LINC01686 affects LPS-induced cytokine expression via the miR-18a-5p/A20/STAT1 axis in THP-1 cells.

BACKGROUND AND OBJECTIVE: Long noncoding RNAs (lncRNAs) are crucial in regulating various physiological and pathological processes, including immune responses. LINC01686 is a lncRNA with previously uncharacterized functions in immune regulation. This study aims to investigate the function of LINC01686 in lipopolysaccharide (LPS)-induced inflammatory responses in the human monocytic leukemia cell line THP-1 and its potential regulatory mechanisms involving miR-18a-5p and the anti-inflammatory protein A20. METHOD: THP-1 cells were stimulated with LPS to induce inflammatory responses, followed by analysis of LINC01686 expression levels. The role of LINC01686 in regulating the expression of interleukin (IL)-6, IL-8, A20, and signal transducer and activator of transcription 1 (STAT1) was examined using small interfering RNA-mediated knockdown. Additionally, the involvement of miR-18a-5p in LINC01686-mediated regulatory pathways was assessed by transfection with decoy RNAs mimicking the miR-18a-5p binding sites of LINC01686 or A20 messenger RNA. RESULTS: LINC01686 expression was upregulated in THP-1 cells following LPS stimulation. Suppression of LINC01686 enhanced LPS-induced expression of IL-6 and IL-8, mediated through increased production of reactive oxygen species. Moreover, LINC01686 knockdown upregulated the expression and activation of IκB-ζ, STAT1, and downregulated A20 expression. Transfection with decoy RNAs reversed the effects of LINC01686 suppression on A20, STAT1, IL-6, and IL-8 expression, highlighting the role of LINC01686 in sponging miR-18a-5p and regulating A20 expression. CONCLUSION: This study provides the first evidence that LINC01686 plays a critical role in modulating LPS-induced inflammatory responses in THP-1 cells by sponging miR-18a-5p, thereby regulating the expression and activation of A20 and STAT1. These findings shed light on the complex regulatory mechanisms involving lncRNAs in immune responses and offer potential therapeutic targets for inflammatory diseases.

Roles of lncRNAs in NF-κB-Mediated Macrophage Inflammation and Their Implications in the Pathogenesis of Human Diseases.

Over the past century, molecular biology's focus has transitioned from proteins to DNA, and now to RNA. Once considered merely a genetic information carrier, RNA is now recognized as both a vital element in early cellular life and a regulator in complex organisms. Long noncoding RNAs (lncRNAs), which are over 200 bases long but do not code for proteins, play roles in gene expression regulation and signal transduction by inducing epigenetic changes or interacting with various proteins and RNAs. These interactions exhibit a range of functions in various cell types, including macrophages. Notably, some macrophage lncRNAs influence the activation of NF-κB, a crucial transcription factor governing immune and inflammatory responses. Macrophage NF-κB is instrumental in the progression of various pathological conditions including sepsis, atherosclerosis, cancer, autoimmune disorders, and hypersensitivity. It orchestrates gene expression related to immune responses, inflammation, cell survival, and proliferation. Consequently, its malfunction is a key contributor to the onset and development of these diseases. This review aims to summarize the function of lncRNAs in regulating NF-κB activity in macrophage activation and inflammation, with a particular emphasis on their relevance to human diseases and their potential as therapeutic targets. The insights gained from studies on macrophage lncRNAs, as discussed in this review, could provide valuable knowledge for the development of treatments for various pathological conditions involving macrophages.

Regulation of inflammatory response by LINC00346 via miR-25-3p-mediated modulation of the PTEN/PI3K/AKT/NF-κB pathway.

Long intergenic non-coding RNA 346 (LINC00346) has been reported to be involved in the development of atherosclerosis and specific cancers by affecting signaling pathways. However, its function in inflammation has not been thoroughly studied. Therefore, its expression pattern and function were determined in the human macrophage-like cell line THP-1. Lipopolysaccharide (LPS) treatment induced the expression of LINC00346. LPS-induced NF-κB activation and proinflammatory cytokine expression were suppressed or enhanced by the overexpression or knockdown of LINC00346, respectively. Analyses using dual luciferase assay and decoy RNAs that could block RNA-RNA interactions indicated that LINC00346 improves phosphatase and tensin homolog (PTEN) expression by sponging miR-25-3p. Subsequently, PTEN suppresses phosphoinositide-3 kinase (PI3K)-mediated conversion of phosphatidylinositol-4,5-bisphosphate (PIP2) into phosphatidylinositol-3,4,5-trisphosphate (PIP3) as well as consequent activation of protein kinase B (AKT) and NF-κB. Interestingly, database analysis revealed that the expression levels of LINC00346 and PTEN were simultaneously decreased in breast cancer tissues. Further analyses conducted using a breast cancer cell line, MDA-MB-231, confirmed the functional relationship among LINC00346, miR-25-3p, and PTEN in LPS-induced activation of NF-κB. These results indicate that miR-25-3p-sponging activity of LINC00346 affects the balance between PTEN and PI3K as well as the downstream activation of AKT/NF-κB pathway in inflammatory conditions.

The microglial innate immune protein PGLYRP1 mediates neuroinflammation and consequent behavioral changes.

Peptidoglycan recognition protein 1 (PGLYRP1) is a pattern-recognition protein that mediates antibacterial actions and innate immune responses. Its expression and role in neuroinflammatory conditions remain unclear. We observed the upregulation of PGLYRP1 in inflamed human and mouse spinal cord and brain, with microglia being the primary cellular source. Experiments using a recombinant PGLYRP1 protein show that PGLYRP1 potentiates reactive gliosis, neuroinflammation, and consequent behavioral changes in multiple animal models of neuroinflammation. Furthermore, shRNA-mediated knockdown of Pglyrp1 gene expression attenuates this inflammatory response. In addition, we identify triggering receptor expressed on myeloid cell-1 (TREM1) as an interaction partner of PGLYRP1 and demonstrate that PGLYRP1 promotes neuroinflammation through the TREM1-Syk-Erk1/2-Stat3 axis in cultured glial cells. Taken together, our results reveal a role for microglial PGLYRP1 as a neuroinflammation mediator. Finally, we propose that PGLYRP1 is a potential biomarker and therapeutic target in various neuroinflammatory diseases.

Lipocalin-2 as a mediator of neuroimmune communication.

Lipocalin-2 (LCN2), a neutrophil gelatinase-associated lipocalin (NGAL), is a 25 kDa secreted protein implicated in a broad range of inflammatory diseases affecting the brain and periphery. It is a pleotropic protein expressed by various immune and non-immune cells throughout the body. Importantly, the surge in LCN2 levels in disease states has been associated with a myriad of undesirable effects, further exacerbating the ongoing pathological processes. In the brain, glial cells are the principal source of LCN2, which plays a definitive role in determining their functional phenotypes. In different central nervous system (CNS) pathologies, an increased expression of glial LCN2 has been linked to neurotoxicity. LCN2 mediates a crosstalk between central and peripheral immune cells under neuroinflammatory conditions. One intriguing aspect is that elevated LCN2 levels in peripheral disorders, such as cancer, metabolic conditions, and liver diseases, potentially incite an inflammatory activation of glial cells while disrupting neuronal functions. This review comprehensively summarizes the influence of LCN2 on the exacerbation of neuroinflammation by regulating various cellular processes. Additionally, this review explores LCN2 as a mediator of neuroimmune crosstalk in various CNS pathologies and highlights the role of LCN2 in carrying inflammatory signals along the neuroimmune axis.

Utilizing databases for astrocyte secretome research.

INTRODUCTION: Astrocytes are the most abundant cell type in the central nervous system (CNS). They play a pivotal role in supporting neuronal function and maintaining homeostasis by releasing a variety of bioactive proteins, collectively known as the astrocyte secretome. Investigating secretome provides insights into the molecular mechanisms underlying astrocyte function and dysfunction, as well as novel strategies to prevent and treat diseases affecting the CNS. AREAS COVERED: Proteomics databases are a valuable resource for studying the role of astrocytes in healthy and diseased brain function, as they provide information about gene expression, protein expression, and cellular function. In this review, we discuss existing databases that are useful for astrocyte secretome research. EXPERT OPINION: Astrocyte secretomics is a field that is rapidly progressing, yet the availability of dedicated databases is currently limited. To meet the increasing demand for comprehensive omics data in glia research, developing databases specifically focused on astrocyte secretome is crucial. Such databases would allow researchers to investigate the intricate molecular landscape of astrocytes and comprehend their involvement in diverse physiological and pathological processes. Expanding resources through the development of databases dedicated to the astrocyte secretome may facilitate further advancements in this field.

Macrophage lncRNAs in cancer development: Long-awaited therapeutic targets.

In the tumor microenvironment, the interplay among macrophages, cancer cells, and endothelial cells is multifaceted. Tumor-associated macrophages (TAMs), which often exhibit an M2 phenotype, contribute to tumor growth and angiogenesis, while cancer cells and endothelial cells reciprocally influence macrophage behavior. This complex interrelationship highlights the importance of targeting these interactions for the development of novel cancer therapies aimed at disrupting tumor progression and angiogenesis. Accumulating evidence underscores the indispensable involvement of lncRNAs in shaping macrophage functionality and contributing to the development of cancer. Animal studies have further validated the therapeutic potential of manipulating macrophage lncRNA activity to ameliorate disease severity and reduce morbidity rates. This review provides a survey of our current understanding of macrophage-associated lncRNAs, with a specific emphasis on their molecular targets and their regulatory impact on cancer progression. These lncRNAs predominantly govern macrophage polarization, favoring the dominance of M2 macrophages or TAMs. Exosomes or extracellular vesicles mediate lncRNA transfer between macrophages and cancer cells, affecting cellular functions of each other. Moreover, this review presents therapeutic strategies targeting cancer-associated lncRNAs. The insights and findings presented in this review pertaining to macrophage lncRNAs can offer valuable information for the development of treatments against cancer.

Analyzing the glial proteome in Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, memory loss, and changes in behavior. Accumulating evidence indicates that dysfunction of glial cells, including astrocytes, microglia, and oligodendrocytes, may contribute to the development and progression of AD. Large-scale analysis of glial proteins sheds light on their roles in cellular processes and diseases. In AD, glial proteomics has been utilized to understand glia-based pathophysiology and identify potential biomarkers and therapeutic targets. AREA COVERED: In this review, we provide an updated overview of proteomic analysis of glia in the context of AD. Additionally, we discuss current challenges in the field, involving glial complexity and heterogeneity, and describe some cutting-edge proteomic technologies to address them. EXPERT OPINION: Unbiased comprehensive analysis of glial proteomes aids our understanding of the molecular and cellular mechanisms of AD pathogenesis. These investigations highlight the crucial role of glial cells and provide novel insights into the mechanisms of AD pathology. A deeper understanding of the AD-related glial proteome could offer a repertoire of potential biomarkers and therapeutics. Further technical advancement of glial proteomics will enable us to identify proteins within individual cells and specific cell types, thus significantly enhancing our comprehension of AD pathogenesis.

Role of Macrophage lncRNAs in Mediating Inflammatory Processes in Atherosclerosis and Sepsis.

Long noncoding RNAs (lncRNAs) are molecules >200 bases in length without protein-coding functions implicated in signal transduction and gene expression regulation via interaction with proteins or RNAs, exhibiting various functions. The expression of lncRNAs has been detected in many cell types, including macrophages, a type of immune cell involved in acute and chronic inflammation, removal of dead or damaged cells, and tissue repair. Increasing evidence indicates that lncRNAs play essential roles in macrophage functions and disease development. Additionally, many animal studies have reported that blockage or modulation of lncRNA functions alleviates disease severity or morbidity rate. The present review summarizes the current knowledge regarding lncRNAs expressed in macrophages, focusing on their molecular targets and the biological processes regulated by them during the development of inflammatory diseases such as atherosclerosis and sepsis. Possible application of this information to lncRNA-targeting therapy is also discussed. The studies regarding macrophage lncRNAs described in this review can help provide valuable information for developing treatments for various pathological conditions involving macrophages.

Bidirectional Communication Between Microglia and Astrocytes in Neuroinflammation.

Neuroinflammation is a common feature of diverse nervous system pathologies. In many instances, it begins at an early stage of the disease, paving the way for further exacerbations. The main drivers of neuroinflammation are brain-resident glial cells, such as microglia and astrocytes. Microglia are the primary responders to any insult to the brain parenchyma, translating the signals into diverse molecules. These molecules derived from microglia can regulate the stimuli-dependent reactivity of astrocytes. Once activated, astrocytes in turn, can control microglia phenotypes. Recent evidence indicates that the crosstalk between these glial cells plays an important role in delaying or accelerating neuroinflammation and overall disease progression. To date, various molecules have been recognized as key mediators of the bidirectional communication between microglia and astrocytes. The current review aims to discuss the novel molecules identified recently, which play a critical role in interglial crosstalk, highlighting their therapeutic potential.

Cathelicidin-Related Antimicrobial Peptide Negatively Regulates Bacterial Endotoxin-Induced Glial Activation.

Recent studies have suggested that mouse cathelicidin-related antimicrobial peptide (CRAMP) and its human homologue leucine leucine-37 (LL-37) play critical roles in innate immune responses. Here, we studied the role of mouse CRAMP in bacterial endotoxin lipopolysaccharide (LPS)-induced neuroinflammation. CRAMP peptide treatment significantly inhibited LPS-mediated inflammatory activation of glial cells in culture. In the animal model of LPS-induced neuroinflammation, CRAMP expression was highly induced in multiple cell types, such as astrocytes, microglia, and neurons. Injection of exogenous CRAMP peptide significantly inhibited inflammatory cytokine expression and the reactivity of glial cells in the mouse brain following intraperitoneal or intracerebroventricular LPS administration. Altogether, results of the study suggest that CRAMP plays an important part in containment of LPS-induced neuroinflammatory responses, and that CRAMP can be exploited for the development of targeted therapies for neuroinflammatory conditions associated with bacterial infection.

Carnitine Protects against MPP+-Induced Neurotoxicity and Inflammation by Promoting Primary Ciliogenesis in SH-SY5Y Cells.

Primary cilia help to maintain cellular homeostasis by sensing conditions in the extracellular environment, including growth factors, nutrients, and hormones that are involved in various signaling pathways. Recently, we have shown that enhanced primary ciliogenesis in dopamine neurons promotes neuronal survival in a Parkinson's disease model. Moreover, we performed fecal metabolite screening in order to identify several candidates for improving primary ciliogenesis, including L-carnitine and acetyl-L-carnitine. However, the role of carnitine in primary ciliogenesis has remained unclear. In addition, the relationship between primary cilia and neurodegenerative diseases has remained unclear. In this study, we have evaluated the effects of carnitine on primary ciliogenesis in 1-methyl-4-phenylpyridinium ion (MPP+)-treated cells. We found that both L-carnitine and acetyl-L-carnitine promoted primary ciliogenesis in SH-SY5Y cells. In addition, the enhancement of ciliogenesis by carnitine suppressed MPP+-induced mitochondrial reactive oxygen species overproduction and mitochondrial fragmentation in SH-SY5Y cells. Moreover, carnitine inhibited the production of pro-inflammatory cytokines in MPP+-treated SH-SY5Y cells. Taken together, our findings suggest that enhanced ciliogenesis regulates MPP+-induced neurotoxicity and inflammation.

Cathelicidin-related antimicrobial peptide promotes neuroinflammation through astrocyte-microglia communication in experimental autoimmune encephalomyelitis.

Cathelicidin-related antimicrobial peptide (CRAMP) is an effector molecule of the innate immune system with direct antimicrobial and immunomodulatory activities; however, its role in neuroinflammatory responses and related diseases is not clearly understood. In particular, the expression of CRAMP and its functional role has not been previously studied in experimental autoimmune encephalomyelitis (EAE) or multiple sclerosis (MS). Here, we investigated the role of CRAMP in neuroinflammation, using an EAE mouse model of MS and postmortem patient tissues. We found that the CRAMP expression was increased in the spinal cords of EAE-induced mice. Immunofluorescence analysis revealed that CRAMP is mainly induced in reactive astrocytes in the inflamed spinal cord of EAE mice. A similar pattern of the LL-37 (human CRAMP) expression was observed in the brain and spinal cord tissues of patients with MS. An intrathecal injection of the CRAMP peptide in EAE mice accelerated the onset of symptoms and increased disease severity with augmented expression of inflammatory mediators, glial activation, infiltration of inflammatory cells, and demyelination. In addition, shRNA-mediated knockdown of Cramp in the spinal cord resulted in a milder disease course with less inflammation in EAE mice. We identified FPR2 on microglia as a CRAMP receptor and demonstrated that CRAMP potentiates IFN-γ-induced microglial activation via the STAT3 pathway. Taken together, our findings suggest that CRAMP is a novel mediator of astrocyte-microglia interactions in neuroinflammatory conditions such as EAE. Thus, CRAMP could be exploited as a biomarker or therapeutic target for the diagnosis or treatment of MS.

Chemogenetic stimulation of the Gi pathway in astrocytes suppresses neuroinflammation.

Engineered G protein-coupled receptors (GPCRs) are commonly used in chemogenetics as designer receptors exclusively activated by designer drugs (DREADDs). Although several GPCRs have been studied in astrocytes using a chemogenetic approach, the functional role of the astrocytic Gi pathway is not clear, as the literature is conflicting depending on the brain regions or behaviors investigated. In this study, we evaluated the role of the astrocytic Gi pathway in neuroinflammation using a Gi -coupled DREADD (hM4Di). Gi -DREADD was expressed in hippocampal astrocytes of a lipopolysaccharide (LPS)-induced neuroinflammation mouse model using adeno-associated viruses. We found that astrocyte Gi -DREADD stimulation using clozapine N-oxide (CNO) inhibits neuroinflammation, as characterized by decreased levels of proinflammatory cytokines, glial activation, and cognitive impairment in mice. Subsequent experiments using primary astrocyte cultures revealed that Gi -DREADD stimulation significantly downregulated LPS-induced expression of Nos2 mRNA and nitric oxide production. Similarly, in vitro calcium imaging showed that activation of the astrocytic Gi pathway attenuated intracellular calcium transients triggered by LPS treatment, suggesting a positive correlation between enhanced calcium transients and the inflammatory phenotype of astrocytes observed in the inflamed brain. Taken together, our results indicate that the astrocytic Gi pathway plays an inhibitory role in neuroinflammation, providing an opportunity to identify potential cellular and molecular targets to control neuroinflammation.

Lipocalin-2 in Diabetic Complications of the Nervous System: Physiology, Pathology, and Beyond.

Lipocalin-2 (LCN2) is a 25 kDa secreted protein that belongs to the family of lipocalins, a group of transporters of small hydrophobic molecules such as iron, fatty acids, steroids, and lipopolysaccharide in circulation. LCN2 was previously found to be involved in iron delivery, pointing toward a potential role for LCN2 in immunity. This idea was further validated when LCN2 was found to limit bacterial growth during infections in mice by sequestering iron-laden siderophores. Recently, LCN2 was also identified as a critical regulator of energy metabolism, glucose and lipid homeostasis, and insulin function. Furthermore, studies using Lcn2 knockout mice suggest an important role for LCN2 in several biobehavioral responses, including cognition, emotion, anxiety, and feeding behavior. Owing to its expression and influence on multiple metabolic and neurological functions, there has emerged a great deal of interest in the study of relationships between LCN2 and neurometabolic complications. Thorough investigation has demonstrated that LCN2 is involved in several neurodegenerative diseases, while more recent studies have shown that LCN2 is also instrumental for the progression of diabetic complications like encephalopathy and peripheral neuropathy. Preliminary findings have shown that LCN2 is also a promising drug target and diagnostic marker for the treatment of neuropathic complications from diabetes. In particular, future translational research related to LCN2, such as the development of small-molecule inhibitors or neutralizing antibodies against LCN2, appears essential for exploring its potential as a therapeutic target.

Satellite glia as a critical component of diabetic neuropathy: Role of lipocalin-2 and pyruvate dehydrogenase kinase-2 axis in the dorsal root ganglion.

Diabetic peripheral neuropathy (DPN) is a common complication of uncontrolled diabetes. The pathogenesis of DPN is associated with chronic inflammation in dorsal root ganglion (DRG), eventually causing structural and functional changes. Studies on DPN have primarily focused on neuronal component, and there is limited knowledge about the role of satellite glial cells (SGCs), although they completely enclose neuronal soma in DRG. Lipocalin-2 (LCN2) is a pro-inflammatory acute-phase protein found in high levels in diverse neuroinflammatory and metabolic disorders. In diabetic DRG, the expression of LCN2 was increased exclusively in the SGCs. This upregulation of LCN2 in SGCs correlated with increased inflammatory responses in DRG and sciatic nerve. Furthermore, diabetes-induced inflammation and morphological changes in DRG, as well as sciatic nerve, were attenuated in Lcn2 knockout (KO) mice. Lcn2 gene ablation also ameliorated neuropathy phenotype as determined by nerve conduction velocity and intraepidermal nerve fiber density. Mechanistically, studies using specific gene KO mice, adenovirus-mediated gene overexpression strategy, and primary cultures of DRG SGCs and neurons have demonstrated that LCN2 enhances the expression of mitochondrial gate-keeping regulator pyruvate dehydrogenase kinase-2 (PDK2) through PPARß/δ, thereby inhibiting pyruvate dehydrogenase activity and increasing production of glycolytic end product lactic acid in DRG SGCs and neurons of diabetic mice. Collectively, our findings reveal a crucial role of glial LCN2-PPARß/δ-PDK2-lactic acid axis in progression of DPN. Our results establish a link between pro-inflammatory LCN2 and glycolytic PDK2 in DRG SGCs and neurons and propose a novel glia-based mechanism and drug target for therapy of DPN. MAIN POINTS: Diabetes upregulates LCN2 in satellite glia, which in turn increases pyruvate dehydrogenase kinase-2 (PDK2) expression and lactic acid production in dorsal root ganglia (DRG). Glial LCN2-PDK2-lactic acid axis in DRG plays a crucial role in the pathogenesis of diabetic neuropathy.

Interrogation of kinase genetic interactions provides a global view of PAK1-mediated signal transduction pathways.

Kinases are critical components of intracellular signaling pathways and have been extensively investigated with regard to their roles in cancer. p21-activated kinase-1 (PAK1) is a serine/threonine kinase that has been previously implicated in numerous biological processes, such as cell migration, cell cycle progression, cell motility, invasion, and angiogenesis, in glioma and other cancers. However, the signaling network linked to PAK1 is not fully defined. We previously reported a large-scale yeast genetic interaction screen using toxicity as a readout to identify candidate PAK1 genetic interactions. En masse transformation of the PAK1 gene into 4,653 homozygous diploid Saccharomyces cerevisiae yeast deletion mutants identified ∼400 candidates that suppressed yeast toxicity. Here we selected 19 candidate PAK1 genetic interactions that had human orthologs and were expressed in glioma for further examination in mammalian cells, brain slice cultures, and orthotopic glioma models. RNAi and pharmacological inhibition of potential PAK1 interactors confirmed that DPP4, KIF11, mTOR, PKM2, SGPP1, TTK, and YWHAE regulate PAK1-induced cell migration and revealed the importance of genes related to the mitotic spindle, proteolysis, autophagy, and metabolism in PAK1-mediated glioma cell migration, drug resistance, and proliferation. AKT1 was further identified as a downstream mediator of the PAK1-TTK genetic interaction. Taken together, these data provide a global view of PAK1-mediated signal transduction pathways and point to potential new drug targets for glioma therapy.

Microglia Gone Awry: Linking Immunometabolism to Neurodegeneration.

Age-related chronic inflammatory activation of microglia and their dysfunction are observed in many neurodegenerative diseases, and the potential contributions of these dysfunctional cells to neurodegeneration have been demonstrated recently. The housekeeping and defensive functions of microglia, such as surveying the brain parenchyma and phagocytosis of neuronal debris after injury, are important for brain homeostasis and immunity. During neurodegenerative diseases, loss of these functions can promote disease pathology by producing proinflammatory cytokines and increasing oxidative stress, which can exaggerate the ongoing neuroinflammation. A recent surge in microglial research has unraveled myriads of microglial phenotypes associated with aging and neurodegenerative diseases, in addition to the conventional M1/M2 paradigm. Each of these phenotypes can be characterized by distinct transcriptional profiles as well as altered metabolism, migration, and phagocytosis characteristics. Mutations in triggering receptor expressed on myeloid cells 2 (Trem2) and granulin (GRN) are associated with various neurodegenerative diseases, and these genes are dysregulated in the majority of recently identified microglial phenotypes. These genes act as checkpoint regulators and maintain microglial inflammatory fitness, principally through metabolic modulation. Dysfunctional microglia typically show mitochondrial deficits, glycolysis elevation, and lipid droplet accumulation, which results in reduced migration and phagocytosis and increased proinflammatory cytokine secretion and reactive oxygen species release. In this mini-review article, we discuss the existing data regarding metabolic perturbations in dysfunctional microglia and their documented associations with neurodegeneration, highlighting how aging-induced chronic microglial activation alters microglial bioenergetics, leading to impaired homeostatic and housekeeping functions. Dysfunctional microglia initiate or exacerbate neurodegeneration, and key pathways involved in the dysfunctional processes, including metabolism, may represent potential intervention targets for correcting imbalances.

Yeast-Based Genetic Interaction Analysis of Human Kinome.

Kinases are critical intracellular signaling proteins. To better understand kinase-mediated signal transduction, a large-scale human-yeast genetic interaction screen was performed. Among 597 human kinase genes tested, 28 displayed strong toxicity in yeast when overexpressed. En masse transformation of these toxic kinase genes into 4653 homozygous diploid yeast deletion mutants followed by barcode sequencing identified yeast toxicity modifiers and thus their human orthologs. Subsequent network analyses and functional grouping revealed that the 28 kinases and their 676 interaction partners (corresponding to a total of 969 genetic interactions) are enriched in cell death and survival (34%), small-molecule biochemistry (18%) and molecular transport (11%), among others. In the subnetwork analyses, a few kinases were commonly associated with glioma, cell migration and cell death/survival. Our analysis enabled the creation of a first draft of the kinase genetic interactome network and identified multiple drug targets for inflammatory diseases and cancer, in which deregulated kinase signaling plays a pathogenic role.

Proteomic examination of the neuroglial secretome: lessons for the clinic.

Introduction: Glial cells are closely associated with neurons located throughout the nervous system and regulate neuronal activity and function through various mechanisms including the secretion of proteins and other signaling molecules. Glia-secreted proteins play crucial roles in modulating neuronal function in physiological and pathological conditions. Aberrant activation of glial cells leading to neuroinflammation is a common phenomenon observed in various neurological disorders. Aberrantly activated glial cells secrete proteins in disease-specific manner and can be exploited as a repository for novel biomarker discovery.Areas covered: In this review, we describe the recent advances in proteomic techniques, highlighting the need for their application to the secretomic field. Studies regarding the secretome profile of glial cells published within the last 5 years are discussed in detail. The use of glia-based biomarkers in various neuroinflammatory and neurodegenerative diseases is also discussed.Expert opinion: Precise diagnosis and timely treatment of neurological disorders remains a challenge and glia-focused research to identify specific biomarkers appears to be a promising approach to combat these disorders. Recent technological advancement in proteomic research would open new frontiers for more rigorous analysis of glial secretome variations over time and the discovery/development of novel biomarkers for neurological disorders.