Arterial calcification is an important characteristic of cardiovascular disease. It has key parallels with skeletal mineralization; however, the underlying cellular mechanisms responsible are not ...fully understood. Mitochondrial dynamics regulate both bone and vascular function. In this study, we therefore examined mitochondrial function in vascular smooth muscle cell (VSMC) calcification. Phosphate (Pi)-induced VSMC calcification was associated with elongated mitochondria (1.6-fold increase, p < 0.001), increased mitochondrial reactive oxygen species (ROS) production (1.83-fold increase, p < 0.001) and reduced mitophagy (9.6-fold decrease, p < 0.01). An increase in protein expression of optic atrophy protein 1 (OPA1; 2.1-fold increase, p < 0.05) and a converse decrease in expression of dynamin-related protein 1 (DRP1; 1.5-fold decrease, p < 0.05), two crucial proteins required for the mitochondrial fusion and fission process, respectively, were noted. Furthermore, the phosphorylation of DRP1 Ser637 was increased in the cytoplasm of calcified VSMCs (5.50-fold increase), suppressing mitochondrial translocation of DRP1. Additionally, calcified VSMCs showed enhanced expression of p53 (2.5-fold increase, p < 0.05) and β-galactosidase activity (1.8-fold increase, p < 0.001), the cellular senescence markers. siRNA-mediated p53 knockdown reduced calcium deposition (8.1-fold decrease, p < 0.01), mitochondrial length (3.0-fold decrease, p < 0.001) and β-galactosidase activity (2.6-fold decrease, p < 0.001), with concomitant mitophagy induction (3.1-fold increase, p < 0.05). Reduced OPA1 (4.1-fold decrease, p < 0.05) and increased DRP1 protein expression (2.6-fold increase, p < 0.05) with decreased phosphorylation of DRP1 Ser637 (3.20-fold decrease, p < 0.001) was also observed upon p53 knockdown in calcifying VSMCs. In summary, we demonstrate that VSMC calcification promotes notable mitochondrial elongation and cellular senescence via DRP1 phosphorylation. Furthermore, our work indicates that p53-induced mitochondrial fusion underpins cellular senescence by reducing mitochondrial function.
Display omitted
•Newly-designed Carboxymethyl cellulose and Graphene Oxide Bio-Nanocomposites.•Excellent switching behaviors of the memory device based on CMC-GO composites.•Flexibility for the ...applications of flexible storage applications.
Nowadays the development of natural biomaterials as promising building polymers for flexible, biodegradable, biocompatible and environmentally friendly electronic devices is of great interest. As the most common natural polymers, cellulose and its derivatives have the potential to be applied in the devices owing to the easy processing, nontoxicity and biodegradability. Here, write-once-read-many-times resistive switching devices based on biodegradable carboxymethyl cellulose-graphene oxide (CMC-GO) nanocomposite are demonstrated for the first time. The hybridization sites formed by the gelation of CMC and GO molecules contribute to the excellent memory behaviors. When compared with devices base on pure GO and CMC, the device with the Al/CMC-GO/Al/SiO2 structure exhibits brilliant write-once-read-many-times (WORM) switching characteristics such as high ON/OFF current ratio of ˜105, low switching voltage of 2.22 V, excellent stability and durability. What's more, the device shows high flexibility and good resistive switching behaviors even with soft PET substrate (Al/CMC-GO/Al/PET structure). This newly designed cellulose-graphene oxide-based polymer nanocomposites are quite cheap and easy processed for large scale manufacturing of memory devices and can further contribute to future biodegradable data storage applications such as portable stretchable displays, wearable electronics and electronic skins in the coming age of artificial intelligence.
AbstractMATRICS Consensus Cognitive Battery (MCCB), packaging 10 tests selected from more than 90 nominated tests, is a method developed by the Measurement and Treatment Research to Improve Cognition ...in Schizophrenia (MATRICS) group to evaluate the efficacy of treatments targeting cognitive impairments in schizophrenia. MCCB had been translated into a number of languages, but only the US and Spain had normative data reported. Inconsistency in translation and cultural differences make direct application of MCCB in China problematic. In this study, we administered the battery to a representative community sample based on Chinese population census in 2005 and obtained normative data. The effects of age, gender, education level, and scale of residence area on test performance were examined. The sample included 656 healthy volunteers from six sites in China. At each site, sample was stratified according to age, gender, and educational level, and scale of the area one was born in, grew up in and currently living in was recorded. We found age, gender, and education had significant effects on the normative data for MCCB in China, which are comparable to those found for the original standardized English version in the U.S. and the Spanish version in Spain. Remarkably, the residence scale effects on neuropsychological performance were significant, which should be taking into account when calculating the standardized T score for each subject. The practice effects were minor and test-retest reliability of MCCB was good, which suggests MCCB as an appropriate measure for clinical and research usage in China.
The mammalian central nervous system is organized by a variety of cells such as neurons and glial cells. These cells are generated from a common progenitor, the neural stem cell (NSC). NSCs are ...defined as undifferentiated neural cells that are characterized by their high proliferative potential while retaining the capacity for self-renewal and multipotency. Glycoconjugates carrying carbohydrate antigens, including glycoproteins, glycolipids, and proteoglycans, are primarily localized on the plasma-membrane surface of cells and serve as excellent biomarkers at various stages of cellular differentiation. Moreover, they also play important functional roles in determining cell fate such as self-renewal, proliferation, and differentiation. In the present review, we discuss the expression pattern and possible functions of glycoconjugates and carbohydrate antigens in NSCs, with an emphasis on stage-specific embryonic antigen-1, human natural killer antigen-1, polysialic acid-neural cell-adhesion molecule, prominin-1, gp130, chondroitin sulfate proteoglycans, heparan sulfate proteoglycans, cystatin C, galectin-1, glycolipids, and Notch.
Gangliosides are sialic acid-containing glycosphingolipids that are most abundant in the nerve tissues. The quantity and expression pattern of gangliosides in brain change drastically throughout ...development and are mainly regulated through stage-specific expression of glycosyltransferase (ganglioside synthase) genes. We previously demonstrated that acetylation of histones H3 and H4 on the
N
-acetylgalactosaminyltransferase I (GalNAcT, GA2/GM2/GD2/GT2-synthase) gene promoter resulted in recruitment of trans-activation factors. In addition, we reported that epigenetic activation of the GalNAcT gene was also detected as accompanied by an apparent induction of neuronal differentiation in neural stem cells responding to an exogenous supplement of ganglioside GM1. Here, we present evidence supporting the concept that nuclear GM1 is associated with gene regulation in neuronal cells. We found that nuclear GM1 binds acetylated histones on the promoters of the GalNAcT and NeuroD1 genes in differentiated neurons. Our study demonstrates for the first time that GM1 interacts with chromatin via acetylated histones at the nuclear periphery of neuronal cells.
Guillain–Barré syndrome (GBS) is an acute immune-mediated polyradiculoneuropathy which can cause acute quadriplegia. Infection with micro-organisms, including Campylobacter jejuni (C. jejuni), ...Haemophilus influenzae, and Cytomegalovirus (CMV), is recognized as a main triggering event for the disease. Lipooligosaccharide (LOS) genes are responsible for the formation of human ganglioside-like LOS structures in infectious micro-organisms that can induce GBS. Molecular mimicry of LOSs on the surface of infectious agents and of ganglioside antigens on neural cells is thought to induce cross-reactive humoral and cellular immune responses. Patients with GBS develop antibodies against those gangliosides, resulting in autoimmune targeting of peripheral nerve sites, leading to neural damage. Heterogeneity of ganglioside expression in the peripheral nervous system (PNS) may underlie the differential clinical manifestation of the GBS variants. Recent studies demonstrate that some GBS sera react with ganglioside complexes consisting of two different gangliosides, such as GD1a and GD1b, or GM1 and GD1a, but not with each constituent ganglioside alone. The discovery of antiganglioside complex antibodies not only improves the detection rate of autoantibodies in GBS, but also provides a new concept in the antibody–antigen interaction through clustered carbohydrate epitopes. Although ganglioside mimicry is one of the possible etiological causes of GBS, unidentified factors may also contribute to the pathogenesis of GBS. While GBS is not considered a genetic disease, host factors, particularly human lymphocyte antigen type, appear to have a role in the pathogenesis of GBS following C. jejuni infection.
Multiple sclerosis (MS) is a CNS disease characterized by immune-mediated demyelination and progressive axonal loss. MS-related CNS damage and its clinical course have two main phases: active and ...inactive/progressive. Reliable biomarkers are being sought to allow identification of MS pathomechanisms and prediction of its course. The purpose of this study was to identify sphingolipid (SL) species as candidate biomarkers of inflammatory and neurodegenerative processes underlying MS pathology. We performed sphingolipidomic analysis by HPLC-tandem mass spectrometry to determine the lipid profiles in post mortem specimens from the normal-appearing white matter (NAWM) of the normal CNS (nCNS) from subjects with chronic MS (active and inactive lesions) as well as from patients with other neurological diseases. Distinctive SL modification patterns occurred in specimens from MS patients with chronic inactive plaques with respect to NAWM from the nCNS and active MS (Ac-MS) lesions. Chronic inactive MS (In-MS) lesions were characterized by decreased levels of dihydroceramide (dhCer), ceramide (Cer), and SM subspecies, whereas levels of hexosylceramide and Cer 1-phosphate (C1P) subspecies were significantly increased in comparison to NAWM of the nCNS as well as Ac-MS plaques. In contrast, Ac-MS lesions were characterized by a significant increase of major dhCer subspecies in comparison to NAWM of the nCNS. These results suggest the existence of different SL metabolic pathways in the active versus inactive phase within progressive stages of MS. Moreover, they suggest that C1P could be a new biomarker of the In-MS progressive phase, and its detection may help to develop future prognostic and therapeutic strategies for the disease.
Patients with nervous system disorders suffer from impaired cognitive, sensory and motor functions that greatly inconvenience their daily life and usually burdens their family and society. It is ...difficult to achieve functional recovery for the damaged central nervous system (CNS) because of its limited ability to regenerate. Glycosphingolipids (GSLs) are abundant in the CNS and are known to play essential roles in cell-cell recognition, adhesion, signal transduction, and cellular migration, that are crucial in all phases of neurogenesis. Despite intense investigation of CNS regeneration, the roles of GSLs in neural regeneration remain unclear. Here we focus on the respective potentials of glycolipids to promote regeneration and repair of the CNS. Mice lacking glucosylceramide, lactosylceramide or gangliosides show lethal phenotypes. More importantly, patients with ganglioside deficiencies exhibit severe clinical phenotypes. Further, neurodegenerative diseases and mental health disorders are associated with altered GSL expression. Accumulating studies demonstrate that GSLs not only delimit physical regions but also play central roles in the maintenance of the biological functions of neurons and glia. We anticipate that the ability of GSLs to modulate behavior of a variety of molecules will enable them to ameliorate biochemical and neurobiological defects in patients. The use of GSLs to treat such defects in the human CNS will be a paradigm-shift in approach since GSL-replacement therapy has not yet been achieved in this manner clinically.
Neural stem cells (NSCs) possess high proliferative potential and the capacity for self-renewal with retention of multipotency to differentiate into brain-forming cells. Several signaling pathways ...have been shown to be involved in the fate determination process of NSCs, but the molecular mechanisms underlying the maintenance of neural cell stemness remain largely unknown. Our previous study showed that human natural killer carbohydrate epitopes expressed specifically by mouse NSCs modulate the Ras-MAPK pathway, raising the possibility of regulatory roles of glycoprotein glycans in the specific signaling pathways involved in NSC fate determination. To address this issue, we performed comparative N-glycosylation profiling of NSCs before and after differentiation in a comprehensive and quantitative manner. We found that Lewis X-carrying N-glycans were specifically displayed on undifferentiated cells, whereas pauci-mannose-type N-glycans were predominantly expressed on differentiated cells. Furthermore, by knocking down a fucosyltransferase 9 with short interfering RNA, we demonstrated that the Lewis X-carrying N-glycans were actively involved in the proliferation of NSCs via modulation of the expression level of Musashi-1, which is an activator of the Notch signaling pathway. Our findings suggest that Lewis X carbohydrates, which have so far been characterized as undifferentiation markers, actually operate as activators of the Notch signaling pathway for the maintenance of NSC stemness during brain development.
Background: Glycosylation is known to be altered upon differentiation of neural stem cells (NSCs).
Results: NSC-specific Lewis X-carrying N-glycans up-regulated the expression of Musashi-1 and the consequent cell proliferation.
Conclusion: Lewis X operates as an activator of the Notch signaling pathway for the maintenance of NSC stemness.
Significance: The well known undifferentiation glycomarker of NSCs is actively involved in their fate determination.
Nucleotide-based drug candidates such as antisense oligonucleotides, aptamers, immunoreceptor-activating nucleotides, or (anti)microRNAs hold great therapeutic promise for many human diseases. ...Phosphorothioate (PS) backbone modification of nucleotide-based drugs is common practice to protect these promising drug candidates from rapid degradation by plasma and intracellular nucleases. Effects of the changes in physicochemical properties associated with PS modification on platelets have not been elucidated so far. Here we report the unexpected binding of PS-modified oligonucleotides to platelets eliciting strong platelet activation, signaling, reactive oxygen species generation, adhesion, spreading, aggregation, and thrombus formation in vitro and in vivo. Mechanistically, the platelet-specific receptor glycoprotein VI (GPVI) mediates these platelet-activating effects. Notably, platelets from GPVI function-deficient patients do not exhibit binding of PS-modified oligonucleotides, and platelet activation is fully abolished. Our data demonstrate a novel, unexpected, PS backbone-dependent, platelet-activating effect of nucleotide-based drug candidates mediated by GPVI. This unforeseen effect should be considered in the ongoing development programs for the broad range of upcoming and promising DNA/RNA therapeutics.
PDF
