Apert syndrome is a genetic disorder characterised by craniosynostosis and structural discrepancy of the craniofacial region as well as the hands and feet. This condition is closely linked with fibroblast growth factor receptor-2 (FGFR2) gene mutations. Gene therapies are progressively being tested in advanced clinical trials, leading to a rise of its potential clinical indications. In recent years, research has made great progress in the gene therapy of craniosynostosis syndromes and several studies have investigated its influences in preventing/diminishing the complications of Apert syndrome. This article reviewed and exhibited different techniques of gene therapy and their influences in Apert syndrome progression. A systematic search was executed using electronic bibliographic databases including PubMed, EMBASE, ScienceDirect, SciFinder and Web of Science for all studies of gene therapy for Apert syndrome. The primary outcomes measurements vary from protein to gene expressions. According to the findings of included studies, we conclude that the gene therapy using FGF in Apert syndrome was critical in the regulation of suture fusion and patency, occurred via alterations in cellular proliferation. The superior outcome could be brought by biological therapies targeting the FGF/FGFR signalling. More studies in molecular genetics in Apert syndrome are recommended. This study reviews the current literature and provides insights to future possibilities of genetic therapy as intervention in Apert syndrome.
Myocardial remodelling is a molecular, cellular, and interstitial adaptation of the heart in response to altered environmental demands. The heart undergoes reversible physiological remodelling in response to changes in mechanical loading or irreversible pathological remodelling induced by neurohumoral factors and chronic stress, leading to heart failure. Adenosine triphosphate (ATP) is one of the potent mediators in cardiovascular signalling that act on the ligand-gated (P2X) and G-protein-coupled (P2Y) purinoceptors via the autocrine or paracrine manners. These activations mediate numerous intracellular communications by modulating the production of other messengers, including calcium, growth factors, cytokines, and nitric oxide. ATP is known to play a pleiotropic role in cardiovascular pathophysiology, making it a reliable biomarker for cardiac protection. This review outlines the sources of ATP released under physiological and pathological stress and its cell-specific mechanism of action. We further highlight a series of cardiovascular cell-to-cell communications of extracellular ATP signalling cascades in cardiac remodelling, which can be seen in hypertension, ischemia/reperfusion injury, fibrosis, hypertrophy, and atrophy. Finally, we summarize current pharmacological intervention using the ATP network as a target for cardiac protection. A better understanding of ATP communication in myocardial remodelling could be worthwhile for future drug development and repurposing and the management of cardiovascular diseases.
Lipid rafts are ubiquitous in cells. They are identified as cholesterol and glycosphingolipid enriched microdomains on cellular membranes. They serve as platforms for cellular communications by functioning in signal transduction and membrane trafficking. Such structural organisation fulfils cellular needs for normal function, but at the same time increases vulnerability of cells to pathogen invasion. Viruses rely heavily on lipid rafts in basically every stage of the viral life cycle for successful infection. Various mechanisms of lipid rafts modification exploited by diverse viruses for attachment, internalisation, membrane fusion, genome replication, assembly and release have been brought to light. This review focuses on virus-raft interactions and how a wide range of viruses manipulate lipid rafts at distinct stages of infection. The importance of virus-raft interactions in viral infections has inspired researchers to discover and develop antivirals that target this interaction, such as statins, methyl-β-cyclodextrin, viperin, 25-hydroxycholesterol and even anti-malarial drugs. The therapeutic modulations of lipid rafts as potential antiviral intervention from in vitro and in vivo evidence are discussed herein.
Inflammation is an essential immune response that helps fight infections and heal tissues. However, chronic inflammation has been linked to several diseases, including cancer, autoimmune disorders, cardiovascular diseases, and neurological disorders. This has increased interest in finding natural substances that can modulate the immune system inflammatory signaling pathways to prevent or treat these diseases. Luteolin is a flavonoid found in many fruits, vegetables, and herbs. It has been shown to have anti-inflammatory effects by altering signaling pathways in immune cells. This review article discusses the current research on luteolin's role as a natural immune system modulator of inflammatory signaling mechanisms, such as its effects on nuclear factor-kappa B, mitogen-activated protein kinases, Janus kinase/signal transducer and activator of transcription, and inflammasome signaling processes. The safety profile of luteolin and its potential therapeutic uses in conditions linked to inflammation are also discussed. Overall, the data point to Luteolin's intriguing potential as a natural regulator of immune system inflammatory signaling processes. More research is needed to fully understand its mechanisms of action and possible therapeutic applications.
For years researchers have exerted every effort to improve the influential roles of microRNA (miRNA) in regulating genes that direct mammalian cell development and function. In spite of numerous advancements, many facets of miRNA generation remain unresolved due to the perplexing regulatory networks. The biogenesis of miRNA, eminently endures as a mystery as no universal pathway defines or explicates the variegation in the rise of miRNAs. Early evidence in biogenesis ignited specific steps of being omitted or replaced that eventuate in the individual miRNAs of different mechanisms. Understanding the basic foundation concerning how miRNAs are generated and function will help with diagnostic tools and therapeutic strategies. This review encompasses the canonical and the non-canonical pathways involved in miRNA biogenesis, while elucidating how miRNAs regulate genes at the nuclear level and also the mechanism that lies behind circulating miRNAs.
Colorectal cancer (CRC), a complex multi-step process involving progressive disruption of homeostatic mechanisms controlling intestinal epithelial proliferation/inflammation, differentiation, and programmed cell death, is the third most common malignant neoplasm worldwide. A number of promising targets such as inducible nitric acid (iNOS), cyclooxygenase (COX)-2, NF-E2-related factor 2 (Nrf2), Wnt/β-catenin, Notch and apoptotic signaling have been identified by researchers as useful targets to prevent or therapeutically inhibit colon cancer development. In this review article, we aimed to explore the current targets available to eliminate colon cancer with an update of dietary and non-nutritional compounds that could be of potential use for interaction with regulatory molecules to prevent CRC.
Almost all drugs approved for use in humans possess potentially beneficial 'off-target' effects in addition to their principal activity. In some cases this has allowed for the relatively rapid repurposing of drugs for other indications. In this review we focus on the potential for re-purposing FTY720 (also known as fingolimod, Gilenya(™)), an immunomodulatory drug recently approved for the treatment of multiple sclerosis (MS). The therapeutic benefit of FTY720 in MS is largely attributed to the immunosuppressive effects that result from its modulation of sphingosine 1-phosphate receptor signalling. However, this drug has also been shown to inhibit other cancer-associated signal transduction pathways in part because of its structural similarity to sphingosine, and consequently shows efficacy as an anti-cancer agent both in vitro and in vivo. Here, we review the effects of FTY720 on signal transduction pathways and cancer-related cellular processes, and discuss its potential use as an anti-cancer drug.
Matched MeSH terms: Signal Transduction/drug effects
Flavokawain C (FKC), a naturally occurring chalcone, has previously been shown to inhibit the growth of colon carcinoma HCT 116 cells through induction of apoptosis and cell cycle arrest. However, the possible underlying mechanisms of cell death as a response to FKC treatment remains unclear. In this study, we performed proteomic analysis of HCT 116 cells treated with FKC to identify proteins that change in abundance. This was followed by bioinformatic analysis to predict possible associated molecular targets or pathways involved in the observed effects of FKC. A total of 35 proteins that changed in abundance (17 increased and 18 decreased) were identified through two-dimensional gel electrophoresis followed by matrix-assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-TOF/TOF MS). Using the Ingenuity Pathway Analysis (IPA), these proteins were predicted to be involved in cell death and survival, cell cycle, cellular growth and proliferation, protein synthesis, post-translational modification and amino acid metabolism by. Further analysis of the transcript levels of selected proteins using qPCR showed that some of the genes exhibited similar change of profile to that of the proteins'. Our results have provided novel insights into the potential molecular mechanisms underlying FKC-induced apoptosis or cell death in colon cancer cells.
Matched MeSH terms: Signal Transduction/drug effects
Climate change-induced abiotic stress results in crop yield and production losses. These stresses result in changes at the physiological and molecular level that affect the development and growth of the plant. Reactive oxygen species (ROS) is formed at high levels due to abiotic stress within different organelles, leading to cellular damage. Plants have evolved mechanisms to control the production and scavenging of ROS through enzymatic and non-enzymatic antioxidative processes. However, ROS has a dual function in abiotic stresses where, at high levels, they are toxic to cells while the same molecule can function as a signal transducer that activates a local and systemic plant defense response against stress. The effects, perception, signaling, and activation of ROS and their antioxidative responses are elaborated in this review. This review aims to provide a purview of processes involved in ROS homeostasis in plants and to identify genes that are triggered in response to abiotic-induced oxidative stress. This review articulates the importance of these genes and pathways in understanding the mechanism of resistance in plants and the importance of this information in breeding and genetically developing crops for resistance against abiotic stress in plants.
Matched MeSH terms: Signal Transduction/physiology*
A model of glucose regulation system was combined with a model of insulin-signaling pathways in this study. A feedback loop was added to link the transportation of glucose into cells (by GLUT4 in the insulin-signaling pathways) and the insulin-dependent glucose uptake in the glucose regulation model using the Michaelis-Menten kinetic model. A value of K(m) for GLUT4 was estimated using Genetic Algorithm. The estimated value was found to be 25.3 mM, which was in the range of K(m) values found experimentally from in vivo and in vitro human studies. Based on the results of this study, the combined model enables us to understand the overall dynamics of glucose at the systemic level, monitor the time profile of components in the insulin-signaling pathways at the cellular level and gives a good estimate of the K(m) value of glucose transportation by GLUT4. In conclusion, metabolic modeling such as displayed in this study provides a good predictive method to study the step-by-step reactions in an organism at different levels and should be used in combination with experimental approach to increase our understanding of metabolic disorders such as type 2 diabetes.
We screened 868 marine extracts in search of hematopoietic molecules resulted in findings of several extracts that proliferated Ba/F3-HuMpl cells but not the cells expressed with other hematopoietic cytokine receptors, EPO and G-CSF. Separation of the most potent extract of a Micronesian sponge Corticium sp., guided by the cell proliferation assay using Ba/F3-HuMpl cells resulted in an isolation of thrombocorticin (ThC), a novel 14 kDa protein as an active principal. ThC displayed concentration-dependent proliferation of Ba/F3-HuMpl cells, and had a stronger activity than that of eltrombopag, a small molecule drug used to treat thrombocytopenia. ThC induced phosphorylation of STAT5, suggesting that it activates Jak/STAT pathway as in the case of TPO. These results together indicated that ThC is a specific agonist for c-Mpl, although the size and shape differs largely from TPO. Here we present isolation, characterization and biological activity of ThC.
Matched MeSH terms: Signal Transduction/drug effects
Co-application of biochar and biosolids to soil has potential to mitigate N leaching due to physical and chemical properties of biochar. Changes in N cycling pathways in soil induced by co-application of biological amendments could further mitigate N loss, but this is largely unexplored. The aim of this study was to determine whether co-application of a biochar and a modified biosolids product to three pasture soils differing in texture could alter the relative abundance of N cycling genes in soil sown with subterranean clover. The biosolids product contained lime and clay and increased subterranean clover shoot biomass in parallel with increases in soil pH and soil nitrate. Its co-application with biochar similarly increased plant growth and soil pH with a marked reduction in nitrate in two coarse textured soils but not in a clayey soil. While application of the biosolids product altered in silico predicted N cycling functional genes, there was no additional change when applied to soil in combination with biochar. This supports the conclusion that co-application of the biochar and biosolids product used here has potential to mitigate loss of N in coarse textured soils due to N adsoption by the biochar and independently of microbial N pathways.
Salinity exerts a severe detrimental effect on crop yields globally. Growth of plants in saline soils results in physiological stress, which disrupts the essential biochemical processes of respiration, photosynthesis, and transpiration. Understanding the molecular responses of plants exposed to salinity stress can inform future strategies to reduce agricultural losses due to salinity; however, it is imperative that signalling and functional response processes are connected to tailor these strategies. Previous research has revealed the important role that plant mitochondria play in the salinity response of plants. Review of this literature shows that 2 biochemical processes required for respiratory function are affected under salinity stress: the tricarboxylic acid cycle and the transport of metabolites across the inner mitochondrial membrane. However, the mechanisms by which components of these processes are affected or react to salinity stress are still far from understood. Here, we examine recent findings on the signal transduction pathways that lead to adaptive responses of plants to salinity and discuss how they can be involved in and be affected by modulation of the machinery of energy metabolism with attention to the role of the tricarboxylic acid cycle enzymes and mitochondrial membrane transporters in this process.
High mobility group box 1 (HMGB1) is a ubiquitous protein, released passively by necrotic tissues or secreted actively by stressed cells. Extracellular HMGB1 is a typical damage-associated molecular pattern (DAMP) molecule which generates different redox types through binding with several receptors and signalling molecules, aggravating a range of cellular responses, including inflammation. HMGB1 is reported to participate in the pathogenesis of inflammatory diseases, through the interaction with pivotal transmembrane receptors, including the receptor for advanced glycation end products (RAGE) and toll-like receptor-4 (TLR-4). This review aims to highlight the role of HMGB1 in the innate inflammatory response describing its interaction with several cofactors and receptors that coordinate its downstream effects. Novel and underexplored HMGB1 binding molecules that have been actively involved in HMGB1-mediated inflammatory diseases/conditions with therapeutic potential are further discussed.
Aldosterone acts through the mineralocorticoid receptor (MR) to modulate gene expression in target tissues. In the kidney, the principal action of aldosterone is to promote sodium conservation in the distal nephron and so indirectly enhance water conservation under conditions of hypotension. Over the last twenty years the rapid activation of protein kinase signalling cascades by aldosterone has been described in various tissues. This review describes the integration of rapid protein kinase D signalling responses with the non-genomic actions of aldosterone and transcriptional effects of MR activation.
Biochemical signaling and mechano-transduction are both critical in regulating stem cell fate. How crosstalk between mechanical and biochemical cues influences embryonic development, however, is not extensively investigated. Using a comparative study of focal adhesion constituents between mouse embryonic stem cell (mESC) and their differentiated counterparts, we find while zyxin is lowly expressed in mESCs, its levels increase dramatically during early differentiation. Interestingly, overexpression of zyxin in mESCs suppresses Oct4 and Nanog. Using an integrative biochemical and biophysical approach, we demonstrate involvement of zyxin in regulating pluripotency through actin stress fibres and focal adhesions which are known to modulate cellular traction stress and facilitate substrate rigidity-sensing. YAP signaling is identified as an important biochemical effector of zyxin-induced mechanotransduction. These results provide insights into the role of zyxin in the integration of mechanical and biochemical cues for the regulation of embryonic stem cell fate.
In solid tumours, cancer cells exist within hypoxic microenvironments, and their metabolic adaptation to this hypoxia is driven by HIF-1 transcription factor, which is overexpressed in a broad range of human cancers. HIF inhibitors are under pre-clinical investigation and clinical trials, but there is evidence that hypoxic cancer cells can adapt metabolically to HIF-1 inhibition, which would provide a potential route for drug resistance. Here, we review accumulating evidence of such adaptions in carbohydrate and creatine metabolism and other HIF-1-independent mechanisms that might allow cancers to survive hypoxia despite anti-HIF-1 therapy. These include pathways in glucose, glutamine, and lipid metabolism; epigenetic mechanisms; post-translational protein modifications; spatial reorganization of enzymes; signalling pathways such as Myc, PI3K-Akt, 2-hyxdroxyglutarate and AMP-activated protein kinase (AMPK); and activation of the HIF-2 pathway. All of these should be investigated in future work on hypoxia bypass mechanisms in anti-HIF-1 cancer therapy. In principle, agents targeted toward HIF-1β rather than HIF-1α might be advantageous, as both HIF-1 and HIF-2 require HIF-1β for activation. However, HIF-1β is also the aryl hydrocarbon nuclear transporter (ARNT), which has functions in many tissues, so off-target effects should be expected. In general, cancer therapy by HIF inhibition will need careful attention to potential resistance mechanisms.
Matched MeSH terms: Signal Transduction/physiology
Jatropha curcas is an oil-rich seed crop with huge potentials for bioenergy production. The inflorescence carries a number of processes that are likely to affect the overall yield potentials; floral development, male-to-female flower ratio, floral abscission and fruit set. In this study, a weighted gene co-expression network analysis which integrates the transcriptome, physical and simple sugar data of J. curcas inflorescence was performed and nine modules were identified by means of hierarchical clustering. Among them, four modules (green4, antiquewhite2, brown2 and lightskyblue4) showed significant correlation to yield factors at p≤0.01. The four modules are categorized into two clusters; cluster 1 of green4 and antiquewhite2 modules correspond to number of flowers/inflorescence, total seed weight/plant, number of seeds/plant, and number of fruits/plant, whereas cluster 2 of brown2 and lightskyblue4 modules correspond to glucose and fructose. Descriptive characterizations of cluster 1 show putative involvement in gibberellin signaling and responses, whereas cluster 2 may have been involved in sugar signaling, signal transductions and regulation of flowerings. Our findings present a list of hub genes for J. curcas yield improvement and reproductive biology enhancement strategies.
Matched MeSH terms: Signal Transduction/physiology*