Chronic neuroinflammation is an integral pathological feature of major neurodegenerative diseases. The recruitment of microglia to affected brain regions and the activation of these cells are the major events leading to disease-associated neuroinflammation. In a previous study, we showed that neuron-released alpha-synuclein can activate microglia through activating the Toll-like receptor 2 (TLR2) pathway, resulting in proinflammatory responses. However, it is not clear whether other signaling pathways are involved in the migration and activation of microglia in response to neuron-released alpha-synuclein. In the current study, we demonstrated that TLR2 activation is not sufficient for all of the changes manifested by microglia in response to neuron-released alpha-synuclein. Specifically, the migration of and morphological changes in microglia, triggered by neuron-released alpha-synuclein, did not require the activation of TLR2, whereas increased proliferation and production of cytokines were strictly under the control of TLR2. Construction of a hypothetical signaling network using computational tools and experimental validation with various peptide inhibitors showed that beta1-integrin was necessary for both the morphological changes and the migration. However, neither proliferation nor cytokine production by microglia was dependent on the activation of beta1-integrin. These results suggest that beta1-integrin signaling is specifically responsible for the recruitment of microglia to the disease-affected brain regions, where neurons most likely release relatively high levels of alpha-synuclein.
Animals ; Antigens, CD29/genetics/*metabolism ; Cell Line, Tumor ; *Cell Movement ; Cells, Cultured ; Culture Media, Conditioned/*pharmacology ; Gene Regulatory Networks ; Humans ; Mice ; Mice, Inbred C57BL ; Microglia/drug effects/metabolism/*physiology ; Neurons/*metabolism ; Rats ; Rats, Sprague-Dawley ; Signal Transduction ; Toll-Like Receptor 2/metabolism ; alpha-Synuclein/*pharmacology

Suicidal cases involving sodium nitrite have been reported worldwide. However, postmortem features, such as brownish or grayish livor mortis, remain difficult to interpret, especially as decomposition advances. Here, we present three fatal cases (2020-2023) presumably caused by sodium nitrite ingestion. In these cases, characteristic nitrite-induced changes were inconsistent or obscured by decomposition, but ingestion traces (cup or bottle near the decedents) were observed at each scene. Additionally, containers labeled “sodium nitrite” were found in two cases; however, since sodium nitrite is designated a suicide-hazardous material in South Korea, future scenes may rarely reveal such clear labeling. Although autopsy, including methemoglobin testing, can confirm the cause of death, any delay in the investigative process risks the loss of critical evidence about the ingestion process and other factors. This underscores the importance of focusing on early scene evidence, particularly ingestion traces, and conducting thorough chemical and forensic examinations. Our findings illustrate that timely detection of ingestion-related evidence and subsequent forensic analysis, in conjunction with autopsy results, can elucidate a decedent’s cause and manner of death and clarify any criminal implications.

Suicidal cases involving sodium nitrite have been reported worldwide. However, postmortem features, such as brownish or grayish livor mortis, remain difficult to interpret, especially as decomposition advances. Here, we present three fatal cases (2020-2023) presumably caused by sodium nitrite ingestion. In these cases, characteristic nitrite-induced changes were inconsistent or obscured by decomposition, but ingestion traces (cup or bottle near the decedents) were observed at each scene. Additionally, containers labeled “sodium nitrite” were found in two cases; however, since sodium nitrite is designated a suicide-hazardous material in South Korea, future scenes may rarely reveal such clear labeling. Although autopsy, including methemoglobin testing, can confirm the cause of death, any delay in the investigative process risks the loss of critical evidence about the ingestion process and other factors. This underscores the importance of focusing on early scene evidence, particularly ingestion traces, and conducting thorough chemical and forensic examinations. Our findings illustrate that timely detection of ingestion-related evidence and subsequent forensic analysis, in conjunction with autopsy results, can elucidate a decedent’s cause and manner of death and clarify any criminal implications.

Suicidal cases involving sodium nitrite have been reported worldwide. However, postmortem features, such as brownish or grayish livor mortis, remain difficult to interpret, especially as decomposition advances. Here, we present three fatal cases (2020-2023) presumably caused by sodium nitrite ingestion. In these cases, characteristic nitrite-induced changes were inconsistent or obscured by decomposition, but ingestion traces (cup or bottle near the decedents) were observed at each scene. Additionally, containers labeled “sodium nitrite” were found in two cases; however, since sodium nitrite is designated a suicide-hazardous material in South Korea, future scenes may rarely reveal such clear labeling. Although autopsy, including methemoglobin testing, can confirm the cause of death, any delay in the investigative process risks the loss of critical evidence about the ingestion process and other factors. This underscores the importance of focusing on early scene evidence, particularly ingestion traces, and conducting thorough chemical and forensic examinations. Our findings illustrate that timely detection of ingestion-related evidence and subsequent forensic analysis, in conjunction with autopsy results, can elucidate a decedent’s cause and manner of death and clarify any criminal implications.

Suicidal cases involving sodium nitrite have been reported worldwide. However, postmortem features, such as brownish or grayish livor mortis, remain difficult to interpret, especially as decomposition advances. Here, we present three fatal cases (2020-2023) presumably caused by sodium nitrite ingestion. In these cases, characteristic nitrite-induced changes were inconsistent or obscured by decomposition, but ingestion traces (cup or bottle near the decedents) were observed at each scene. Additionally, containers labeled “sodium nitrite” were found in two cases; however, since sodium nitrite is designated a suicide-hazardous material in South Korea, future scenes may rarely reveal such clear labeling. Although autopsy, including methemoglobin testing, can confirm the cause of death, any delay in the investigative process risks the loss of critical evidence about the ingestion process and other factors. This underscores the importance of focusing on early scene evidence, particularly ingestion traces, and conducting thorough chemical and forensic examinations. Our findings illustrate that timely detection of ingestion-related evidence and subsequent forensic analysis, in conjunction with autopsy results, can elucidate a decedent’s cause and manner of death and clarify any criminal implications.

Fibroblast-like synoviocytes (FLSs) constitute a major cell subset of rheumatoid arthritis (RA) synovia. Dysregulation of microRNAs (miRNAs) has been implicated in activation and proliferation of RA-FLSs. However, the functional association of various miRNAs with their targets that are characteristic of the RA-FLS phenotype has not been globally elucidated. In this study, we performed microarray analyses of miRNAs and mRNAs in RA-FLSs and osteoarthritis FLSs (OA-FLSs), simultaneously, to validate how dysregulated miRNAs may be associated with the RA-FLS phenotype. Global miRNA profiling revealed that miR-143 and miR-145 were differentially upregulated in RA-FLSs compared to OA-FLSs. miR-143 and miR-145 were highly expressed in independent RA-FLSs. The miRNA-target prediction and network model of the predicted targets identified insulin-like growth factor binding protein 5 (IGFBP5) and semaphorin 3A (SEMA3A) as potential target genes downregulated by miR-143 and miR-145, respectively. IGFBP5 level was inversely correlated with miR-143 expression, and its deficiency rendered RA-FLSs more sensitive to TNFα stimulation, promoting IL-6 production and NF-κB activity. Moreover, SEMA3A was a direct target of miR-145, as determined by a luciferase reporter assay, antagonizing VEGF165-induced increases in the survival, migration and invasion of RA-FLSs. Taken together, our data suggest that enhanced expression of miR-143 and miR-145 renders RA-FLSs susceptible to TNFα and VEGF165 stimuli by downregulating IGFBP5 and SEMA3A, respectively, and that these miRNAs could be therapeutic targets.
Arthritis, Rheumatoid* ; Fibroblasts* ; Insulin-Like Growth Factor Binding Protein 5 ; Interleukin-6 ; Luciferases ; MicroRNAs ; Osteoarthritis ; Phenotype* ; RNA, Messenger ; Semaphorin-3A ; Synovial Fluid