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Focal Adhesion Kinase (FAK) is a non-receptor tyrosine kinase pivotal in cellular signal transduction, regulating cell adhesion, migration, growth, and survival. However, the regulatory mechanisms of FAK during tumorigenesis and progression still need to be fully understood. Our previous study demonstrated that O-GlcNAcylation regulates integrin-mediated cell adhesion. To further elucidate the underlying molecular mechanism, we focused on FAK in this study and purified it from 293T cells. Using liquid chromatography–mass spectrometry (LC-MS/MS), we identified the O-GlcNAcylation of FAK at Ser708, Thr739, and Ser886. Compared with wild-type FAK expressed in FAK-knockout 293T cells, the FAK mutant, in which Ser708, Thr739, and Ser886 were replaced with Ala, exhibited lower phosphorylation levels of Tyr397 and AKT. Cell proliferation and migration, assessed through MTT and wound healing assays, were significantly suppressed in the FAK mutant cells compared to the wild-type FAK cells. Additionally, the interaction among FAK, paxillin, and talin was enhanced, and cell adhesion was increased in the mutant cells. These data indicate that specific O-GlcNAcylation of FAK plays a critical regulatory role in integrin-mediated cell adhesion and migration. This further supports the idea that O-GlcNAcylation is essential for tumorigenesis and progression and that targeting the O-GlcNAcylation of FAK could offer a promising therapeutic strategy for cancer treatment. [ABSTRACT FROM AUTHOR]

Retinal vascular diseases encompass several retinal disorders, including diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, and retinal vascular occlusion; these disorders are classified as similar groups of disorders due to impaired retinal vascularization. The aim of this review is to address the main signaling pathways involved in the pathogenesis of retinal vascular diseases and to identify crucial molecules and the importance of their interactions. Vascular endothelial growth factor (VEGF) is recognized as a crucial and central molecule in abnormal neovascularization and a key phenomenon in retinal vascular occlusion; thus, anti-VEGF therapy is now the most successful form of treatment for these disorders. Interaction between angiopoietin 2 and the Tie2 receptor results in aberrant Tie2 signaling, resulting in loss of pericytes, neovascularization, and inflammation. Notch signaling and hypoxia-inducible factors in ischemic conditions induce pathological neovascularization and disruption of the blood–retina barrier. An increase in the pro-inflammatory cytokines—TNF-α, IL-1β, and IL-6—and activation of microglia create a persistent inflammatory milieu that promotes breakage of the blood–retinal barrier and neovascularization. Toll-like receptor signaling and nuclear factor-kappa B are important factors in the dysregulation of the immune response in retinal vascular diseases. Increased production of reactive oxygen species and oxidative damage follow inflammation and together create a vicious cycle because each factor amplifies the other. Understanding the complex interplay among various signaling pathways, signaling cascades, and molecules enables the development of new and more successful therapeutic options. [ABSTRACT FROM AUTHOR]

Cutaneous melanoma accounts for the majority of skin cancer-related deaths, and its incidence increases each year. The growing number of melanoma cases, especially in advanced stages, poses a significant socio-medical challenge throughout the world. Extensive research on melanoma pathogenesis identifies UV radiation as the most important factor in melanocytic transformation. Oxidative effects of UV irradiation exert their influence on melanoma pathogenesis primarily through modification of nucleic acids, proteins, and lipids, further disrupting cellular signaling and cell cycle regulation. Its effects extend beyond melanocytes, leading to immunosuppression in the exposed skin tissue, which consequently creates conditions for immune surveillance evasion and further progression. In this review, we focus on the specific molecular changes observed in the UV-dependent oxidative stress environment and their biological consequences in the course of the disease, which have not been considered in previous reviews on melanoma. Nonetheless, data show that the exact role of oxidative stress in melanoma initiation and progression remains unclear, as it affects cancerous cells differently depending on the specific context. A better understanding of the pathophysiological basis of melanoma development holds promise for identifying potential targets, which could lead to effective melanoma prevention strategies. [ABSTRACT FROM AUTHOR]

Successful pregnancy depends on precise molecular regulation of uterine physiology, especially during the menstrual cycle. Deregulated oxidative stress (OS), often influenced by inflammatory changes but also by environmental factors, represents a constant threat to this delicate balance. Oxidative stress induces a reciprocally regulated nuclear factor erythroid 2-related factor 2/peroxisome proliferator-activated receptor-gamma (Nrf2/PPARγ) pathway. However, increased PPARγ activity appears to be a double-edged sword in endometrial physiology. Activated PPARγ attenuates inflammation and attenuates OS to restore redox homeostasis. However, it also interferes with physiological processes during the menstrual cycle, such as hormonal signaling and angiogenesis. This review provides an elucidation of the molecular mechanisms that support the interplay between PPARγ and OS. Additionally, it offers fresh perspectives on the Nrf2/PPARγ pathway concerning endometrial receptivity and its potential implications for infertility. [ABSTRACT FROM AUTHOR]

Acetylcholine-activated receptors are divided broadly into two major structurally distinct classes: ligand-gated ion channel nicotinic and G-protein-coupled muscarinic receptors. Each class encompasses several structurally related receptor subtypes with distinct patterns of tissue expression and post-receptor signal transduction mechanisms. The activation of both nicotinic and muscarinic cholinergic receptors has been associated with the induction and progression of gastrointestinal neoplasia. Herein, after briefly reviewing the classification of acetylcholine-activated receptors and the role that nicotinic and muscarinic cholinergic signaling plays in normal digestive function, we consider the mechanics of acetylcholine synthesis and release by neuronal and non-neuronal cells in the gastrointestinal microenvironment, and current methodology and challenges in measuring serum and tissue acetylcholine levels accurately. Then, we critically evaluate the evidence that constitutive and ligand-induced activation of acetylcholine-activated receptors plays a role in promoting gastrointestinal neoplasia. We focus primarily on adenocarcinomas of the stomach, pancreas, and colon, because these cancers are particularly common worldwide and, when diagnosed at an advanced stage, are associated with very high rates of morbidity and mortality. Throughout this comprehensive review, we concentrate on identifying novel ways to leverage these observations for prognostic and therapeutic purposes. [ABSTRACT FROM AUTHOR]

We explored the functional redundancy of three structurally related KCTD (Potassium Channel Tetramerization Domain) proteins, KCTD2, KCTD5, and KCTD17, by progressively knocking them out in HEK 293 cells using CRISPR/Cas9 genome editing. After validating the knockout, we assessed the effects of progressive knockout on cell growth and gene expression. We noted that the progressive effects of knockout of KCTD isoforms on cell growth were most pervasive when all three isoforms were deleted, suggesting some functions were conserved between them. This was also reflected in progressive changes in gene expression. Our previous work indicated that Gβ1 was involved in the transcriptional control of gene expression, so we compared the gene expression patterns between GNB1 and KCTD KO. Knockout of GNB1 led to numerous changes in the expression levels of other G protein subunit genes, while knockout of KCTD isoforms had the opposite effect, presumably because of their role in regulating levels of Gβ1. Our work demonstrates a unique relationship between KCTD proteins and Gβ1 and a global role for this subfamily of KCTD proteins in maintaining the ability of cells to survive and proliferate. [ABSTRACT FROM AUTHOR]

Mitochondria provide energy for all cellular processes, including reactions associated with cell cycle progression, DNA damage repair, and cilia formation. Moreover, mitochondria participate in cell fate decisions between death and survival. Nek family members have already been implicated in DNA damage response, cilia formation, cell death, and cell cycle control. Here, we discuss the role of several Nek family members, namely Nek1, Nek4, Nek5, Nek6, and Nek10, which are not exclusively dedicated to cell cycle-related functions, in controlling mitochondrial functions. Specifically, we review the function of these Neks in mitochondrial respiration and dynamics, mtDNA maintenance, stress response, and cell death. Finally, we discuss the interplay of other cell cycle kinases in mitochondrial function and vice versa. Nek1, Nek5, and Nek6 are connected to the stress response, including ROS control, mtDNA repair, autophagy, and apoptosis. Nek4, in turn, seems to be related to mitochondrial dynamics, while Nek10 is involved with mitochondrial metabolism. Here, we propose that the participation of Neks in mitochondrial roles is a new functional axis for the Nek family. [ABSTRACT FROM AUTHOR]

Since the evolution of the aerobic metabolism, reactive oxygen species (ROS) have represented significant challenges to diverse life forms. In recent decades, increasing knowledge has revealed a dual role for ROS in cell physiology, showing they serve as a major source of cellular damage while also functioning as important signaling molecules in various biological processes. Our understanding of ROS homeostasis and ROS-mediated cellular signaling pathways has presumed that they are ancient and highly conserved mechanisms shared by most organisms. However, emerging evidence highlights the complexity and plasticity of ROS signaling, particularly in animals that have evolved in extreme environments. In this review, we focus on ROS generation, antioxidative systems and the main signaling pathways that are influenced by ROS. In addition, we discuss ROS's responsive transcription regulation and how it may have been shaped over the course of evolution. [ABSTRACT FROM AUTHOR]

Synchronized contractions of cardiomyocytes within the heart are tightly coupled to electrical stimulation known as excitation-contraction coupling. Calcium plays a key role in this process and dysregulated calcium handling can significantly impair cardiac function and lead to the development of cardiomyopathies and heart failure. Here, we describe a method and analytical technique to study myofilament-localized calcium signaling using the intensity-based fluorescent biosensor, RGECO-TnT. Dilated cardiomyopathy is a heart muscle disease that negatively impacts the heart's contractile function following dilatation of the left ventricle. We demonstrate how this biosensor can be used to characterize 2D hiPSC-CMs monolayers generated from a healthy control subject compared to two patients diagnosed with dilated cardiomyopathy. Lastly, we provide a step-by-step guide for single-cell data analysis and describe a custom Transient Analysis application, specifically designed to quantify features of calcium transients. All in all, we explain how this analytical approach can be applied to phenotype hiPSC-CM behaviours and stratify patient responses to identify perturbations in calcium signaling. [ABSTRACT FROM AUTHOR]

Exosomal regulation is intimately involved in key cellular processes, such as migration, proliferation, and adhesion. By participating in the regulation of basic mechanisms, extracellular vesicles are important in intercellular signaling and the functioning of the mammalian reproductive system. The complexity of intercellular interactions in the ovarian follicle is also based on multilevel intercellular signaling, including the mechanisms involving cadherins, integrins, and the extracellular matrix. The processes in the ovary leading to the formation of a fertilization-ready oocyte are extremely complex at the molecular level and depend on the oocyte's ongoing relationship with granulosa cells. An analysis of gene expression from material obtained from a primary in vitro culture of porcine granulosa cells was employed using microarray technology. Genes with the highest expression (LIPG, HSD3B1, CLIP4, LOX, ANKRD1, FMOD, SHAS2, TAGLN, ITGA8, MXRA5, and NEXN) and the lowest expression levels (DAPL1, HSD17B1, SNX31, FST, NEBL, CXCL10, RGS2, MAL2, IHH, and TRIB2) were selected for further analysis. The gene expression results obtained from the microarrays were validated using quantitative RT-qPCR. Exosomes may play important roles regarding intercellular signaling between granulosa cells. Therefore, exosomes may have significant applications in regenerative medicine, targeted therapy, and assisted reproduction technologies. [ABSTRACT FROM AUTHOR]

Environmental biophysical interactions are recognized to play an essential part in the human biological processes associated with trauma recovery. Many studies over several decades have furthered our understanding of the effects that Pulsed Electromagnetic Fields (PEMF) have on the human body, as well as on cellular and biophysical systems. These investigations have been driven by the observed positive clinical effects of this non-invasive treatment on patients, mainly in orthopedics. Unfortunately, the diversity of the various study setups, with regard to physical parameters, molecular and cellular response, and clinical outcomes, has made it difficult to interpret and evaluate commonalities, which could, in turn, lead to finding an underlying mechanistic understanding of this treatment modality. In this review, we give a birds-eye view of the vast landscape of studies that have been published on PEMF, presenting the reader with a scaffolded summary of relevant literature starting from categorical literature reviews down to individual studies for future research studies and clinical use. We also highlight discrepancies within the many diverse study setups to find common reporting parameters that can lead to a better universal understanding of PEMF effects. [ABSTRACT FROM AUTHOR]

Simple Summary: Optimization of metamorphosis, a key stage in development where fish undergo several morphological and physiological changes, may assure the efficient mass production of greater amberjack (Seriola dumerili) juveniles. Application of probiotics as feed and/or water additive benefits nutrient utilization through modulation of the digestive enzymes. Therefore, following the addition of biofilters with the probiotic Phaeobacter inhibens in the rearing water throughout the early development of greater amberjack, crucial in metamorphosis, cellular pathways were investigated. The probiotic treatment increased the growth of greater amberjack, while hypertrophy was the main growth process in the metamorphosis. Additionally, the rearrangement of structures and tissues may have been facilitated through the observed induced cell death. The present findings are of great importance and may be applied in the aquaculture industry in order to enhance greater amberjack development and growth. Metamorphosis entails hormonally regulated morphological and physiological changes requiring high energy levels. Probiotics as feed supplements generate ameliorative effects on host nutrient digestion and absorption. Thereby, the aim of the present research was to investigate the impact of the probiotic Phaeobacter inhibens as a water additive on cellular signaling pathways in the metamorphosis of greater amberjack (Seriola dumerili). Activation of insulin-like growth factor type 1 receptor (IGF-1R), protein kinase B (Akt), mitogen-activated protein kinases (MAPKs) and AMP-activated protein kinase (AMPK), induction of heat shock proteins (Hsps), and programmed cell death were assessed through SDS-Page/immunoblot analysis, while energy metabolism was determined through enzymatic activities. According to the results, greater amberjack reared in P. inhibens-enriched water entered the metamorphic phase with greater body length, while protein synthesis was triggered to facilitate the hypertrophic growth as indicated by IGF-1/Akt activation and AMPK inhibition. Contrarily, MAPKs levels were reduced, whereas variations in Hsps response were evident in the probiotic treatment. Apoptosis and autophagy were mobilized potentially for the structural remodeling processes. Furthermore, the elevated enzymatic activities of intermediary metabolism highlighted the excess energy demands of metamorphosis. Collectively, the present findings demonstrate that P. inhibens may reinforce nutrient utilization, thus leading greater amberjack to an advanced growth and developmental state. [ABSTRACT FROM AUTHOR]

The dynamic interplay of signaling networks in most major cellular processes is characterized by the orchestration of reversible protein phosphorylation. Consequently, analytic methods such as quantitative phospho-peptidomics have been pushed forward from a highly specialized edge-technique to a powerful and versatile platform for comprehensively analyzing the phosphorylation profile of living organisms. Despite enormous progress in instrumentation and bioinformatics, a high number of missing values caused by the experimental procedure remains a major problem, due to either a random phospho-peptide enrichment selectivity or borderline signal intensities, which both cause the exclusion for fragmentation using the commonly applied data dependent acquisition (DDA) mode. Consequently, an incomplete dataset reduces confidence in the subsequent statistical bioinformatic processing. Here, we successfully applied data independent acquisition (DIA) by using the filamentous fungus Magnaporthe oryzae as a model organism, and could prove that while maintaining data quality (such as phosphosite and peptide sequence confidence), the data completeness increases dramatically. Since the method presented here reduces the LC-MS/MS analysis from 3 h to 1 h and increases the number of phosphosites identified up to 10-fold in contrast to published studies in Magnaporthe oryzae, we provide a refined methodology and a sophisticated resource for investigation of signaling processes in filamentous fungi. [ABSTRACT FROM AUTHOR]

Protein kinase B (AKT1) is a serine/threonine kinase and central transducer of cell survival pathways. Typical approaches to study AKT1 biology in cells rely on growth factor or insulin stimulation that activates AKT1 via phosphorylation at two key regulatory sites (Thr308, Ser473), yet cell stimulation also activates many other kinases. To produce cells with specific AKT1 activity, we developed a novel system to deliver active AKT1 to human cells. We recently established a method to produce AKT1 phospho-variants from Escherichia coli with programmed phosphorylation. Here, we fused AKT1 with an N-terminal cell penetrating peptide tag derived from the human immunodeficiency virus trans-activator of transcription (TAT) protein. The TAT-tag did not alter AKT1 kinase activity and was necessary and sufficient to rapidly deliver AKT1 protein variants that persisted in human cells for 24 h without the need to use transfection reagents. TAT-pAKT1T308 induced selective phosphorylation of the known AKT1 substrate GSK-3α, but not GSK-3β, and downstream stimulation of the AKT1 pathway as evidenced by phosphorylation of ribosomal protein S6 at Ser240/244. The data demonstrate efficient delivery of AKT1 with programmed phosphorylation to human cells, thus establishing a cell-based model system to investigate signaling that is dependent on AKT1 activity. [ABSTRACT FROM AUTHOR]

Simple Summary: DGKα is being considered as a target in immunotherapy. An advantage of targeting this enzyme is that it potentially has a dual role, i.e., it would both decrease the proliferation of cancer cells and incite the immunological response of T-lymphocytes. Here, the modulation of DGKα enzymatic activity and substrate acyl chain specificity by membrane shape and its potential implications in cancer and immune cell biology are reviewed. Cancer immunotherapy has revolutionized the oncology field. Despite the success, new molecular targets are needed to increase the percentage of patients that benefits from this therapy. Diacylglycerol kinase α (DGKα) has gathered great attention as a potential molecular target in immunotherapy because of its role in cancer proliferation and immunosuppression. DGKα catalyzes the ATP-dependent phosphorylation of diacylglycerol (DAG) to produce phosphatidic acid (PA). Since both lipids are potent signaling messengers, DGKα acts as a switch between different signaling pathways. Its role in cancer and immunosuppression has long been ascribed to the regulation of DAG/PA levels. However, this paradigm has been challenged with the identification of DGKα substrate acyl chain specificity, which suggests its role in signaling could be specific to DAG/PA molecular species. In several biological processes where DGKα plays a role, large membrane morphological changes take place. DGKα substrate specificity depends on the shape of the membrane that the enzyme binds to. Hence, DGKα can act as a bridge between large membrane morphological changes and the regulation of specific molecular species of DAG/PA. Bearing in mind the potential therapeutic benefits of targeting DGKα, here, the role of DGKα in cancer and T cell biology with a focus on the modulation of its enzymatic properties by membrane shape is reviewed. The goal is to contribute to a global understanding of the molecular mechanisms governing DGKα biology. This will pave the way for future experimentation and, consequently, the design of better, more potent therapeutic strategies aiming at improving the health outcomes of cancer patients. [ABSTRACT FROM AUTHOR]

Sterol regulatory element-binding proteins (SREBPs) play vital roles in fatty acid metabolism and other metabolic processes in mammals. However, in penaeid shrimp, the repertoire of genes modulated by SREBP is unknown. Here, RNA interference-mediated knockdown followed by transcriptome sequencing on the Illumina Novaseq 6000 platform was used to explore the genes modulated by SREBP in Penaeus vannamei hepatopancreas. A total of 706 differentially expressed genes (DEGs) were identified, out of which 282 were upregulated and 424 downregulated. Although gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that most of the downregulated DEGs were involved in physiological processes related to immunity, metabolism, and cellular signaling pathways, many of the dysregulated genes have uncharacterized functions. While most of the dysregulated genes were annotated in metabolic processes, such as carbohydrate metabolism, lipid metabolism, signal transduction, and immune system, a large number (42.21%) are uncharacterized. Collectively, our current data revealed that SREBP modulates many genes involved in crucial physiological processes, such as energy metabolism, immune response, and cellular signaling pathways, as well as numerous genes with unannotated functions, in penaeid shrimp. These findings indicated that our knowledge of the repertoire of genes modulated by SREBP in shrimp lags behind that of mammals, probably due to limited research or because the complete genome of P. vannamei has just been sequenced. [ABSTRACT FROM AUTHOR]

Simple Summary: Numerous factors, such as genomic mutations, chromosomal changes, transcriptional controls, phosphorylation, and protein–protein interactions, among others, can affect the activation status of proteins. Although each data type only partially reveals the status of a particular gene's disruption, downstream expression changes ultimately indicate the functional effects of cancer driver protein alterations. By combining data on transcriptome and genomic alterations, we have developed a Bayesian framework to infer driver activation state, and further tested our method to highlight both statistical and biological significance by applying our model to TCGA HNSCC patient data. Head and neck squamous cell cancer (HNSCC) is an aggressive cancer resulting from heterogeneous causes. To reveal the underlying drivers and signaling mechanisms of different HNSCC tumors, we developed a novel Bayesian framework to identify drivers of individual tumors and infer the states of driver proteins in cellular signaling system in HNSCC tumors. First, we systematically identify causal relationships between somatic genome alterations (SGAs) and differentially expressed genes (DEGs) for each TCGA HNSCC tumor using the tumor-specific causal inference (TCI) model. Then, we generalize the most statistically significant driver SGAs and their regulated DEGs in TCGA HNSCC cohort. Finally, we develop machine learning models that combine genomic and transcriptomic data to infer the protein functional activation states of driver SGAs in tumors, which enable us to represent a tumor in the space of cellular signaling systems. We discovered four mechanism-oriented subtypes of HNSCC, which show distinguished patterns of activation state of HNSCC driver proteins, and importantly, this subtyping is orthogonal to previously reported transcriptomic-based molecular subtyping of HNSCC. Further, our analysis revealed driver proteins that are likely involved in oncogenic processes induced by HPV infection, even though they are not perturbed by genomic alterations in HPV+ tumors. [ABSTRACT FROM AUTHOR]

Calcium (Ca2+) ions play a pivotal role in physiology and cellular signaling. The intracellular Ca2+ concentration ([Ca2+]i) is about three orders of magnitude lower than the extracellular concentration, resulting in a steep transmembrane concentration gradient. Thus, the spatial and the temporal dynamics of [Ca2+]i are ideally suited to modulate Ca2+-mediated cellular responses to external signals. A variety of highly sophisticated methods have been developed to gain insight into cellular Ca2+ dynamics. In addition to electrophysiological measurements and the application of synthetic dyes that change their fluorescent properties upon interaction with Ca2+, the introduction and the ongoing development of genetically encoded Ca2+ indicators (GECI) opened a new era to study Ca2+-driven processes in living cells and organisms. Here, we have focused on one well-established GECI, i.e., GCaMP3.0. We have systematically modified the protein with sequence motifs, allowing localization of the sensor in the nucleus, in the mitochondrial matrix, at the mitochondrial outer membrane, and at the plasma membrane. The individual variants and a cytosolic version of GCaMP3.0 were overexpressed and purified from E. coli cells to study their biophysical properties in solution. All versions were examined to monitor Ca2+ signaling in stably transfected cell lines and in primary cortical neurons transduced with recombinant Adeno-associated viruses (rAAV). In this comparative study, we provide evidence for a robust approach to reliably trace Ca2+ signals at the (sub)-cellular level with pronounced temporal resolution. [ABSTRACT FROM AUTHOR]

The catecholamines norepinephrine and epinephrine regulate important physiological functions in vertebrates. In insects; these neuroactive substances are functionally replaced by the phenolamines octopamine and tyramine. Phenolamines activate specific guanine nucleotide-binding (G) protein-coupled receptors (GPCRs). Type 1 tyramine receptors are better activated by tyramine than by octopamine. In contrast; type 2 tyramine receptors are almost exclusively activated by tyramine. Functionally; activation of type 1 tyramine receptors leads to a decrease in the intracellular concentration of cAMP ([cAMP]i) whereas type 2 tyramine receptors can mediate Ca2+ signals or both Ca2+ signals and effects on [cAMP]i. Here; we report that the American cockroach (Periplaneta americana) expresses a second type 1 tyramine receptor (PeaTAR1B) in addition to PeaTAR1A (previously called PeaTYR1). When heterologously expressed in flpTM cells; activation of PeaTAR1B by tyramine leads to a concentration-dependent decrease in [cAMP]i. Its activity can be blocked by a series of established antagonists. The functional characterization of two type 1 tyramine receptors from P. americana; PeaTAR1A and PeaTAR1B; which respond to tyramine by changing cAMP levels; is a major step towards understanding the actions of tyramine in cockroach physiology and behavior; particularly in comparison to the effects of octopamine. [ABSTRACT FROM AUTHOR]

Nanoparticles (NPs) possess unique physical and chemical properties that make them appropriate for various applications. The structural alteration of metallic NPs leads to different biological functions, specifically resulting in different potentials for the generation of reactive oxygen species (ROS). The amount of ROS produced by metallic NPs correlates with particle size, shape, surface area, and chemistry. ROS possess multiple functions in cellular biology, with ROS generation a key factor in metallic NP-induced toxicity, as well as modulation of cellular signaling involved in cell death, proliferation, and differentiation. In this review, we briefly explained NP classes and their biomedical applications and describe the sources and roles of ROS in NP-related biological functions in vitro and in vivo. Furthermore, we also described the roles of metal NP-induced ROS generation in stem cell biology. Although the roles of ROS in metallic NP-related biological functions requires further investigation, modulation and characterization of metallic NP-induced ROS production are promising in the application of metallic NPs in the areas of regenerative medicine and medical devices. [ABSTRACT FROM AUTHOR]

Protein Phosphatase 2A (PP2A) is a major serine/threonine phosphatase in cells. It consists of a catalytic subunit (C), a structural subunit (A), and a regulatory/variable B-type subunit. PP2A has a critical role to play in homeostasis where its predominant function is as a phosphatase that regulates the major cell signaling pathways in cells. Changes in the assembly, activity and substrate specificity of the PP2A holoenzyme have a direct role in disease and are a major contributor to the maintenance of the transformed phenotype in cancer. We have learned a lot about how PP2A functions from specific mutations that disrupt the core assembly of PP2A and from viral proteins that target PP2A and inhibit its effect as a phosphatase. This prompted various studies revealing that restoration of PP2A activity benefits some cancer patients. However, our understanding of the mechanism of action of this is limited because of the complex nature of PP2A holoenzyme assembly and because it acts through a wide variety of signaling pathways. Information on PP2A is also conflicting as there are situations whereby inactivation of PP2A induces apoptosis in many cancer cells. In this review we discuss this relationship and we also address many of the pertinent and topical questions that relate to novel therapeutic strategies aimed at altering PP2A activity. [ABSTRACT FROM AUTHOR]

We have isolated a cDNA coding for a putative invertebrate-type dopamine receptor (Peadop2) from P. americana brain by using a PCR-based strategy. The mRNA is present in samples from brain and salivary glands. We analyzed the distribution of the PeaDOP2 receptor protein with specific affinity-purified polyclonal antibodies. On Western blots, PeaDOP2 was detected in protein samples from brain, subesophageal ganglion, thoracic ganglia, and salivary glands. In immunocytochemical experiments, we detected PeaDOP2 in neurons with their somata being located at the anterior edge of the medulla bilaterally innervating the optic lobes and projecting to the ventro-lateral protocerebrum. In order to determine the functional and pharmacological properties of the cloned receptor, we generated a cell line constitutively expressing PeaDOP2. Activation of PeaDOP2-expressing cells with dopamine induced an increase in intracellular cAMP. In contrast, a C-terminally truncated splice variant of this receptor did not exhibit any functional property by itself. The molecular and pharmacological characterization of the first dopamine receptor from P. americana provides the basis for forthcoming studies focusing on the significance of the dopaminergic system in cockroach behavior and physiology. [ABSTRACT FROM AUTHOR]

Transient receptor potential canonical (TRPC) channels are membrane proteins involved in regulating Ca2+ homeostasis, and whose functions are modulated by G protein-coupled receptors (GPCR). In this study, we developed bioluminescent resonance energy transfer (BRET) biosensors to better study channel conformational changes following receptor activation. For this study, two intramolecular biosensors, GFP10-TRPC7-RLucII and RLucII-TRPC7-GFP10, were constructed and were assessed following the activation of various GPCRs. We first transiently expressed receptors and the biosensors in HEK293 cells, and BRET levels were measured following agonist stimulation of GPCRs. The activation of GPCRs that engage Gαq led to a Gαq-dependent BRET response of the functional TRPC7 biosensor. Focusing on the Angiotensin II type-1 receptor (AT1R), GFP10-TRPC7-RLucII was tested in rat neonatal cardiac fibroblasts, expressing endogenous AT1R and TRPC7. We detected similar BRET responses in these cells, thus validating the use of the biosensor in physiological conditions. Taken together, our results suggest that activation of Gαq-coupled receptors induce conformational changes in a novel and functional TRPC7 BRET biosensor. [ABSTRACT FROM AUTHOR]

Biogenic amines constitute an important group of neuroactive substances that control and modulate various neural circuits. These small organic compounds engage members of the guanine nucleotide-binding protein coupled receptor (GPCR) superfamily to evoke specific cellular responses. In addition to dopamine- and 5-hydroxytryptamine (serotonin) receptors, arthropods express receptors that are activated exclusively by tyramine and octopamine. These phenolamines functionally substitute the noradrenergic system of vertebrates Octopamine receptors that are the focus of this study are classified as either α- or β-adrenergic-like. Knowledge on these receptors is scarce for the American cockroach (Periplaneta americana). So far, only an α–adrenergic-like octopamine receptor that primarily causes Ca2+ release from intracellular stores has been studied from the cockroach (PaOctα1R). Here we succeeded in cloning a gene from cockroach brain tissue that encodes a β-adrenergic-like receptor and leads to cAMP production upon activation. Notably, the receptor is 100-fold more selective for octopamine than for tyramine. A series of synthetic antagonists selectively block receptor activity with epinastine being the most potent. Bioinformatics allowed us to identify a total of 19 receptor sequences that build the framework of the biogenic amine receptor clade in the American cockroach. Phylogenetic analyses using these sequences and receptor sequences from model organisms showed that the newly cloned gene is an β2-adrenergic-like octopamine receptor. The functional characterization of PaOctβ2R and the bioinformatics data uncovered that the monoaminergic receptor family in the hemimetabolic P. americana is similarly complex as in holometabolic model insects like Drosophila melanogaster and the honeybee, Apis mellifera. Thus, investigating these receptors in detail may contribute to a better understanding of monoaminergic signaling in insect behavior and physiology. [ABSTRACT FROM AUTHOR]

Bone morphogenetic proteins (BMPs) are a diverse class of growth factors that belong to the transforming growth factor-beta (TGFβ) superfamily. Although originally discovered to possess osteogenic properties, BMPs have since been identified as critical regulators of many biological processes, including cell-fate determination, cell proliferation, differentiation and morphogenesis, throughout the body. In the ocular lens, BMPs are important in orchestrating fundamental developmental processes such as induction of lens morphogenesis, and specialized differentiation of its fiber cells. Moreover, BMPs have been reported to facilitate regeneration of the lens, as well as abrogate pathological processes such as TGFβ-induced epithelial-mesenchymal transition (EMT) and apoptosis. In this review, we summarize recent insights in this topic and discuss the complexities of BMP-signaling including the role of individual BMP ligands, receptors, extracellular antagonists and cross-talk between canonical and non-canonical BMP-signaling cascades in the lens. By understanding the molecular mechanisms underlying BMP activity, we can advance their potential therapeutic role in cataract prevention and lens regeneration. [ABSTRACT FROM AUTHOR]

Lipid composition in cellular membranes plays an important role in maintaining the structural integrity of cells and in regulating cellular signaling that controls functions of both membrane-anchored and cytoplasmic proteins. ATP-dependent ABC and P4-ATPase lipid transporters, two integral membrane proteins, are known to contribute to lipid translocation across the lipid bilayers on the cellular membranes. In this review, we will highlight current knowledge about the role of cholesterol and phospholipids of cellular membranes in regulating cell signaling and how lipid transporters participate this process. [ABSTRACT FROM AUTHOR]

Main forms of cellular signal transmission are known to be autocrine and paracrine signaling. Several cells secrete messengers called autocrine or paracrine agents that can bind the corresponding receptors on the surface of the cells themselves or their microenvironment. Follistatin and follistatin-like proteins can be called one of the most important bifunctional messengers capable of displaying both autocrine and paracrine activity. Whilst they are not as diverse as protein hormones or protein kinases, there are only five types of proteins. However, unlike protein kinases, there are no minor proteins among them; each follistatin-like protein performs an important physiological function. These proteins are involved in a variety of signaling pathways and biological processes, having the ability to bind to receptors such as DIP2A, TLR4, BMP and some others. The activation or experimentally induced knockout of the protein-coding genes often leads to fatal consequences for individual cells and the whole body as follistatin-like proteins indirectly regulate the cell cycle, tissue differentiation, metabolic pathways, and participate in the transmission chains of the pro-inflammatory intracellular signal. Abnormal course of these processes can cause the development of oncology or apoptosis, programmed cell death. There is still no comprehensive understanding of the spectrum of mechanisms of action of follistatin-like proteins, so the systematization and study of their cellular functions and regulation is an important direction of modern molecular and cell biology. Therefore, this review focuses on follistatin-related proteins that affect multiple targets and have direct or indirect effects on cellular signaling pathways, as well as to characterize the directions of their practical application in the field of biomedicine. [ABSTRACT FROM AUTHOR]

Drought is a severe and complex abiotic stress that negatively affects plant growth and crop yields. Numerous genes with various functions are induced in response to drought stress to acquire drought stress tolerance. The phytohormone abscisic acid (ABA) accumulates mainly in the leaves in response to drought stress and then activates subclass III SNF1-related protein kinases 2 (SnRK2s), which are key phosphoregulators of ABA signaling. ABA mediates a wide variety of gene expression processes through stress-responsive transcription factors, including ABA-RESPONSIVE ELEMENT BINDING PROTEINS (AREBs)/ABRE-BINDING FACTORS (ABFs) and several other transcription factors. Seed plants have another type of SnRK2s, ABA-unresponsive subclass I SnRK2s, that mediates the stability of gene expression through the mRNA decay pathway and plant growth under drought stress in an ABA-independent manner. Recent research has elucidated the upstream regulators of SnRK2s, RAF-like protein kinases, involved in early responses to drought stress. ABA-independent transcriptional regulatory systems and ABA-responsive regulation function in drought-responsive gene expression. DEHYDRATION RESPONSIVE ELEMENT (DRE) is an important cis-acting element in ABA-independent transcription, whereas ABA-RESPONSIVE ELEMENT (ABRE) cis-acting element functions in ABA-responsive transcription. In this review article, we summarize recent advances in research on cellular and molecular drought stress responses and focus on phosphorylation signaling and transcription networks in Arabidopsis and crops. We also highlight gene networks of transcriptional regulation through two major regulatory pathways, ABA-dependent and ABA-independent pathways, that ABA-responsive subclass III SnRK2s and ABA-unresponsive subclass I SnRK2s mediate, respectively. We also discuss crosstalk in these regulatory systems under drought stress. [ABSTRACT FROM AUTHOR]

Under aerobic conditions, mitochondrial oxidative phosphorylation (OXPHOS) converts the energy released by nutrient oxidation into ATP, the currency of living organisms. The whole biochemical machinery is hosted by the inner mitochondrial membrane (mtIM) where the protonmotive force built by respiratory complexes, dynamically assembled as super-complexes, allows the F1FO-ATP synthase to make ATP from ADP + Pi. Recently mitochondria emerged not only as cell powerhouses, but also as signaling hubs by way of reactive oxygen species (ROS) production. However, when ROS removal systems and/or OXPHOS constituents are defective, the physiological ROS generation can cause ROS imbalance and oxidative stress, which in turn damages cell components. Moreover, the morphology of mitochondria rules cell fate and the formation of the mitochondrial permeability transition pore in the mtIM, which, most likely with the F1FO-ATP synthase contribution, permeabilizes mitochondria and leads to cell death. As the multiple mitochondrial functions are mutually interconnected, changes in protein composition by mutations or in supercomplex assembly and/or in membrane structures often generate a dysfunctional cascade and lead to life-incompatible diseases or severe syndromes. The known structural/functional changes in mitochondrial proteins and structures, which impact mitochondrial bioenergetics because of an impaired or defective energy transduction system, here reviewed, constitute the main biochemical damage in a variety of genetic and age-related diseases. [ABSTRACT FROM AUTHOR]

The productivity of agricultural produce is fairly dependent on the availability of nutrients and efficient use. Magnesium (Mg2+) is an essential macronutrient of living cells and is the second most prevalent free divalent cation in plants. Mg2+ plays a role in several physiological processes that support plant growth and development. However, it has been largely forgotten in fertilization management strategies to increase crop production, which leads to severe reductions in plant growth and yield. In this review, we discuss how the Mg2+ shortage induces several responses in plants at different levels: morphological, physiological, biochemical and molecular. Additionally, the Mg2+ uptake and transport mechanisms in different cellular organelles and the role of Mg2+ transporters in regulating Mg2+ homeostasis are also discussed. Overall, in this review, we critically summarize the available information about the responses of Mg deficiency on plant growth and development, which would facilitate plant scientists to create Mg2+-deficiency-resilient crops through agronomic and genetic biofortification. [ABSTRACT FROM AUTHOR]

The catecholamines norepinephrine and epinephrine are important regulators of vertebrate physiology. Insects such as honeybees do not synthesize these neuroactive substances. Instead, they use the phenolamines tyramine and octopamine for similar physiological functions. These biogenic amines activate specific members of the large protein family of G protein-coupled receptors (GPCRs). Based on molecular and pharmacological data, insect octopamine receptors were classified as either α- or β-adrenergic-like octopamine receptors. Currently, one α- and four β-receptors have been molecularly and pharmacologically characterized in the honeybee. Recently, an α2-adrenergic-like octopamine receptor was identified in Drosophila melanogaster (DmOctα2R). This receptor is activated by octopamine and other biogenic amines and causes a decrease in intracellular cAMP ([cAMP]i). Here, we show that the orthologous receptor of the honeybee (AmOctα2R), phylogenetically groups in a clade closely related to human α2-adrenergic receptors. When heterologously expressed in an eukaryotic cell line, AmOctα2R causes a decrease in [cAMP]i. The receptor displays a pronounced preference for octopamine over tyramine. In contrast to DmOctα2R, the honeybee receptor is not activated by serotonin. Its activity can be blocked efficiently by 5-carboxamidotryptamine and phentolamine. The functional characterization of AmOctα2R now adds a sixth member to this subfamily of monoaminergic receptors in the honeybee and is an important step towards understanding the actions of octopamine in honeybee behavior and physiology. [ABSTRACT FROM AUTHOR]

Prolactin-releasing peptide (PrRP), a natural ligand for the GPR10 receptor, is a neuropeptide with anorexigenic and antidiabetic properties. Due to its role in the regulation of food intake, PrRP is a potential drug for obesity treatment and associated type 2 diabetes mellitus (T2DM). Recently, the neuroprotective effects of lipidized PrRP analogs have been proven. In this study, we focused on the molecular mechanisms of action of natural PrRP31 and its lipidized analog palm11-PrRP31 in the human neuroblastoma cell line SH-SY5Y to describe their cellular signaling and possible anti-apoptotic properties. PrRP31 significantly upregulated the phosphoinositide-3 kinase-protein kinase B/Akt (PI3K-PKB/Akt) and extracellular signal-regulated kinase/cAMP response element-binding protein (ERK-CREB) signaling pathways that promote metabolic cell survival and growth. In addition, we proved via protein kinase inhibitors that activation of signaling pathways is mediated specifically by PrRP31 and its palmitoylated analog. Furthermore, the potential neuroprotective properties were studied through activation of anti-apoptotic pathways of PrRP31 and palm11-PrRP31 using the SH-SY5Y cell line and rat primary neuronal culture stressed with toxic methylglyoxal (MG). The results indicate increased viability of the cells treated with PrRP and palm11-PrRP31 and a reduced degree of apoptosis induced by MG, suggesting their potential use in the treatment of neurological disorders. [ABSTRACT FROM AUTHOR]

DYRK (dual-specificity tyrosine-regulated kinases) are an evolutionary conserved family of protein kinases with members from yeast to humans. In humans, DYRKs are pleiotropic factors that phosphorylate a broad set of proteins involved in many different cellular processes. These include factors that have been associated with all the hallmarks of cancer, from genomic instability to increased proliferation and resistance, programmed cell death, or signaling pathways whose dysfunction is relevant to tumor onset and progression. In accordance with an involvement of DYRK kinases in the regulation of tumorigenic processes, an increasing number of research studies have been published in recent years showing either alterations of DYRK gene expression in tumor samples and/or providing evidence of DYRK-dependent mechanisms that contribute to tumor initiation and/or progression. In the present article, we will review the current understanding of the role of DYRK family members in cancer initiation and progression, providing an overview of the small molecules that act as DYRK inhibitors and discussing the clinical implications and therapeutic opportunities currently available. [ABSTRACT FROM AUTHOR]

Inositol phospholipids play an important role in cell physiology. The inositol head groups are reversibly phosphorylated to produce seven distinct phosphorylated inositides, commonly referred to as phosphoinositides (PIs). These seven PIs are dynamically interconverted from one PI to another by the action of PI kinases and PI phosphatases. The PI signals regulate a wide variety of cellular functions, including organelle distinction, vesicular transport, cytoskeletal organization, nuclear events, regulation of ion channels, cell signaling, and host–pathogen interactions. Most of the studies of PIs in ocular tissues are based on the PI enzymes and PI phosphatases. In this study, we examined the PI levels in the cornea, retinal pigment epithelium (RPE), and retina using PI-binding protein as probes. We have examined the lipids PI(3)P, PI(4)P, PI(3,4)P2, PI(4,5)P2, and PI(3,4,5)P3, and each is present in the cornea, RPE, and retina. Alterations in the levels of these PIs in mouse models of retinal disease and corneal infections have been reported, and the results of our study will help in the management of anomalous phosphoinositide metabolism in ocular tissues. [ABSTRACT FROM AUTHOR]

The chromosome is a functionally dynamic structure. The dynamic nature of chromosome functionally connects it to almost every event within a cell, in health and sickness. Chromatin remodeling system acts in unison with the cell survival pathway in mediating a variety of cellular functions, including mitosis, differentiation, DNA damage repair, and apoptosis. In humans, the 16 SWI/SNF complexes are a class of nucleosome remodelers, and ARID1A, an epigenetic tumor suppressor, is a member of mammalian 17 chromatin remodeling complex, SWI/SNF. Alterations of chromatin remodeling system contribute to tumorigenic events in various cancers, including ovarian cancers. Oncogenic changes of genes of the PI3K pathway are one of the potential genetic determinants of ovarian carcinomas. In this review, we present the data demonstrating the co-occurrence of mutations of ARID1A and the PI3K pathway in our cohort of ovarian cancers from the Avera Cancer Institute (SD, USA). Taking into account data from our cohort and the cBioPortal, we interrogate the opportunity provided by this co-occurrence in the context of mutation-driven signals in the life cycle of a tumor cell and its response to the targeted anti-tumor drugs. [ABSTRACT FROM AUTHOR]

The extracellular signal-regulated kinases (ERKs) comprise a particular branch of the mitogen-activated protein kinase cascades (MAPK) that transmits extracellular signals into the intracellular environment to trigger cellular growth responses. Similar to other MAPK cascades, the MAPK-ERK pathway signals through three core kinases—Raf, MAPK/ERK kinase (MEK), and ERK—which drive the signaling mechanisms responsible for the induction of cellular responses from extracellular stimuli including differentiation, proliferation, and cellular survival. However, pathogens like DNA viruses alter MAPK-ERK signaling in order to access DNA replication machineries, induce a proliferative state in the cell, or even prevent cell death mechanisms in response to pathogen recognition. Differential utilization of this pathway by multiple DNA viruses highlights the dynamic nature of the MAPK-ERK pathway within the cell and the importance of its function in regulating a wide variety of cellular fates that ultimately influence viral infection and, in some cases, result in tumorigenesis. [ABSTRACT FROM AUTHOR]

The intestinal microbiota is well known to have multiple benefits on human health, including cancer prevention and treatment. The effects are partially mediated by microbiota-produced short chain fatty acids (SCFAs) such as butyrate, propionate and acetate. The anti-cancer effect of butyrate has been demonstrated in cancer cell cultures and animal models of cancer. Butyrate, as a signaling molecule, has effects on multiple signaling pathways. The most studied effect is its inhibition on histone deacetylase (HDAC), which leads to alterations of several important oncogenic signaling pathways such as JAK2/STAT3, VEGF. Butyrate can interfere with both mitochondrial apoptotic and extrinsic apoptotic pathways. In addition, butyrate also reduces gut inflammation by promoting T-regulatory cell differentiation with decreased activities of the NF-κB and STAT3 pathways. Through PKC and Wnt pathways, butyrate increases cancer cell differentiation. Furthermore, butyrate regulates oncogenic signaling molecules through microRNAs and methylation. Therefore, butyrate has the potential to be incorporated into cancer prevention and treatment regimens. In this review we summarize recent progress in butyrate research and discuss the future development of butyrate as an anti-cancer agent with emphasis on its effects on oncogenic signaling pathways. The low bioavailability of butyrate is a problem, which precludes clinical application. The disadvantage of butyrate for medicinal applications may be overcome by several approaches including nano-delivery, analogue development and combination use with other anti-cancer agents or phytochemicals. [ABSTRACT FROM AUTHOR]

The mechanistic target of rapamycin (mTOR) is a ubiquitous serine/threonine kinase that regulates anabolic and catabolic processes, in response to environmental inputs. The existence of mTOR in numerous cell compartments explains its specific ability to sense stress, execute growth signals, and regulate autophagy. mTOR signaling deregulation is closely related to aging and age-related disorders, among which progeroid laminopathies represent genetically characterized clinical entities with well-defined phenotypes. These diseases are caused by LMNA mutations and feature altered bone turnover, metabolic dysregulation, and mild to severe segmental progeria. Different LMNA mutations cause muscular, adipose tissue and nerve pathologies in the absence of major systemic involvement. This review explores recent advances on mTOR involvement in progeroid and tissue-specific laminopathies. Indeed, hyper-activation of protein kinase B (AKT)/mTOR signaling has been demonstrated in muscular laminopathies, and rescue of mTOR-regulated pathways increases lifespan in animal models of Emery-Dreifuss muscular dystrophy. Further, rapamycin, the best known mTOR inhibitor, has been used to elicit autophagy and degradation of mutated lamin A or progerin in progeroid cells. This review focuses on mTOR-dependent pathogenetic events identified in Emery-Dreifuss muscular dystrophy, LMNA-related cardiomyopathies, Hutchinson-Gilford Progeria, mandibuloacral dysplasia, and type 2 familial partial lipodystrophy. Pharmacological application of mTOR inhibitors in view of therapeutic strategies is also discussed. [ABSTRACT FROM AUTHOR]

Intracellular signaling pathways mediate the rapid response of cells to environmental cues. To control the fidelity of these responses, cells coordinate the activities of signaling enzymes with the strength, timing, and localization of the upstream stimuli. Protein kinase Akt links the PI3K-coupled receptors to cellular anabolic processes by phosphorylating multiple substrates. How the cells ensure that Akt activity remains proportional to upstream signals and control its substrate specificity is unclear. In this review, I examine how cell-autonomous and intrinsic allosteric mechanisms cooperate to ensure localized, context-specific signaling in the PI3K/Akt axis. [ABSTRACT FROM AUTHOR]

Mitogen-Activated Protein Kinase (MAPK) genes encode proteins that regulate biotic and abiotic stresses in plants through signaling cascades comprised of three major subfamilies: MAP Kinase (MPK), MAPK Kinase (MKK), and MAPKK Kinase (MKKK). The main objectives of this research were to conduct genome-wide identification of MAPK genes in Helianthus annuus and examine functional divergence of these genes in relation to those in nine other plant species (Amborella trichopoda, Aquilegia coerulea, Arabidopsis thaliana, Daucus carota, Glycine max, Oryza sativa, Solanum lycopersicum, Sphagnum fallax, and Vitis vinifera), representing diverse taxonomic groups of the Plant Kingdom. A Hidden Markov Model (HMM) profile of the MAPK genes utilized reference sequences from A. thaliana and G. max, yielding a total of 96 MPKs and 37 MKKs in the genomes of A. trichopoda, A. coerulea, C. reinhardtii, D. carota, H. annuus, S. lycopersicum, and S. fallax. Among them, 28 MPKs and eight MKKs were confirmed in H. annuus. Phylogenetic analyses revealed four clades within each subfamily. Transcriptomic analyses showed that at least 19 HaMPK and seven HaMKK genes were induced in response to salicylic acid (SA), sodium chloride (NaCl), and polyethylene glycol (Peg) in leaves and roots. Of the seven published sunflower microRNAs, five microRNA families are involved in targeting eight MPKs. Additionally, we discussed the need for using MAP Kinase nomenclature guidelines across plant species. Our identification and characterization of MAP Kinase genes would have implications in sunflower crop improvement, and in advancing our knowledge of the diversity and evolution of MAPK genes in the Plant Kingdom. [ABSTRACT FROM AUTHOR]

The NF-κB pathway is a critical regulator of immune responses and is often dysregulated in cancer. Two NF-κB pathways have been described to mediate these responses, the canonical and the noncanonical. While understudied compared to the canonical NF-κB pathway, noncanonical NF-κB and its components have been shown to have effects, usually protumorigenic, in many different cancer types. Here, we review noncanonical NF-κB pathways and discuss its important roles in promoting cancer. We also discuss alternative NF-κB-independent functions of some the components of noncanonical NF-κB signaling. Finally, we discuss important crosstalk between canonical and noncanonical signaling, which blurs the two pathways, indicating that understanding the full picture of NF-κB regulation is critical to deciphering how this broad pathway promotes oncogenesis. [ABSTRACT FROM AUTHOR]

Enterovirus 71 (EV71) infection has become a major threat to global public health, especially in infants and young children. Epidemiological studies have indicated that EV71 infection is responsible for severe and even fatal cases of hand, foot, and mouth disease (HFMD). Accumulated evidence indicates that EV71 infection triggers a plethora of interactive signaling pathways, resulting in host immune evasion and inflammatory response. This review mainly covers the effects of EV71 infection on major antiviral and inflammatory cellular signal pathways. EV71 can activate cellular signaling networks including multiple cell surface and intracellular receptors, intracellular kinases, calcium flux, and transcription factors that regulate antiviral innate immunity and inflammatory response. Cellular signaling plays a critical role in the regulation of host innate immune and inflammatory pathogenesis. Elucidation of antiviral and inflammatory cellular signaling pathways initiated by EV71 will not only help uncover the potential mechanisms of EV71 infection-induced pathogenesis, but will also provide clues for the design of therapeutic strategies against EV71 infection. [ABSTRACT FROM AUTHOR]

Nanoparticles (NPs) possess unique physical and chemical properties that make them appropriate for various applications. The structural alteration of metallic NPs leads to different biological functions, specifically resulting in different potentials for the generation of reactive oxygen species (ROS). The amount of ROS produced by metallic NPs correlates with particle size, shape, surface area, and chemistry. ROS possess multiple functions in cellular biology, with ROS generation a key factor in metallic NP-induced toxicity, as well as modulation of cellular signaling involved in cell death, proliferation, and differentiation. In this review, we briefly explained NP classes and their biomedical applications and describe the sources and roles of ROS in NP-related biological functions in vitro and in vivo. Furthermore, we also described the roles of metal NP-induced ROS generation in stem cell biology. Although the roles of ROS in metallic NP-related biological functions requires further investigation, modulation and characterization of metallic NP-induced ROS production are promising in the application of metallic NPs in the areas of regenerative medicine and medical devices., Competing Interests: The authors declare no conflicts of interest.