Amyloid-β Processing in Aged S100B Transgenic Mice Is Sex Dependent

(1) Background: Calcium-binding protein S100B is involved in neuroregeneration but has also been associated with neurodegeneration. These contrasting effects may result from concentration or duration of exposure. We investigated the effect of long-term increased S100B levels on amyloid-β processing in one-year-old transgenic (tg) mice with 12 copies of the murine S100B gene with specific consideration of sex and specific brain regions. (2) Methods: S100B and amyloid-β 42 (Aβ42) were quantified in serum, cerebrospinal fluid (CSF), adipose tissue, and different brain regions by ELISA in wild-type (wt) and S100Btg mice (each n = 7 per group). Thioflavin T (ThT) and Aβ immunostaining were performed for visualization of Aβ deposition. (3) Results: S100B in serum, CSF, and brain was significantly increased in S100Btg mice of both sexes. Aβ42 was significantly increased in the hippocampus of male S100Btg mice (p = 0.0075), and the frontal cortex of female S100Btg mice (p = 0.0262). ThT and Aβ immunostaining demonstrated Aβ deposition in different brain regions in S100Btg mice of both sexes and female wt. (4) Conclusion: Our data validate this experimental model for studying the role of S100B in neurodegeneration and indicate that Aβ processing is sex-dependent and brain region-specific, which deserves further investigation of signaling pathways and behavioral responses.

Persephin as a diagnostic marker of acute brain injury in critically ill newborns: a clinical trial

Aim. To study the correlation of serum persephin with clinical, instrumental and biochemical indicators of brain damage and with an adverse outcome in critically ill newborns.Materials and Methods. The study included 44 critically ill newborns. Blood samples were collected on the 1st and 7th day of life. Brain injury was assessed by recording Apgar score, depression of consciousness and brainstem reflexes in unsedated patients over 7 days of life, convulsions, neurosonographic signs of cerebral edema, serum protein S100B on the 1st and 7th day of life, and using indicators of adverse neurological outcome. The correlation of serum persephin on the 1st and 7th day of life with signs of brain damage was evaluated using the Spearman's rank correlation coefficient and Mann-Whitney U-test.Results. No statistically significant correlation was found between the concentrations of serum persephin on the 1st and 7th day of life and Apgar score (p = 0.721 and 0.222, respectively), depression of consciousness and stem reflexes (p < 0.05), convulsions (p = 0.673 and 0.432, respectively), cerebral edema (p = 0.737 and 0.558, respectively), and serum protein S100B both on the 1st day (p = 0.095 and 0.475, respectively) and 7th day of life (p = 0.988 and p = 0.775, respectively). Further, there was no statistically significant association of the serum persephin on the 1st day of line with an unfavorable outcome (p = 0.294). Yet, we revealed an association of serum persephin on the 7th day of life with an unfavorable outcome (p = 0.013), with a cut-off point of 828 ng/mL, a sensitivity of 39%, and a specificity of 100%.Conclusion. Persephin has poor diagnostic and prognostic significance for assessing the severity of brain damage in critically ill newborns. The obtained data on the correlation of the concentration of persephin for 7 days with an unfavorable outcome are doubtful due to the lack of data on its correlation with signs of severe brain damage.

Assessment of the diagnostic significance of modern biomarkers and hemodynamic alterations in workers of vibration-hazardous occupations

Introduction. One of the most significant tasks in modern labor medicine is to reduce the indicators of early disability in persons in contact with harmful and dangerous factors of the production environment. The issue of finding markers of early preclinical manifestations of vibrational disease and establishing comorbid conditions that are prognostically unfavorable for the course of the underlying occupational disease remains relevant. The purpose of the study is assessment of diagnostic significance of current neurospecific biomarkers and hemodynamic changes in workers of the profession related to vibration. Material and methods. The results of two studies were the basis for this work. The first, aimed at determining the concentration of neurospecific markers in the blood of miners, includes 154 working vibration hazardous professions. At the same time, groups were identified depending on the type of exposure to vibration: total (69 workers), local (24 workers) and combined general and local (61 miners) and control group of workers not in contact with vibration (49 people). The second study was performed to assess the change in hemodynamic parameters among 216 industrial workers, of which 114 people were in contact with vibration generating equipment, and 102 workers were included in the control group. Results. Data from the first study showed an increase in the titer of neuron-specific indicators, mainly protein S100B, depending on the type of exposure vibration and its seniority dose. The second study results indicated an increase in systolic blood pressure and total peripheral vascular resistance in miners under exposure to vibration factor. Conclusion. The results of both studies suggest that hemodynamic disorders and changes in the performance of neuro specific proteins may be interconnected. It seems advisable to continue the study in workers in vibrant occupations with comorbid pathology.

The calcium-binding protein S100B reduces IL6 production in malignant melanoma via inhibition of RSK cellular signaling

S100B is frequently elevated in malignant melanoma. A regulatory mechanism was uncovered here in which elevated S100B lowers mRNA and secreted protein levels of interleukin-6 (IL6) and inhibits an autocrine loop whereby IL6 activates STAT3 signaling. Our results showed that S100B affects IL6 expression transcriptionally. S100B was shown to form a calcium-dependent protein complex with the p90 ribosomal S6 kinase (RSK), which in turn sequesters RSK into the cytoplasm. Consistently, S100B inhibition was found to restore phosphorylation of a nuclear located RSK substrate, CREB, which is a potent transcription factor for IL6 expression. Thus, elevated S100B reduces IL6-STAT3 signaling via RSK signaling pathway in malignant melanoma. Indeed, the elevated S100B levels in malignant melanoma cell lines correspond to low levels of IL6 and p-STAT3.

Time-Dependent Internalization of S100B by Mesenchymal Stem Cells via the Pathways of Clathrin- and Lipid Raft-Mediated Endocytosis

Mesenchymal stem cells (MSCs) are promising tools for cancer therapy, but there is a risk of malignant transformation in their clinical application. Our previous work revealed that the paracrine protein S100B in the glioma microenvironment induces malignant transformation of MSCs and upregulates intracellular S100B, which could affect cell homeostasis by interfering with p53. The purpose of this study was to investigate whether extracellular S100B can be internalized by MSCs and the specific endocytic pathway involved in S100B internalization. By using real-time confocal microscopy and structured illumination microscopy (SIM), we visualized the uptake of fluorescently labeled S100B protein (S100B-Alexa488) and monitored the intracellular trafficking of internalized vesicles. The results showed that S100B-Alexa488 was efficiently internalized into MSCs in a time-dependent manner and transported through endolysosomal pathways. After that, we used chemical inhibitors and RNA interference approaches to investigate possible mechanisms involved in S100B-Alexa488 uptake. The internalization of S100B-Alexa488 was inhibited by pitstop-2 or dyngo-4a treatment or RNA-mediated silencing of clathrin or dynamin, and the lipid raft-mediated endocytosis inhibitors nystatin and MβCD. In conclusion, our findings show that clathrin and lipid rafts contribute to the internalization of S100B-Alexa488, which provides promising interventions for the safe application of MSCs in glioma therapy.

Circulating neurotrophins and hemostatic risk factors of atherothrombotic cardiovascular disease at baseline and during sympathetic challenge: the SABPA study

Sympathetic activation may trigger acute coronary syndromes. We examined the relation between circulating neurotrophic factors and hemostatic risk factors of atherothrombotic cardiovascular disease at baseline and in response to acute mental stress to establish a brain–heart link. In 409 black and white South Africans, brain-derived neurotrophic factor (BDNF) and fibrinolytic measures were assessed at baseline. Glial cell-derived neurotrophic factor (GDNF), S100 calcium-binding protein (S100B), von Willebrand factor (VWF), fibrinogen and D-dimer were assessed at baseline and 10 min after the Stroop test. Neurotrophins were regressed on hemostatic measures adjusting for demographics, comorbidities, cardiometabolic factors and health behaviors. Higher baseline BDNF was associated with greater stress-induced increase in fibrinogen (p = 0.003) and lower D-dimer increase (p = 0.016). Higher baseline S100B was significantly associated with higher baseline VWF (p = 0.031) and lower fibrinogen increase (p = 0.048). Lower baseline GDNF was associated with higher baseline VWF (p = 0.035) but lower VWF increase (p = 0.001). Greater GDNF (p = 0.006) and S100B (p = 0.042) increases were associated with lower VWF increase. All associations showed small-to-moderate effect sizes. Neurotrophins and fibrinolytic factors showed no significant associations. The findings support the existence of a peripheral neurothrophin-hemostasis interaction of small-to-moderate clinical relevance. The implications for atherothrombotic cardiovascular disease need further exploration.