S100 Calcium-binding Protein Research Articles

Efficacy of biomarkers and imaging techniques for the diagnosis of traumatic brain injury: challenges and opportunities.

Concussion is a pervasive health issue in the present day. Increased prevalence in recent years has indicated a need to improve the current understanding of minor traumatic brain injury (mTBI). Effort has been devoted to understanding the underlying pathophysiology of TBIs, but some mechanisms remain unknown. Potentially lethal secondary effects of concussion include second impact syndrome and chronic traumatic encephalopathy (CTE), introducing long-term considerations for the management of mTBI. Post-concussion syndrome is another long-term consequence of concussion and may be influenced by both neuroinflammation and hormonal imbalances resulting from head trauma. Genetically mutated apolipoprotein E may also contribute to the severity and persistence of concussion symptoms, perhaps even acting as a risk factor for CTE. As it stands, the diagnosis of concussion is nuanced, depending primarily on subjective diagnostic tools that incorporate patient-reported symptoms and neurocognitive tests. Diagnostic tools provide some assistance in concussion diagnosis, but still lack accuracy and inherently leave room for uncertainty. To mitigate some of this uncertainty, considerable research has been devoted to the development of methods to diagnose concussions objectively. Biomarkers such as S100 calcium binding protein B (S100B), glial fibrillary acidic protein (GFAP), neurofilament light protein (Nf-L), interleukin-6 (IL-6) and microRNAs (miRNAs) as well as imaging techniques including diffusion tensor imaging (DTI) and blood-oxygen level dependent functional magnetic resonance imaging (BOLD-fMRI) show great promise in this regard. This review aims to compile the relevant literature in these areas in the hopes of being used as a reference point for future research regarding concussions.

S100A2 upregulates GLUT1 expression to promote glycolysis in the progression of nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is a malignant epithelial tumor. Among the S100 protein family members, the imbalance of S100 calcium-binding protein A2 (S100A2) was related to the pathogenesis of several types of cancer, and S100A2 has been reported to be upregulated in the plasma of NPC patients; however, its specific role in NPC pathogenesis remains unclear. Thus, this study aims to determine the potential role of S100A2 in NPC to provide novel insights into NPC management. C666-1 and NPC/HK-1 cells were transfected with S100A2 silencing/overexpression (si/oe) constructs. For in vivo investigations, NPC/HK-1 cells were transfected with si/oe-S100A2 to induce tumor formation in nude mice. Cellular viability and apoptosis were assessed using the CCK8 assay, colony-forming assay, and flow cytometry. Glucose uptake and lactate production levels were quantified using biochemical assays. S100A2 expression was measured via RT-qPCR, Western blot, immunohistochemistry, and immunofluorescence were performed to determine the levels of S100A2, PI3K, AKT, p-PI3K, p-AKT, GLUT1, HK-2, LDHA, and ki-67 proteins. S100A2 expression levels were significantly higher in NPC cancer tissues than in adjacent tissues. Similarly, C666-1 and NPC/HK-1 cells exhibited increased S100A2 expression, and silencing S100A2 significantly inhibited NPC cell viability, proliferation, glucose uptake, and lactate production, and induced apoptosis and decreased the protein levels of GLUT1, LDHA, and HK2 in NPC cells. Conversely, S100A2 overexpression enhanced these characteristics in NPC cells but could be mitigated by the PI3K/AKT inhibitor (LY294002). Silencing S100A2 suppressed the tumor formation of NPC/HK-1 cells, while S100A2 overexpression promoted tumor formation and could be hindered by a GLUT1 inhibitor (WZB117). S100A2 is upregulated in cancer tissues of NPC patients and was found to promote proliferation, glycolysis, and tumor formation in NPC cells through its interaction with GLUT1.

Human Leukocyte Antigen Polymorphism and Blood Biomarker Profiles in Parkinson’s Disease: A Pilot Study in a Latvian Cohort

Background: Parkinson’s disease (PD) is a neurodegenerative disorder characterised by a high prevalence of sporadic cases. Various molecular mechanisms are involved in its pathogenesis. This pilot study aimed to identify potential risk and protective human leukocyte antigen (HLA) alleles in PD, discover candidate alleles for further research, and evaluate potential blood biomarkers. Methods: A total of 43 PD patients and 79 unrelated sex-matched controls were enrolled in this study. We analysed the polymorphism of HLA-DRB1, HLA-DQA1, and HLA-DQB1 alleles and the blood levels of biomarkers such as S100 calcium-binding protein A9 (S1000A9), kynurenic acid (KYNA), neurofilament light chain (NfL), and glutamate decarboxylase (GAD1). Results: We found that the frequencies of the HLA-DRB1*04, -DQA1*02:01, and -DQA1*03:01 alleles were significantly higher in the PD patients than in the controls, suggesting that these alleles are potential risk factors. Furthermore, the HLA-DQA1*02:01 allele was detected more frequently in the PD group when the disease onset was at 60 years or older. On the contrary, the HLA-DRB1*01 and HLA-DQA1*05:01 alleles were less common in the PD patients, indicating a possible protective effect. Regarding biomarkers, the blood levels of S100 calcium-binding protein A9 were significantly higher, and the kynurenic acid levels were significantly lower in the PD group. The NfL levels were also higher in the PD group but did not reach statistical significance, possibly due to the sensitivity limitations of the ELISA method used. The GAD1 levels showed no significant differences between the two groups. Conclusions: Our findings indicate that the HLA-DRB1*01 and -DRB1*04 alleles and the HLA-DQA1*02:01, -DQA1*03:01, and -DQA1*05:01 alleles are associated with PD. Moreover, S100 calcium-binding protein A9 and kynurenic acid can be considered potential blood biomarkers for PD. These findings contribute to the growing body of knowledge on PD and offer new directions for further research in Latvian cohorts.

VDAC1-NF-κB/p65-mediated S100A16 contributes to myocardial ischemia/reperfusion injury by regulating oxidative stress and inflammatory response via Calmodulin/CaMKK2/AMPK pathway

Myocardial injury triggers intense inflammatory reactions and oxidative stress responses. S100 calcium-binding protein A16 (S100A16), a multi-functional calcium (Ca2+)-binding protein, participates in inflammatory responses and contributes to ischemia/reperfusion (I/R) injury. Nevertheless, the precise mechanism by which S100A16 operates in myocardial I/R injury remains uncertain. Cardiac I/R injury was produced by ligation/release of the left anterior descending artery, and mouse cardiac cells were subjected to hypoxia/reoxygenation (H/R) to determine the biological effects in vitro. We demonstrated that S100A16 was upregulated in the ischemic hearts and cardiac cells after I/R and H/R injury. Adenovirus-mediated S100A16 inhibition led to a considerable improvement in cardiac function with a reduced infarct size, accompanied by a reduction in cardiomyocyte apoptosis. Similar effects of S100A16 inhibition on inflammation and reactive oxygen species (ROS) production were observed in cultured cardiomyocytes. Importantly, we showed that I/R and H/R treatment upregulated the expression of voltage-dependent anion channel 1 (VDAC1), which subsequently activated NF-κB/p65 to facilitate the binding of NF-κB/p65 to the S100A16 promoter, thereby activating the transcription and expression of S100A16. Mechanically, S100A16 responded to increasing Ca2+ and interacted with calmodulin (CaM) to regulate the activation of calcium/calmodulin-dependent protein kinase 2 (CAMKK2)/AMPK pathway. In conclusion, VDAC1 sustained the NF-κB p65 pathway activation to elicit increased S100A16 expression, contributing to myocardial damage and heart failure post-I/R via the CaM/CaMKK2/AMPK pathway. This study revealed a crucial role of the VDAC1-S100A16 axis in the process of myocardial I/R injury, providing novel molecular targets for the treatment of cardiac conditions associated with I/R injury.

The diagnostic value investigation of programmed cell death genes in heart failure

BackgroundWe aimed to identify the potential diagnostic markers and associated molecular mechanisms based on programmed cell death (PCD)-related genes in patients with heart failure (HF).MethodsThree HF gene expression data were extracted from the GEO database, including GSE57345 (training data), GSE141910 and GSE76701 (validation data), followed by differentially PCD related genes (DPCDs) was shown between HF and control samples. Enrichment and protein-protein interaction (PPI) network analyses were performed based on the DPCDs. Subsequently, a diagnostic model was constructed and validated after exploring the diagnostic markers using machine learning. A nomogram was used to determine the clinical diagnostic value. Diagnostic marker-based immune, transcription network, and gene set enrichment (GSE) analyses were performed. Finally, the drug-target network was investigated.ResultsTwenty DPCDs were revealed between the two groups. These genes, such as Serpin Family E Member 1 (SERPINE1), are mainly enriched in pathways such as the regulation of the inflammatory response. A PPI network was constructed using 14 DPCDs. Eight diagnostic markers, such as SERPINE1, CD38 molecule (CD38), and S100 calcium-binding protein A9 (S100A9), were explored using machine learning algorithms, followed by diagnostic model construction. A nomogram and immune-associated analysis was used to validate the diagnostic value of these genes and the model. Moreover, the transcription regulation network and drug-target interactions were further investigated. Finally, qRT-PCR confirmed that the expression levels of eight signature genes (CD14, CD38, CTSK, LAPTM5, S100A9, SERPINE1, SLC11A1, and STAT3) were significantly elevated in the observation group, consistent with the results of bioinformatics analysis.ConclusionsThis study constructed a valuable diagnostic model for HF using the eight identified DPCDs as diagnostic markers.

KL‑6, ET‑1 and S100A9 levels in patients with idiopathic pulmonary fibrosis and obstructive sleep apnea.

Obstructive sleep apnea (OSA) and idiopathic pulmonary fibrosis (IPF) frequently coexist. Elevated levels of Krebs von den Lungen-6 (KL-6), endothelin-1 (ET-1) and S100 calcium-binding protein A9 (S100A9) have been observed in patients with IPF, suggesting their potential role as biomarkers for lung fibrosis. The aim of the present study was to measure the levels of KL-6, ET-1 and S100A9 in patients with IPF-OSA and to test the potential of these biomarkers as a characteristic OSA signature with diagnostic and prognostic potential for IPF. A total of 55 subjects with newly-diagnosed IPF participated in the present cross-sectional study. In addition to performing overnight attended polysomnography and pulmonary function tests, serum and bronchoalveolar lavage (BAL) levels of KL-6, along with serum levels of ET-1 and S100A9, were also assessed. A total of 15 patients with IPF and 40 patients with IPF-OSA were included. Age, sex, comorbidities and pulmonary function tests did not differ between the groups. Although there was no significant difference between groups in the levels of KL-6, ET-1 and S100A9 (P>0.05), the serum ET-1 levels tended to be elevated in patients with OSA-IPF compared with patients with IPF (1.78 vs. 1.07 pg/ml; P=0.06). Additionally, a significant association was observed between serum KL-6 levels and the severity of IPF, and also between BAL KL-6 levels and nocturnal mean SaO2 levels, even after taking into account factors such as obesity and smoking. S100A9 levels were associated with the oxygen desaturation index, even after adjustments for obesity, smoking and the gender-age-physiology index, only in the IPF-OSA group. Conclusively, the present findings suggested significant associations between serum ET-1, S100A9 and BAL KL-6 levels and specific OSA severity parameters in the IPF-OSA group. This evidence suggested that these molecules could serve as biomarkers for the identification of patients with IPF-OSA, offering a distinct OSA signature that has diagnostic and potential treatment value. Larger studies are crucial to substantiate the present findings and reinforce this hypothesis.

Neutrophil and mononuclear leukocyte pathways and upstream regulators revealed by serum proteomics of adult and juvenile dermatomyositis

ObjectivesSerum protein abundance was assessed in adult and juvenile dermatomyositis (DM and JDM) patients to determine differentially regulated proteins, altered pathways, and candidate disease activity biomarkers.MethodsSerum protein expression from 17 active adult DM and JDM patients each was compared to matched, healthy control subjects by a multiplex immunoassay. Pathway analysis and protein clustering of the differentially regulated proteins were examined to assess underlying mechanisms. Candidate disease activity biomarkers were identified by correlating protein expression with disease activity measures.ResultsSeventy-eight of 172 proteins were differentially expressed in the sera of DM and JDM patients compared to healthy controls. Forty-eight proteins were differentially expressed in DM, 32 proteins in JDM, and 14 proteins in both DM and JDM. Twelve additional differentially expressed proteins were identified after combining the DM and JDM cohorts. C-X-C motif chemokine ligand 10 (CXCL10) was the most strongly upregulated protein in both DM and JDM sera. Other highly upregulated proteins in DM included S100 calcium binding protein A12 (S100A12), CXCL9, and nicotinamide phosphoribosyltransferase (NAMPT), while highly upregulated proteins in JDM included matrix metallopeptidase 3 (MMP3), growth differentiation factor 15 (GDF15), and von Willebrand factor (vWF). Pathway analysis indicated that phosphoinositide 3-kinase (PI3K), p38 mitogen-activated protein kinase (MAPK), and toll-like receptor 7 (TLR7) signaling were activated in DM and JDM. Additional pathways specific to DM or JDM were identified. A protein cluster associated with neutrophils and mononuclear leukocytes and a cluster of interferon-associated proteins were observed in both DM and JDM. Twenty-two proteins in DM and 24 proteins in JDM sera correlated with global, muscle, and/or skin disease activity. Seven proteins correlated with disease activity measures in both DM and JDM sera. IL-1 receptor like 1 (IL1RL1) emerged as a candidate global disease activity biomarker in DM and JDM.ConclusionCoordinate analysis of protein expression in DM and JDM patient sera by a multiplex immunoassay validated previous gene expression studies and identified novel dysregulated proteins, altered signaling pathways, and candidate disease activity biomarkers. These findings may further inform the assessment of DM and JDM patients and aid in the identification of potential therapeutic targets.

Icariin ameliorates Coxsackievirus B3-induced viral myocarditis by modulating the S100 calcium binding protein A6/β-catenin/c-Myc signaling pathway

BackgroundCoxsackievirus B3 (CVB3) is a leading cause of viral myocarditis and is currently lacking specific pharmacological treatments, highlighting the critical need for therapeutic development. Icariin (ICA), a prenylated flavonol glycoside, was previously found to exhibit several pharmacological effects, but its potential to combat CVB3 remains uninvestigated. PurposeThis study aimed to elucidate the anti-CVB3 efficacy of ICA and elucidate its molecular mechanisms. MethodsCVB3-infected HeLa cells, H9C2 cells and neonate rat ventricular cardiomyocytes (NRVCs) were selected as in vitro models, and were treated with ICA at 1 and 10 μM. Additionally, BALB/c mice that were infected with CVB3 via intraperitoneal injection were chosen as in vivo model and were treated with ICA or ribavirin over 3 days. The effect of ICA against CVB3 was determined by Cell Counting Kit-8 (CCK-8) assay, western blot, real-time fluorescence quantitative PCR (RT–qPCR), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, hematoxylin and eosin (H&E) staining, immunohistochemistry (IHC) and flow cytometry. ResultsIn this study, it was found that ICA is capable of reducing CVB3 viral load both in vitro and in vivo. Mechanistic studies suggested that ICA prevents cardiomyocyte apoptosis by attenuating the S100 calcium binding protein A6 (S100A6)/β-catenin/c-Myc signaling pathway. Additionally, ICA inhibits the secretion of proinflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin-1beta (IL-1β) and CXC motif chemokine ligand 2 (CXCL2) in heart tissue, thereby mitigating CVB3-induced myocarditis. Moreover, ICA also regulates the immune response of CD4+ T, CD8+ T and Treg cells by changing the cells numbers in spleen tissue. Lastly, ICA can reduce the load of other enteroviruses (such as CVA6, CVA16 and EV71) in rhabdomyosarcoma (RD) cells as well. ConclusionOur findings indicate that ICA provides significant protection against CVB3 infection by modulating the S100A6/β-catenin/c-Myc signaling pathway, suggesting its potential use as a novel drug against CVB3 infection in clinical application.

Astrocyte-TREM2 alleviates brain injury by regulating reactive astrocyte states following ischemic stroke.

Triggering receptor expressed on myeloid cells 2 (TREM2) has been shown to confer strong neuroprotective effects in acute ischemic stroke (AIS). However, as the vast majority of research findings to date are based on its functions in microglia, the precise role of TREM2 in astrocytes after AIS is unknown. Here, both loss- and gain-of-function experiments were employed to investigate how astrocytic TREM2 influences the pathogenesis of AIS in vivo and in vitro. Our results demonstrated that cerebral ischemia triggered induction of TREM2 expression on reactive astrocytes following AIS. In addition, astrocyte-specific TREM2 knockout mice exhibited much greater brain injury than TREM2 flox/flox controls following AIS, as evidenced by increased cerebral infarct volume, neuronal apoptosis and neurological deficit, which was associated with an increased expression of pro-inflammatory molecule complement component 3 (C3) on reactive astrocytes and activation of microglia/macrophages but decreased expression of S100 calcium binding protein A10 (S100A10) and arginase1 (Arg1) on reactive astrocytes. Mechanistic analyses revealed that astrocytic TREM2 alleviated brain injury by inhibiting detrimental actions of reactive astrocytes but promoting their neuro- and glioprotective actions via the kruppel-like transcription factor-4-nuclear factor-κB axis. Together, this study provides novel evidence for a critical protective role of astrocyte-derived TREM2 in AIS and highlights a potential therapeutic target for the treatment of AIS.

S100A4 Exerts Neuroprotective Effects by Attenuating Blood-Brain Barrier Disruption and Oxidative Stress via the PI3K/Akt/Nrf2 Axis in Ischemic Stroke

Ischemic stroke is a major cause of disability and mortality worldwide, with oxidative stress and blood-brain barrier (BBB) injury playing crucial roles in its pathogenesis. Our RNA sequencing results revealed that S100 calcium-binding protein A4 (S100A4) is highly expressed in the middle cerebral artery occlusion (MCAO) mouse model. We analyzed S100A4 expression in ischemic stroke patients and in mice subjected to the MCAO model. Moreover, using adeno-associated virus (AAV)-mediated knockdown of S100A4 in mice, we evaluated its effects on neurological deficits, BBB integrity, and oxidative stress in MCAO mice. Bioinformatic analyses explored the potential downstream pathways of S100A4.S100A4 expression was significantly elevated in the serum of ischemic stroke patients and brain tissues of MCAO mice. AAV-mediated knockdown of S100A4 exacerbated neurological deficits, BBB disruption, and oxidative stress in MCAO mice. The upregulation of S100A4 mitigated these outcomes, which were facilitated through the stimulation of the PI3K/Akt/Nrf2 signaling cascade.Our results illustrate that S100A4 plays a protective role in preventing neuronal damage during ischemic stroke by reducing oxidative stress and preserving BBB integrity through the PI3K/Akt/Nrf2 pathway. This highlights its promise as a potential therapeutic approach for ischemic stroke.

The Effect of Acute Stroke Treatment on S100B, IMA, and Thiol-Disulfide Balance.

A variety of processes, ranging from blood-brain barrier disruption to circulating biomarkers, contributes to reperfusion injury in acute stroke treatment. We aimed to investigate the effects of thrombolytic therapy and endovascular thrombectomy therapy on serum S100 calcium-binding protein B, ischemia-modified albumin and thiol-disulfide balance in patients who arrived within the first 6 h of acute ischemic stroke. The study considered 66 patients with the diagnosis of acute ischemic stroke who underwent thrombolytic therapy or EVT in the first 6 h, as well as 32 healthy volunteers. Venous blood samples were collected before tPA and EVT and 24 h after treatment. S100B, native thiol, disulfide, total thiol, and Ischemia-modified albumin (IMA) levels were measured. The S100B, total thiol, and native thiol values of the patients in the tPA group before and after the treatment showed statistical significance (P < 0.001). S100B, total thiol, and native thiol values were shown to be lower. The disulfide and IMA values of the patients in the tPA group did not differ significantly (respectively, P = 0.302, P = 0.054). However, disulfide and IMA levels were found to increase after treatment compared to pretreatment. The patients in the EVT group showed a significant difference in terms of S100B values (P < 0.001) and IMA values (P = 0.024). Determining how to protect the brain from free radical damage is important. More research should be carried out on treatments that prevent free radical damage in ischemia-reperfusion injury, as well as treatments for acute ischemic stroke.

Honey Enriched with Additives Alleviates Behavioral, Oxidative Stress, and Brain Alterations Induced by Heavy Metals and Imidacloprid in Zebrafish.

Environmental concerns have consistently been a focal point for the scientific community. Pollution is a critical ecological issue that poses significant threats to human health and agricultural production. Contamination with heavy metals and pesticides is a considerable concern, a threat to the environment, and warrants special attention. In this study, we investigated the significant issues arising from sub-chronic exposure to imidacloprid (IMI), mercury (Hg), and cadmium (Cd), either alone or in combination, using zebrafish (Danio rerio) as an animal model. Additionally, we assessed the potential protective effects of polyfloral honey enriched with natural ingredients, also called honey formulation (HF), against the combined sub-chronic toxic effects of the three contaminants. The effects of IMI (0.5 mg·L-1), Hg (15 μg·L-1), and Cd (5 μg·L-1), both individually and in combination with HF (500 mg·L-1), on zebrafish were evaluated by quantifying acetylcholinesterase (AChE) activity, lipid peroxidation (MDA), various antioxidant enzyme activities like superoxide dismutase and glutathione peroxidase (SOD and GPx), 2D locomotor activity, social behavior, histological and immunohistochemical factors, and changes in body element concentrations. Our findings revealed that all concentrations of pollutants may disrupt social behavior, diminish swimming performances (measured by total distance traveled, inactivity, and swimming speed), and elevate oxidative stress (OS) biomarkers of SOD, GPx, and MDA in zebrafish over the 21-day administration period. Fish exposed to IMI and Hg + Cd + IMI displayed severe lesions and increased GFAP (Glial fibrillary acidic protein) and S100B (S100 calcium-binding protein B) protein expression in the optic tectum and cerebellum, conclusively indicating astrocyte activation and neurotoxic effects. Furthermore, PCNA (Proliferating cell nuclear antigen) staining revealed reduced cell proliferation in the IMI-exposed group, contrasting with intensified proliferation in the Hg + Cd group. The nervous system exhibited significant damage across all studied concentrations, confirming the observed behavioral changes. Moreover, HF supplementation significantly mitigated the toxicity induced by contaminants and reduced OS. Therefore, the exposure to chemical mixtures offers a more complete picture of adverse impacts on aquatic ecosystems and the supplementation with bioactive compounds can help to reduce the toxicity induced by exposure to environmental pollutants.

Omega-3 Fatty Acids and Neuroinflammation in Depression: Targeting Damage-Associated Molecular Patterns and Neural Biomarkers.

Major Depressive Disorder (MDD) is a prevalent mental health condition with a complex pathophysiology involving neuroinflammation, neurodegeneration, and disruptions in neuronal and glial cell function. Microglia, the innate immune cells of the central nervous system, release inflammatory cytokines in response to pathological changes associated with MDD. Damage-associated molecular patterns (DAMPs) act as alarms, triggering microglial activation and subsequent inflammatory cytokine release. This review examines the cellular mechanisms underlying MDD pathophysiology, focusing on the lipid-mediated modulation of neuroinflammation. We explore the intricate roles of microglia and astrocytes in propagating inflammatory cascades and discuss how these processes affect neuronal integrity at the cellular level. Central to our analysis are three key molecules: High Mobility Group Box 1 (HMGB1) and S100 Calcium Binding Protein β (S100β) as alarmins, and Neuron-Specific Enolase (NSE) as an indicator of neuronal stress. We present evidence from in vitro and ex vivo studies demonstrating how these molecules reflect and contribute to the neuroinflammatory milieu characteristic of MDD. The review then explores the potential of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) as neuroinflammation modulators, examining their effects on microglial activation, cytokine production, and neuronal resilience in cellular models of depression. We critically analyze experimental data on how ω-3 PUFA supplementation influences the expression and release of HMGB1, S100β, and NSE in neuronal and glial cultures. By integrating findings from lipidomic and cellular neurobiology, this review aims to elucidate the mechanisms by which ω-3 PUFAs may exert their antidepressant effects through modulation of neuroinflammatory markers. These insights contribute to our understanding of lipid-mediated neuroprotection in MDD and may inform the development of targeted, lipid-based therapies for both depression and neurodegenerative disorders.

NSE and S100β as serum alarmins in predicting neurological outcomes after cardiac arrest

Cardiac arrest (CA) is a serious health concern that often results in mortality or severe neurological dysfunction in the case of survival. Our aim was to explore the neurological prognostic factors in patients with CA. This retrospective observational study included adult patients with CA. We investigated serum neuron-specific enolase (NSE), S100 calcium-binding protein β (S100β), and indices and parameters at 1, 3, 5, 7 and intensive care unit (ICU) discharge days after CA. The primary study endpoint was the Cerebral Performance Category (CPC) scale score at ICU discharge, which was dichotomized as good neurological outcome (CPC 1–2: full recovery or moderate disability) and poor neurological outcome (CPC 3–5: severe disability, vegetative state, or death). Of the 191 adult patients with CA, 42 (22%) had good neurological outcomes, and 149 (78%) had poor neurological outcomes. NSE at 1,3,5,7 and ICU discharge days showed excellent predictive accuracy for neurological outcomes (area under the curve [AUC]: 0.666, 0.716, 0.870, 0.739, and 0.901, respectively). However, S100β exhibited general predictive power (AUC: 0.666, 0.573, 0.607, 0.594, 0.727). Finally, the early warning model, which combined day 1 NSE, day 1 S100β, cardiac arrest time, SOFA scores, APACHE II scores, and age, was used to screen CA patients with poor neurological prognosis at early stages and had an AUC of 0.792. Serum concentrations of NSE and S100β were significantly elevated in CA patients and could be prognostic biomarkers to predict neurological outcomes. Day 1 NSE and S100β combined with multiple indicators could be a decent early warning model for poor neurological prognosis in patients with CA.

Bifunctional MoO3-x/CuS Heterojunction Nanozyme-Driven "Turn-On" SERS Signal for the Sensitive Detection of Cerebral Infarction Biomarker S100B.

The use of nanozymes has become a promising auxiliary approach to "turn on" surface-enhanced Raman scattering (SERS) signals for the label-free detection of disease markers. Nevertheless, there are still major challenges to develop bifunctional nanomaterials with both excellent enzyme-like activity and high SERS performance. To this end, a novel Z-scheme MoO3-x/CuS heterojunction was first constructed as a powerful "two-in-one" substrate, which can not only catalyze leucomalachite green (LMG) to SERS-active malachite green (MG) but also serve as an efficient substrate to amplify the SERS signal of catalysate. Due to the strong interfacial coupling effect between the MoO3-x and CuS nanomaterial, which promoted the separation and transport of carriers in the heterojunction, the MoO3-x/CuS heterojunction showed higher peroxidase-like activity compared to individual components and the previously reported heterojunction nanozymes. Inspired by these results, a sandwich-type SERS immunoassay for the detection of the cerebral infarction biomarker S100 calcium-binding protein (S100B) was proposed based on the output signal of MG at 1620 cm-1. Furthermore, introducing the antifouling material chitosan on the surface of the MoO3-x/CuS heterojunction can effectively resist nonspecific protein adsorption and significantly improve the detection accuracy of the immunoassay. Therefore, the SERS immunoassay based on the MoO3-x/CuS heterojunction realized highly sensitive and selective detection of S100B in the concentration range of 0.001 to 100 ng/mL, with a low limit of detection of 0.47 pg/mL. The developed method has been successfully used for the accurate detection of S100B in clinical serum. The results showed that the level of S100B in the serum of cerebral infarction patients can be distinguished from those of healthy individuals and intracranial tumor patient controls. In addition, the acquired values of S100B in the serum of cerebral infarction patients based this strategy were well consistent with the results of electrochemiluminescence (ECL) detection with a relative error of less than ±7.3. It is expected that this work may open up a paradigm for improving detection sensitivity and accuracy for the early diagnosis and treatment monitoring of cerebral infarction in the clinic.

Role of Calcium in an Experimental Breast Cancer Model Induced by Radiation and Estrogen.

Background: Breast cancer, a global health challenge, significantly impacts women worldwide, causing morbidity, disability, and mortality. Objectives: To analyze the role of genes encoding S100 calcium-binding proteins and their relationship with radiation as possible markers in breast carcinogenesis. Methods: The normal MCF-10F cell line was used to study the role of ionizing radiation and estrogen to induce distinct stages of malignancy giving rise to an in vitro experimental breast cancer model. Results: Analysis of an Affymetrix system revealed that the gene expression levels of the S100 calcium-binding protein P (S100P), the S100 calcium-binding protein A14 (S100A14), and the S100 calcium-binding protein A2 (S100A2) were greater in the Tumor2 than the non-tumorigenic Alpha3 or the tumorigenic Alpha5 cell lines; however, the S100 calcium-binding protein A8 (S100A8) and the S100 calcium-binding protein A9 (S100A9) expression levels were higher in A5 than T2 and A3 cell lines. A significant positive association was found between the estrogen receptor alpha gene (ESR1) and S100A14 in Basal and Her2 patients. The association between ESR1 and S100A8 and S100A9 expression levels was positive in Basal patients but negative in Her2, Luminal A, and Luminal B. S100P and S100A14 expression levels were higher in tumor tissues than in normal ones. The estrogen receptor status was positive in patients with high levels of the S10014 gene, but negative in S100A2, S100A8, and S100A9 expression levels. Conclusion: Cell dependence needs to be considered while designing new breast cancer treatments since gene signatures might vary depending on the type of tumor.

Paquinimod attenuates retinal injuries by suppressing the S100A9/TLR4 signaling in an experimental model of diabetic retinopathy

Diabetic retinopathy (DR), the most common ocular complication of diabetes mellitus (DM), has exhibited an increase in incidence over the past decade. S100 calcium-binding protein A9 (S100A9) plays a significant role in inflammation and cancer. Toll-like receptor 4 (TLR4), a transmembrane receptor, initiates signaling cascades upon ligand binding. S100A9 activates TLR4, and their involvement in various diseases is well-established. We found elevated S100A9/TLR4 pathway proteins in the vitreous of DR patients. Bioinformatics analysis revealed differential gene expression related to this pathway. These proteins were also detected in diabetic rat retinas and induced structural damage. Paquinimod, an S100A9 inhibitor, decreased pathway protein expression and reduced retinal damage. Our study validates the S100A9/TLR4 pathway in diabetic retinas and suggests its potential as a therapeutic target for DR. Targeting S100A9 could offer a novel approach to prevention and treatment.

Effect of intravenous versus inhaled anesthetics on blood-brain barrier dysfunction and neuroinflammation in elderly patients undergoing major surgery: study protocol of a randomized controlled trial

BackgroundPostoperative cognitive dysfunction (POCD) is one of the major complications after surgery, with devastating clinical outcomes. Although POCD is a condition with a multifactorial pathophysiology, blood-brain barrier (BBB) dysfunction and neuronal injury have been shown to play a critical role, especially in the elderly. Previous studies have demonstrated that the choice of anesthetics affect BBB permeability and neuroinflammation. However, most studies are carried out on animals, with limited research undertaken on humans. Therefore, we will compare the effect of intravenous anesthetics and inhaled anesthetics on BBB dysfunction and the change of inflammatory markers after surgery.MethodsOne hundred and fifty-four patients who are 60 years of age or older undergoing major surgery for more than 2 h will be randomly allocated to two anesthetics groups (intravenous, inhaled) in a 1:1 ratio. In the intravenous anesthetics group (group P), propofol will be infused with a target-controlled infusion (TCI) system throughout the entire surgery. In the inhaled anesthetics group (group G), bolus injection of propofol will be administered for loss of consciousness, and simultaneously sevoflurane will be initiated for the maintenance of anesthesia. The primary outcome is the change in serum S100 calcium binding protein β (S100β) at four time points: before induction of anesthesia, at the end of surgery, 4 h after surgery, postoperative day 1. Secondary outcomes include changes in the inflammatory markers, serum interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α, and C-reactive protein; the incidence of delirium; and the change in the cognitive function between groups. In patients pre-scheduled for postoperative intensive care unit admission, the cerebrospinal fluid/serum albumin quotient (Qalb) between the two groups will be compared before and after surgery, and change in inflammatory markers in serum and CSF will be analyzed in relation to the Qalb.DiscussionThe current study will compare the effect of intravenous versus inhaled anesthetics on blood-brain barrier permeability and, as a result, the difference in neuroinflammation in elderly patients. Also, the study results will provide additional information to develop intraoperative anesthetic strategies to reduce POCD.Trial registrationThe trial was prospectively registered at Clinical Trials protocol registration with identifier 2310-117-126 on April 9, 2024.

TMT-Based Quantitative Proteomic Profiling of Human Esophageal Cancer Cells Reveals the Potential Mechanism and Potential Therapeutic Targets Associated With Radioresistance.

The recurrence of esophageal squamous cell carcinoma (ESCC) in radiation therapy treatment presents a complex challenge due to its resistance to radiation. However, the mechanism underlying the development of radioresistance in ESCC remains unclear. In this study, we aim to uncover the mechanisms underlying radioresistance in ESCC cells and identify potential targets for radiosensitization. We established two radio-resistant cell lines, TE-1R and KYSE-150R, from the parental ESCC cell lines TE-1 and KYSE-150 through fractionated irradiation. A TMT-based quantitative proteomic profiling approach was applied to identify changes in protein expression patterns. Cell Counting Kit-8, colony formation, γH2AX foci immunofluorescence and comet assays were utilized to validate our findings. The downstream effectors of the DNA repair pathway were confirmed using an HR/NHEJ reporter assay and Western blot analysis. Furthermore, we evaluated the expression of potential targets in ESCC tissues through immunohistochemistry combined with mass spectrometry. Over 2,000 proteins were quantitatively identified in the ESCC cell lysates. A comparison with radio-sensitive cells revealed 61 up-regulated and 14 down-regulated proteins in the radio-resistant cells. Additionally, radiation treatment induced 24 up-regulated and 12 down-regulated proteins in the radio-sensitive ESCC cells. Among the differentially expressed proteins, S100 calcium binding protein A6 (S100A6), glutamine gamma-glutamyltransferase 2 (TGM2), glycogen phosphorylase, brain form (PYGB), and Thymosin Beta 10 (TMSB10) were selected for further validation studies as they were found to be over-expressed in the accumulated radio-resistant ESCC cells and radio-resistant cells. Importantly, high S100A6 expression showed a positive correlation with cancer recurrence in ESCC patients. Our results suggest that several key proteins, including S100A6, TGM2, and PYGB, play a role in the development of radioresistance in ESCC. Our results revealed that several proteins including Protein S100-A6 (S100A6), Protein-glutamine gamma-glutamyltransferase 2 (TGM2), Glycogen phosphorylase, brain form (PYGB) were involved in radio-resistance development. These proteins could potentially serve as biomarkers for ESCC radio-resistance and as therapeutic targets to treat radio-resistant ESCC cells.

Insights for possible association and impact of thyroidectomy to osteoarthritis

Background and aim of studyThyroidectomy and osteoarthritis have drawn more attention in last decades due to increase various local and systemic risk factors. This study is aimed to determine the association and impact between thyroidectomy and osteoarthritis by serological measurement of most specific related markers.ResultsMeasurement of thyroid markers showed the level of thyroid-stimulating hormone (TSH) was significantly increased, while parathyroid hormone (PTH), triiodothyronine (T3), and thyroxine (T4) levels were decreased in osteoarthritis subjected to thyroidectomy group (OTG) when compared to hyperthyroidism subjected to thyroidectomy group (TG), osteoarthritis group (OG), and healthy control group (CG). Detection the activity of bone markers showed the level of R-factor was significantly elevated concomitant with significant reduction in Dickkopf related protein 1 (DKK1), human hyaluronan-binding protein 2 (HABP2), osteocalcin (OC) in OG and OTG groups, while osteopontin (OPN) and procollagen I C-terminal propeptide (PICP) were significantly increased and decreased in TG and OTG. Furthermore, the level of S100 Calcium binding protein (S100CBP) showed significant decreased in patient’s groups, while TG with OTG groups exhibited significant reduction in sclerostin (SOST) concentration. Regarding the inflammatory markers, the levels of interleukin-1 (IL-1) was increased in the OTG, while the level of interleukin-10 (IL-10) was increased in OG and TG groups, and reduced in OTG. While, the level of transforming growth factor-beta (TGF-β) was decreased in OG and TG associated with significant increases in tumor necrosis factor-alpha level (TNF-α) in OTG. Measurement of oxidant and antioxidant activity markers showed the levels of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) were significantly reduced in all patient’s groups compared to control, except the level of CAT in TG, whereas, malondialdehyde (MDA) level was increased in OG and OTG patients. Furthermore, the levels of Alkaline phosphatase (ALP), C-Reactive protein (CRP), and erythrocyte sedimentation rate (ESR) were increased in all patient groups compared to control, while fatty acid-binding protein (FABP) level was increased in OTG only.ConclusionThis unique study in Iraq is identified the interaction effect and impact of thyroidectomy to osteoarthritis according to the results that showed various changes and degree of correlation of study biomarkers in all patient groups, however more depth of specific quantitative and qualitative studies are required to support this association and the impact claim at molecular level.