Expression Levels Of S100B Research Articles

Anakinra Promotes M2 Microglia Activation during the Latent Phase of the Lithium-Pilocarpine Model of Temporal Lobe Epilepsy

Astrocytes and microglia and their polarization are thought to contribute to the progression of epilepsy. One of the processes affecting polarization is neuroinflammation, which plays an important role in epileptogenesis. However, the specific mechanisms of its involvement in shifting the pro- and anti-inflammatory reactivation of astro- and microglia have not been clarified. In this study, we examined the effect of 7-day interleukin-1 receptor antagonist (anakinra) administration on glial cell polarization during the latent phase of the lithium-pilocarpine model in 7-week-old male Wistar rats. In temporal cortex, dorsal and ventral hippocampus the mRNA expression levels of the following genes were analyzed: (i) markers of astroglia (S100b) and microglia (Aif1) activation, (ii) astrocytic proteins involved in glutamate transport and metabolism (Slc1a3, Glul, Gja1), (iii) pro-inflammatory pathway interleukin-1β (Nlrp3, Il1b, Il1rn) and transforming growth factor β1 (Tgfb1), (iv) markers of astroglia polarization (Lcn2, S100a10, Gbp2, Ptx3), and (v) microglia polarization (Nos2 and Arg1). The mRNA expression levels of S100b and Aif1 were significantly increased, and anakinra administration did not reduce their overexpression. This indicates reactivation of astroglia and microglia regardless of the anakinra administered. The expression of Slc1a3, Glul, and Gja1 genes increased in the hippocampus; anakinra administration did not affect their hyperexpression, but promoted increased expression of Gja1 in the temporal cortex. The mRNA production of Lcn2, S100a10, Gbp2, Ptx3, Nlrp3, Il1b, Il1rn and Tgfb1 increased in all structures. Administration of anakinra reduced the gene expression of Il1b. Among the markers of microglia polarization, downregulation of Arg1 expression in the dorsal hippocampus and Nos2 expression in the temporal cortex was detected. Anakinra administration enhanced the decrease in Nos2 expression and restored the level of Arg1 expression to control values. Thus, anakinra administration did not affect the intensity of glial cell reactivation, but improved M2 reactivation of microglia.

Enrofloxacin hydrochloride toxicological effects on crucian carp reflected by serological changes and neurotoxicity

Due to its water solubility and wide applicability, enrofloxacin hydrochloride (EH) may enter aquatic ecosystems and cause negative effects on aquatic organisms. This study aimed to explore toxicological effects via serological changes and neurotoxicity, which were induced by EH exposure in crucian carp (Carassius auratus var. Pengze). The drug residues in brain tissue and protein content in serum were determined to analyze serological changes. Alterations in brain tissue structure and function, cerebral microvessels permeability, and the expressions of gene and protein regarding blood-brain barrier (BBB) were studied to reflect the neurotoxicity. Employing a validated high-performance liquid chromatography (HPLC) method, EH residues could be detected at various time-points throughout the experiment. Enzyme-linked immunosorbent assay (ELISA) showed that EH increased the levels of S100B, NSE and GFAP proteins in serum. Additionally, there was a significant positive correlation between serum S100B, NSE protein contents and EH residues (P < 0.05). Hematoxylin and eosin (H&E) staining revealed brain damage from EH exposure by the formation of vacuoles in brain glial cells, pyknosis of the nucleus, and a decrease in cell population density. Transmission electron microscope (TEM) revealed morphological changes in microvessels and condensation of astrocyte nucleus. Evans blue (EB) permeability test visualized an obvious increase in cerebral microvessels leakage. The real-time quantitative PCR (qPCR) results indicated that EH up-regulated the mRNA expression levels of S100B, NSE and GFAP, down-regulated the mRNA expression levels of P-gp, ZO-1, Occludin and Claudin-5. The Western blot (WB) results demonstrated increased NSE and GFAP protein expressions, decreased P-gp and Occludin protein expressions following EH exposure in brain, in consistent with the gene expressions, respectively. In conclusion, these findings indicated that EH brought about marked rise in serum biomarker levels and disrupted the central nervous system (CNS) of crucian carp. These data would help elucidate the mechanism underlying EH-induced neurotoxicological effects.

The effect of charge-balanced transcutaneous electrical nerve stimulation on rodent facial nerve regeneration

This study aimed to investigate the effect of charge-balanced transcutaneous electrical nerve stimulation (cb-TENS) in accelerating recovery of the facial function and nerve regeneration after facial nerve (FN) section in a rat model. The main trunk of the left FN was divided and immediately sutured just distal to the stylomastoid foramen in 66 Sprague–Dawley rats. The control group had no electrical stimulus. The other two groups received cb-TENS at 20 Hz (20 Hz group) or 40 Hz (40 Hz group). Cb-TENS was administered daily for seven days and then twice a week for three weeks thereafter. To assess the recovery of facial function, whisker movement was monitored for four weeks. Histopathological evaluation of nerve regeneration was performed using transmission electron microscopy (TEM) and confocal microscopy with immunofluorescence (IF) staining. In addition, the levels of various molecular biological markers that affect nerve regeneration were analyzed. Whisker movement in the cb-TENS groups showed faster and better recovery than the control group. The 40 Hz group showed significantly better movement at the first week after injury (p < 0.0125). In histopathological analyses using TEM, nerve axons and Schwann cells, which were destroyed immediately after the injury, recovered in all groups over time. However, the regeneration of the myelin sheath was remarkably rapid and thicker in the 20 Hz and 40 Hz groups than in the control group. Image analysis using IF staining showed that the expression levels of S100B and NF200 increased over time in all groups. Specifically, the expression of NF200 in the 20 Hz and 40 Hz groups increased markedly compared to the control group. The real-time polymerase chain reaction was performed on ten representative neurotrophic factors, and the levels of IL-1β and IL-6 were significantly higher in the 20 and 40 Hz groups than in the control group (p < 0.015). Cb-TENS facilitated and accelerated FN recovery in the rat model, as it significantly reduced the recovery time for the whisker movement. The histopathological study and analysis of neurotrophic factors supported the role of cb-TENS in the enhanced regeneration of the FN.

Increased Expression of S100B and RAGE in a Mouse Model of Bile Duct Ligation-induced Liver Fibrosis.

BackgroundLiver fibrosis is defined as the accumulation of the extracellular matrix and scar formation. The receptor for advanced glycation end products (RAGE) has been demonstrated to participate in fibrogenesis. S100B is a ligand of RAGE and exerts extracellular functions by inducing a series of signal transduction cascades. However, the involvement of S100B and RAGE in cholestasis-induced liver fibrosis remains unclear. In this study, we investigated S100B and RAGE expression during liver fibrosis in mice that underwent common bile duct ligation (BDL).MethodsBDL was performed in 10-week-old male C57BL/6J mice with sham control (n = 26) and BDL (n = 26) groups. Expression levels of S100B, RAGE and fibrotic markers in the livers from both groups at week 1 and 3 after BDL were examined by western blot and quantitative real-time reverse transcription polymerase chain reaction analysis. Liver fibrotic changes were examined by histological and ultrastructural analysis.ResultsHistological staining with Sirius Red and the evaluation of the messenger RNA expression of fibrotic markers showed noticeable periportal fibrosis and bile duct proliferation. S100B was mainly present in bile duct epithelial cells, and its expression was upregulated in proportion to the ductular reaction during fibrogenesis by BDL. RAGE expression was also increased, and interestingly, triple immunofluorescence staining and transmission electron microscopy showed that both S100B and RAGE were expressed in proliferating bile duct epithelial cells and activated hepatic stellate cells (HSCs) of the BDL livers. In addition, in rat HSCs (HSC-T6), treatment with recombinant S100B protein significantly increased fibrotic markers in a dose-dependent manner, and RAGE small interfering RNA (siRNA) suppressed S100B-stimulated upregulation of fibrotic markers compared with cells treated with scramble siRNA and S100B.ConclusionThese findings suggest that the increased expression of S100B and RAGE and the interaction between S100B and RAGE may play an important role in ductular reaction and liver fibrosis induced by BDL.

SBi4211 alleviates gp120-induced central nervous system injury via inhibiting S100B/ RAGE

To explore the protective effect of SBi4211 (heptamidine), an inhibitor of S100B, against central nervous system injury induced by HIV-1 envelope protein gp120. In an in vitro model, U251 glioma cells were co-cultured with SH-SY5Y cells to explore the protective effect of SBi4211 against gp120-induced central nervous system injury. In a gp120 transgenic (Tg) mouse model (8 months old) mimicking HIV-associated neurocognitive disorder (HAND), the effect of treatment with gp120 or both gp120 and SBi4211 on neuronal activity and apoptosis were assessed using Cell Counting kit-8 (CCK-8) and flow cytometry. ELISA, Western blotting and immunohistochemistry were used to determine the expression levels of S100B, RAGE, GFAP, NeuN, Syn, MAP-2 and the inflammatory factors IL-6 and TNF-α. In the cell co-culture system, SBi4211 treatment significantly inhibited gp120-induced expression of S100B, RAGE and GFAP in U251 cells (P < 0.001), reduced the levels of inflammatory factors iNOS, IL-6 and TNF-α (P < 0.001) and enhanced the expressions of neuron-related proteins NeuN, Syn and MAP-2 (P < 0.001). In the transgenic mouse model, SBi4211 treatment significantly reduced the expressions of S100B, RAGE and inflammation levels (P < 0.05), inhibited the activation of astrocytes in the brain, and maintained the integrity of the neurons (P < 0.05). SBi4211 can protect neurons from gp120-induced neurotoxicity possibly by inhibiting the S100B/ RAGE-mediated signaling pathway.

Cell Culture Experiments Reveal that High S100B and Clusterin Levels may Convey Hypoxia-tolerance to the Hooded Seal (Cystophora cristata) Brain

While the brain of most mammals suffers from irreversible damage after only short periods of low oxygen levels (hypoxia), marine mammals are excellent breath-hold divers that have adapted to hypoxia. In addition to physiological adaptations, such as large oxygen storing capacity and strict oxygen economy during diving, the neurons of the deep-diving hooded seal (Cystophora cristata) have an intrinsic tolerance to hypoxia. We aim to understand the molecular basis of this neuronal hypoxia tolerance.Previously, transcriptomics of the cortex of the hooded seal have revealed remarkably high expression levels of S100B and clusterin (apolipoprotein J) when compared to the ferret, a non-diving carnivore. Both genes have much-debated roles in hypoxia and oxidative stress. Here, we evaluated the effects of S100B and of two isoforms of clusterin (soluble and nucleus clusterin) on the survival, metabolic activity and the amount of reactive oxygen species (ROS) in HN33 neuronal mouse cells exposed to hypoxia and oxidative stress. S100B and soluble clusterin had neuroprotective effects, with reduced ROS-levels and retention of normoxic energy status of cells during both stress conditions. The protective effects of nucleus clusterin were restricted to hypoxia. S100B and clusterin showed purifying selection in marine and terrestrial mammals, indicating a functional conservation across species. Immunofluorescence revealed identical cellular distributions of S100B and clusterin in mice, ferrets and hooded seals, further supporting the functional conservation. Taken together, our data suggest that the neuroprotective effects of all three proteins are exclusively facilitated by their increased expression in the brain of the hooded seal.

Distribution and Relative Abundance of S100 Proteins in the Brain of the APP23 Alzheimer's Disease Model Mice.

Increasing evidence links proteins of the S100 family to the pathogenesis of Alzheimer’s disease (AD). S100 proteins are EF-hand calcium-binding proteins with intra- and extracellular functions related to regulation of proliferation, differentiation, apoptosis, and trace metal homeostasis, and are important modulators of inflammatory responses. For example, S100A6, S100A8, and S100B expression levels were found increased in inflammatory diseases, but also neurodegenerative disorders, and S100A8/A9 complexes may provide a mechanistic link between amyloid-beta (Aβ) plaque formation and neuroinflammation. On the other hand, S100B, a proinflammatory protein that is chronically up-regulated in AD and whose elevation precedes plaque formation, was recently shown to suppress Aβ aggregation. Here, we report expression of S100A6 and S100B in astrocytes and less so in neurons, and low level of expression of S100A8 in both neurons and glial cells in vitro. In vivo, S100A8 expression is almost absent in the brain of aged wildtype mice, while S100A6 and S100B are expressed in all brain regions and most prominently in the cortex and cerebellum. S100B seems to be enriched in Purkinje cells of the cerebellum. In contrast, in the brain of APP23 mice, a mouse model for Alzheimer’s disease, S100B, S100A6, and S100A8 show co-localization with Aβ plaques, compatible with astrocyte activation, and the expression level of S100A8 is increased in neural cells. While S100A6 and S100B are enriched in the periphery of plaques where less fibrillar Aβ is found, S100A8 is more intense within the center of the inclusion. In vitro assays show that, similarly to S100B, S100A6, and S100A8 also delay Aβ aggregation suggesting a regulatory action over protein aggregation. We posit that elevated expression levels and overlapping spatial distribution of brain S100 proteins and plaques translates functional relationships between these inflammatory mediators and AD pathophysiology processes that uncover important molecular mechanisms linking the aggregation and neuroinflammation cascades.

Regulatory Genetic Variation at the S100B Gene Associates with Vaso-Occlusive Manifestations in Sickle Cell Disease

In sickle cell disease (SCD) polymerization of hemoglobin S under deoxygenated conditions causes vaso-occlusion, which can manifest as acute pain crisis and progressive bone/organ damage. Molecular studies have attributed vaso-occlusion to elevated vascular adhesion and inflammatory responses, whereas the genetic regulation has only recently been assessed.Genomic DNA isolated from peripheral blood mononuclear cells (PBMCs) was hybridized to Illumina Human 610-Quad SNP array for the PUSH and Walk-PHaSST cohorts and to Affrymetrix SNP 6.0 array for the Howard SCD expression cohort. Single nucleotide polymorphisms (SNPs) for 381 PUSH, 525 Walk-PHaSST, and 55 Howard patients were imputed to 1000 genomes project phase 3 data. Messenger RNA from PBMCs was profiled using Affymetrix Human Exon 1.0 ST Array for the Howard expression cohort and Affymetrix Human gene 2.0 ST array for the UIC expression cohort.Patients within the PUSH and Walk-PHaSST cohorts were classified to four groups according to a cumulative pain score, calculated based on pain frequency and questionnaire description of pain intensity. Pain grouping was examined for correlation with other SCD complications using Cochran Armitage test. History of acute chest syndrome (ACS, PUSH P=3.8×10-9, Walk-PHaSST P=2.4×10-5) and avascular necrosis (AVN, PUSH P=4.1×10-4, Walk-PHaSST P=3.7×10-5) were the most significant clinical manifestations that consistently associated with pain in the two cohorts.To investigate the genetic control of vaso-occlusive manifestations with appropriate power, we leveraged genetic association of pain, ACS, and AVN with genetic regulation of disease-specific gene expression. We mapped expression quantitative trait loci (eQTL) in the Howard expression cohort for SNPs<1 Mb away from gene ends per expression trait. At a permutation based false discovery rate of 5%, 1004 independent eQTL (linkage disequilibrium r2 ≤0.3 per trait) were identified for 880 genes. Focusing on 129 genes whose expression was altered in PBMCs in sickle cell anemia by at least 1.5-fold [1], we identified six eQTL for five differential genes (up-regulated: OSBP2, SLC14A1, RNF182, CCRL2; down-regulated: S100B).The six eQTL were assessed for association with pain, ACS, and AVN, using the Walk-PHaSST cohort for discovery and the PUSH cohort for validation. At a significance of Bonferroni corrected P=0.05 (nominal P=0.0083), an eQTL of S100B (rs2154586) significantly associated with AVN in the Walk-PHaSST cohort (OR=1.8, P=0.00061) and the association was replicated in the PUSH cohort (OR=2.7, P=0.0052). The A allele of the eQTL (frequency=0.18) associated with increased risk for AVN and increased expression level of S100B in the Howard expression cohort (β=0.40, P=1.6 ×10-6). In an additional 64 sickle cell anemia patients without hydroxyurea treatment from the UIC expression cohort, expression levels of S100B were significantly elevated in the individuals with AVN (β=0.28, P=0.029). The 24 SNPs in linkage disequilibrium with the eQTL (r2 >0.7) constituted the third most significant peak in a meta-analysis of genome-wide association of AVN in the PUSH and Walk-PHaSST cohorts.To test the hypothesis that genes involved in vaso-occlusion in SCD may affect thrombotic risk in non SCD individuals, we examined the association of the locus with venous thromboembolism (VTE) in the ARIC, JHS and CHS cohorts from dbGaP. The locus was imputed in African Americans and VTE was defined as being told by a doctor to have a blood clot in the leg or lung as answered in questionnaires during medical exams. The SNPs were associated with VTE using logistic linear regression adjusting for age, gender, enrollment site, and the first 15 principal components per cohort. The risk allele of the leading SNP for AVN consistently associated with increased risk of VTE across the cohorts, with a combined P=0.0041 and OR=1.4.S100B encodes a calcium sensor that appears to intervene in a variety of biological functions. S100B can mediate the inflammatory effects of damage-associated molecular pattern molecules (DAMPs) produced by erythrocyte hemolysis [2, 3]. Serum concentration of S100B correlates with LDH and with TCD-determined peak velocity of the left middle cerebral artery in thalassemia patients[4]. Polymorphisms of S100B that lead to increased serum levels are associated with increased risk of ischemic stroke in the Chinese population[5]. DisclosuresNekhai:NIMHD, NIH: Research Funding; NHLBI, NIH: Research Funding; NIAID, NIH: Research Funding.

S100B regulates inflammatory response during osteoarthritis via fibroblast growth factor receptor 1 signaling.

The present study aimed to investigate the role of S100B in the inflammation process during osteoarthritis (OA). OA cartilage samples were collected for S100B expression analysis. S100B expression levels were significantly increased in patients with OA compared with the Controls (1.28±0.66 vs. 0.42±0.31; P=0.01) and were determined to be correlated with TNF-α (r=0.42; P=0.04) and IL-1β (r=0.73; P=0.001) expression levels. Orthopedic casting tape was used to immobilize the right knee at 180° extension of adult female New Zealand white rabbits for 4 weeks to establish an OA model. Cartilage specimens from the medial femoral condyle of these rabbits were used for histological confirmation and immunohistochemical analyses, whereas synovial fluid was used in ELISA assays for tumor necrosis factor (TNF)-α and interleukin (IL)-1β expression levels. Human synovial fibroblasts from the knee synovial tissues of normal patients with traumatic injury were transfected with S100B overexpression and knockdown plasmids and subjected to lipopolysaccharide (LPS) stimulation; subsequently, TNF-α and IL-1β expression levels in conditioned medium were determined by ELISA; S100B overexpression and knockdown significantly increased and decreased the TNF-α and IL-1β expression levels, respectively. Increased TNF-α (573.3±15.4 vs. 102.6±8.7 pg) and IL-1β (378.6±7.2 vs. 170.1±5.8 pg) expression levels were detected in OA model rabbits compared with the Control rabbits. Additionally, S100B, fibroblast growth factor (FGF)-1 and FGF receptor (FGFR)-1 mRNA and protein expression levels were increased in OA model rabbits compared with the Control group. FGFR1 knockdown significantly decreased TNF-α and IL-1β expression levels in LPS-stimulated S100B-overexpressing human synovial fibroblasts. S100B is involved in FGFR1 signaling-mediated inflammatory response during OA, which may be considered as a potential therapeutic target.

Electrical stimulation promotes regeneration and re-myelination of axons of injured facial nerve in rats

ObjectiveTo investigate the effects of electrical stimulation (ES) on the nerve regeneration and functional recovery of facial expression muscles in facial nerve defect rats.MethodsSixty rats were surgically introduced with a 1-cm defect on the right facial nerves and evenly divided into the Surgery group (Group A, the main trunk of the right facial nerve was surgically cut-off with a 1.0 cm at the foramina stylomastoideum) and the Surgery + ES group (Group B). Twenty normal rats were as normal control group (without receiving surgery or ES). For rats in group B, the orbicularis oris muscle of the right paralyzed face was stimulated with an electrical pulse of 3 V, 20 Hz and 0.3 mA for 1 h each day. The effects of ES on the facial muscle movement, compound muscle action potentials (CMAPs), histological structure, and the expression levels of S100B and NF200 proteins were comparatively studied.ResultsIn group A, facial paralysis scores were slightly improved from day 1 to 28; the facial nerve trunks had swelled and malformed till day 14; and CMAPs could be induced in fewer animals and were abnormal, resulting in a slow recovery of the facial muscle movement. In group B, facial paralysis scores were improved from 4 to 2.6 during the 4 weeks; more rats showed a higher amplitude and shorter latency of CMAPs from day 14 to 28 after surgery; and increased axons and the expression of S100B and NF200 proteins and gradually decreased swelling in the injured facial nerve.ConclusionES promotes outgrowth and myelination of axons and a partial functional recovery of facial muscles in injured facial nerve rats.

Chronic LiCl pretreatment suppresses thrombin-stimulated intracellular calcium mobilization through TRPC3 in astroglioma cells.

Transient receptor potential canonical type 3 (TRPC3) channels are activated in B lymphoblast cell lines from patients with bipolar disorder (BD), and its expression is reduced by chronic lithium treatment, implicating TRPC3 in the intracellular calcium (Ca2+ ) dyshomeostasis of BD. Thrombin, via a protease-activated receptor, moderates Ca2+ signaling and TRPC3 in astrocytes, and also cell proliferation. We examined whether lithium pretreatment attenuates thrombin-stimulated TRPC3 expression and function in astrocytes, and levels of the calcium-binding peptide, S100B, which is expressed mainly in these cells. Human astroglioma, U-87MG, cells were pretreated with 1mmolL-1 LiCl for 1day (acute), 3days (subacute), and 7days (chronic). To examine the role of TRPC3, genetically stable knockdown TRPC3 cells (TRPC3Low cells) were constructed using U-87MG cells. Thrombin (2.0U/mL)-stimulated Ca2+ mobilization was measured by ratiometric fluorimetry. Changes in TRPC3 and S100B expression levels were determined by quantitative reverse transcription-polymerase chain reaction and immunoblotting, respectively. Cell proliferation was also measured using the WST-8 assay. In this cell model, thrombin-stimulated Ca2+ mobilization, and both TRPC3 and S100B expression were suppressed by chronic LiCl pretreatment and the knockdown of TRPC3. Additionally, cell proliferation was attenuated in TRPC3Low cells, compared with the negative control vector-transfected cell. The reduced Ca2+ mobilization and S100B expression levels following chronic LiCl pretreatment and in TRPC3Low cells support the notion that TRPC3 modulates S100B expression and is the target of the LiCl effect. Downregulation of TRPC3 may be an important mechanism by which lithium ameliorates pathophysiological intracellular Ca2+ disturbances as observed in BD, accounting, in part, for its mood-stabilizing effects.

The expression of endothelial barrier antigen (EBA) and S100B in the rat parietal cortex following brain irradiation

Objective: To visualize the dynamic expression of endothelial barrier antigen (EBA) and S100B in the rat parietal cortex at the acute phase of radiation-induced brain injury using computed tomography (CT). Methods: A rat model of brain injury was established by CT scanning. The expression of EBA and S100B in the parietal cortex was analyzed at different time points by immunohistochemistry (IHC) and western blotting. Results: Significantly increased EBA expression was detected in the animals in the control group compared with the animals receiving CT radiation, which exhibited significantly reduced EBA levels within the vessel walls (F=33.29, p<0.05), particularly at day 3 after radiation. Both immunohistochemical staining and western blot analysis indicated that the positive expression levels of S100B among radiation groups were increased compared with the control group (IHC, F=28.05, p<0.05; WB, F=175.3, p<0.05). The expression of S100B peaked at day 3 (IHC, 102718±8710; WB, 2320±0.129), and subsequently decreased. Conclusion: CT radiation can induce altered EBA and S100B protein expression. Decreased EBA expression levels indicated that the integrity of the blood–brain barrier (BBB) was affected by radiation. The destruction of the BBB and the expression of S100B might play important roles in the incidence and repair of the early radiation-induced brain injury, and radiation represents a cause of mental disorders.

Human muscle satellite cells show age-related differential expression of S100B protein and RAGE

During aging, skeletal muscles show reduced mass and functional capacity largely due to loss of the regenerative ability of satellite cells (SCs), the quiescent stem cells located beneath the basal lamina surrounding each myofiber. While both the external environment and intrinsic properties of SCs appear to contribute to the age-related SC deficiency, the latter ones have been poorly investigated especially in humans. In the present work, we analyzed several parameters of SCs derived from biopsies of vastus lateralis muscle from healthy non-trained young (28.7 ± 5.9 years; n = 10) and aged (77.3 ± 6.4 years; n = 11) people. Compared with young SCs, aged SCs showed impaired differentiation when cultured in differentiation medium, and exhibited the following: (1) reduced proliferation; (2) higher expression levels of S100B, a negative regulator of myoblast differentiation; (3) undetectable levels in growth medium of full-length RAGE (receptor for advanced glycation end products), a multiligand receptor of the immunoglobulin superfamily, the engagement of which enhances myoblast differentiation; and (4) lower expression levels of the transcription factors, MyoD and Pax7. Also, either overexpression of full-length RAGE or knockdown of S100B in aged SCs resulted in enhanced differentiation, while overexpression of either a non-transducing mutant of RAGE (RAGEΔcyto) or S100B in young SCs resulted in reduced differentiation compared with controls. Moreover, while aged SCs maintained the ability to respond to mitogenic factors (e.g., bFGF and S100B), they were no longer able to secrete these factors, unlike young SCs. These data support a role for intrinsic factors, besides the extracellular environment in the defective SC function in aged skeletal muscles.

S100B Protein in the Nervous System and Cardiovascular Apparatus in Normal and Pathological Conditions

Accumulating evidence suggests that S100B, a Ca2+-binding protein of the EF-hand type, functions as a regulator of intracellular activities and as an extracellular signal. Within cells, S100B interacts with a relatively large number of target proteins thereby regulating their functions (Figure 1). While most of these interactions are Ca2+ dependent, in some instances S100B/target protein interactions are not. S100B is also secreted by certain cell types and released by activated/damaged/necrotic cells. Secreted/released S100B can affect cellular functions with varying effects depending on its local concentration. Figure 1 Schematic representation of intracellular regulatory effects of S100B. S100B is not a ubiquitous protein, its expression being restricted to astrocytes, Schwann cells, ependymocytes, certain neuronal populations, adipocytes, chondrocytes, melanocytes, dendritic cells, muscle satellite cells, skeletal myofibers, arterial smooth muscle cells, and bronchial epithelium, in normal physiological conditions. However, the S100B cell expression pattern during prenatal and postnatal development might be different (there is limited information about this issue); S100B expression levels in certain cell types may be varied in response to extracellular factors; levels of S100B are high in several cancer cells; S100B expression may be induced in cardiomyocytes and arterial endothelium in response to norepinephrine. Serum levels of S100B in normal prepubescent and postpubescent human subjects are relatively high and low, respectively, and increases in S100B serum levels are found in physiological conditions (such as intense physical exercise) and in several pathological conditions (mostly, brain diseases, certain psychiatric disorders, melanoma, and heart infarction and insufficiency). The present special issue of “Cardiovascular Psychiatry and Neurology” focuses on the brain-heart role of S100B. In the adult brain, S100B amounts to ~0.5% of cytoplasmic protein content and is most abundant in astrocytes (with an estimated concentration of ~10 μM), where the protein is found diffusely in the cytoplasm and associated with microtubules, GFAP intermediate filaments, and intracellular membranes. Such a high concentration and its diffuse localization in the cytoplasm explain S100B's ability to interact with enzymes, enzyme substrates, scaffold/adaptor proteins, transcription factors, and cytoskeleton constituents thereby regulating energy metabolism, Ca2+ homeostasis, transcription, and cell shape, proliferation, differentiation, and motility (Figure 1). Besides, ~5% of S100B is being constitutively secreted by astrocytes; S100B secretion can be enhanced or reduced by a number of factors and/or conditions; in case of brain damage, large amounts of S100B are being passively released, with a fraction of the protein diffusing into the cerebrospinal fluid (CSF) and blood. Whereas increases in the CFS and/or serum S100B content are taken as an indication of brain damage (yet increases in serum S100B content might point to nonbrain damage as well), a large body of evidence indicates that brain extracellular S100B behaves as a neurotrophin in normal physiological conditions and as a damage-associated molecular pattern (DAMP) factor upon massive release consequent to astrocyte activation or necrosis. In this latter case, S100B participates in the amplification of the brain inflammatory response by activating microglia and astrocytes and exerting toxic effects on neurons. RAGE (receptor for advanced glycation end products) has been identified as the receptor transducing both trophic and toxic effects of S100B in the brain and might act as a coreceptor supporting certain S100B effects on microglia (Figure 2). Figure 2 Schematic representation of extracellular regulatory effects of S100B on neurons, microglia, and astrocytes. As an intracellular regulator, S100B also participates in myocardium remodeling post infarction inhibiting the hypertrophic response in cardiomyocytes surviving the insult, and once released from necrotic cardiomyocytes, it acts as a DAMP factor causing cell death again via RAGE engagement. Adipocytes also release S100B in response to catecholamines with unidentified effects, though. Lastly, as a DAMP factor, S100B also participates in the pathophysiology of atherosclerosis stimulating vascular smooth cell proliferation and activating monocytes/macrophages. The present issue of “Cardiovascular Psychiatry and Neurology” attempts to delineate the functional roles of S100B in the brain and the cardiovascular apparatus and to update the information about this multifaceted protein. We are confident that both cell biologists and clinicians will benefit by the reading of the papers presented therein. Rosario Donato Claus W. Heizmann