Chaperones of the 70 kDa heat shock protein (Hsp70) superfamily are key components of the cellular proteostasis system. Together with its co-chaperones, Hsp70 forms proteostasis subsystems that antagonize protein damage during physiological and stress conditions. This function stems from highly regulated binding and release cycles of protein substrates, which results in a flow of unfolded, partially folded and misfolded species through the Hsp70 subsystem. Specific factors control how Hsp70 makes decisions regarding folding and degradation fates of the substrate proteins. In this review, we summarize how the flow of Hsp70 substrates is controlled in the cell with special emphasis on recent advances regarding substrate release mechanisms.
The molecular and chemical properties of neuronal nitric oxide synthase (nNOS) have made it a key mediator in many physiological functions and signaling transduction. The NOS monomer is inactive, but the dimer form is active. There are three forms of NOS, which are neuronal (nNOS), inducible (iNOS), and endothelial (eNOS) nitric oxide synthase. nNOS regulates nitric oxide (NO) synthesis which is the mechanism used mostly by neurons to produce NO. nNOS expression and activation is regulated by some important signaling proteins, such as cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB), calmodulin (CaM), heat shock protein 90 (HSP90)/HSP70. nNOS-derived NO has been implicated in modulating many physiological functions, such as synaptic plasticity, learning, memory, neurogenesis, etc. In this review, we have summarized recent studies that have characterized structural features, subcellular localization, and factors that regulate nNOS function. Finally, we have discussed the role of nNOS in the developing brain under a wide range of physiological conditions, especially long-term potentiation and depression.
Objective To evaluate the expression of inducible nitric oxide synthases (iNOS/NOS2) in human glioma and its correlation with patients’ prognoses.
Methods IiNOS/NOS2 expression in tumor and corresponding normal tissues of glioma patients was analyzed using the TCGA database and the online analysis tool GEPIA. The mutation statuses of iNOS/NOS2 genes were also explored in the TCGA database using cBioPortal. Co-expressed genes relevant to iNOS/NOS2 were screened by LinkedOmics. Gene ontology (GO) and KEGG pathway enrichment for iNOS/NOS2 and co-expressed genes was performed using LinkedOmics. Overall survival (OS) and disease-free survival (DFS) outcomes between iNOS/NOS2 mRNA high and low expression groups were compared using a log-rank test. Twenty-two glioma patients who underwent operation were included in the present work. A real-time PCR assay was used to detect iNOS/NOS2 mRNA expression in tumor tissue and normal brain tissue.
Results There was no statistical difference in iNOS/NOS2 mRNA expression levelss between tumor and normal tissues of glioma. A real-time PCR assay indicated that iNOS/NOS2 mRNA expression in tumor tissue and normal brain tissues were not statistical difference (p>0.05). A mutation rate of 0.8% for the iNOS/NOS2 gene was found using 1044 glioma patients from two datasets. The mutation types include deep deletion (0.4%), truncating (0.2%) and missense (0.2%). The top positive and negative co-expressed gene with iNOS/NOS2 were COL25A1 (rpearson=0.4734, p<0.05) and ALCAM (rpearson=0.4734, p<0.05), respectively. For KEGG pathway analysis, iNOS/NOS2 was mainly enriched in calcium signaling pathway, Wnt signaling pathway, GnRH signaling pathway, HIF-1 signaling pathway and pathways in cancer. The overall survival (HR=2.0, p<0.05) and disease-free survival (HR=1.6, p<0.05) values were significantly different between iNOS/NOS2 high and low expression groups.
Conclusion OS and DFS were significantly decreased in high iNOS/NOS2 mRNA expression groups. iNOS/NOS2 can be used as a poor prognostic biomarker for glioma.
The chondroitin sulfate proteoglycans (CSPGs) are large groups of heterogenous proteoglycans that are mainly expressed by reactive astrocytes in the central nervous system (CNS). They share similar core proteins and are post-transcriptionally modified by chondroitin sulfate glycosaminoglycans. CSPGs are the major components of the perineuronal nets (PNN) that regulate the opening and closure of the critical period. Mounting reports have documented the crucial roles of CSPGs in restricting neuronal plasticity, axonal growth, and pathfinding during development as well as axonal regeneration after CNS injury. Moreover, CSPGs and PNNs modulate long-term memory, which impairments frequently happened in several neurodegenerative and psychiatric disorders. This review will shortly introduce the expression patterns of CSPGs during development and after injury, the PNNs constitutions, the roles of CSPGs and PNNs in axonal regrowth, discuss the most recently identified roles of CSPGs and PNNs in mediating long-term memory and their correlation with brain disorders, and finally, propose a short perspective of future investigations. Hopefully, further explorations may validate the therapeutic potentials of PNNs and CSPGs.
Ants (Hymenoptera, Apocrita, Aculeata, Formicoidea) comprise a well-succeeded group of animals. Like bees and wasps, ants are mostly venomous, having a sting system to deliver a mixture of bioactive organic compounds and peptides. The predatory giant ant Dinoponera quadriceps belongs to the subfamily Ponerinae that includes one of the largest known ant species in the world. In the present study, low molecular weight compounds and peptides were identified by online peptide mass fingerprint. These include neuroactive biogenic amines (histamine, tyramine, and dopamine), monoamine alkaloid (phenethylamine), free amino acids (e.g. glutamic acid and proline), free thymidine, and cytosine. To the best of our knowledge, most of these components are described for the first time in an ant venom. Multifunctional dinoponeratoxin peptide variants (pilosulin- and ponericin-like peptides) were characterized that possess antimicrobial, hemolytic, and histamine-releasing properties. These venom components, particularly peptides, might synergistically contribute to the overall venom activity and toxicity, for immobilizing live prey, and for defending D. quadriceps against aggressors, predators, and potential microbial infection.
The polycomb repressive complex 2 (PRC2) consists of three core components EZH2, SUZ12 and EED. EZH2 catalyzes the methylation of lysine 27 of histone H3, a modification associated with gene silencing. Through gene duplication higher vertebrate genomes also encode a second partially redundant methyltransferase, EZH1. Within the mammalian immune system most research has concentrated on EZH2 which is expressed predominantly in proliferating cells. EZH2 and other PRC2 components are required for hematopoietic stem cell function and lymphocyte development, at least in part by repressing cell cycle inhibitors. At later stages of immune cell differentiation, EZH2 plays essential roles in humoral and cell-mediated adaptive immunity, as well as the maintenance of immune homeostasis. EZH2 is often overactive in cancers, through both gain-of-function mutations and over-expression, an observation that has led to the development and clinical testing of specific EZH2 inhibitors. Such inhibitors may also be of use in inflammatory and autoimmune settings, as EZH2 inhibition dampens the immune response. Here, we will review the current state of understanding of the roles for EZH2, and PRC2 more generally, in the development and function of the immune system.
The diagnostic and therapeutic potential of Maackia amurensis agglutinin (MAA) have been reported in various malignancies. Earlier, we have found that MAA specifically interacted with human non-small cell lung-cancer (NSCLC) cells and induced apoptosis in these cells. The present study was designed to identify M. amurensis leukoagglutinin (MAL-I, one of the components of MAA, having the same carbohydrate specificity as MAA) interacting membrane sialoglycoprotein(s) of two subtypes of human NSCLC cell lines. Nine proteins were identified using two-dimensional (2D)-polyacrylamide gel electrophoresis (PAGE) followed by MAL-I-overlay transblotting and matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF-MS). Among these proteins, HSP60 was selected for further characterization. The sialoglycoprotein nature of membrane-HSP60 of NSCLC cell lines was confirmed by its reduced reactivity with MAL-I in Western blots in the presence of GM2 and by dual staining of the cell lines with MAL-I and HSP60-antibody. These findings were further substantiated by enzymatic analysis of membrane-HSP60 as well as in-silico evidence regarding this protein. Our observations were validated by immunohistochemical analysis of both subtypes of NSCLC tissue sections. Membrane-HSP60 was found to be involved in the inhibition of MAL-I-induced morphological alteration of NSCLC cells and also in the proliferation and migration of these cells, indicating the probable role of sialylated membrane-HSP60 in this disease.