/
en
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1. Introduction
5.058594
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Review
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MicroRNAs (miRNAs) constitute a class of diminutive non-coding RNAs, encoded by endogenous genes of approximately 18–25 nucleotides in length, which play crucial roles in development and disease . The cellular biogenesis of miRNAs is a complex, multistep process that involves transcription from various genomic regions, including the exons and introns of host genes as well as intergenic fragments . The biosynthesis of miRNAs begins in the nucleus, and mature miRNAs are produced in the cytoplasm. MiRNAs are predominantly transcribed via RNA polymerase II-dependent transcription, and then undergo capping, splicing, and polyadenylation to form primary miRNAs (pri-miRNAs), which have one or more hairpin structures and can be up to thousands of nucleotides in length . The Drosha–DiGeorge Syndrome Critical Region 8 (DGCR8) complex mediates the processing of pri-miRNAs into precursor hairpins, which have an approximate length of 70 nucleotides. These precursor hairpins, known as pre-miRNAs, are then translocated into the cytoplasm via exportin-5 through the nuclear pore . Another RNA enzyme, Dicer, breaks down pre-miRNAs into double-stranded RNA duplexes in the cytoplasm, i.e., miRNA strands and their complementary sequences (miRNA/miRNA*). MiRNAs orchestrate post-transcriptional gene silencing by precisely targeting the 3′ untranslated region (UTR) of mRNA, with particular emphasis on the seed region located at the 5′ end spanning nucleotides 2–7 . Mature miRNAs can bind to the Ago-2-containing RNA-induced silencing complex (RISC) and mediate gene silencing, resulting in mRNA breakage or translational repression, while the other miRNA* strand is degraded . As a major regulator of basic biological processes, miRNAs are able to regulate cell differentiation, proliferation, and apoptosis . MiRNAs exert their biological functions by inhibiting downstream gene expression, mainly through transcriptional inhibition and mRNA cleavage or degradation, and indirectly regulate pathophysiological states . MiRNAs bind to complementary target sequences in mRNA, interfere with translation mechanisms, alter or prevent the production of protein products, and thus regulate mRNA expression through different pathways . The binding of miRNAs to target mRNAs also triggers the binding of mRNA attenuators, leading to mRNA instability, decreased expression levels, and even degradation . MiRNAs have garnered extensive research attention due to their pivotal role in neuronal development and brain function . Numerous studies have unequivocally demonstrated the active involvement of miRNAs in the pathophysiological mechanisms underlying SCZ . The process of miRNA biogenesis is illustrated in Figure 1 .
[ "Ke Li", "Lin Zhu", "Haibing Lv", "Yulong Bai", "Chuang Guo", "Kuanjun He" ]
https://doi.org/10.3390/ijms25147673
N/A
https://creativecommons.org/licenses/by/4.0/
en
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1. Introduction
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Review
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MiRNAs play major roles in brain development and function, regulation of neural development, neurotransmitter synthesis, and neural signaling . Studies have shown that miRNAs are implicated in the pathophysiology and pathogenesis of many diseases . This review provides a comprehensive overview of dysregulated miRNA expression patterns in individuals with SCZ, alongside recent advancements in the pathogenesis hypothesis involving miRNAs for this disorder.
[ "Ke Li", "Lin Zhu", "Haibing Lv", "Yulong Bai", "Chuang Guo", "Kuanjun He" ]
https://doi.org/10.3390/ijms25147673
N/A
https://creativecommons.org/licenses/by/4.0/
en
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2. Method
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The present scope review was carried out following the PRISMA-ScR methodology (the preferred reporting item for extended meta-analysis of systematic Review and Scope evaluation) . A comprehensive search of research articles published between 2003 and 2024 was conducted using both the PubMed database and the Google Scholar database. The most recent search was performed on 15 June 2024. At least two authors conducted a thorough screening of the title and abstract of each article to determine its eligibility for full-text review. Further evaluation was only conducted on studies that could not be definitively excluded based on the information provided in the title and abstract. Subsequently, two other authors assessed each remaining full-text article to ascertain its eligibility for inclusion in the study. This study has set up a file in the OSF database registration, registration DOI: https://doi.org/10.17605/OSF.IO/863RE .
[ "Ke Li", "Lin Zhu", "Haibing Lv", "Yulong Bai", "Chuang Guo", "Kuanjun He" ]
https://doi.org/10.3390/ijms25147673
N/A
https://creativecommons.org/licenses/by/4.0/
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Inclusion criteria: Articles written in English. Articles containing relevant keywords related to SCZ, miRNA, biomarkers, etiology, and mechanism of action. Articles with an abstract available
[ "Ke Li", "Lin Zhu", "Haibing Lv", "Yulong Bai", "Chuang Guo", "Kuanjun He" ]
https://doi.org/10.3390/ijms25147673
N/A
https://creativecommons.org/licenses/by/4.0/
en
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Exclusion criteria: Incomplete or unavailable full text. Articles written in languages other than English. Articles with weak relevance to the scope of this review.
[ "Ke Li", "Lin Zhu", "Haibing Lv", "Yulong Bai", "Chuang Guo", "Kuanjun He" ]
https://doi.org/10.3390/ijms25147673
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999995
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PMC11277492
sec[2]/p[0]
3. Results
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Review
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The studies included in this review all investigate the role of miRNAs in SCZ. Initially, a comprehensive search yielded a total of 1488 articles related to the association between SCZ and miRNAs. After removing duplicates, the remaining articles underwent screening based on their titles and abstracts. Subsequently, 254 articles were thoroughly analyzed in full text and selected for inclusion in this study. Among these 254 articles, 49 compared miRNA expression differences between SCZ patients and healthy controls (HCs), observing improvements in miRNA expression levels following medication. Additionally, significant differences in miRNA expression before and after treatment were found by some studies, suggesting their potential as biomarkers for SCZ. Furthermore, certain studies have elucidated the regulatory mechanisms through which miRNAs may contribute to the pathogenesis of SCZ. The process of article selection is illustrated in Figure 2 using the PRISMA Flowchart.
[ "Ke Li", "Lin Zhu", "Haibing Lv", "Yulong Bai", "Chuang Guo", "Kuanjun He" ]
https://doi.org/10.3390/ijms25147673
N/A
https://creativecommons.org/licenses/by/4.0/
en
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3. Results
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biomedical
Review
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The review presents a comprehensive review of the role of miRNAs in SCZ. It details the differential expression of various miRNAs across tissues, including peripheral blood, prefrontal cortex (PFC), and temporal gyrus, in SCZ patients compared to HCs. MiRNAs exhibit a close association with SCZ, wherein their aberrant expression extensively contributes to the initiation and progression of the disorder, thereby potentially serving as crucial biomarkers for its diagnosis. The relevant pieces of research regarding miRNA dysregulation in SCZ can be seen in Table 1 . Key findings include the upregulation of miR-195, miR-574-5p, miR-1827, miR-4429, miR-30e-3p, and miR-137 in peripheral blood , with miR-195 linked to cognitive impairment in female patients . In monocytes from peripheral blood, miR-124-3p was upregulated , while miR-21-5p was downregulated . Additionally, a two-fold increase in miR-206 expression was detected in extracellular vesicles from patient blood samples . MiR-9 and miR-9-5p showed decreased expression levels in both peripheral blood and the PFC of SCZ patients ; however, miR-9-5p was upregulated in the superior temporal gyrus (STG) . Conversely, the expression levels of miR-181b were up-regulated in PFC, STG, and the dorsolateral prefrontal cortex (DLPFC) . These findings suggest that different patterns of miRNA upregulation or downregulation may influence neuronal differentiation and development processes in both peripheral blood and brain tissue, contributing to the pathogenesis of SCZ.
[ "Ke Li", "Lin Zhu", "Haibing Lv", "Yulong Bai", "Chuang Guo", "Kuanjun He" ]
https://doi.org/10.3390/ijms25147673
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
PMC11277492_p8
PMC11277492
sec[2]/p[2]
3. Results
4.214844
biomedical
Review
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In recent years, miRNAs have emerged as promising diagnostic biomarkers for SCZ. For example, in two studies, miR-34a showed the most significant differential expression in mononuclear cells and the PFC of SCZ patients, suggesting its potential as a diagnostic marker for SCZ . MiR-130b and miR-193a-3p were significantly elevated in patient plasma samples but were notably suppressed following antipsychotic treatment, indicating their potential as prognostic biomarkers for SCZ . Additionally, abnormal expression of miR-675-3p, miR-1262, and miR-218-5p in peripheral blood accurately diagnosed treatment-resistant schizophrenia (TRS) patients , contributing to a more accurate diagnosis of SCZ. The identification of miRNAs as biomarkers offers promising avenues for early detection, monitoring of disease progression, and evaluation of treatment efficacy in SCZ. Modulating these miRNAs, either promoting or inhibiting their activity, can be achieved through targeted manipulation. This approach provides potential therapeutic benefits for treating psychiatric disorders.
[ "Ke Li", "Lin Zhu", "Haibing Lv", "Yulong Bai", "Chuang Guo", "Kuanjun He" ]
https://doi.org/10.3390/ijms25147673
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999996
PMC11277492_p9
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sec[2]/p[3]
3. Results
4.347656
biomedical
Review
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Increasing evidence suggests that dysregulation of miRNAs may play a significant role in the etiology of SCZ by disrupting the mechanisms of neuronal development and plasticity, thereby leading to the onset of the disorder. Dopamine and glutamate are important in the pathophysiology of SCZ . MiRNAs, as a new class of dopamine and glutamate modulators, can influence neurotransmission and neural signaling by modulating the synthesis and release of neurotransmitters, such as dopamine and glutamate, and thus influence the pathogenesis of SCZ . In recent years, SCZ and the immune-inflammatory response have received close attention . Abnormalities in immune inflammation are present in patients with SCZ , and miRNAs have been found to regulate the function of immune cells and the expression of inflammatory factors and thus influence the immune inflammatory response in studies of SCZ. The regulation of gene expression is critically influenced by miRNAs, which exert their effects on SCZ-related behaviors through targeting epigenetic processes, synaptic signaling, and cell–cell interactions within the brain.
[ "Ke Li", "Lin Zhu", "Haibing Lv", "Yulong Bai", "Chuang Guo", "Kuanjun He" ]
https://doi.org/10.3390/ijms25147673
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
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4. Discussion
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Study
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MiRNAs can modulate the expression of specific genes through the RNA interference pathway, thereby affecting the function and development of various glial cells in the brain . The brain and blood of patients with SCZ exhibit differential miRNA expression compared to NCs , suggesting that these variations may underlie the pathogenesis of SCZ, and the targets have the potential to serve as therapeutic targets for antipsychotic drugs.
[ "Ke Li", "Lin Zhu", "Haibing Lv", "Yulong Bai", "Chuang Guo", "Kuanjun He" ]
https://doi.org/10.3390/ijms25147673
N/A
https://creativecommons.org/licenses/by/4.0/
en
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The expression level of miR-195 in peripheral blood was significantly elevated in patients diagnosed with SCZ ; however, there were also studies that reported no significant difference . High expression of miR-195 is closely associated with decreased levels of brain-derived neurotrophic factor (BDNF) protein, and miR-195 can specifically target the 3′UTR of BDNF, thereby leading to alterations in cognitive function . Studies on cognitive impairment have revealed an association between miR-195 and cognitive deficits in SCZ patients, particularly among female individuals . Therefore, it is plausible that miR-195 may be involved in the underlying mechanism of gender-related cognitive deficits in SCZ. The expression of miR-124-3p was upregulated in the peripheral blood mononuclear cells (PBMCs) of patients with SCZ, while the expression of miR-206 and miR-132-3p did not show significant differences . Following 12 weeks of continuous administration of antipsychotics, BDNF expression was upregulated, whereas all three miRNAs were downregulated; furthermore, a positive correlation was observed between BDNF and all three miRNAs . In another study, the expression of miR-206 in blood exosomes from SCZ patients tripled . The dependent regulation of SCZ protective alleles on 5′-nucleotidase, cytoplasmic II (NT5C2) may lead to the promotion of SCZ by miR-206 . In animal experiments using a neurodevelopmental model of SCZ mice with N-methyl-D-aspartate receptor (NMDAR) dysfunction and treated with ketamine, the expression of miR-132-3p significantly increased in the PFC of female mice but showed no significant change in male mice, indicating sexual dimorphism . Future studies could further explore whether similar sex differences exist for miR-132-3p in humans. Pri-miR-9-2 is a neurogenic precursor that primarily regulates the production of miR-9. Studies have indicated that the expression of miR-9 and miR-9-5p in the peripheral blood and PFC of patients with SCZ is down-regulated, while the expression of miR-9-5p is up-regulated in the STG. This suggests that miR-9 may be involved in the etiology of SCZ . Another study discovered that miR-9-5p is down-regulated in peripheral blood samples from patients experiencing first-episode SCZ, and its target genes are involved in the biological pathways related to neuronal differentiation and nervous system development . Additionally, there exists a strong correlation between miR-9-5p and miR-137 , which has been proven as a potential diagnostic biomarker for SCZ . The expression of miR-21-5p in the PBMCs of SCZ patients was downregulated , and the expression of miR-21 significantly decreased after treatment with antipsychotic drugs . Studies have indicated that there are miRNA binding site variants (MBSVs) present in the genes targeted by miR-21-5p , which may be associated with SCZ. Additionally, miR-574-5p, miR-1827, and miR-4429 were upregulated in the blood of patients with SCZ, showing predictive and diagnostic value . Multiple studies have demonstrated that the expression of miR-181b is upregulated in the PFC and STG regions among SCZ patients, while its expression is also significantly altered in PBMCs . These findings contribute to a deeper understanding of the role played by miRNAs in the pathogenesis of SCZ. The abnormal expression of miRNA in patients with SCZ is associated with the regulation of receptors and genes in the nervous system. The up-regulation of miR-30e-3p has been observed in peripheral blood samples from SCZ patients . NMDAR dysfunction plays a role in the pathophysiology of SCZ, which may be influenced by miRNA-mediated regulation . In rat models with down-regulated NMDAR subunits, miR-146a-5p and miR-200b-3p were found to be up-regulated . Whole blood tests revealed elevated levels of miR-137 expression in both early-onset schizophrenia (EOS) and adult SCZ (AOS) patients . Furthermore, miR-137 expression may be linked to underlying mechanisms contributing to genetic susceptibility for SCZ . Using SCZ experimental animal models, it was found that olanzapine treatment of SCZ mice resulted in the downregulation of miR-223 expression in neuronal granules and neuronal exosomes . Previous studies have shown that miR-223 is enriched in mouse astrocytes and secreted by exosomes, and this enrichment may contribute to the occurrence of SCZ . After treating an MK-801-induced rat SCZ model with clozapine (CLO), hippocampal analysis showed significant differences in the expression of 14 miRNAs between the MK-801 + CLO group and the MK-801 group. Eight miRNAs were differentially expressed in the MK-801 group, including six upregulated and two downregulated (miR-455-3p and miR-483-3p). In particular, after MK-801 treatment there was an upregulation of miR-184 followed by a downregulation after MK801 + CLO treatment . Further research is needed to determine whether miR-184 can be used as a diagnostic marker for SCZ. The abnormal expression of miRNAs in peripheral blood and brain has an impact on SCZ, and it can be concluded that miRNAs have important theoretical, experimental, and clinical significance for SCZ. MiRNAs as a biological diagnostic marker for SCZ are still being explored, and although the mechanism of action is still unclear, miRNAs as diagnostic markers for SCZ have great potential.
[ "Ke Li", "Lin Zhu", "Haibing Lv", "Yulong Bai", "Chuang Guo", "Kuanjun He" ]
https://doi.org/10.3390/ijms25147673
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
PMC11277492_p12
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sec[3]/p[2]
4. Discussion
4.246094
biomedical
Review
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Several studies have demonstrated the utility of miRNAs as biomarkers for the diagnosis of SCZ. The most significant difference in miR-34a expression was observed in the monocytes and PFC of SCZ patients, suggesting its potential as a diagnostic marker for SCZ. In plasma samples from SCZ patients, there were significantly elevated levels of miR-130b and miR-193a-3p . After one year of treatment with aripiprazole and risperidone, the expression levels of miR-130b and miR-193a-3p were significantly suppressed, suggesting their potential as prognostic biomarkers for SCZ . The changes of plasma exosomal miRNA in patients with TRS are closely related to neuronal function . miR-675-3p , miR-1262, and miR-218-5-p have been found, in the peripheral blood of TRS patients, to have potential as diagnostic markers for TRS, contributing to a more accurate diagnosis of SCZ. Studies related to miRNAs as biomarkers of SCZ are still in the exploratory stage, and more research is needed to support the relationship between the two. In the future, it is possible to treat SCZ by modulating the expression of specific miRNAs, which may become a new therapeutic strategy for the treatment of SCZ. Research on miRNAs as biomarkers of SCZ can also help to reveal the pathogenesis of psychiatric disorders.
[ "Ke Li", "Lin Zhu", "Haibing Lv", "Yulong Bai", "Chuang Guo", "Kuanjun He" ]
https://doi.org/10.3390/ijms25147673
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
PMC11277492_p13
PMC11277492
sec[3]/p[3]
4. Discussion
4.652344
biomedical
Review
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MiRNAs are involved in the regulation of gene expression and play a crucial role in brain development and neuroplasticity . The role of miRNA in the pathogenesis of SCZ is still being explored, but the significance of miRNA in the pathogenesis of SCZ should not be disregarded. The expression levels of certain miRNAs in the blood of patients with SCZ are significantly different compared with those of normal people, and these abnormally expressed miRNAs may be involved in the onset and development of SCZ. Patients with SCZ have abnormal neurodevelopment and plasticity, which in turn leads to brain dysfunction. MiRNAs affect neural development and plasticity and play a key role in the regulation of brain neural development and function , which suggests that the two are closely related. Abnormal expression of miRNAs in SCZ patients may disrupt neural structural functions, such as normal neuronal function, dendritic development, and synaptic connectivity, thus affecting neural network construction in the brain . Some studies have now identified potential mechanisms of miRNA action in SCZ. Dopamine and glutamate are important in the pathophysiology of SCZ . MiRNAs, as a new class of dopamine and glutamate modulators, can influence neurotransmission and neural signaling by modulating the synthesis and release of neurotransmitters, such as dopamine and glutamate, and thus influence the pathogenesis of SCZ . In recent years, SCZ and the immune-inflammatory response have received close attention . Abnormalities in immune inflammation are present in patients with SCZ , and miRNAs have been found to regulate the function of immune cells and the expression of inflammatory factors and thus influence the immune inflammatory response in studies of SCZ. Studies have shown that increased neuroinflammation is associated with the pathogenesis of SCZ, with increased oxidative stress and inflammation in blood and brain tissue in SCZ patients .
[ "Ke Li", "Lin Zhu", "Haibing Lv", "Yulong Bai", "Chuang Guo", "Kuanjun He" ]
https://doi.org/10.3390/ijms25147673
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
PMC11277492_p14
PMC11277492
sec[3]/p[4]
4. Discussion
4.070313
biomedical
Review
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The regulation of gene expression is critically influenced by miRNAs, which can modulate behaviors related to SCZ through their targeting of epigenetic processes, synaptic signaling, and cell–cell interactions within the brain. Consequently, the investigation of miRNAs’ involvement in neurogenesis and pathogenesis of neurological disorders has garnered significant attention . Elucidating and revealing the neuronal mechanism of miRNA has been the key to research. Finding a potential mechanism to treat psychiatric disorders could guide the development of targeted drugs that target specific sites of action to improve patients’ symptoms.
[ "Ke Li", "Lin Zhu", "Haibing Lv", "Yulong Bai", "Chuang Guo", "Kuanjun He" ]
https://doi.org/10.3390/ijms25147673
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
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This review has several limitations. The included studies show variability in patient demographics, disease severity, and treatment status, all of which could affect miRNA expression levels. Additionally, many studies have small sample sizes, which reduces their statistical power and limits the generalizability of their findings. Despite these limitations, a consistent trend of specific dysregulated miRNAs in individuals with SCZ was identified. Most studies are cross-sectional and do not provide longitudinal data, making it difficult to track changes in miRNA expression over time or to understand their relationship to disease progression and treatment response. Future research should focus on increasing sample sizes and employing longitudinal designs to better understand the dynamic changes in dysregulated miRNAs throughout the course of SCZ. In this scoping review, the evidence sources were not critically assessed; thus, no data regarding the critical evaluation of evidence sources was provided.
[ "Ke Li", "Lin Zhu", "Haibing Lv", "Yulong Bai", "Chuang Guo", "Kuanjun He" ]
https://doi.org/10.3390/ijms25147673
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999995
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5. Conclusions
4.1875
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[ 0.9990234375, 0.0006213188171386719, 0.0005168914794921875 ]
[ 0.69091796875, 0.0010929107666015625, 0.3076171875, 0.00046539306640625 ]
The dysregulation of miRNAs in SCZ has been extensively investigated, encompassing their potential roles as well as the diverse mechanisms underlying their dysregulation. We conducted a comprehensive search of the PubMed database and the Google Scholar database and ultimately identified 49 studies that met our predetermined criteria. Through meticulous sorting and analysis of these papers, we have reached the conclusion that differentially expressed miRNAs play a pivotal role in promoting the onset and progression of SCZ. Furthermore, our findings suggest that miRNAs may be involved in the pathogenesis of SCZ through regulatory mechanisms that involve dopamine, glutamate, and the immunoinflammatory response. These conclusions provide cutting-edge evidence regarding the role and potential mechanisms underlying miRNA involvement in SCZ. The findings from all the selected studies indicate the significance of miRNAs in SCZ. However, it is important to note that, due to variations in the tissue samples utilized across studies, there exists variability in evaluating the impact of miRNA on SCZ. Further elucidation of their regulatory mechanisms and involvement in SCZ can shed light on the disease’s pathophysiological features, offering insights into its diagnosis, treatment, and prevention. Modulating miRNA expression or activity holds promise for restoring normal gene expression and neurobiological functions to ameliorate SCZ symptoms, thus paving the way for improved treatments and management strategies.
[ "Ke Li", "Lin Zhu", "Haibing Lv", "Yulong Bai", "Chuang Guo", "Kuanjun He" ]
https://doi.org/10.3390/ijms25147673
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
PMC11277504_p0
PMC11277504
sec[0]/p[0]
1. Introduction
3.542969
biomedical
Other
[ 0.99853515625, 0.000972747802734375, 0.0007271766662597656 ]
[ 0.048095703125, 0.70654296875, 0.2431640625, 0.00223541259765625 ]
Stroke stands out as the most significant and devastating clinical manifestation among all cerebrovascular disorders . The most recent statistics estimated that stroke caused 6.55 million deaths (84.69 per 100,000) in 2022, making it the second leading cause of death after ischemic heart disease, with an incidence of new cases of around 7.6 million (94.51 per 100,000) .
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999996
PMC11277504_p1
PMC11277504
sec[0]/p[1]
1. Introduction
3.607422
biomedical
Other
[ 0.998046875, 0.001239776611328125, 0.0004901885986328125 ]
[ 0.03369140625, 0.95068359375, 0.01340484619140625, 0.0020046234130859375 ]
Ischemic stroke is caused by the occlusion of a cerebral artery, resulting in a reduction in blood supply, and, consequently, oxygen and nutrients, which leads to alterations in the functionality of brain cells.
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999995
PMC11277504_p2
PMC11277504
sec[0]/p[2]
1. Introduction
3.589844
biomedical
Other
[ 0.9990234375, 0.0006666183471679688, 0.00047898292541503906 ]
[ 0.125244140625, 0.84423828125, 0.029022216796875, 0.00159454345703125 ]
In various cerebrovascular diseases, microglia play a fundamental role in the preservation of the Central Nervous System (CNS) by eliminating necrotic tissue and apoptotic cells .
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999996
PMC11277504_p3
PMC11277504
sec[0]/p[3]
1. Introduction
4.0625
biomedical
Study
[ 0.99951171875, 0.00025463104248046875, 0.0001933574676513672 ]
[ 0.86865234375, 0.10125732421875, 0.0293731689453125, 0.0008683204650878906 ]
In ischemic stroke, microglia quickly activate and accumulate at the infarction site, demonstrating the ability to phagocytize vital cells instead of just eliminating cellular debris, thereby exacerbating brain damage or disrupting normal pathophysiological mechanisms, as observed in the penumbra of stroke or neurodegenerative diseases .
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
PMC11277504_p4
PMC11277504
sec[0]/p[4]
1. Introduction
3.974609
biomedical
Study
[ 0.99951171875, 0.00040435791015625, 0.00018727779388427734 ]
[ 0.54248046875, 0.329345703125, 0.1263427734375, 0.0019817352294921875 ]
Neuroinflammation, guided by microglial cells, is a key component in the ischemic cascade that results in cell damage, disability, and poor prognosis after cerebral ischemia due to the chronic release of high levels of pro-inflammatory cytokines and chemokines .
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
PMC11277504_p5
PMC11277504
sec[0]/p[5]
1. Introduction
3.568359
biomedical
Other
[ 0.99853515625, 0.0007228851318359375, 0.000972747802734375 ]
[ 0.0693359375, 0.9248046875, 0.00463104248046875, 0.0012178421020507812 ]
Triggering receptors expressed on myeloid cells (TREM-1 and TREM-2) are a family of receptors involved in the immune system expressed on a variety of innate cells of the myeloid lineage, including microglia .
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999996
PMC11277504_p6
PMC11277504
sec[0]/p[6]
1. Introduction
3.857422
biomedical
Study
[ 0.99951171875, 0.0002834796905517578, 0.00044846534729003906 ]
[ 0.60986328125, 0.38525390625, 0.003936767578125, 0.0011138916015625 ]
The shedding of the receptor ectodomain by secretases produces soluble forms of the receptors, sTREM-1 and sTREM-2, detectable in the peripheral blood and cerebrospinal fluid (CSF) .
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999996
PMC11277504_p7
PMC11277504
sec[0]/p[7]
1. Introduction
3.230469
biomedical
Other
[ 0.99755859375, 0.00045108795166015625, 0.00208282470703125 ]
[ 0.350341796875, 0.6328125, 0.01543426513671875, 0.0013341903686523438 ]
The mechanisms of the release of soluble forms remain uncertain, and it is hypothesized that may function as a regulatory mechanism, enhancing or decreasing the activity of TREM receptors. Soluble TREMs can act as natural antagonists of membrane receptors .
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999995
PMC11277504_p8
PMC11277504
sec[0]/p[8]
1. Introduction
3.060547
biomedical
Other
[ 0.99853515625, 0.0006418228149414062, 0.0009617805480957031 ]
[ 0.053985595703125, 0.62158203125, 0.3212890625, 0.0030078887939453125 ]
TREM-1 was initially described as a useful pro-inflammatory prognostic biomarker in sepsis, and it has also been described in different neurological diseases, such as stroke, Alzheimer’s disease, and Parkinson’s .
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999996
PMC11277504_p9
PMC11277504
sec[0]/p[9]
1. Introduction
4.066406
biomedical
Study
[ 0.99951171875, 0.00013840198516845703, 0.0001093149185180664 ]
[ 0.99365234375, 0.00113677978515625, 0.00519561767578125, 0.00013005733489990234 ]
Regarding acute ischemic stroke (AIS), studies in animals have found that pharmacological induction of ischemia promotes TREM-1 receptor activation, which induces the production of pro-inflammatory cytokines and chemokines in microglia, suggesting a critical role in post-ischemic neuroinflammation .
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999996
PMC11277504_p10
PMC11277504
sec[0]/p[10]
1. Introduction
4.085938
biomedical
Study
[ 0.99951171875, 0.00021064281463623047, 0.00013947486877441406 ]
[ 0.9990234375, 0.00027298927307128906, 0.0004341602325439453, 0.00007027387619018555 ]
In humans experiencing acute ischemic stroke, the serum levels of sTREM-1 exhibited a strong correlation with the concentrations of human S100 calcium-binding protein B, along with the serum levels of pro-inflammatory cytokines, such as TNF-α, IL1β, IL6, IL8, and IFN-γ, as well as the stroke volume and the NIHSS .
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
PMC11277504_p11
PMC11277504
sec[0]/p[11]
1. Introduction
3.292969
biomedical
Study
[ 0.99853515625, 0.0003197193145751953, 0.0011491775512695312 ]
[ 0.58740234375, 0.2734375, 0.1378173828125, 0.0015106201171875 ]
On the other hand, TREM-2 appears to play a critical role in maintaining tissue homeostasis by promoting the removal of cellular debris through phagocytosis and modulating inflammation, particularly neuroinflammation. However, the role of TREM-2 in ischemic stroke remains uncertain.
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999995
PMC11277504_p12
PMC11277504
sec[0]/p[12]
1. Introduction
4
biomedical
Study
[ 0.99951171875, 0.00012683868408203125, 0.0001499652862548828 ]
[ 0.9892578125, 0.0077972412109375, 0.00250244140625, 0.0002751350402832031 ]
Studies in TREM-2 knockout mice show reduced quantities of activated microglia and phagocytes, leading to impaired clearance of apoptotic or necrotic cells and hindering ischemic tissue elimination .
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999996
PMC11277504_p13
PMC11277504
sec[0]/p[13]
1. Introduction
3.300781
biomedical
Study
[ 0.99853515625, 0.0002765655517578125, 0.0013799667358398438 ]
[ 0.78271484375, 0.208251953125, 0.008056640625, 0.0007252693176269531 ]
By contrast, elevated levels of soluble TREM-2 (sTREM-2) are associated with higher inflammatory markers (e.g., hsCRP) .
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999996
PMC11277504_p14
PMC11277504
sec[0]/p[14]
1. Introduction
2.515625
biomedical
Other
[ 0.99755859375, 0.0004451274871826172, 0.00189208984375 ]
[ 0.315673828125, 0.66162109375, 0.021087646484375, 0.001583099365234375 ]
As several studies have reported that sTREM-2 appears to be involved in different pathways, such as cardiovascular events and the immune response after AIS, it makes sTREM-2 an interesting biomarker to investigate .
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999996
PMC11277504_p15
PMC11277504
sec[0]/p[15]
1. Introduction
4.082031
biomedical
Study
[ 0.9990234375, 0.000652313232421875, 0.00020015239715576172 ]
[ 0.9990234375, 0.0003211498260498047, 0.0003464221954345703, 0.00009417533874511719 ]
As data regarding the assessment of soluble TREMs in patients with ischemic stroke are limited in the literature and controversial for sTREM-2, the aim of our study was to investigate the role of sTREM-2 and its interaction with sTREM-1 during the hyperacute post-ischemic phase, analyzing their plasma concentrations in relation to stroke severity and outcomes at three months post-acute event.
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
PMC11277504_p16
PMC11277504
sec[1]/p[0]
2. Results
2.509766
biomedical
Study
[ 0.99072265625, 0.0085296630859375, 0.0008554458618164062 ]
[ 0.9892578125, 0.00836944580078125, 0.0005030632019042969, 0.0018224716186523438 ]
A total of 38 patients with hyperacute stroke (within 4.5 h from the beginning of symptoms), 23 males and 15 females, were studied. Briefly, the average age of the participants was 72.9 years. The percentage of smokers was 23.7%.
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
PMC11277504_p17
PMC11277504
sec[1]/p[1]
2. Results
2.128906
biomedical
Study
[ 0.9814453125, 0.016754150390625, 0.00176239013671875 ]
[ 0.927734375, 0.0640869140625, 0.0023345947265625, 0.00605010986328125 ]
Additionally, 23.7% of the patients had a history of previous stroke or transient ischemic attack (TIA).
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
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en
0.999996
PMC11277504_p18
PMC11277504
sec[1]/p[2]
2. Results
2.744141
biomedical
Study
[ 0.9873046875, 0.01218414306640625, 0.0006780624389648438 ]
[ 0.9853515625, 0.01174163818359375, 0.0009341239929199219, 0.0019397735595703125 ]
A total of 63.2% of the patients had hypertension, 15.8% had diabetes, and 31.6% experienced prior episodes of atrial fibrillation. ( Table 1 ).
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
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en
0.999997
PMC11277504_p19
PMC11277504
sec[1]/p[3]
2. Results
3.822266
biomedical
Study
[ 0.99853515625, 0.0012445449829101562, 0.00021088123321533203 ]
[ 0.98046875, 0.01543426513671875, 0.0035533905029296875, 0.00040221214294433594 ]
Based on the Trial of Org 10,172 in the Acute Stroke Treatment (TOAST) classification, a higher percentage of people was affected by cardioembolic (50.0%), atherothrombotic (13.4%), lacunar (5.3%), and undetermined etiology (31.6%) stroke.
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
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en
0.999997
PMC11277504_p20
PMC11277504
sec[1]/p[4]
2. Results
2.742188
biomedical
Study
[ 0.9951171875, 0.0038394927978515625, 0.0010461807250976562 ]
[ 0.9658203125, 0.030792236328125, 0.0007314682006835938, 0.002765655517578125 ]
Both the hemispheres (right and left) were involved in equal parts (47.3%), with two exceptions of bilateral involvement (5.26%).
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
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en
0.999998
PMC11277504_p21
PMC11277504
sec[1]/p[5]
2. Results
2.285156
biomedical
Study
[ 0.9892578125, 0.00858306884765625, 0.0020008087158203125 ]
[ 0.93017578125, 0.06365966796875, 0.001529693603515625, 0.0045928955078125 ]
The vascular territory involved was anterior in the highest percentage of people (81.58%).
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
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en
0.999996
PMC11277504_p22
PMC11277504
sec[1]/p[6]
2. Results
3.166016
biomedical
Study
[ 0.99853515625, 0.001148223876953125, 0.0004968643188476562 ]
[ 0.99853515625, 0.0010786056518554688, 0.00042176246643066406, 0.00019538402557373047 ]
Categorizing the patients according to the TOAST classification, we did not show any difference between the groups ( Supplementary Table S1 ). Regarding the vascular territory, there was a slight significance between anterior and posterior territory with sTREM-1 but not sTREM-2 concentrations ( Supplementary Table S2 ). Regarding the hemispheres, we did not show any differences. ( Supplementary Table S3 ).
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
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en
0.999997
PMC11277504_p23
PMC11277504
sec[1]/p[7]
2. Results
2.152344
clinical
Study
[ 0.267822265625, 0.72802734375, 0.0043487548828125 ]
[ 0.5244140625, 0.234619140625, 0.00527191162109375, 0.2354736328125 ]
A total of twenty-three patients underwent therapy in the two hours after admission: fifteen received IV rtPA, four received only thrombectomy, and four received a combination of IV rtPA and thrombectomy. The other patients did not receive therapy.
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
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en
0.999998
PMC11277504_p24
PMC11277504
sec[1]/p[8]
2. Results
3.603516
biomedical
Study
[ 0.923828125, 0.07562255859375, 0.0007348060607910156 ]
[ 0.9462890625, 0.039794921875, 0.00144195556640625, 0.012451171875 ]
The NIHSS at the admission had a mean of 9.84; one week after the ischemic event, the mean was 6.07, and the mRS after three months was 2.85.
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
PMC11277504_p25
PMC11277504
sec[1]/p[9]
2. Results
2.240234
biomedical
Study
[ 0.77587890625, 0.2178955078125, 0.006359100341796875 ]
[ 0.84619140625, 0.11004638671875, 0.004734039306640625, 0.03924560546875 ]
Ten patients died within 3 months ( Table 1 ).
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
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en
0.999998
PMC11277504_p26
PMC11277504
sec[1]/p[10]
2. Results
2.960938
biomedical
Study
[ 0.998046875, 0.0014009475708007812, 0.0007200241088867188 ]
[ 0.99755859375, 0.0018301010131835938, 0.0003466606140136719, 0.0002161264419555664 ]
The concentration of sTREM-1 at T0 was not associated with the NIHSS scale at T0 , and it showed a significant positive association with the mRS scale at three months .
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
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en
0.999998
PMC11277504_p27
PMC11277504
sec[1]/p[11]
2. Results
2.777344
biomedical
Study
[ 0.9970703125, 0.0017871856689453125, 0.0011701583862304688 ]
[ 0.99609375, 0.0028438568115234375, 0.0005497932434082031, 0.0002739429473876953 ]
The sTREM-2 at T0 was positively associated with the NIHSS scale at T0 , as well as with the mRS scale at three months .
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
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en
0.999998
PMC11277504_p28
PMC11277504
sec[1]/p[12]
2. Results
2.048828
biomedical
Study
[ 0.98876953125, 0.001789093017578125, 0.0096435546875 ]
[ 0.97265625, 0.02459716796875, 0.0018310546875, 0.0007796287536621094 ]
Interestingly, the concentrations of sTREM-1 and sTREM-2 at T0 correlated with each other .
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
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en
0.999997
PMC11277504_p29
PMC11277504
sec[1]/p[13]
2. Results
4.019531
biomedical
Study
[ 0.99951171875, 0.0004222393035888672, 0.00023818016052246094 ]
[ 0.99951171875, 0.00036597251892089844, 0.0002033710479736328, 0.00007110834121704102 ]
A general linear model adjusted for the age, sex, and subject that received or did not receive therapy (confounding factors) was performed to determine whether the plasma concentration of sTREM-1 and sTREM-2 differed during follow-up (T0 and TW) in a subgroup of patients ( Table 2 ).
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
PMC11277504_p30
PMC11277504
sec[1]/p[14]
2. Results
2.734375
biomedical
Study
[ 0.9970703125, 0.0013484954833984375, 0.0016117095947265625 ]
[ 0.99755859375, 0.0017366409301757812, 0.0004887580871582031, 0.00019288063049316406 ]
While sTREM-1 concentrations did not appear to vary significantly, the concentrations of sTREM-2 significantly decreased across the two follow-up times ( Table 2 ).
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
PMC11277504_p31
PMC11277504
sec[1]/p[15]
2. Results
3.857422
biomedical
Study
[ 0.99951171875, 0.00037407875061035156, 0.0003063678741455078 ]
[ 0.99951171875, 0.0003082752227783203, 0.00028443336486816406, 0.00007408857345581055 ]
The associations between the plasmatic concentrations of sTREM-1 and sTREM-2 with the mRS scale adjusted for the presence of therapy showed a significant positive association for both sTREMs ( Table 3 ).
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
PMC11277504_p32
PMC11277504
sec[1]/p[16]
2. Results
3.921875
biomedical
Study
[ 0.99951171875, 0.00045371055603027344, 0.0002448558807373047 ]
[ 0.9990234375, 0.0006694793701171875, 0.0003292560577392578, 0.00009179115295410156 ]
Receiver operating characteristic curve (ROC) analysis was employed to evaluate the ability of the plasmatic concentrations at T0 of sTREM-1 and sTREM-2 to predict negative prognosis (death of the patients in three months) .
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
PMC11277504_p33
PMC11277504
sec[1]/p[17]
2. Results
4.0625
biomedical
Study
[ 0.99951171875, 0.00045013427734375, 0.0002601146697998047 ]
[ 0.9990234375, 0.0004620552062988281, 0.0003337860107421875, 0.00007790327072143555 ]
The total area under the curve (AUC) of the concentration of sTREM-1 at T0 in predicting a worse prognosis was 78% (95% CI: 0.61–0.93; sensitivity: 83%; specificity: 35%).
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999995
PMC11277504_p34
PMC11277504
sec[1]/p[18]
2. Results
4.042969
biomedical
Study
[ 0.99951171875, 0.00044846534729003906, 0.000263214111328125 ]
[ 0.9990234375, 0.0005106925964355469, 0.00031185150146484375, 0.00008195638656616211 ]
The AUC of the concentration of sTREM-2 at T0 in predicting a worse prognosis was 78% (95% CI: 0.60–0.94; sensitivity: 83%; specificity: 35%).
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999996
PMC11277504_p35
PMC11277504
sec[2]/p[0]
3. Discussion
3.894531
biomedical
Study
[ 0.9990234375, 0.00046539306640625, 0.00030875205993652344 ]
[ 0.99951171875, 0.00025653839111328125, 0.00020301342010498047, 0.00006985664367675781 ]
The main findings of this study were the association observed between the concentrations of sTREMs in the very early acute phase of AIS (within 4.5 h after arrival at the hospital) and the following decrease in the concentration of sTREM-2 during time, while the concentration of sTREM-1 remained similar.
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999999
PMC11277504_p36
PMC11277504
sec[2]/p[1]
3. Discussion
4.066406
biomedical
Study
[ 0.99951171875, 0.00036263465881347656, 0.00017845630645751953 ]
[ 0.99951171875, 0.000225067138671875, 0.00038433074951171875, 0.00007718801498413086 ]
Interestingly, the concentration of sTREM-2 on admission was correlated with both the NIHSS score at T0 and the mRS score at three months, while sTREM-1 only correlated with the mRS. Even after adjusting for the presence of therapy, the concentrations of both sTREMs on admission were associated with a worse prognostic outcome (mRS), and both sTREMs at admission were associated with mortality at three months by the means of ROC analyses.
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
PMC11277504_p37
PMC11277504
sec[2]/p[2]
3. Discussion
3.755859
biomedical
Study
[ 0.99951171875, 0.00029754638671875, 0.0003237724304199219 ]
[ 0.99853515625, 0.0009069442749023438, 0.0006051063537597656, 0.00011307001113891602 ]
These data are in line with our previous findings, showing that acute autonomic dysfunction was associated with a negative prognosis at three months. Similarly, the acute activation of intercellular and intersystemic pathways (e.g., specific subtypes of extracellular vesicles) has a poor prognostic value .
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999996
PMC11277504_p38
PMC11277504
sec[2]/p[3]
3. Discussion
3.765625
biomedical
Other
[ 0.9990234375, 0.0005002021789550781, 0.00025844573974609375 ]
[ 0.328369140625, 0.388427734375, 0.28076171875, 0.0024318695068359375 ]
Neuroinflammation following stroke plays a crucial role in pathological processes that lead to adverse outcomes . Even though the inflammatory cascade activates immediately after blood vessel occlusion, functional impairment develops days or weeks after the acute event .
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999995
PMC11277504_p39
PMC11277504
sec[2]/p[4]
3. Discussion
4.058594
biomedical
Study
[ 0.99951171875, 0.0004582405090332031, 0.00019669532775878906 ]
[ 0.6796875, 0.27001953125, 0.04833984375, 0.0019369125366210938 ]
This abnormal activation of neuroinflammation involves microglia activation, the infiltration of circulating leukocytes, the release of damage-associated molecular pattern molecules, and, finally, the production of pro-inflammatory cytokines and chemokines .
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999995
PMC11277504_p40
PMC11277504
sec[2]/p[5]
3. Discussion
4.191406
biomedical
Study
[ 0.99951171875, 0.00018775463104248047, 0.00015294551849365234 ]
[ 0.9990234375, 0.0003027915954589844, 0.0005040168762207031, 0.00007206201553344727 ]
Several studies have shown that TREM-1 has a significant role in the activation of post-ischemic pro-inflammatory pathways both intracellularly (phosphorylation of DAP12, activation of the transcription factor NF-κB) and extracellularly (interaction with ligands, e.g., DAMP) . In a mouse model in which ischemia was pharmacologically induced, it was observed that TREM-1 promotes the production of IL-1β, IL-18, IL-6, CXCL-2, MCP-1, and CXCL-1 in microglia .
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
PMC11277504_p41
PMC11277504
sec[2]/p[6]
3. Discussion
3.947266
biomedical
Study
[ 0.99951171875, 0.00015747547149658203, 0.00014066696166992188 ]
[ 0.96728515625, 0.004276275634765625, 0.0279388427734375, 0.000293731689453125 ]
Significant increase in serum TREM-1 levels after intracerebral hemorrhage (ICH) suggests its association with the inflammatory response, hemorrhage severity, and long-term functional prognosis. Consequently, sTREM-1 shows promising features as an inflammatory biomarker to assess ICH severity and predict early neurological function decline .
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999996
PMC11277504_p42
PMC11277504
sec[2]/p[7]
3. Discussion
4.042969
biomedical
Study
[ 0.99951171875, 0.00043129920959472656, 0.00016796588897705078 ]
[ 0.99951171875, 0.00028014183044433594, 0.0003211498260498047, 0.00009495019912719727 ]
The results that we obtained on sTREM-1 concentration confirm what has been reported in the literature, that sTREM-1 has a role in enhancing stroke ischemic inflammation . Indeed, in our patients, we found an association between sTREM-1 at T0 and the outcome three months after the acute event (mRS scale). This positive association with the prognosis at three months could be due to the fact that sTREM-1 rises in the acute phase, triggering such an elevated inflammatory state, with dose-dependent effects in the post-acute phase.
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
PMC11277504_p43
PMC11277504
sec[2]/p[8]
3. Discussion
3.625
biomedical
Study
[ 0.99951171875, 0.0001888275146484375, 0.0002703666687011719 ]
[ 0.9970703125, 0.0011682510375976562, 0.001750946044921875, 0.00013256072998046875 ]
Furthermore, a recent study observed a correlation between the plasma levels of sTREM-1 and an increased risk of stroke at one month and six months after the acute event .
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999996
PMC11277504_p44
PMC11277504
sec[2]/p[9]
3. Discussion
3.96875
biomedical
Study
[ 0.99951171875, 0.0004475116729736328, 0.0002219676971435547 ]
[ 0.99951171875, 0.000278472900390625, 0.00021314620971679688, 0.00007551908493041992 ]
In contrast, we observed that the levels of sTREM-1 showed no variation in a small subset of patients between the acute phase (T0) and one week after the acute event (TW), presuming that the inflammatory state due to the initial insult remains unchanged over time. Vice versa, in our patients, we did not observe any correlation between sTREM-1 and the NIHSS scale at T0. A possible explanation might be due to the relatively small sample size of our patient group. In addition, other factors (stress, anxiety, comorbidities) might have altered acutely the outcome/status of the patients during ischemic stroke .
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999996
PMC11277504_p45
PMC11277504
sec[2]/p[10]
3. Discussion
3.669922
biomedical
Study
[ 0.99951171875, 0.00016498565673828125, 0.0005464553833007812 ]
[ 0.9677734375, 0.006633758544921875, 0.0254364013671875, 0.0002892017364501953 ]
On the contrary, the role of sTREM-2 is not yet fully understood in AIS. The results of previous studies have not established whether this receptor has a pro-inflammatory role or an anti-inflammatory role. Numerous studies have focused on the role of TREM-2 as a microglial receptor, while few investigations have examined its soluble form in humans, likely due to the limited knowledge of the formation mechanisms and cellular implications of sTREM-2 .
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
PMC11277504_p46
PMC11277504
sec[2]/p[11]
3. Discussion
4.304688
biomedical
Study
[ 0.99951171875, 0.00023734569549560547, 0.00014734268188476562 ]
[ 0.99560546875, 0.0003230571746826172, 0.00389862060546875, 0.00012433528900146484 ]
The upregulation of TREM-2 in mice has been demonstrated to be neuroprotective, as evidenced by enhanced microglial polarization towards the M2 anti-inflammatory phenotype, while, by contrast, the reduction in TREM-2 levels in vivo exacerbated neuronal damage by increasing the release of pro-inflammatory cytokines . In another study, the role of TREM-2 in microglial phagocytosis was examined in a mouse model of stroke, highlighting worsened post-stroke neurological outcomes due to microglial hyperactivation . Hyperactivated microglia may lead to the release of various inflammation-related molecules and further compromise the blood–brain barrier function. This could allow inflammatory substances to pass into the brain, further amplifying the inflammatory response and contributing to neuronal damage .
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
PMC11277504_p47
PMC11277504
sec[2]/p[12]
3. Discussion
3.794922
biomedical
Study
[ 0.9990234375, 0.00038123130798339844, 0.00045013427734375 ]
[ 0.99951171875, 0.0003323554992675781, 0.000148773193359375, 0.00006014108657836914 ]
The novelty of our study is a significant decrease during the iperacute phase in the plasma concentration levels of sTREM-2 between the two time points (T0 and TW) in a small subgroup of patients after adjusting for age, sex, and presence of therapy, which are all confounding factors.
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
PMC11277504_p48
PMC11277504
sec[2]/p[13]
3. Discussion
3.673828
biomedical
Study
[ 0.99951171875, 0.0002715587615966797, 0.0003299713134765625 ]
[ 0.9306640625, 0.0633544921875, 0.005329132080078125, 0.0005450248718261719 ]
Since ischemic stroke is a time-dependent condition , the analysis of the concentration of biomarkers within 4.5 h of the ischemic event could help untangle the biological mechanisms in the early phase of the event and give insight regarding the future prognostic course.
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
PMC11277504_p49
PMC11277504
sec[2]/p[14]
3. Discussion
4.40625
biomedical
Study
[ 0.99951171875, 0.0003783702850341797, 0.0001373291015625 ]
[ 0.998046875, 0.0008172988891601562, 0.0009317398071289062, 0.00017714500427246094 ]
The reduction in sTREM-2 levels after one week may reflect the activation of the M1 microglial phenotype by sTREM-2. sTREM-2, which could enhance the recruitment of factors acting as compensatory mechanisms, triggered by an excess of pro-inflammatory cytokines released after the ischemic event during the acute phase. Subsequently, the activation of an appropriate inflammatory pathway (as evidenced by its activation at T0) could trigger the M2 microglial phenotype, which may secrete neurotrophic substances, remove necrotic or apoptotic neuronal debris, and attempt to try to resolve inflammation . However, this heightened inflammation in the acute phase may disrupt the surrounding cellular and molecular environment, compromising the abilities of cells, including microglia, to perform their role in cellular debris removal and tissue homeostasis maintenance, leading to an ineffective resolution of the inflammatory state.
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
PMC11277504_p50
PMC11277504
sec[2]/p[15]
3. Discussion
3.888672
biomedical
Study
[ 0.99951171875, 0.0002715587615966797, 0.00026726722717285156 ]
[ 0.9990234375, 0.0005383491516113281, 0.0003330707550048828, 0.00008213520050048828 ]
Furthermore, we observed a strong positive correlation between the concentration of both sTREM-1 and sTREM-2 during the acute phase of the ischemic event, suggesting the presence of some mutual interaction between TREM concentrations.
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
PMC11277504_p51
PMC11277504
sec[2]/p[16]
3. Discussion
3.611328
biomedical
Study
[ 0.998046875, 0.00033283233642578125, 0.0015125274658203125 ]
[ 0.7763671875, 0.2200927734375, 0.00269317626953125, 0.00081634521484375 ]
This mutual interaction seems to get lost after one week when the concentration of sTREM-2 decreases, while sTREM-1 remains the same, probably because prolonged TREM-1 signaling may activate negative feedback mechanisms that modulate TREM-2 .
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
PMC11277504_p52
PMC11277504
sec[2]/p[17]
3. Discussion
4.140625
biomedical
Study
[ 0.99951171875, 0.00033593177795410156, 0.0001615285873413086 ]
[ 0.9990234375, 0.0003192424774169922, 0.0003230571746826172, 0.00009042024612426758 ]
This trend could explain why, in our cohort, we observed a correlation between the plasma concentration of sTREM-2 at the acute phase and in both the NIHSS score at the same time and three months after the acute event (mRS scale), while sTREM-1 only correlated with the mRS scale. The association between sTREM-2 concentration and the NIHSS score at admission may confirm the existence of a compensatory process that counteracts inflammation during the hyperacute phase after AIS. sTREM-2 is no longer able to cope with the high inflammatory state that remains persistent over time, which can lead to the chronicization of the inflammatory state and, consequently, may be associated with a negative outcome after three months.
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
PMC11277504_p53
PMC11277504
sec[2]/p[18]
3. Discussion
3.515625
biomedical
Study
[ 0.9990234375, 0.0005879402160644531, 0.0005698204040527344 ]
[ 0.99755859375, 0.001922607421875, 0.00031495094299316406, 0.0001417398452758789 ]
These observations are further confirmed by the ROC curve in which the concentrations of both at T0, with mortality within 3 months, could predict an inauspicious prognosis.
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999999
PMC11277504_p54
PMC11277504
sec[2]/p[19]
3. Discussion
3.941406
biomedical
Study
[ 0.99951171875, 0.00012409687042236328, 0.00028014183044433594 ]
[ 0.998046875, 0.0008916854858398438, 0.0008330345153808594, 0.00006264448165893555 ]
In conclusion, we could hypothesize that the advantage of analyzing plasma concentrations of sTREM-1 and sTREM-2 lies in the fact that, being the soluble forms of receptors expressed on microglia cells, they could provide indications of what happens in the brain post-stroke. So, exploring these relationships, we sought to clarify the role of sTREMs as potential biomarkers that can provide useful indications regarding negative outcomes, even in the long term.
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
PMC11277504_p55
PMC11277504
sec[2]/p[20]
3. Discussion
4.019531
biomedical
Study
[ 0.99951171875, 0.0004019737243652344, 0.00022685527801513672 ]
[ 0.99951171875, 0.00026106834411621094, 0.00026154518127441406, 0.00007641315460205078 ]
Our study has some limitations. Firstly, the patient cohort is relatively small, and different types of stroke are present. In addition, the blood samples after one week were only collected for a small subgroup of patients. However, all patients were recruited within 4.5 h from the onset of the event, ensuring accurate and homogeneous assessment times and consistent stroke pathophysiological phases. Moreover, sTREM-1 and sTREM-2 have not yet been well characterized in the very early phase of AIS at soluble levels and represent a novelty in neuroinflammation studies. Finally, we have the opportunity to analyze severity not only in the hyperacute phase but also after three months, in which long-term outcomes are poorly characterized.
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999996
PMC11277504_p56
PMC11277504
sec[2]/p[21]
3. Discussion
3.789063
biomedical
Study
[ 0.99951171875, 0.0001537799835205078, 0.0002868175506591797 ]
[ 0.9111328125, 0.066650390625, 0.0215301513671875, 0.0004906654357910156 ]
In conclusion, future studies on the interaction between sTREM-1 and sTREM-2 in a larger patient cohort could define a potential promising pathway in the early diagnosis of stroke severity and a potential therapeutic target for long-term outcomes.
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999996
PMC11277504_p57
PMC11277504
sec[3]/sec[0]/p[0]
4.1. Study Design
2.8125
biomedical
Study
[ 0.984375, 0.0145111083984375, 0.0008907318115234375 ]
[ 0.9931640625, 0.005046844482421875, 0.0003390312194824219, 0.0013208389282226562 ]
For this study, patients admitted to the Emergency Department of Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico in Milan from September 2016 to March 2018 who were diagnosed by a Computed Tomography scan (as the primary diagnostic method of screening) with AIS were enrolled.
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
PMC11277504_p58
PMC11277504
sec[3]/sec[0]/p[1]
4.1. Study Design
1.991211
biomedical
Study
[ 0.94873046875, 0.0484619140625, 0.0028820037841796875 ]
[ 0.94580078125, 0.0408935546875, 0.003993988037109375, 0.00945281982421875 ]
Upon admission, demographic, anthropometric, clinical data, and biochemical analyses were also recorded.
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
PMC11277504_p59
PMC11277504
sec[3]/sec[0]/p[2]
4.1. Study Design
3.083984
biomedical
Study
[ 0.888671875, 0.10992431640625, 0.0014734268188476562 ]
[ 0.87646484375, 0.1156005859375, 0.0010080337524414062, 0.0071563720703125 ]
Inclusion criteria required patients to exhibit new neurological symptoms within 4.5 h, persisting for at least 30 min. Eligible participants were adults over 18 years old with stable spontaneous sinus rhythm on the ECG at presentation.
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999995
PMC11277504_p60
PMC11277504
sec[3]/sec[0]/p[3]
4.1. Study Design
3.078125
biomedical
Study
[ 0.9384765625, 0.060394287109375, 0.001056671142578125 ]
[ 0.90234375, 0.09033203125, 0.0017728805541992188, 0.005710601806640625 ]
Exclusion criteria comprised primary intracerebral hemorrhage, pre-existing neurological conditions, epilepsy at the onset of stroke symptoms, severe organ failure, active oncological conditions, mechanical ventilation, or refusal of consent.
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999996
PMC11277504_p61
PMC11277504
sec[3]/sec[0]/p[4]
4.1. Study Design
1.487305
biomedical
Other
[ 0.98779296875, 0.003704071044921875, 0.00873565673828125 ]
[ 0.09600830078125, 0.8984375, 0.0026912689208984375, 0.002750396728515625 ]
Informed consent was obtained from all participants, and this study adhered to the principles of the Declaration of Helsinki.
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999995
PMC11277504_p62
PMC11277504
sec[3]/sec[0]/p[5]
4.1. Study Design
2.470703
biomedical
Study
[ 0.966796875, 0.031951904296875, 0.00112152099609375 ]
[ 0.66552734375, 0.318115234375, 0.00817108154296875, 0.00787353515625 ]
All enrolled participants underwent diagnostic and therapeutic procedures in compliance with both the International and Internal Guidelines for the treatment of acute ischemic stroke, which have been in effect since 2016–2018 .
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
PMC11277504_p63
PMC11277504
sec[3]/sec[0]/p[6]
4.1. Study Design
4.003906
biomedical
Other
[ 0.63232421875, 0.365234375, 0.0026226043701171875 ]
[ 0.39306640625, 0.57470703125, 0.00498199462890625, 0.0273284912109375 ]
In adherence to the guidelines, intravenous thrombolytic therapy (r-tPA at 0.9 mg/kg; maximum total dose of 90 mg; 10% as IV bolus, and the remainder infused over 60 min) was planned for enrolled participants meeting specific criteria, excluding those with prior or current cerebral hemorrhage, bleeding disorders, and coagulopathy, prolonged activated partial thromboplastin time (aPTT), or those who had not received heparin in the previous 48 h . Mechanical thrombectomy was planned for AIS participants with large-vessel occlusion who received intravenous r-tPA at admission, if eligible, and had symptom onset within 6 h or cases of contraindications to IV r-tPA .
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999999
PMC11277504_p64
PMC11277504
sec[3]/sec[0]/p[7]
4.1. Study Design
0.917969
other
Other
[ 0.431884765625, 0.007061004638671875, 0.56103515625 ]
[ 0.005588531494140625, 0.9931640625, 0.0005273818969726562, 0.0006499290466308594 ]
The protocol received approval from the local Ethics Committee “Comitato Etico—Milano Area 2”, Milan, Italy .
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
PMC11277504_p65
PMC11277504
sec[3]/sec[1]/p[0]
4.2. Stroke Measurement
4.066406
biomedical
Study
[ 0.99609375, 0.003734588623046875, 0.00018966197967529297 ]
[ 0.99267578125, 0.0057373046875, 0.00086212158203125, 0.0005364418029785156 ]
Stroke severity was gauged using the National Institutes of Health Stroke Scale (NIHSS), a comprehensive assessment tool consisting of 11 neurological items, with scores ranging from 0 to 42 (lower scores indicating less severe neurological impairment). The NIHSS evaluations were conducted at admission (T0) and one week later (Tw) , with an NIHSS score of ≥14 signifying severe conditions .
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
PMC11277504_p66
PMC11277504
sec[3]/sec[1]/p[1]
4.2. Stroke Measurement
3.589844
biomedical
Study
[ 0.935546875, 0.0634765625, 0.001049041748046875 ]
[ 0.96630859375, 0.029876708984375, 0.0015134811401367188, 0.0025196075439453125 ]
For mid-term outcome assessment and evaluation of residual functional disability, participants underwent a follow-up after 3 months, employing the Modified Rankin Scale (mRS), which ranges from 0 (no symptoms) to 6 (death) .
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999994
PMC11277504_p67
PMC11277504
sec[3]/sec[2]/p[0]
4.3. Plasma Samples Analysis
3.941406
biomedical
Study
[ 0.9970703125, 0.0027256011962890625, 0.00025534629821777344 ]
[ 0.99853515625, 0.0011415481567382812, 0.0002665519714355469, 0.0002582073211669922 ]
All patients underwent venous sampling for the evaluation of the plasmatic concentrations of triggering receptors expressed on myeloid cells 1 (sTREM-1) and triggering receptors expressed on myeloid cells 2 (sTREM-2). Fasting blood samples were collected in ethylenediaminetetraacetic acid (EDTA) tubes (7 mL), at admission within 4.5 h from the arrival at the hospital (T0) and after one week (Tw).
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
PMC11277504_p68
PMC11277504
sec[3]/sec[2]/p[1]
4.3. Plasma Samples Analysis
3.783203
biomedical
Study
[ 0.99951171875, 0.0004286766052246094, 0.00029587745666503906 ]
[ 0.98583984375, 0.0130462646484375, 0.0007281303405761719, 0.0003287792205810547 ]
The blood samples were centrifuged at 1200× g for 15 min at room temperature to obtain platelet-free plasma. The resulting plasma was rapidly frozen and stored at −20 °C.
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999996
PMC11277504_p69
PMC11277504
sec[3]/sec[2]/p[2]
4.3. Plasma Samples Analysis
2.980469
biomedical
Study
[ 0.998046875, 0.0003349781036376953, 0.0014429092407226562 ]
[ 0.88525390625, 0.11322021484375, 0.0008726119995117188, 0.0006771087646484375 ]
To quantify sTREM-1 and sTREM-2, the Human Simple Plex assays (ProteinSimple, Bio-Techne, Minneapolis, MN, USA) on an Ella device (Ella System, Bio-Techne, Minneapolis, MN, USA) were utilized.
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999994
PMC11277504_p70
PMC11277504
sec[3]/sec[2]/p[3]
4.3. Plasma Samples Analysis
3.990234
biomedical
Study
[ 0.99951171875, 0.00024771690368652344, 0.0002677440643310547 ]
[ 0.9853515625, 0.01369476318359375, 0.0005526542663574219, 0.0002110004425048828 ]
Briefly, instrument calibration was carried out using the in-cartridge factory standard curve, and plasma samples were measured with dilution in a sample diluent as per the manufacturer’s instructions (ProteinSimple, CA, USA). Each sample was allocated to a single well, as the Simple Plex microfluidic platform automatically performs triplicate assays .
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
PMC11277504_p71
PMC11277504
sec[3]/sec[3]/p[0]
4.4. Statistical Analysis
1.551758
biomedical
Other
[ 0.9794921875, 0.001247406005859375, 0.0193634033203125 ]
[ 0.38916015625, 0.607421875, 0.002277374267578125, 0.00138092041015625 ]
The statistical analyses were carried out using IBM SPSS Statistics software (version 29, IBM Inc., Chicago, IL, USA).
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999994
PMC11277504_p72
PMC11277504
sec[3]/sec[3]/p[1]
4.4. Statistical Analysis
3.533203
biomedical
Study
[ 0.9990234375, 0.00044155120849609375, 0.0002987384796142578 ]
[ 0.9921875, 0.0069122314453125, 0.0006442070007324219, 0.00017952919006347656 ]
The distribution of the demographic and clinical parameters was evaluated by a Kolmogorov–Smirnov test to assess possible deviations from the Gaussian model. Continuous data were expressed as the mean standard deviation (SD). Categorical data were presented as frequencies and percentages.
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
PMC11277504_p73
PMC11277504
sec[3]/sec[3]/p[2]
4.4. Statistical Analysis
3.886719
biomedical
Study
[ 0.99951171875, 0.0002434253692626953, 0.00022780895233154297 ]
[ 0.9990234375, 0.0004703998565673828, 0.00027298927307128906, 0.00006538629531860352 ]
Linear general models were performed to compare the level of plasmatic concentration of sTREMs in the three time points and between the time points, adjusting by age, sex, and therapy.
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999995
PMC11277504_p74
PMC11277504
sec[3]/sec[3]/p[3]
4.4. Statistical Analysis
3.964844
biomedical
Study
[ 0.99951171875, 0.0003180503845214844, 0.0001685619354248047 ]
[ 0.9990234375, 0.00036025047302246094, 0.00033855438232421875, 0.00007134675979614258 ]
Pearson’s correlations were performed for the parametric variable to explore the association between sTREM-1 and sTREM-2 concentrations (dependent variable) and the association with the severity of stroke by the NIHSS scale and the mRS scale.
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
PMC11277504_p75
PMC11277504
sec[3]/sec[3]/p[4]
4.4. Statistical Analysis
3.800781
biomedical
Study
[ 0.9990234375, 0.0004107952117919922, 0.0003230571746826172 ]
[ 0.9990234375, 0.0007500648498535156, 0.0002810955047607422, 0.00009071826934814453 ]
Linear regression was performed to investigate the association of sTREM-1 and sTREM-2 with the mRS scale adjusted for the presence or absence of therapy.
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
PMC11277504_p76
PMC11277504
sec[3]/sec[3]/p[5]
4.4. Statistical Analysis
3.910156
biomedical
Study
[ 0.99951171875, 0.0003719329833984375, 0.00023448467254638672 ]
[ 0.9990234375, 0.000484466552734375, 0.00019943714141845703, 0.00007659196853637695 ]
Data of the plasmatic concentration of sTREM-1 and sTREM-2 were used in receiver operating characteristic (ROC) analysis to draw the ROC curve and to calculate the area under the curve (AUC) to observe the association of the level of sTREM-1 and sTREM-2 with the death of the patient.
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999996
PMC11277504_p77
PMC11277504
sec[3]/sec[3]/p[6]
4.4. Statistical Analysis
2.289063
biomedical
Study
[ 0.9873046875, 0.002044677734375, 0.01080322265625 ]
[ 0.66162109375, 0.324951171875, 0.011474609375, 0.0018329620361328125 ]
Statistical significance was set at p < 0.05.
[ "Greta Salafia", "Angelica Carandina", "Roberto Maria Sacco", "Evelyn Ferri", "Nicola Montano", "Beatrice Arosio", "Eleonora Tobaldini" ]
https://doi.org/10.3390/ijms25147611
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
PMC11277516_p0
PMC11277516
sec[0]/p[0]
1. Introduction
4.28125
biomedical
Review
[ 0.9970703125, 0.001399993896484375, 0.0012950897216796875 ]
[ 0.042388916015625, 0.0036678314208984375, 0.95361328125, 0.0005316734313964844 ]
Obesity, the condition of excessive fat accumulation, occurs when energy intake is greater than energy expenditure, resulting in an energy surplus stored in white adipose tissue (WAT). This imbalance in energy homeostasis leads to various metabolic disorders, including type 2 diabetes mellitus (T2DM). On the other hand, brown adipose tissue (BAT), characterized by brown multilocular adipocytes, stimulates thermogenesis, increasing energy expenditure to combat excessive fat accumulation in WAT, thereby emerging as a promising target for treating obesity and metabolic disorders . Obesity is a significant risk factor for the development and progression of T2DM . The prevalence of T2DM is further amplified by unhealthy dietary patterns, obesity, and physical inactivity . As global health challenges, both obesity and T2DM are influenced by various environmental factors, including climate change and rising air pollution levels.
[ "Radoslav Stojchevski", "Preethi Chandrasekaran", "Nikola Hadzi-Petrushev", "Mitko Mladenov", "Dimiter Avtanski" ]
https://doi.org/10.3390/ijms25147849
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999996
PMC11277516_p1
PMC11277516
sec[0]/p[1]
1. Introduction
4.144531
biomedical
Study
[ 0.99951171875, 0.0002410411834716797, 0.0002818107604980469 ]
[ 0.87744140625, 0.001323699951171875, 0.12109375, 0.0002994537353515625 ]
The current literature supports the hypothesis that some environmental pollutants, such as dichlorodiphenyltrichloroethane (DDT) and its metabolite dichlordiphenylethylene (DDE), are associated with increased obesity by impairing the mass and function of BAT. DDE and DDT are persistent organic pollutants that were widely used as pesticides in the past and continue to be present in the environment due to their slow degradation . Air pollutants, particularly fine particulate matter (PM2.5), induce insulin resistance (IR) due to BAT mitochondrial dysfunction . BAT is stimulated by cold exposure and insulin and is inversely correlated with body mass index (BMI). In addition, alterations in thermogenic gene expression are key features of obesity and IR .
[ "Radoslav Stojchevski", "Preethi Chandrasekaran", "Nikola Hadzi-Petrushev", "Mitko Mladenov", "Dimiter Avtanski" ]
https://doi.org/10.3390/ijms25147849
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999996
PMC11277516_p2
PMC11277516
sec[0]/p[2]
1. Introduction
3.839844
biomedical
Review
[ 0.99951171875, 0.00029349327087402344, 0.0003204345703125 ]
[ 0.3134765625, 0.153076171875, 0.5322265625, 0.0013866424560546875 ]
The link between increasing adiposity and rising temperatures leads to reduced adaptive thermogenesis, decreased physical activity, and increased carbon footprint production. Additionally, the impact of climate change makes obese individuals more prone to developing T2DM. Impaired responses to heat stress, compromised vasodilation, and sweating due to the effects of climate change increase the risk of diabetes-related comorbidities.
[ "Radoslav Stojchevski", "Preethi Chandrasekaran", "Nikola Hadzi-Petrushev", "Mitko Mladenov", "Dimiter Avtanski" ]
https://doi.org/10.3390/ijms25147849
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999996
PMC11277516_p3
PMC11277516
sec[0]/p[3]
1. Introduction
4
biomedical
Review
[ 0.98291015625, 0.010040283203125, 0.00710296630859375 ]
[ 0.0021381378173828125, 0.0023822784423828125, 0.99462890625, 0.0007276535034179688 ]
This review aims to provide a comprehensive analysis of the effects of climate change, air pollution, and environmental factors on adipose tissue function and metabolic health. We also explore how rising temperatures and environmental pollutants affect WAT and BAT, contributing to obesity and T2DM. Additionally, we discuss potential adaptation and mitigation strategies with which to address the adverse effects of these global challenges.
[ "Radoslav Stojchevski", "Preethi Chandrasekaran", "Nikola Hadzi-Petrushev", "Mitko Mladenov", "Dimiter Avtanski" ]
https://doi.org/10.3390/ijms25147849
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
PMC11277516_p4
PMC11277516
sec[1]/p[0]
2. Adipose Tissue and Metabolic Health
4.738281
biomedical
Study
[ 0.99853515625, 0.0009765625, 0.0005207061767578125 ]
[ 0.556640625, 0.004215240478515625, 0.437744140625, 0.0015392303466796875 ]
Adipose tissue functions as a metabolic sink, playing a versatile role in regulating lipid metabolism and glucose homeostasis. Metabolic diseases, such as IR, inflammation, lipid overload, and endoplasmic reticulum (ER) stress, are closely linked to adipose tissue dysfunction. Dysfunctional adipose tissue leads to differences in adipocyte characteristics and the distribution of fat deposits in obese individuals . Under surplus energy conditions, adipocytes synthesize triglycerides (TGs) from the free fatty acids (FFAs) released into circulation, in addition to utilizing the fatty acids converted from acetyl CoA within the cells by de novo lipogenesis . Additionally, the size of the adipocytes increases (hypertrophy), and additional adipocytes are recruited from the pre-adipocytes (hyperplasia). During these processes, the extensive tissue remodeling and activation of inflammation that occurs subsequently lead to obesity, IR, and metabolic dysfunction . In line with this, adverse metabolic consequences, such as the accumulation of visceral fat in ectopic sites, dyslipidemia, and lipodystrophy, are evident .
[ "Radoslav Stojchevski", "Preethi Chandrasekaran", "Nikola Hadzi-Petrushev", "Mitko Mladenov", "Dimiter Avtanski" ]
https://doi.org/10.3390/ijms25147849
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998