RESUMEN

Icariside II, a flavonoid glycoside, is the main component found invivo after the administration of Herba epimedii and has shown some pharmacological effects, such as prevention of osteoporosis and enhancement of immunity. Increased levels of marrow adipose tissue are associated with osteoporosis. S100 calcium-binding protein A16 (S100A16) promotes the differentiation of bone marrow mesenchymal stem cells (BMSCs) into adipocytes. This study aimed to confirm the anti-lipidogenesis effect of Icariside II in the bone marrow by inhibiting S100A16 expression. We used ovariectomy (OVX) and BMSC models. The results showed that Icariside II reduced bone marrow fat content and inhibited BMSCs adipogenic differentiation and S100A16 expression, which correlated with lipogenesis. Overexpression of S100A16 eliminated the inhibitory effect of Icariside II on lipid formation. ß-catenin participated in the regulation adipogenesis mediated by Icariside II/S100A16 in the bone. In conclusion, Icariside II protects against OVX-induced bone marrow adipogenesis by downregulating S100A16, in which ß-catenin might also be involved.

Asunto(s)

Adipogénesis , Tejido Adiposo , Estrógenos , Flavonoides , Células Madre Mesenquimatosas , Ovariectomía , Animales , Adipogénesis/efectos de los fármacos , Femenino , Tejido Adiposo/metabolismo , Tejido Adiposo/efectos de los fármacos , Flavonoides/farmacología , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/efectos de los fármacos , Ratones , Estrógenos/metabolismo , Estrógenos/farmacología , Diferenciación Celular/efectos de los fármacos , Proteínas S100/metabolismo , Proteínas S100/genética , Médula Ósea/metabolismo , Médula Ósea/efectos de los fármacos , beta Catenina/metabolismo , Adipocitos/metabolismo , Adipocitos/efectos de los fármacos

RESUMEN

Proteins' fuzziness are features for communicating changes in cell signaling instigated by binding with secondary messengers, such as calcium ions, associated with the coordination of muscle contraction, neurotransmitter release, and gene expression. Binding with the disordered parts of a protein, calcium ions must balance their charge states with the shape of calcium-binding proteins and their versatile pool of partners depending on the circumstances they transmit, but it is unclear whether the limited experimental data available can be used to train models to accurately predict the charges of calcium-binding protein variants. Here, we developed a chemistry-informed, machine-learning algorithm that implements a game theoretic approach to explain the output of a machine-learning model without the prerequisite of an excessively large database for high-performance prediction of atomic charges. We used the ab initio electronic structure data representing calcium ions and the structures of the disordered segments of calcium-binding peptides with surrounding water molecules to train several explainable models. Network theory was used to extract the topological features of atomic interactions in the structurally complex data dictated by the coordination chemistry of a calcium ion, a potent indicator of its charge state in protein. With our designs, we provided a framework of explainable machine learning model to annotate atomic charges of calcium ions in calcium-binding proteins with domain knowledge in response to the chemical changes in an environment based on the limited size of scientific data in a genome space.

RESUMEN

S100 calcium-binding protein P (S100P) is a secretory protein that is expressed in various healthy tissues and tumors. Megakaryocyte-secreted S100P promotes osteoclast differentiation and function; however, its receptor and cellular signaling in osteoclasts remain unclear. Receptor for advanced glycation end products (RAGE), which is the receptor for S100P on cancer cells, was expressed in osteoclast precursors, and S100P-RAGE binding was confirmed through co-immunoprecipitation. Additionally, the phosphorylation of ERK and NF-κB was increased in S100P-stimulated osteoclast precursors but was inhibited by addition of the RAGE antagonistic peptide (RAP). S100P-induced osteoclast differentiation and excessive bone resorption activity were also reduced by the addition of RAP. This study demonstrates that S100P, upon binding with RAGE, activates the ERK and NF-κB signaling pathways in osteoclasts, leading to increased cell differentiation and bone resorption activity.

RESUMEN

INTRODUCTION: Variants in the CABP4 gene cause a phenotype to be included in the spectrum of congenital stationary night blindness, though some reports suggest that the clinical abnormalities are more accurately categorized as a synaptic disease of the cones and rods. We report a novel homozygous nonsense variant in CABP4 in a patient complaining of non-progressive reduced visual acuity and photophobia but not nyctalopia. METHODS: Complete ocular examination, fundus photographs, autofluorescence, optical coherence tomography, electroretinography, and targeted sequencing of known inherited retinal disease-associated genes. RESULTS: A 25-year-old man monitored for 13 years complains of a lifelong history of stable reduced visual acuity (20/150), impaired color vision (1 of 14 plates), small-amplitude nystagmus, and photophobia without nyctalopia. He is also hyperopic (+7D), and his electroretinography shows significantly reduced rod and cone responses. Targeted genetic analysis revealed a novel homozygous variant in the CABP4 gene at c.181C>T, p. (Gln61*) underlying his clinical presentation. CONCLUSIONS: A novel variant in CABP4 is associated with stationary cone and rod dysfunction resulting in decreased acuity, color deficit, and photophobia, but not nyctalopia.

RESUMEN

The S100 family proteins (S100s) participate in multiple stages of tumorigenesis and are considered to have potential value as biomarkers for detecting and predicting various cancers. But the role of S100s in lung adenocarcinoma (LUAD) prognosis is elusive. Transcriptional data of LUAD patients were retrieved from TCGA, and relevant literature was extensively reviewed to collect S100 genes. Differential gene expression analysis was performed on the LUAD data, followed by intersection analysis between the differentially expressed genes (DEGs) and S100 genes. Unsupervised consensus clustering analysis identified two clusters. Significant variations in overall survival between the two clusters were shown by Kaplan-Meier analysis. DEGs between the two clusters were analyzed using Lasso regression and univariate/multivariate Cox regression analysis, leading to construction of an 11-gene prognostic signature. The signature exhibited stable and accurate predictive capability in TCGA and GEO datasets. Subsequently, we observed distinct immune cell infiltration, immunotherapy response, and tumor mutation characteristics in high and low-risk groups. Finally, small molecular compounds targeting prognostic genes were screened using CellMiner database, and molecular docking confirmed the binding of AMG-176, Estramustine, and TAK-632 with prognostic genes. In conclusion, we generated a prognostic signature with robust and reliable predictive ability, which may provide guidance for prognosis and treatment of LUAD.

RESUMEN

INTRODUCTION: We examined whether the aging suppressor KLOTHO gene's functionally advantageous KL-VS variant (KL-VS heterozygosity [KL-VSHET]) confers resilience against deleterious effects of aging indexed by cerebrospinal fluid (CSF) biomarkers of neuroinflammation (interleukin-6 [IL-6], S100 calcium-binding protein B [S100B], triggering receptor expressed on myeloid cells [sTREM2], chitinase-3-like protein 1 [YKL-40], glial fibrillary acidic protein [GFAP]), neurodegeneration (total α-synuclein [α-Syn], neurofilament light chain protein), and synaptic dysfunction (neurogranin [Ng]). METHODS: This Alzheimer disease risk-enriched cohort consisted of 454 cognitively unimpaired adults (Mage = 61.5 ± 7.75). Covariate-adjusted multivariate regression examined relationships between age (mean-split[age ≥ 62]) and CSF biomarkers (Roche/NeuroToolKit), and whether they differed between KL-VSHET (N = 122) and non-carriers (KL-VSNC; N = 332). RESULTS: Older age was associated with a poorer biomarker profile across all analytes (Ps ≤ 0.03). In age-stratified analyses, KL-VSNC exhibited this same pattern (Ps ≤ 0.05) which was not significant for IL-6, S100B, Ng, and α-Syn (Ps ≥ 0.13) in KL-VSHET. Although age-related differences in GFAP, sTREM2, and YKL-40 were evident for both groups (Ps ≤ 0.01), the effect magnitude was markedly stronger for KL-VSNC. DISCUSSION: Higher levels of neuroinflammation, neurodegeneration, and synaptic dysfunction in older adults were attenuated in KL-VSHET. HIGHLIGHTS: Older age was associated with poorer profiles across all cerebrospinal fluid biomarkers of neuroinflammation, neurodegeneration, and synaptic dysfunction. KLOTHO KL-VS non-carriers exhibit this same pattern, which is does not significantly differ between younger and older KL-VS heterozygotes for interleukin-6, S100 calcium-binding protein B, neurogranin, and total α-synuclein. Although age-related differences in glial fibrillary acidic protein, triggering receptor expressed on myeloid cells, and chitinase-3-like protein 1 are evident for both KL-VS groups, the magnitude of the effect is markedly stronger for KL-VS non-carriers. Higher levels of neuroinflammation, neurodegeneration, and synaptic dysfunction in older adults are attenuated in KL-VS heterozygotes.

Asunto(s)

Envejecimiento , Biomarcadores , Proteína 1 Similar a Quitinasa-3 , Heterocigoto , Proteínas Klotho , Humanos , Femenino , Masculino , Persona de Mediana Edad , Biomarcadores/líquido cefalorraquídeo , Anciano , Envejecimiento/genética , Proteína 1 Similar a Quitinasa-3/líquido cefalorraquídeo , Proteína 1 Similar a Quitinasa-3/genética , Glucuronidasa/genética , Glucuronidasa/líquido cefalorraquídeo , Interleucina-6/líquido cefalorraquídeo , Interleucina-6/genética , Receptores Inmunológicos/genética , Enfermedades Neuroinflamatorias/genética , Enfermedades Neuroinflamatorias/líquido cefalorraquídeo , Subunidad beta de la Proteína de Unión al Calcio S100/líquido cefalorraquídeo , Subunidad beta de la Proteína de Unión al Calcio S100/genética , Estudios de Cohortes , Proteína Ácida Fibrilar de la Glía/líquido cefalorraquídeo , Proteína Ácida Fibrilar de la Glía/genética , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/genética , alfa-Sinucleína/líquido cefalorraquídeo , alfa-Sinucleína/genética , Neurogranina/líquido cefalorraquídeo , Neurogranina/genética , Glicoproteínas de Membrana

RESUMEN

Calreticulin (CRT) is an intrinsically disordered multifunctional protein that plays essential roles intra-and extra-cellularly. The Michalak laboratory has proposed that CRT was initially identified in 1974 by the MacLennan laboratory as the high-affinity Ca2+-binding protein (HACBP) of the sarcoplasmic reticulin (SR). This widely accepted belief has been ingrained in the scientific literature but has never been rigorously tested. In our report, we have undertaken a comprehensive reexamination of this assumption by meticulously examining the majority of published studies that present a proteomic analysis of the SR. These analyses have utilized proteomic analysis of purified SR preparations or purified components of the SR, namely the longitudinal tubules and junctional terminal cisternae. These studies have consistently failed to detect the HACBP or CRT in skeletal muscle SR. We propose that the existence of the HACBP has failed the test of reproducibility and should be retired to the annals of antiquity. Therefore, the scientific dogma that the HACBP and CRT are identical proteins is a non sequitur.

Asunto(s)

Calreticulina , Animales , Calreticulina/química , Calreticulina/historia , Calreticulina/metabolismo , Historia del Siglo XX , Músculo Esquelético/metabolismo , Proteómica , Reproducibilidad de los Resultados , Retículo Sarcoplasmático/metabolismo , Conejos

RESUMEN

Background: The calcium-binding protein 4 (CABP4) gene is a newly identified epilepsy-related gene that might be associated with a rare type of genetic focal epilepsy; that is, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). In vitro, mutant CABP4 causes an increased inward flow voltage of calcium ions and a significant increase in the electrical signal discharge in hippocampus neurons; however, the role of CABP4 in epilepsy has not yet been specifically described, and there is not yet a CABP4 mutant animal model recapitulating the epilepsy phenotype. Methods: We introduced a human CABP4 missense mutation into the C57BL/6J mouse genome and generated a knock-in strain carrying a glycine-to-aspartic acid mutation in the gene. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were performed to evaluate the CABP4 expression level. Slice patch-clamp recording was carried out on pyramidal cells of prefrontal cortex layers II and III. Results: The CABP4G155D/+ mutant mice were viable and born at an expected Mendelian ratio. Surprisingly, the heterozygous (HE) mice did not display either an abnormal appearance or an overt seizure phenotype, and there was no statistically significant difference between the HE and wild-type (WT) mice in terms of overall messenger RNA (mRNA) and protein expression. However, the HE mutant mice showed an imbalance in the amount of protein expressed in the brain regions. Additionally, the patch-clamp recordings from the HE mouse layer II/III cortical pyramidal cells revealed an increase in the frequency of micro-excitatory post-synaptic currents (mEPSCs) but no change in the amplitude was observed. Conclusions: The findings of this study suggest that the CABP4 p.G155D mutation might be one of the mechanisms underlying seizure onset.

RESUMEN

Introduction: Traumataic brain injury (TBI) represents a significant global health burden. This systematic review delves into the comparison of S100B and Neuron-Specific Enolase (NSE) regarding their diagnostic and prognostic accuracy in TBI within the adult population. Methods: Conducted on October 21, 2023, the search identified 24 studies encompassing 6454 adult patients. QUADAS-2 and QUAPAS tools were employed to assess the risk of bias. The analyses aimed to evaluate the diagnostic and prognostic performance of S100B and NSE based on sensitivity, specificity, and area under the curve (AUC). The outcomes were detecting intracranial injury, mortality, and unfavorable outcome. Results: Pooled data analysis tended towards favoring S100B for diagnostic and prognostic purposes. S100B exhibited a diagnostic AUC of 0.74 (95% confidence interval (CI): 0.70-0.78), sensitivity of 80% (95% CI: 63%-90%), and specificity of 59% (95% CI: 45%-72%), outperforming NSE with an AUC of 0.66 (95% CI: 0.61-0.70), sensitivity of 74% (95% CI: 53%-88%), and specificity of 46% (95% CI: 24%-69%). Notably, both biomarkers demonstrated enhanced diagnostic value when blood samples were collected within 12 hours post-injury. The analyses also revealed the excellent diagnostic ability of S100B with a sensitivity of 99% (95% CI: 4%-100%) and a specificity of 76% (95% CI: 51%-91%) in mild TBI patients (AUC = 0.89 [0.86-0.91]). In predicting mortality, S100B showed a sensitivity of 90% (95% CI: 65%-98%) and specificity of 61% (95% CI: 39%-79%), slightly surpassing NSE's performance with a sensitivity of 88% (95% CI: 76%-95%) and specificity of 56% (95% CI: 47%-65%). For predicting unfavorable outcomes, S100B exhibited a sensitivity of 83% (95% CI: 74%-90%) and specificity of 51% (95% CI: 30%-72%), while NSE had a sensitivity of 80% (95% CI: 64%-90%) and specificity of 59% (95% CI: 46%-71%). Conclusion: Although neither biomarker has shown promising diagnostic performance in detecting abnormal computed tomography (CT) findings, they have displayed acceptable outcome prediction capabilities, particularly with regard to mortality.

RESUMEN

OBJECTIVE: To investigate the effect of ultrasound-guided stellate ganglion block (SGB) on cerebral oxygen metabolism and serum S100B during carotid endarterectomy (CEA). METHODS: Patients who were prospectively enrolled to receive CEA under elective general anesthesia were randomized into an SGB group and a control group (ChiCTR2000033385). Before anesthesia, the SGB group underwent ipsilateral SGB under ultrasound guidance, while the control group did not. Ultrasound-guided right subclavian internal jugular vein catheterization was performed under general anesthesia. Mean arterial pressure (MAP) and heart rate (HR) were monitored at various time points (T0-T4). Arterial and internal jugular venous bulb blood were collected for blood gas analysis, determining jugular venous oxygen saturation (SjvO2), arteriovenous oxygen difference (AVDO2), cerebral oxygen extraction ratio (COER), lactate production rate (LPR), and lactate-oxygen index (LOI). The serum concentration of S100B in the internal jugular venous bulb at each time point was measured. RESULTS: The results revealed significantly lower HR during anesthesia induction and surgery in the SGB group, with more stable MAP and HR during endotracheal intubation and surgery compared to the control group (P<0.05). The control group exhibited decreases at T3 and a slight increase at T4. SjvO2 was significantly higher in the SGB group, while AVDO2 and COER gradually decreased over time, but they were significantly higher in the control group (P<0.05). LPR and LOI in both groups peaked at T3 and were significantly different between T4 and T2 (P<0.05). Serum S100B levels in both groups rose and then decreased at each time point, but they were consistently lower in the SGB group (P<0.05). CONCLUSION: SGB before CEA effectively suppresses the stress response, maintains intraoperative hemodynamic stability, improves brain tissue oxygen supply, and demonstrates a neuroprotective effect.

RESUMEN

Odontoblastic differentiation of human stem cells from the apical papilla (hSCAPs) is crucial for continued root development and dentin formation in immature teeth with apical periodontitis (AP). Fat mass and obesity-associated protein (FTO) has been reported to regulate bone regeneration and osteogenic differentiation profoundly. However, the effect of FTO on hSCAPs remains unknown. This study aimed to identify the potential function of FTO in hSCAPs' odontoblastic differentiation under normal and inflammatory conditions and to investigate its underlying mechanism preliminarily. Histological staining and micro-computed tomography were used to evaluate root development and FTO expression in SD rats with induced AP. The odontoblastic differentiation ability of hSCAPs was assessed via alkaline phosphatase and alizarin red S staining, qRT-PCR, and Western blotting. Gain- and loss-of-function assays and online bioinformatics tools were conducted to explore the function of FTO and its potential mechanism in modulating hSCAPs differentiation. Significantly downregulated FTO expression and root developmental defects were observed in rats with AP. FTO expression notably increased during in vitro odontoblastic differentiation of hSCAPs, while lipopolysaccharide (LPS) inhibited FTO expression and odontoblastic differentiation. Knockdown of FTO impaired odontoblastic differentiation, whereas FTO overexpression alleviated the inhibitory effects of LPS on differentiation. Furthermore, FTO promoted the expression of secreted modular calcium-binding protein 2 (SMOC2), and the knockdown of SMOC2 in hSCAPs partially attenuated the promotion of odontoblastic differentiation mediated by FTO overexpression under LPS-induced inflammation. This study revealed that FTO positively regulates the odontoblastic differentiation ability of hSCAPs by promoting SMOC2 expression. Furthermore, LPS-induced inflammation compromises the odontoblastic differentiation of hSCAPs by downregulating FTO, highlighting the promising role of FTO in regulating hSCAPs differentiation under the inflammatory microenvironment.

Asunto(s)

Lipopolisacáridos , Osteogénesis , Humanos , Animales , Ratas , Ratas Sprague-Dawley , Microtomografía por Rayos X , Inflamación/genética , Proteínas de Unión al Calcio , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genética

RESUMEN

In contrast to other S100 protein members, the function of S100 calcium-binding protein Z (S100Z) remains largely uncharacterized. It is expressed in the olfactory epithelium of fish, and it is closely associated with the vomeronasal organ (VNO) in mammals. In this study, we analyzed the expression pattern of S100Z in the olfactory system of the anuran amphibian Xenopus laevis. Using immunohistochemistry in whole mount and slice preparations of the larval olfactory system, we found exclusive S100Z expression in a subpopulation of olfactory receptor neurons (ORNs) of the main olfactory epithelium (MOE). S100Z expression was not co-localized with TP63 and cytokeratin type II, ruling out basal cell and supporting cell identity. The distribution of S100Z-expressing ORNs was laterally biased, and their average number was significantly increased in the lateral half of the olfactory epithelium. The axons of S100Z-positive neurons projected exclusively into the lateral and intermediate glomerular clusters of the main olfactory bulb (OB). Even after metamorphic restructuring of the olfactory system, S100Z expression was restricted to a neuronal subpopulation of the MOE, which was then located in the newly formed middle cavity. An axonal projection into the ventro-lateral OB persisted also in postmetamorphic frogs. In summary, S100Z is exclusively associated with the main olfactory system in the amphibian Xenopus and not with the VNO as in mammals, despite the presence of a separate accessory olfactory system in both classes.

Asunto(s)

Neuronas Receptoras Olfatorias , Proteínas S100 , Órgano Vomeronasal , Animales , Bulbo Olfatorio/metabolismo , Mucosa Olfatoria , Neuronas Receptoras Olfatorias/metabolismo , Proteínas S100/metabolismo , Órgano Vomeronasal/metabolismo , Xenopus laevis/metabolismo

RESUMEN

PURPOSE: To investigate the mechanism by which S100 calcium-binding protein A6 (S100A6) affects colorectal cancer (CRC) cells to oxaliplatin (L-OHP) chemotherapy, and to explore new strategies for CRC treatment. METHODS: S100A6 expression was assessed in both parental and L-OHP-resistant CRC cells using western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), and enzyme-linked immunosorbent assays (ELISA). Lentiviral vectors were utilized to induce the knockdown of S100A6 expression, followed by comprehensive evaluations of cell proliferation, apoptosis, and epithelial-mesenchymal transition (EMT). Additionally, RNA-seq analysis was conducted to identify genes associated with the knockdown of S100A6. RESULTS: Elevated S100A6 expression in CRC tissues correlated with an adverse prognosis in patients with CRC. Higher expression of S100A6 was also observed in L-OHP-resistant CRC cells, which showed enhanced proliferation, migration, invasion, and antiapoptotic capabilities. Notably, the knockdown of S100A6 expression resulted in decreased proliferation, increased apoptosis, and suppression of EMT and tumorigenicity in L-OHP-resistant CRC cells. Transcriptome sequencing reveals a noteworthy association between S100A6 and vimentin expression. Application of the EMT agonist, transforming growth factor ß (TGF-ß), induces EMT in CRC cells. S100A6 expression positively correlates with TGF-ß expression. TGF-ß facilitated the expression of EMT-related molecules and reduced the chemosensitivity of L-OHP in S100A6-knockdown cells. CONCLUSION: In conclusion, the knockdown of S100A6 may overcome the L-OHP resistance of CRC cells by modulating EMT.

Asunto(s)

Apoptosis , Proteínas de Ciclo Celular , Proliferación Celular , Neoplasias Colorrectales , Resistencia a Antineoplásicos , Transición Epitelial-Mesenquimal , Oxaliplatino , Proteína A6 de Unión a Calcio de la Familia S100 , Transición Epitelial-Mesenquimal/efectos de los fármacos , Humanos , Oxaliplatino/farmacología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Resistencia a Antineoplásicos/genética , Proteína A6 de Unión a Calcio de la Familia S100/genética , Proteína A6 de Unión a Calcio de la Familia S100/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Animales , Antineoplásicos/farmacología , Femenino , Masculino , Ratones , Técnicas de Silenciamiento del Gen , Vimentina/metabolismo , Vimentina/genética , Pronóstico , Factor de Crecimiento Transformador beta/metabolismo

RESUMEN

Apoptosis linked Gene-2 (ALG-2) is a multifunctional intracellular Ca2+ sensor and the archetypal member of the penta-EF hand protein family. ALG-2 functions in the repair of damage to both the plasma and lysosome membranes and in COPII-dependent budding at endoplasmic reticulum exit sites (ERES). In the presence of Ca2+, ALG-2 binds to ESCRT-I and ALIX in membrane repair and to SEC31A at ERES. ALG-2 also binds directly to acidic membranes in the presence of Ca2+ by a combination of electrostatic and hydrophobic interactions. By combining giant unilamellar vesicle-based experiments and molecular dynamics simulations, we show that charge-reversed mutants of ALG-2 at these locations disrupt membrane recruitment. ALG-2 membrane binding mutants have reduced or abrogated ERES localization in response to Thapsigargin-induced Ca2+ release but still localize to lysosomes following lysosomal Ca2+ release. In vitro reconstitution shows that the ALG-2 membrane-binding defect can be rescued by binding to ESCRT-I. These data thus reveal the nature of direct Ca2+-dependent membrane binding and its interplay with Ca2+-dependent protein binding in the cellular functions of ALG-2.

Asunto(s)

Fenómenos Fisiológicos Celulares , Membranas Intracelulares , Membranas , División Celular , Complejos de Clasificación Endosomal Requeridos para el Transporte/genética

RESUMEN

OBJECTIVES: Neurologic outcomes of patients under venoarterial extracorporeal membrane oxygenation (VA-ECMO) may be worsened by secondary insults of systemic origin. We aimed to assess whether sepsis, commonly observed during ECMO support, is associated with brain injury and outcomes. DESIGN: Single-center cohort study of the "exposed-non-exposed" type on consecutive adult patients treated by VA-ECMO. SETTING: Medical ICU of a university hospital, France, 2013-2020. PATIENTS: Patients with sepsis at the time of VA-ECMO cannulation ("sepsis" group) were compared with patients without sepsis ("no sepsis" group). The primary outcome measure was poor functional outcome at 90 days, defined by a score greater than or equal to 4 on the modified Rankin scale (mRS), indicating severe disability or death. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 196 patients were included ("sepsis," n = 128; "no sepsis," n = 68), of whom 87 (44.4%) had presented cardiac arrest before VA-ECMO cannulation. A poor functional outcome (mRS ≥ 4) was observed in 99 of 128 patients (77.3%) of the "sepsis" group and 46 of 68 patients (67.6%) of the "no sepsis" group (adjusted logistic regression odds ratio (OR) 1.21, 95% CI, 0.58-2.47; inverse probability of treatment weighting (IPTW) OR 1.24; 95% CI, 0.79-1.95). Subsequent analyses performed according to pre-ECMO cardiac arrest status suggested that sepsis was independently associated with poorer functional outcomes in the subgroup of patients who had experienced pre-ECMO cardiac arrest (adjusted logistic regression OR 3.44; 95% CI, 1.06-11.40; IPTW OR 3.52; 95% CI, 1.68-7.73), whereas no such association was observed in patients without pre-ECMO cardiac arrest (adjusted logistic regression OR 0.69; 95% CI, 0.27-1.69; IPTW OR 0.76; 95% CI, 0.42-1.35). Compared with the "no sepsis" group, "sepsis" patients presented a significant increase in S100 calcium-binding protein beta concentrations at day 1 (0.94 µg/L vs. 0.52 µg/L, p = 0.03), and more frequent EEG alterations (i.e., severe slowing, discontinuous background, and a lower prevalence of sleep patterns), suggesting brain injury. CONCLUSION: We observed a detrimental role of sepsis on neurologic outcomes in the subgroup of patients who had experienced pre-ECMO cardiac arrest, but not in other patients.

RESUMEN

Two calcium-binding proteins, CaBP1 and CaBP2, cooperate to keep calcium channels in the hair cells of the inner ear open.

Asunto(s)

Calcio , Células Ciliadas Auditivas , Calcio/metabolismo , Células Ciliadas Auditivas/metabolismo , Canales de Calcio/metabolismo , Calcio de la Dieta , Células Ciliadas Auditivas Internas/metabolismo , Proteínas de Unión al Calcio/metabolismo

RESUMEN

IQM is a plant-specific calcium-binding protein that plays a pivotal role in various aspects of plant growth response to stressors. We investigated the IQM gene family and its expression patterns under diverse abiotic stresses and conducted a comprehensive analysis and characterization of the AeIQMs, including protein structure, genomic location, phylogenetic relationships, gene expression profiles, salt tolerance, and expression patterns of this gene family under different abiotic stresses. Based on phylogenetic analysis, these 10 AeIQMs were classified into three distinct subfamilies (I-III). Analysis of the protein motifs revealed a considerable level of conservation among these AeIQM proteins within their respective subfamilies in kiwifruit. The genomic distribution of the 10 AeIQM genes spanned across eight chromosomes, where four pairs of IQM gene duplicates were associated with segmental duplication events. qRT-PCR analysis revealed diverse expression patterns of these AeIQM genes under different hormone treatments, and most AeIQMs showed inducibility by salt stress. Further investigations indicated that overexpression of AeIQMs in yeast significantly enhanced salt tolerance. These findings suggest that AeIQM genes might be involved in hormonal signal transduction and response to abiotic stress in Actinidia eriantha. In summary, this study provides valuable insights into the physiological functions of IQMs in kiwifruit.

Asunto(s)

Actinidia , Genoma de Planta , Actinidia/genética , Filogenia , Perfilación de la Expresión Génica , Estrés Fisiológico/genética

RESUMEN

Calcium is a ubiquitous second messenger that is indispensable in regulating neurotransmission and memory formation. A precise intracellular calcium level is achieved through the concerted action of calcium channels, and calcium exerts its effect by binding to an array of calcium-binding proteins, including calmodulin (CAM), calcium-calmodulin complex-dependent protein kinase-II (CAMK-II), calbindin (CAL), and calcineurin (CAN). Calbindin orchestrates a plethora of signaling events that regulate synaptic transmission and depolarizing signals. Vitamin D, an endogenous fat-soluble metabolite, is synthesized in the skin upon exposure to ultraviolet B radiation. It modulates calcium signaling by increasing the expression of the calcium-sensing receptor (CaSR), stimulating phospholipase C activity, and regulating the expression of calcium channels such as TRPV6. Vitamin D also modulates the activity of calcium-binding proteins, including CAM and calbindin, and increases their expression. Calbindin, a high-affinity calcium-binding protein, is involved in calcium buffering and transport in neurons. It has been shown to inhibit apoptosis and caspase-3 activity stimulated by presenilin 1 and 2 in AD. Whereas CAM, another calcium-binding protein, is implicated in regulating neurotransmitter release and memory formation by phosphorylating CAN, CAMK-II, and other calcium-regulated proteins. CAMK-II and CAN regulate actin-induced spine shape changes, which are further modulated by CAM. Low levels of both calbindin and vitamin D are attributed to the pathology of Alzheimer's disease. Further research on vitamin D via calbindin-CAMK-II signaling may provide newer insights, revealing novel therapeutic targets and strategies for treatment.

Asunto(s)

Enfermedad de Alzheimer , Vitamina D , Humanos , Señalización del Calcio , Calbindinas , Calmodulina , Calcio , Proteínas de Unión al Calcio , Canales de Calcio , Calcineurina , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina

RESUMEN

Obesity is a health problem that involves fat accumulation in adipose and other tissues and causes cell dysfunction. Long-chain saturated fatty acids can induce and propagate inflammation, which may also contribute to the brain alterations found in individuals with obesity. Fatty acids accumulate in astrocytes in situations of blood‒brain barrier disruption, such as inflammatory conditions. Furthermore, the increase in tumor necrosis factor-alpha (TNF-α) and S100 calcium-binding protein B (S100B) secretion is considered an essential component of the inflammatory response. We hypothesize that through their action on astrocytes, long-chain saturated fatty acids mediate some of the brain alterations observed in individuals with obesity. Here, we investigate the direct effect of long-chain fatty acids on astrocytes. Primary astrocyte cultures were incubated for 24 hours with myristic, palmitic, stearic, linoleic, or α-linolenic acids (25-100 µM). All saturated fatty acids tested led to an increase in TNF-α secretion, but only palmitic acid, one of the most common fatty acids, increased S100B secretion, indicating that S100B secretion is probably not caused in response to TNF-α release. Palmitic acid also caused nuclear migration of nuclear factor kappa B. Long-chain saturated fatty acids did not alter cell viability or redox status. In conclusion, long-chain saturated fatty acids can alter astrocytic homeostasis and may contribute to brain disorders associated with obesity, such as neuroinflammation.

Asunto(s)

Ácido Palmítico , Factor de Necrosis Tumoral alfa , Humanos , Ácido Palmítico/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Astrocitos/metabolismo , Ácidos Grasos/farmacología , Ácidos Grasos/metabolismo , Obesidad , Subunidad beta de la Proteína de Unión al Calcio S100/farmacología

RESUMEN

Calcium binding proteins are essential for neural development and cellular activity. Calretinin, encoded by calb2a and calb2b, plays a role during early zebrafish development and has been proposed as a marker for distinct neuronal populations within the locomotor network. We generated a calb2b:hs:eGFP transgenic reporter line to characterize calretinin expressing cells in the developing spinal cord and describe morphological and behavioral defects in calretinin knock-down larvae. eGFP was detected in primary and secondary motor neurons, as well as in dI6 and V0v interneurons. Knock-down of calretinin lead to disturbed development of motor neurons and dI6 interneurons, revealing a crucial role during early development of the locomotor network. Primary motor neurons showed delayed axon outgrowth and the distinct inhibitory CoLo neurons, originating from the dI6 lineage, were absent. These observations explain the locomotor defects we observed in calretinin knock-down animals where the velocity, acceleration and coordination were affected during escapes. Altogether, our analysis suggests an essential role for calretinin during the development of the circuits regulating escape responses and fast movements within the locomotor network.

Asunto(s)

Neuronas Motoras , Pez Cebra , Animales , Pez Cebra/genética , Pez Cebra/metabolismo , Calbindina 2/genética , Larva/genética , Larva/metabolismo , Neuronas Motoras/fisiología , Médula Espinal/metabolismo , Interneuronas/fisiología