* Calcium binding peptide - Astrocyte neurotrophic (inflammatory) cytokine
** S100B - calcium binding peptide - neurobiochemical marker of brain damage
Neuroscience. 2019 Mar 10;406:167-175. doi: 10.1016/j.neuroscience.2019.03.004. [Epub ahead of print]
The Effects of Astrocyte and Oligodendrocyte Lineage Cell Interaction on White Matter Injury under Chronic Cerebral Hypoperfusion.
Oligodendrocytes (OLGs) differentiate from oligodendrocyte-precursor-cells (OPCs) for myelination in white matter. This differentiation is maintained by cell-cell interactions through trophic factors such as brain-derived-neurotrophic-factor (BDNF). However, differentiation is impaired when white matter injury occurs in a chronic cerebral hypoperfusion model. Thus, we examined the effects of the interaction between astrocyte and oligodendrocyte lineage cells on myelination regarding the mechanism of impairment. A microcoil was applied to the bilateral common carotid arteries in male C57BL/6 mice as an in vivo cerebral chronic hypoperfusion model (BCAS model). A nonlethal concentration of CoCl2 was added to the primary cell culture from the postnatal rat cortex and incubated in vitro. White matter injury progressed in the BCAS model as myelin decreased. The numbers of OPCs and astrocytes increased after the operation, whereas that of OLGs decreased at day 28. BDNF continuously decreased until day 28. Differentiation was disrupted under the stressed conditions in the cell culture, but improved after administration of astrocyte-conditioned medium containing BDNF. Astrocytes with BDNF underwent differentiation, but differentiation was impaired under the stressed conditions due to the reduction of BDNF. We examined S100B regarding the mechanism of impairment. S100B is mainly expressed by mature astrocytes, and has neuroprotective and neurotoxic effects inside and outside of cells. GFAP-positive astrocytes increased in the corpus callosum in the BCAS model, whereas the number of mature astrocytes continued to decrease, resulting in reduced BDNF. The reduction in mature astrocytes due to the discharge of S100B in ischemic conditions caused the reduction in BDNF.
** The reduction in mature astrocytes due to the discharge of S100B in ischemic conditions caused the reduction in BDNF.
Neurol India. 2019 Jan-Feb;67(1):163-168. doi: 10.4103/0028-3886.253616.
Neuroprotective role of dexmedetomidine in epilepsy surgery: A preliminary study.
Long standing temporal lobe epilepsy (TLE) causes cerebral insult and results in elevated brain injury biomarkers, S100b and neuron specific enolase (NSE). Surgery for TLE, has the potential to cause additional cerebral insult. Dexmedetomidine is postulated to have neuroprotective effects. The aim of this study was to assess the effect of intraoperative dexmedetomidine on S100b and NSE during TLE surgery.
MATERIALS AND METHODS:
19 consenting adult patients with TLE undergoing anteromedial temporal lobectomy were enrolled and divided into two groups. Patients in Group D (n = 9) received dexmedetomidine whereas patients in Group C (n = 10) received saline as placebo in addition to the standard anaesthesia technique. Blood samples of these patients were drawn, before induction of anaesthesia, at the end of surgery, as well at 24 hours and 48 hours postoperatively, and analysed for serum S100b and NSE.
The demographic and clinical profile was comparable in both the groups. The baseline S100b in group C and group D was 66.7 ± 26.5 pg/ml and 34.3 ± 21.7 pg/ml (P = 0.013) respectively. After adjustment for the baseline, the overall value of S100b was 71.0 ± 39.8 pg/ml and 40.5 ± 22.5 pg/ml (P = 0.002) in the control and study group, respectively. The values of S100b (79.3 ± 53.6 pg/ml) [P = 0.017] were highest at 24 hours postoperatively. The mean value of NSE in the control and study group was 32.8 ± 43.4 ng/ml (log 3.0 ± 0.1) and 13.51 ± 9.12 ng/ml (log 2.42 ± 0.60), respectively. The value of NSE in both the groups was comparable at different time points.
Lower perioperative values of S100b were observed in patients who received intraoperative dexmedetomidine. Dexmedetomidine may play a role in cerebroprotection during epilepsy surgery.
Environ Sci Pollut Res Int. 2019 Mar 25. doi: 10.1007/s11356-019-04806-x. [Epub ahead of print]
Mitigating effect of biotin against irradiation-induced cerebral cortical and hippocampal damage in the rat brain tissue.
Radiation-induced brain injury is common and mainly occurs in patients receiving radiotherapy for malignant head and neck tumors. The brain is oversensitive to oxidant injury induced by radiation.
Biotin is a member of the vitamin B complex family and its deficiency has been associated with neurogenesis impairment in animals and humans. The present study was undertaken to investigate the mitigating effect of biotin on the cerebral cortical and hippocampal damage induced by radiation exposure. Animals were exposed to radiation in the presence or absence of biotin and sacrificed on day 10. The results demonstrated that the administration of biotin 2 mg to irradiated rats had no significant effect on the radiation-induced damage of the cerebral cortex and the hippocampus, while the administration of biotin 6 mg has significantly attenuated oxidative stress in the hippocampus, manifested by a reduction of 4-hydroxynonenal (4HNE), total nitrate/nitrite (NOx), and xanthine oxidase (XO) levels associated with an elevation of glutathione (GSH) content as well as superoxide dismutase (SOD) and catalase (CAT) activities. In addition, biotin decreased the pro-inflammatory cytokines (interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrotic factor alpha (TNF-α)), caspase-3, poly(ADP-ribose) polymerase 1 (PARP1) level, and PARP1 gene expression. Moreover, biotin 6 mg treatment diminished serum S100 protein (S100B) and neuron-specific enolase (NSE) levels. In conclusion, biotin treatment at high dose post-irradiation has efficiently neutralized the effect of free radicals in the hippocampal region of rats. Thus, it could be applicable as a radio-mitigator for reducing or delayed radiation-induced brain injury in patients post-radiotherapy.
Can J Diabetes. 2019 Jan 11. pii: S1499-2671(18)30172-2. doi: 10.1016/j.jcjd.2019.01.003. [Epub ahead of print]
Associations of Serum S100B and S100P with the Presence and Classification of Diabetic Peripheral Neuropathy in Adults With Type 2 Diabetes: A Case-Cohort Study.
Novel biomarkers of diabetic peripheral neuropathy provide potentially useful information for early identification and treatment of diabetic neuropathy, ultimately serving to reduce the burden of disease. This study was designed to investigate the potential associations of serum S100B and S100P (calcium-modulated proteins) with the presence and classification of diabetic peripheral neuropathy in adults with type 2 diabetes.
In a case-cohort setting, the data of 44 participants diagnosed with diabetic peripheral neuropathy, 44 control participants with type 2 diabetes but free of peripheral neuropathy and 87 healthy control individuals were collected and analyzed.
Serum S100P concentrations were elevated in participants with diabetic peripheral neuropathy compared with their controls with type 2 diabetes (median [IQR]: 2,235 pg/mL [1,497.5 to 2,680] vs. 1,200 pg/mL [975 to 1,350)], respectively; p<0.001). Conversely, serum S100B values were comparable in these 2 groups (p=0.570). Those with the typical diabetic peripheral neuropathy had significantly higher serum S100P levels compared to their counterparts with the atypical group of diabetic peripheral neuropathies (p=0.048). The independent significant association between serum S100P and diabetic peripheral neuropathy persisted into the multivariable adjusted logistic regression model (OR for S100P: 1.004 [95% CI 1.002 to 1.006]; p<0.001).
The present study's findings demonstrated that serum S100P is a more significant indicator of peripheral neuropathy in type 2 diabetes than is serum S100B. Prospective longitudinal studies are required to confirm the prognostic value of baseline serum S100P to predict incident peripheral neuropathy in people with diabetes.
Clin Chem Lab Med. 2018 Jun 20. pii: /j/cclm.ahead-of-print/cclm-2018-0471/cclm-2018-0471.xml. doi: 10.1515/cclm-2018-0471.
Clinical validation of S100B in the management of a mild traumatic brain injury: issues from an interventional cohort of 1449 adult patients.
This study's primary objective was to validate the routine use of S100B via a prospective study. The aim was a reduction of cranial computed tomography (CCT) scans by 30%. The secondary goal was to investigate the influence of age and associated risk factors on the reduction of CCT.
S100B (sampling within 3 h postinjury) was used for patients with mild traumatic brain injury (mTBIs) presenting a medium risk of complications and requiring a CCT scan. Patients with negative S100B (S100B-) were discharged without a CCT scan.
Of the 1449 patients included in this study, 468 (32.3%) had S100B- with a sensitivity of 96.4% (95% CI: 87.5%-99.6%), a specificity of 33.4% (95% CI: 31%-36%) and a negative predictive value of 99.6% (95% CI: 98.5%-99.9%). No significant difference in serum levels or the S100B+ rate was observed if patients had retrograde amnesia (0.16 μg/L; 63.8%), loss of consciousness (0.13; 63.6%) or antiplatelet therapy (0.20; 77.9%). Significant differences were found between the S100B concentrations and S100B positivity rates in patients >65 years old and all the groups with patients <55 years old (18-25, 26-35, 36-45 and 46-55). From 18 to 65 years old (n=874), the specificity is 39.3% (95% CI: 36%-42.6%) compared to 18.7% (95% CI: 15.3%-22.3%) for patients >65 years old (n=504).
The clinical use of S100B in mTBI management reduces the use of CCTs by approximately one-third; furthermore, the percentage of CCTs reduction is influenced by the age of the patient.
Acta Med Port. 2018 Apr 30;31(4):201-206. doi: 10.20344/amp.9073.
Association of S100B Serum Levels with Metabolic Syndrome and its Components.
We aimed to compare serum levels of S100B between patients with metabolic syndrome and healthy subjects and to investigate the association of S100B with components of the metabolic syndrome.
MATERIALS AND METHODS:
In this study, 44 patients with metabolic syndrome and 44 healthy subjects participated. The participants' body mass index, waist circumference, systolic and diastolic blood pressure were measured. Serum levels of low and high density lipoprotein cholesterol, total cholesterol, triglyceride, fasting blood glucose, insulin, S100B protein were determined by enzymatic and ELISA methods.
The participants with metabolic syndrome had significantly higher levels of S100B than those in the control group (p < 0.0001). Serum levels of S100B protein were positively correlated with abdominal obesity (rho = 0.26; p = 0.01) and serum levels of triglyceride (rho = 0.26; p = 0.01). Moreover, serum levels of S100B were higher in subjects with abdominal obesity (p = 0.02), with higher serum triglyceride levels (p = 0.03) and with hypertension (p = 0.01).
The findings indicate that there may be a link between S100B protein with abdominal obesity and serum levels of triglycerides. This warrants further research to elucidate whether increased S100B levels in patients with metabolic syndrome are involved in the pathogenesis of cardiovascular disorders.
Biomed Res Int. 2018 Apr 23;2018:6954045. doi: 10.1155/2018/6954045. eCollection 2018.
Serum S100B Levels Can Predict Computed Tomography Findings in Paediatric Patients with Mild Head Injury.
Traumatic brain injuries (TBIs) are very common in paediatric populations, in which they are also a leading cause of death. Computed tomography (CT) overuse in these populations results in ionization radiation exposure, which can lead to lethal malignancies. The aims of this study were to investigate the accuracy of serum S100B levels with respect to the detection of cranial injury in children with mild TBI and to determine whether decisions regarding the performance of CT can be made based on biomarker levels alone.
MATERIALS AND METHODS:
This was a single-center prospective cohort study that was carried out from December 2016 to December 2017. A total of 80 children with mild TBI who met the inclusion criteria were included in the study. The patients were between 2 and 16 years of age. We determined S100B protein levels and performed head CTs in all the patients.
Patients with cranial injury, as detected by CT, had higher S100B protein levels than those without cranial injury (p < 0.0001). We found that patients with cranial injury (head CT+) had higher mean S100B protein levels (0.527 μg L-1, 95% confidence interval (CI) 0.447-0.607 μg L-1) than did patients without cranial injury (head CT-) (0.145 μg L-1, 95% CI 0.138-0.152 μg L-1). Receiver operating characteristic (ROC) curve analysis clearly showed that S100B protein levels differed between patients with and without cranial injury at 3 hours after TBI (AUC = 0.893, 95% CI 0.786-0.987, p = 0.0001).
Serum S100B levels cannot replace clinical examinations or CT as tools for identifying paediatric patients with mild head injury; however, serum S100B levels can be used to identify low-risk patients to prevent such patients from being exposed to radiation unnecessarily.
Cancer Lett. 2018 Aug 1. pii: S0304-3835(18)30498-1. doi: 10.1016/j.canlet.2018.07.034. [Epub ahead of print]
S100B Suppression Alters Polarization of Infiltrating Myeloid-Derived Cells in Gliomas and Inhibits Tumor Growth.
S100B, a member of the multigene family of Ca2+-binding proteins, is overexpressed by most malignant gliomas but its biological role in gliomagenesis is unclear. Recently, we demonstrated that low concentrations of S100B attenuated microglia activation through the induction of STAT3. Furthermore, S100B downregulation in a murine glioma model inhibited macrophage trafficking and tumor growth. Based on these observations, we hypothesized that S100B inhibitors may have antiglioma properties through modulation of tumor microenvironment. To discover novel S100B inhibitors, we developed a high-throughput screening cell-based S100B promoter-driven luciferase reporter assay. Initial screening of 768 compounds in the NIH library identified 36 hits with >85% S100B inhibitory activity. Duloxetine (Dul, an SNRI) was selected for the initial proof-of-concept studies. At low concentrations (1-5 μM) Dul inhibited S100B and CCL2 production in mouse GL261 glioma cells, but had minimal cytotoxic activity in vitro. In vivo, however, Dul (30 mg/kg/14 days) inhibited S100B production, altered the polarization and trafficking of tumor-associated myeloid-derived cells, and inhibited the growth of intracranial GL261 gliomas. Dul therapeutic efficacy, however, was not observed in the K-Luc glioma model that expresses low levels of S100B. These findings affirm the role of S100B in gliomagenesis and justify the development of more potent S100B inhibitors for glioma therapy.
Pediatrics. 2018 Jun;141(6). pii: e20180037. doi: 10.1542/peds.2018-0037. Epub 2018 May 1.
The Biomarker S100B and Mild Traumatic Brain Injury: A Meta-analysis.
The usefulness of S100B has been noted as a biomarker in the management of mild traumatic brain injury (mTBI) in adults. However, S100B efficacy as a biomarker in children has previously been relatively unclear.
A meta-analysis is conducted to assess the prognostic value of S100B in predicting intracerebral lesions in children after mTBI.
Medline, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, Scopus, and Google Scholar.
Studies including children suffering mTBI who underwent S100B measurement and computed tomography (CT) scans were included.
Of 1030 articles screened, 8 studies met the inclusion criteria.
The overall pooled sensitivity and specificity were 100% (95% confidence interval [CI]: 98%-100%) and 34% (95% CI: 30%-38%), respectively. A second analysis was based on the collection of 373 individual data points from 4 studies. Sensitivity and specificity results, obtained from reference ranges in children with a sampling time <3 hours posttrauma, were 97% (95% CI: 84.2%-99.9%) and 37.5% (95% CI: 28.8%-46.8%), respectively. Only 1 child had a low S100B level and a positive CT scan result without clinically important traumatic brain injury.
Only patients undergoing both a CT scan and S100B testing were selected for evaluation.
S100B serum analysis as a part of the clinical routine could significantly reduce the number of CT scans performed on children with mTBI. Sampling should take place within 3 hours of trauma. Cutoff levels should be based on pediatric reference ranges.
J Biol Regul Homeost Agents. 2018 Jul-Aug;32(4):1039-1043.
Performance assessment of a fully automated electro-chemiluminescence immunoassay system for serum S100B protein.
The altered expression levels of S100 proteins can lead to four different categories of diseases: diseases of the heart and of the central nervous system, inflammatory disorders and cancer. Various studies have shown the lack of harmonization of the results obtained with different methods, mainly due to different performances and measurements of S100B. The purpose of this work was to compare quantitatively the fully automated Elecsys® immunoassay with the reference immunoenzimatic method CanAg® EIA for serum S100Bprotein. In the study serum samples were analyzed of 161 patients: 85 females (aged 22-83 years) and 76 males (aged 16-90 years), affected by oncological and non-oncological pathologies. PassingBablok regression was used to analyze the comparison between the assays; it showed a strong interassay correlation: r = 0.9350 (95% CI =0.9122 0.9520), with an intercept of 0.02063 (95% CI=-0.02850 0.01400) and a slope of 1.1125 (95% CI=1.0200 1.2417). Elecsys® S100 assay should be preferred to CanAg® S100 for better standardization, good reliability and precision but also with the aim to reduce costs and obtain results in a shorter time.
Oncol Rep. 2018 Sep;40(3):1574-1582. doi: 10.3892/or.2018.6527. Epub 2018 Jun 27.
S100B promotes chemoresistance in ovarian cancer stem cells by regulating p53.
Chemoresistance is one of the most important causes of ovarian cancer‑related deaths. Recently, cancer stem cells (CSCs) have been recognized as the source of chemoresistance in ovarian cancer. However, the underlying mechanisms that regulate the chemoresistance of ovarian CSCs (OCSCs) remain unclear. The aim of the present study was to investigate the roles of S100B in the regulation of OCSC chemoresistance, which provides a novel therapeutic target. We observed high expression of S100B in CD133+ OCSCs derived from ovarian cancer cell lines and primary tumors and in cisplatin‑resistant patient samples. Then, we determined that S100B knockdown promoted the apoptosis of OCSCs after treatment with different concentrations of cisplatin. The underlying mechanism of S100B‑mediated chemoresistance in OCSCs may be through p53 inhibition. Furthermore, drug‑resistance genes, including MDR1 and MRP1, were involved in the process of S100B‑mediated OCSC chemoresistance. In conclusion, our results elucidated the importance of S100B in the maintenance of OCSC chemoresistance, which may provide a promising therapeutic target for ovarian cancer.
J Neurol. 2018 Sep 1. doi: 10.1007/s00415-018-9026-1. [Epub ahead of print]
Effect of anti-seizure drugs on serum S100B in patients with focal seizure: a randomized controlled trial.
S100B, a cytokine produced by astrocytes, has been studied as a biomarker of glial and neuronal damage in epilepsy. The present study investigated the reliability of serum S100B as a biomarker and the effect of carbamazepine and oxcarbazepine on serum S100B in patients with focal seizure.
The present randomized, open-label, active-controlled, parallel design clinical trial (NCT02705768) conducted on 60 patients with focal seizure. After recruitment, clinical evaluations were performed including Chalfont-National Hospital seizure severity scale (NHS3), Quality of Life in Epilepsy Inventory (QOLIE-31) and serum S100B was estimated. Thirty healthy individuals were recruited for evaluation of serum S100B at baseline only. After randomization, the study groups received either tablet oxcarbazepine or tablet carbamazepine. At follow-up after 2 weeks, clinical status was checked and at 4 weeks, NHS3 and QOLIE-31 were scored along with serum S100B level estimation.
Serum S100B level in patients with focal seizure increased significantly in comparison to healthy volunteers. The decrease in serum S100B was significantly higher with carbamazepine group (0.004; 95% CI 0.001-0.006; p = 0.01) over oxcarbazepine group. In logistic regression analysis, there was an increase in the log odds of 0.17 for focal seizure positivity against healthy controls if S100B level increases by 1 pg and area under curve obtained by ROC analysis was 0.96 (p < 0.001).
Serum S100B increases in the patients with focal seizure and therapy with carbamazepine can decrease serum S100B level significantly over oxcarbazepine. Serum S100B can be used as a prognostic biomarker in a focal seizure.
Childs Nerv Syst. 2018 Aug 31. doi: 10.1007/s00381-018-3955-y. [Epub ahead of print]
Serial measurement of S100B and NSE in pediatric traumatic brain injury.
Increased serum biomakers, such as S100 calcium-binding protein B (S100B) and neuron-specific enolase (NSE), are associated with traumatic brain injury (TBI). The purpose of this study is to investigate the serum levels of S100B and NSE in pediatric TBI patients and to predict a clinical outcome.
Peripheral venous blood was collected within 6 h of injury and at 1 week to measure S100B and NSE. The serum S100B and NSE levels were measured using commercially available enzyme-linked immunosorbent assay kits. The authors divided participants into two groups at admission: a favorable group (patients with Glasgow Coma Scale [GCS] scores of 10-15) and an unfavorable group (patients with GCS scores of less than 9). Both S100B and NSE levels were compared between the two groups at the time of admission and 1 week later.
Ten pediatric patients were enrolled (5 in the favorable group, 5 in the unfavorable group). The median serum S100B level of 134.21 pg/ml (range, 51.00-789.65 pg/ml) in patients with TBI at admission dropped to 41.49 pg/ml (range, 25.65-260.93 pg/ml) after 1 week, with significant differences between the traumatic event and 1 week later (p = 0.007). The median serum NSE level of 14.76 ng/ml (range, 6.48-21.23 ng/ml) in patients with TBI at admission was higher than that after 1 week (4.96 ng/ml, range, 3.01-31.21 ng/ml), with significant differences (p = 0.015). A significant difference was observed in S100B after 1 week between patients in the favorable and unfavorable groups (p = 0.047). One patient whose serum S100B and NSE levels were elevated 1 week after TBI eventually died.
Elevated serum S100B and NSE levels in pediatric TBI patients decreased 1 week after traumatic events. The serum S100B level 1 week after TBI was related to the severity of brain damage. These results indicated that serum S100B and NSE might play a role in predicting the prognosis and monitoring ongoing brain injury in pediatric TBI patients.
Biol Trace Elem Res. 2018 Aug 14. doi: 10.1007/s12011-018-1463-2. [Epub ahead of print]
Chronic Oral Arsenic Exposure and Its Correlation with Serum S100B Concentration.
Arsenic is one of the most important environmental pollutants especially in drinking water. The S100B protein is presented as a sensitive biomarker for assessment of the blood-brain barrier integrity previously. The objective of this study was to determine the impact of chronic arsenic exposure in drinking water and serum S100B correlation. Fifty-four male BALB/c mice were randomly divided into three groups. Group I and II subjects were treated with arsenic trioxide (1 ppm and 10 ppm, respectively), while the rest received normal drinking water. Arsenic concentration in serum and brain was measured by an atomic absorption spectrometer (Varian model 220-Z) conjugated with a graphite furnace atomizer (GTA-110). Also, a serum S100B protein concentration was determined using commercial ELISA kit during different times of exposure. It was observed that body weight gain was significantly lower from the 10th week onwards in arsenic-treated subjects. However, it did not induce any visible clinical signs of toxicity. Measured arsenic level in serum and brain was higher in espoused groups as compared to the control subjects (p < 0.001 and p < 0.0001, respectively). In addition, serum S100B content was increased over a period of 3 months and had significant differences as compared to the control and 1-ppm group especially after 3 months of exposure in the 10-ppm group (p < 0.0001). In conclusion, it could be inferred that long-term arsenic exposure via drinking water leads to brain arsenic accumulation with serum S100B elevated concentration as a probable BBB disruption consequence.
Serum S100A12 as a prognostic biomarker of severe traumatic brain injury.
Clin Chim Acta 2018 Jan 31;480:84-91. Epub 2018 Jan 31.
Department of Neurosurgery, The Changxing People's Hospital, The Second Affiliated Hospital of Zhejiang University School of Medicine Changxing Campus, 66 Taihu Middle Road, Changxing 313100, China.
Background: S100A12 is related to acute brain injury and inflammation. We investigated the clinical prognostic value of serum S100A12 in patients with severe traumatic brain injury (sTBI).
Methods: Serum S100A12, S100B, C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) concentrations were measured in 102 healthy controls and 102 sTBI patients. We recorded 30-day mortality and in-hospital major adverse events (IMAEs) including acute lung injury, acute traumatic coagulopathy, progressive hemorrhagic injury and posttraumatic cerebral infarction. Trauma severity was assessed by admission Glasgow Coma Scale scores.
ts: When compared to the controls, serum S100A12, S100B, CRP, IL-6 and TNF-α concentrations were significantly increased in the patients. Serum concentrations of S100A12 significantly correlated with admission Glasgow Coma Scale scores and serum concentrations of S100B, CRP, IL-6 and TNF-α. Patients with any IMAEs or non-survivors within 30 days had obviously higher serum concentrations of S100A12, S100B, CRP, IL-6 and TNF-α than other remaining ones. Serum S100A2 was independently associated with IMAEs and 30-day mortality and overall survival. Receiver operating characteristic curve analysis showed that S100A12 concentrations had significant discriminatory ability for patients at risk of any IMAEs and death within 30 days.
Conclusion: S100A12 might be associated with brain inflammation and evaluation of serum concentrations of S100A12 could be helpful in the early prognostic prediction in sTBI patients.
Validation of S100B use in a cohort of Spanish patients with mild traumatic brain injury: a multicentre study.
Brain Inj 2018 22;32(4):459-463. Epub 2018 Jan 22.
a NeuroCritical Care Unit , Virgen del Rocío University Hospital, IBIS/CSIC/University of Seville , Seville , Spain.
Introduction: The aim of this study was to validate the S100B protein as a diagnostic tool for ruling out the presence of intracranial lesion (IL) after mild traumatic brain injury (mTBI). Subjects with a Glasgow Coma Scale (GCS) score of 15 and at least one neurological symptom post-trauma were selected from a large Spanish cohort.
Methods: A number of 260 patients with mTBI were enrolled. Blood samples were extracted within 6 h and CT scan performed within 24 h post-injury. Blood samples were also drawn from 18 healthy subjects.
Results: CT scan revealed the presence of IL in 22 patients (8.5%). Patients with mTBI had higher S100B serum levels (p = 0.008) than the healthy subjects (p < 0.001). The ROC analysis of S100B discriminated between patients with and without IL (AUC: 0.671; 95%CI: 0.574-0.769; p = 0.008). The multivariate analysis identified male gender (OR: 5.39; 95%CI: 1.45-20.10; p = 0.012), age > 65 (OR: 2.97; 95%CI: 1.04-8.44; p = 0.041) and S100B level >0.10 µg/L (OR: 7.93; 95%CI: 1.03-60.76; p = 0.046) as independent risk factors for IL in patients with mTBI.
Conclusion: Measurement of S100B within 6 h of mTBI accurately predicts risk of IL in patients with a GCS score of 15 and at least one neurological symptom.
Serum levels of S100B from jugular bulb as a biomarker of poor prognosis in patients with severe acute brain injury.
J Neurol Sci 2018 Feb 18;385:109-114. Epub 2017 Dec 18.
Service of Intensive Care, Marqués de Valdecilla University Hospital, IDIVAL, School of Medicine, University of Cantabria, Avda. Valdecilla, s/n 39008, Santander, Spain. Electronic address:
Aims/background: To evaluate the correlation between protein S100B concentrations measured in the jugular bulb as well as at peripheral level and the prognostic usefulness of this marker.
Methods: A prospective study of all patients admitted to the intensive care unit with acute brain damage was carried out. Peripheral and jugular bulb blood samples were collected upon admission and every 24h for three days. The endpoints were brain death diagnosis and the Glasgow Outcome Scale score after 6months.
Results: A total of 83 patients were included. Jugular protein S100B levels were greater than systemic levels upon admission and also after 24 and 72h (mean difference>0). Jugular protein S100B levels showed acceptable precision in predicting brain death both upon admission [AUC 0.67 (95% CI 0.53-0.80)] and after 48h [AUC 0.73 (95% CI 0.57-0.89)]. Similar results were obtained regarding the capacity of jugular protein S100B levels upon admission to predict an unfavourable outcome (AUC 0.69 (95% CI 0.56-0.79)). The gradient upon admission (jugular-peripheral levels) showed its capacity to predict the development of brain death [AUC 0.74 (95% CI 0.62-0.86)] and together with the Glasgow Coma Scale constituted the independent factors associated with the development of brain death.
Conclusion: Regional protein S100B determinations are higher than systemic determinations, thus confirming the cerebral origin of protein S100B. The transcranial protein S100B gradient is correlated to the development of brain death.
Zinc Binding to S100B Affords Regulation of Trace Metal Homeostasis and Excitotoxicity in the Brain.
Front Mol Neurosci 2017 17;10:456. Epub 2018 Jan 17.
Cellular Neurobiology and Neuro-Nanotechnology Lab, Department of Biological Sciences, University of Limerick, Limerick, Ireland.
Neuronal metal ions such as zinc are essential for brain function. In particular synaptic processes are tightly related to metal and protein homeostasis, for example through extracellular metal-binding proteins. One such protein is neuronal S100B, a calcium and zinc binding damage-associated molecular pattern (DAMP), whose chronic upregulation is associated with aging, Alzheimer's disease (AD), motor neuron disease and traumatic brain injury (TBI).
Despite gained insights on the structure of S100B, it remains unclear how its calcium and zinc binding properties regulate its function on cellular level. Here we report a novel role of S100B in trace metal homeostasis, in particular the regulation of zinc levels in the brain.
Our results show that S100B at increased extracellular levels is not toxic, persists at high levels, and is taken up into neurons, as shown by cell culture and biochemical analysis. Combining protein bioimaging and zinc quantitation, along with a zinc-binding impaired S100B variant, we conclude that S100B effectively scavenges zinc ions through specific binding, resulting in a redistribution of the intracellular zinc pool. Our results indicate that scavenging of zinc by increased levels of S100B affects calcium levels. Thereby S100B is able to mediate the cross talk between calcium and zinc homeostasis. Further, we investigated a possible new neuro-protective role of S100B in excitotoxicity via its effects on calcium and zinc homeostasis. Exposure of cells to zinc-S100B but not the zinc-binding impaired S100B results in an inhibition of excitotoxicity. We conclude that in addition to its known functions, S100B acts as sensor and regulator of elevated zinc levels in the brain and this metal-buffering activity is tied to a neuroprotective role.
RNA interference-mediated silencing of S100B improves nerve function recovery and inhibits hippocampal cell apoptosis in rat models of ischemic stroke.
J Cell Biochem 2018 Jan 31. Epub 2018 Jan 31.
Department of Neurology, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou 450003, P.R. China.
Objective: Ischemic stroke is the leading cause of worldwide mortality and long-term disability in adults. This study aims to explore the effects of RNA interference (RNAi)-mediated silencing of the S100B gene on nerve function recovery and morphological changes of hippocampus cells in rat models with ischemic stroke.
Methods: Sixty Wistar rats were assigned into different group. S100B and Caspase 3 mRNA and protein expressions were evaluated by RT-qPCR and Western blotting. Positive rate of S100B, NeuN, and MAP2 expressions were detected by immunohistochemistry (IHC). Water content, malondialdehyde (MDA) levels, and superoxide dismutase (SOD) activity in brain tissues were measured. Enzyme-linked immunosorbent assay (ELISA) was employed to detect serum levels of TNF-α and IL-1β. A neurological severity score (NSS) was used to test nerve function. TUNEL assay was used to determine hippocampal cell apoptosis.
Results: Downregulation of S100B showed a lower number of S100B immune positive cells, but higher NeuN and MAP2-positive cells, increased SOD level, declined MDA level, prominently faster recovery of neurological function, decreased TRCS, TCTP, TCFP and IE levels, an obvious increase in the number of survival neurons, a decrease in the number of apoptotic cells, notably decreased TNF-α and IL-1β contents, as well as infarct volume, an obvious decrease in positive hippocampal cell Caspase 3 expression and protein expressions of Caspase 3 and cleaved Caspase 3.
Conclusion: This study provides data to suggest that RNAi-mediated silencing of S100B gene could improve the recovery of nerve function while inhibiting apoptosis of hippocampal cells in rats with ischemic stroke.
Curr Med Chem. 2016;23(15):1571-96.
Identifying S100B as a Biomarker and a Therapeutic Target For Brain Injury and Multiple Diseases.
The calcium binding protein S100B has attracted great attention as a biomarker for a variety of diseases. S100B is mainly expressed in glial cells and functions through intracellular and extracellular signaling pathways. The biological roles of S100B have been closely associated with its concentrations and its physiological states. The released S100B can bind to the receptor of advanced glycation end products and induce the initiation of multiple cell signaling transductions. The regulation of S100B bioactivities has been suggested through phosphoinositide 3 kinase/Akt, p53, mitogen-activated protein kinases, transcriptional factors including nuclear factor-kappaB, and cyclic adenosine monophosphate. The levels of S100B in the blood may function to predict the progress or the prognosis of many kinds of diseases, such as cerebrovascular diseases, neurodegenerative diseases, motor neuron diseases, traumatic brain injury, schizophrenia, depression, diabetes mellitus, myocardial infarction, cancer, and infectious diseases. Given that the activity of S100B has been implicated in the pathological process of these diseases, S100B should not be simply regarded as a biomarker, it may also function as therapeutic target for these diseases. Further elucidation of the roles of S100B may formulate innovative therapeutic strategies for multiple diseases.
Neurol Sci. 2016 Apr;37(4):533-9. doi: 10.1007/s10072-016-2521-1. Epub 2016 Feb 29.
Re-exposure to the hypobaric (Long Haul Flights) hypoxic brain injury of high altitude: plasma S100B levels and the possible effect of acclimatisation on blood-brain barrier dysfunction.
Winter CD1,2, Whyte T3, Cardinal J4,5, Kenny R6, Ballard E7.
Hypobaric hypoxic brain injury results in elevated peripheral S100B levels which may relate to blood-brain barrier (BBB) dysfunction. A period of acclimatisation or dexamethasone prevents altitude-related illnesses and this may involve attenuation of BBB compromise. We hypothesised that both treatments would diminish the S100B response (a measure of BBB dysfunction) on re-ascent to the hypobaric hypoxia of high altitude, in comparison to an identical ascent completed 48 h earlier by the same group. Twelve healthy volunteers, six of which were prescribed dexamethasone, ascended Mt Fuji (summit 3700 m) and serial plasma S100B levels measured. The S100B values reduced from a baseline 0.183 µg/l (95 % CI 0.083-0.283) to 0.145 µg/l (95 % CI 0.088-0.202) at high altitude for the dexamethasone group (n = 6) and from 0.147 µg/l (95 % CI 0.022-0.272) to 0.133 µg/l (95 % CI 0.085-0.182) for the non-treated group (n = 6) [not statistically significant (p = 0.43 and p = 0.82) for the treated and non-treated groups respectively]. [These results contrasted with the statistically significant increase during the first ascent, S100B increasing from 0.108 µg/l (95 % CI 0.092-0.125) to 0.216 µg/l (95 % CI 0.165-0.267) at high altitude].
In conclusion, an increase in plasma S100B was not observed in the second ascent and this may relate to the effect of acclimatisation (or hypoxic pre-conditioning) on the BBB. An exercise stimulated elevation of plasma S100B levels was also not observed during the second ascent. The small sample size and wide confidence intervals, however, precludes any statistically significant conclusions and a larger study would be required to confirm these findings.
BMC Neurol. 2016 Jun 17;16:93. doi: 10.1186/s12883-016-0614-3.
Kinetic modelling of serum S100b after traumatic brain injury.
An understanding of the kinetics of a biomarker is essential to its interpretation. Despite this, little kinetic modelling of blood biomarkers can be found in the literature. S100b is an astrocyte related marker of brain injury used primarily in traumatic brain injury (TBI). Serum levels are expected to be the net result of a multi-compartmental process. The optimal sample times for TBI prognostication, and to follow injury development, are unclear. The purpose of this study was to develop a kinetic model to characterise the temporal course of serum S100b concentration after primary traumatic brain injury.
Data of serial serum S100b samples from 154 traumatic brain injury patients in a neurointensive care unit were retrospectively analysed, including only patients without secondary peaks of this biomarker. Additionally, extra-cranial S100b can confound samples earlier than 12 h after trauma and were therefore excluded. A hierarchical, Bayesian gamma variate kinetic model was constructed and the parameters estimated by Markov chain Monte Carlo sampling.
We demonstrated that S100b concentration changes dramatically over timescales that are clinically important for early prognostication with a peak at 27.2 h (95 % credible interval [25.6, 28.8]). Baseline S100b levels was found to be 0.11 μg/L (95 % credible interval [0.10, 0.12]).
Even small differences in injury to sample time may lead to marked changes in S100b during the first days after injury. This must be taken into account in interpretation. The model offers a way to predict the peak and trajectory of S100b from 12 h post trauma in TBI patients, and to identify deviations from this, possibly indicating a secondary event. Kinetic modelling, providing an equation for the peak and projection, may offer a way to reduce the ambiguity in interpretation of, in time, randomly sampled acute biomarkers and may be generally applicable to biomarkers with, in time, well defined hits.
J Clin Neurosci. 2017 Jan;35:104-108. doi: 10.1016/j.jocn.2016.09.006. Epub 2016 Sep 30.
Elevation of oxidative stress indicators in a pilot study of plasma following traumatic brain injury.
Traumatic brain injury (TBI) encompasses a broad range of injury mechanisms and severity. A detailed determination of TBI severity can be a complex challenge, with current clinical tools sometimes insufficient to tailor a clinical response to a spectrum of patient needs. Blood biomarkers of TBI may supplement clinical assessments but currently available biomarkers have limited sensitivity and specificity. While oxidative stress is known to feature in damage mechanisms following TBI, investigation of blood biomarkers of oxidative stress has been limited. This exploratory pilot study of a subset of 18 trauma patients with TBI of varying severity, quantifies circulating concentrations of the structural damage indicators S100b, and myelin basic protein (MBP), and the biomarkers of oxidative stress hydroxynonenal (HNE), malondialdehyde (MDA), carboxy-methyl-lysine (CML), and 8-hydroxy-2'-deoxy-guanosine (8-OHDG). Significant increases in circulating S100b, MBP, and HNE were observed in TBI patient samples compared to 8 uninjured controls, and there was a significant decrease in CML. This small exploratory study supports the current literature on S100b and MBP elevation in TBI, and reveals potential for the use of peripheral oxidative stress markers to assist in determination of TBI severity. Further investigation is required to validate results and confirm trends.