ERK in Learning and Memory: A Review of Recent Research

The extracellular signal-regulated kinase (ERK) pathway is a member of the mitogen-activated protein kinase (MAPK) superfamily, which is an important, highly conserved family of enzymes associated with cell membrane receptors and regulative targets. In the central nervous system, there is almost no mature neuronal proliferation and differentiation, but the regulation of MAPK and its upstream and downstream molecular pathways is still widespread, with the ERK signaling pathway being one of the most actively studied signal transduction pathways. It is activated by a variety of cell growth factors and substances which promote mitotic activity, and transmits extracellular signals from the cell surface to the nucleus, which transmission plays an important role in the process of cell proliferation and differentiation. In recent years, accumulating evidence has shown that the ERK signaling pathway has an important link with the higher functions of learning and memory.     

From Channels to Canonical Wnt Signaling: A Pathological Perspective

Wnt signaling is an important pathway mainly active during embryonic development and controlling cell proliferation. This regulatory pathway is aberrantly activated in several human diseases. Ion channels are known modulators of several important cellular functions ranging from the tuning of the membrane potential to modulation of intracellular pathways, in particular the influence of ion channels in Wnt signaling regulation has been widely investigated. This review will discuss the known links between ion channels and canonical Wnt signaling, focusing on their possible roles in human metabolic diseases, neurological disorders, and cancer.     

State of the art in silico tools for the study of signaling pathways in cancer

In the last several years, researchers have exhibited an intense interest in the evolutionarily conserved signaling pathways that have crucial roles during embryonic development. Interestingly, the malfunctioning of these signaling pathways leads to several human diseases, including cancer. The chemical and biophysical events that occur during cellular signaling, as well as the number of interactions within a signaling pathway, make these systems complex to study. In silico resources are tools used to aid the understanding of cellular signaling pathways. Systems approaches have provided a deeper knowledge of diverse biochemical processes, including individual metabolic pathways, signaling networks and genome-scale metabolic networks. In the future, these tools will be enormously valuable, if they continue to be developed in parallel with growing biological knowledge. In this study, an overview of the bioinformatics resources that are currently available for the analysis of biological networks is provided.     

The pLysRS-Ap4A Pathway in Mast Cells Regulates the Switch from Host Defense to a Pathological State

The innate and adaptive immune systems play an essential role in host defense against pathogens. Various signal transduction pathways monitor and balance the immune system since an imbalance may promote pathological states such as allergy, inflammation, and cancer. Mast cells have a central role in the regulation of the innate/adaptive immune system and are involved in the pathogenesis of many inflammatory and allergic diseases by releasing inflammatory mediators such as histamines, proteases, chemotactic factors, and cytokines. Although various signaling pathways are associated with mast cell activation, our discovery and characterization of the pLysRS-Ap₄A signaling pathway in these cells provided an additional important step towards a full understanding of the intracellular mechanisms involved in mast cell activation. In the present review, we will discuss in depth this signaling pathway’s contribution to host defense and the pathological state.     

Taurine Attenuates Catabolic Processes Related to the Onset of Sarcopenia

Sarcopenia that occurs with advancing age is characterized by a gradual loss of muscle protein component due to the activation of catabolic pathways, increased level of inflammation, and mitochondrial dysfunction. Experimental evidence demonstrates that several physio-pathological processes involved in the onset of sarcopenia may be counteracted by the intake of specific amino acids or antioxidant molecules, suggesting that diet may represent an effective strategy for improving the anabolic response of muscle during aging. The non-essential amino acid taurine is highly expressed in several mammalian tissues, including skeletal muscle where it is involved in the ion channel regulation, in the modulation of intracellular calcium concentration, and where it plays an important role as an antioxidant and anti-inflammatory factor. Here, with the purpose to reproduce the chronic low-grade inflammation characteristics of senescent muscle in an in vitro system, we exploited the role of Tumor Necrosis Factor α (TNF) and we analyzed the effect of taurine in the modulation of different signaling pathways known to be dysregulated in sarcopenia. We demonstrated that the administration of high levels of taurine in myogenic L6 cells stimulates the differentiation process by downregulating the expression of molecules involved in inflammatory pathways and modulating processes such as autophagy and apoptosis. Although further studies are currently ongoing in our laboratory to better elucidate the molecular mechanisms responsible for the positive effect of taurine on myogenic differentiation, this study suggests that taurine supplementation may represent a strategy to delay the loss of mass and functionality characteristic of senescent muscles.     

Role of Cytokine Signaling during Nervous System Development

Cytokines are signaling proteins that were first characterized as components of the immune response, but have been found to have pleiotropic effects in diverse aspects of body function in health and disease. They are secreted by numerous cells and are used extensively in intercellular communications to produce different activities, including intricate processes engaged in the ontogenetic development of the brain. This review discusses factors involved in brain growth regulation and recent findings exploring cytokine signaling pathways during development of the central nervous system. In view of existing data suggesting roles for neurotropic cytokines in promoting brain growth and repair, these molecules and their signaling pathways might become targets for therapeutic intervention in neurodegenerative processes due to diseases, toxicity, or trauma.     

Multiple Myeloma Bone Disease: Implication of MicroRNAs in Its Molecular Background

Multiple myeloma (MM) is a common hematological malignancy arising from terminally differentiated plasma cells. In the majority of cases, symptomatic disease is characterized by the presence of bone disease. Multiple myeloma bone disease (MMBD) is a result of an imbalance in the bone-remodeling process that leads to increased osteoclast activity and decreased osteoblast activity. The molecular background of MMBD appears intriguingly complex, as several signaling pathways and cell-to-cell interactions are implicated in the pathophysiology of MMBD. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate the expression of their target mRNAs. Numerous miRNAs have been witnessed to be involved in cancer and hematological malignancies and their role has been characterized either as oncogenic or oncosuppressive. Recently, scientific research turned towards miRNAs as regulators of MMBD. Scientific data support that miRNAs finely regulate the majority of the signaling pathways implicated in MMBD. In this review, we provide concise information regarding the molecular pathways with a significant role in MMBD and the miRNAs implicated in their regulation. Moreover, we discuss their utility as molecular biomarkers and highlight the putative usage of miRNAs as novel molecular targets for targeted therapy in MMBD.     

Comparative Proteomics Analysis Reveals Unique Early Signaling Response of Saccharomyces cerevisiae to Oxidants with Different Mechanism of Action

The early signaling events involved in oxidant recognition and triggering of oxidant-specific defense mechanisms to counteract oxidative stress still remain largely elusive. Our discovery driven comparative proteomics analysis revealed unique early signaling response of the yeast Saccharomyces cerevisiae on the proteome level to oxidants with a different mechanism of action as early as 3 min after treatment with four oxidants, namely H₂O₂, cumene hydroperoxide (CHP), and menadione and diamide, when protein abundances were compared using label-free quantification relying on a high-resolution mass analyzer (Orbitrap). We identified significant regulation of 196 proteins in response to H₂O₂, 569 proteins in response to CHP, 369 proteins in response to menadione and 207 proteins in response to diamide. Only 17 proteins were common across all treatments, but several more proteins were shared between two or three oxidants. Pathway analyses revealed that each oxidant triggered a unique signaling mechanism associated with cell survival and repair. Signaling pathways mostly regulated by oxidants were Ran, TOR, Rho, and eIF2. Furthermore, each oxidant regulated these pathways in a unique way indicating specificity of response to oxidants having different modes of action. We hypothesize that interplay of these signaling pathways may be important in recognizing different oxidants to trigger different downstream MAPK signaling cascades and to induce specific responses.     

Molecular Mechanism of Cannabinoids in Cancer Progression

Cannabinoids are a family of heterogeneous compounds that mostly interact with receptors eliciting several physiological effects both in the central and peripheral nervous systems and in peripheral organs. They exert anticancer action by modulating signaling pathways involved in cancer progression; furthermore, the effects induced by their use depend on both the type of tumor and their action on the components of the endocannabinoid system. This review will explore the mechanism of action of the cannabinoids in signaling pathways involved in cancer proliferation, neovascularisation, migration, invasion, metastasis, and tumor angiogenesis.     

Glial Modulation of Energy Balance: The Dorsal Vagal Complex Is No Exception

The avoidance of being overweight or obese is a daily challenge for a growing number of people. The growing proportion of people suffering from a nutritional imbalance in many parts of the world exemplifies this challenge and emphasizes the need for a better understanding of the mechanisms that regulate nutritional balance. Until recently, research on the central regulation of food intake primarily focused on neuronal signaling, with little attention paid to the role of glial cells. Over the last few decades, our understanding of glial cells has changed dramatically. These cells are increasingly regarded as important neuronal partners, contributing not just to cerebral homeostasis, but also to cerebral signaling. Our understanding of the central regulation of energy balance is part of this (r)evolution. Evidence is accumulating that glial cells play a dynamic role in the modulation of energy balance. In the present review, we summarize recent data indicating that the multifaceted glial compartment of the brainstem dorsal vagal complex (DVC) should be considered in research aimed at identifying feeding-related processes operating at this level.     

Insulin-Like Peptide Receptor-Mediated Signaling Pathways Orchestrate Regulation of Growth in the Pacific Oyster (Crassostrea gigas), as Revealed by Gene Expression Profiles

The involvement of insulin/insulin-like growth factor signaling (IIS) pathways in the growth regulation of marine invertebrates remains largely unexplored. In this study, we used a fast-growing Pacific oyster (Crassostrea gigas) variety “Haida No.1” as the material with which to unravel the role of IIS systems in growth regulation in oysters. Systematic bioinformatics analyses allowed us to identify major components of the IIS signaling pathway and insulin-like peptide receptor (ILPR)-mediated signaling pathways, including PI3K-AKT, RAS-MAPK, and TOR, in C. gigas. The expression levels of the major genes in IIS and its downstream signaling pathways were significantly higher in “Haida No.1” than in wild oysters, suggesting their involvement in the growth regulation of C. gigas. The expression profiles of IIS and its downstream signaling pathway genes were significantly altered by nutrient abundance and culture temperature. These results suggest that the IIS signaling pathway coupled with the ILPR-mediated signaling pathways orchestrate the regulation of energy metabolism to control growth in Pacific oysters.     

Inhibition Effect of Chloroquine and Integrin-Linked Kinase Knockdown on Translation in Melanoma Cells

The twofold role of autophagy in cancer is often the therapeutic target. Numerous regulatory pathways are shared between autophagy and other molecular processes needed in tumorigenesis, such as translation or survival signaling. Thus, we have assumed that ILK knockdown should promote autophagy, and used together with chloroquine, an autophagy inhibitor, it could generate a better anticancer effect by dysregulation of common signaling pathways. Expression at the protein level was analyzed using Western Blot; siRNA transfection was done for ILK. Analysis of cell signaling pathways was monitored with phospho-specific antibodies. Melanoma cell proliferation was assessed with the crystal violet test, and migration was evaluated by scratch wound healing assays. Autophagy was monitored by the accumulation of its marker, LC3-II. Our data show that ILK knockdown by siRNA suppresses melanoma cell growth by inducing autophagy through AMPK activation, and simultaneously initiates apoptosis. We demonstrated that combinatorial treatment of melanoma cells with CQ and siILK has a stronger antitumor effect than monotherapy with either of these. It generates the synergistic antitumor effects by the decrease of translation of both global and oncogenic proteins synthesis. In our work, we point to the crosstalk between translation and autophagy regulation.     

Plant Secondary Metabolites as Defense Tools against Herbivores for Sustainable Crop Protection

Plants have evolved several adaptive strategies through physiological changes in response to herbivore attacks. Plant secondary metabolites (PSMs) are synthesized to provide defensive functions and regulate defense signaling pathways to safeguard plants against herbivores. Herbivore injury initiates complex reactions which ultimately lead to synthesis and accumulation of PSMs. The biosynthesis of these metabolites is regulated by the interplay of signaling molecules comprising phytohormones. Plant volatile metabolites are released upon herbivore attack and are capable of directly inducing or priming hormonal defense signaling pathways. Secondary metabolites enable plants to quickly detect herbivore attacks and respond in a timely way in a rapidly changing scenario of pest and environment. Several studies have suggested that the potential for adaptation and/or resistance by insect herbivores to secondary metabolites is limited. These metabolites cause direct toxicity to insect pests, stimulate antixenosis mechanisms in plants to insect herbivores, and, by recruiting herbivore natural enemies, indirectly protect the plants. Herbivores adapt to secondary metabolites by the up/down regulation of sensory genes, and sequestration or detoxification of toxic metabolites. PSMs modulate multi-trophic interactions involving host plants, herbivores, natural enemies and pollinators. Although the role of secondary metabolites in plant-pollinator interplay has been little explored, several reports suggest that both plants and pollinators are mutually benefited. Molecular insights into the regulatory proteins and genes involved in the biosynthesis of secondary metabolites will pave the way for the metabolic engineering of biosynthetic pathway intermediates for improving plant tolerance to herbivores. This review throws light on the role of PSMs in modulating multi-trophic interactions, contributing to the knowledge of plant-herbivore interactions to enable their management in an eco-friendly and sustainable manner.     

Transcriptional Profiling of Cardiac Cells Links Age-Dependent Changes in Acetyl-CoA Signaling to Chromatin Modifications

Metabolism has emerged as a regulator of core stem cell properties such as proliferation, survival, self-renewal, and multilineage potential. Metabolites serve as secondary messengers, fine-tuning signaling pathways in response to microenvironment alterations. Studies show a role for central metabolite acetyl-CoA in the regulation of chromatin state through changes in histone acetylation. Nevertheless, metabolic regulators of chromatin remodeling in cardiac cells in response to increasing biological age remains unknown. Previously, we identified novel cardiac-derived stem-like cells (CTSCs) that exhibit increased functional properties in the neonatal heart (nCTSC). These cells are linked to a unique metabolism which is altered with CTSC aging (aCTSC). Here, we present an in-depth, RNA-sequencing-based (RNA-Seq) bioinformatic with cluster analysis that details a distinct epigenome present in nCTSCs but not in aCTSCs. Gene Ontology (GO) and pathway enrichment reveal biological processes, including metabolism, gene regulation enriched in nCTSCs, and STRING analysis that identifies a network of genes related to acetyl-CoA that can potentially influence chromatin remodeling. Additional validation by Western blot and qRT-PCR shows increased acetyl-CoA signaling and histone acetylation in nCTSCs compared to aCTSCs. In conclusion, our data reveal that the link between metabolism and histone acetylation in cardiac cells is altered with the aging of the cardiac tissue.     

Transcriptional Modulation of the Hippo Signaling Pathway by Drugs Used to Treat Bipolar Disorder and Schizophrenia

Recent reports suggest a link between positive regulation of the Hippo pathway with bipolar disorder (BD), and the Hippo pathway is known to interact with multiple other signaling pathways previously associated with BD and other psychiatric disorders. In this study, neuronal-like NT2 cells were treated with amisulpride (10 µM), aripiprazole (0.1 µM), clozapine (10 µM), lamotrigine (50 µM), lithium (2.5 mM), quetiapine (50 µM), risperidone (0.1 µM), valproate (0.5 mM), or vehicle control for 24 h. Genome-wide mRNA expression was quantified and analyzed using gene set enrichment analysis (GSEA), with genes belonging to Hippo, Wnt, Notch, TGF- β, and Hedgehog retrieved from the KEGG database. Five of the eight drugs downregulated the genes of the Hippo pathway and modulated several genes involved in the interacting pathways. We speculate that the regulation of these genes, especially by aripiprazole, clozapine, and quetiapine, results in a reduction of MAPK and NFκB pro-inflammatory signaling through modulation of Hippo, Wnt, and TGF-β pathways. We also employed connectivity map analysis to identify compounds that act on these pathways in a similar manner to the known psychiatric drugs. Thirty-six compounds were identified. The presence of antidepressants and antipsychotics validates our approach and reveals possible new targets for drug repurposing.     

Molecular Aspects of Seed Development Controlled by Gibberellins and Abscisic Acids

Plants have evolved seeds to permit the survival and dispersion of their lineages by providing nutrition for embryo growth and resistance to unfavorable environmental conditions. Seed formation is a complicated process that can be roughly divided into embryogenesis and the maturation phase, characterized by accumulation of storage compound, acquisition of desiccation tolerance, arrest of growth, and acquisition of dormancy. Concerted regulation of several signaling pathways, including hormonal and metabolic signals and gene networks, is required to accomplish seed formation. Recent studies have identified the major network of genes and hormonal signals in seed development, mainly in maturation. Gibberellin (GA) and abscisic acids (ABA) are recognized as the main hormones that antagonistically regulate seed development and germination. Especially, knowledge of the molecular mechanism of ABA regulation of seed maturation, including regulation of dormancy, accumulation of storage compounds, and desiccation tolerance, has been accumulated. However, the function of ABA and GA during embryogenesis still remains elusive. In this review, we summarize the current understanding of the sophisticated molecular networks of genes and signaling of GA and ABA in the regulation of seed development from embryogenesis to maturation.