Browsing by Subject "DOWN-REGULATION"
Now showing items 1-20 of 43
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(2020)The cultivated strawberry (Fragaria × ananassa) is an allo-octoploid species, originating nearly 300 years ago from wild progenitors from the Americas. Since that time the strawberry has become the most widely cultivated fruit crop in the world, universally appealing due to its sensory qualities and health benefits. The recent publication of the first high-quality chromosome-scale octoploid strawberry genome (cv. Camarosa) is enabling rapid advances in genetics, stimulating scientific debate and provoking new research questions. In this forward-looking review we propose avenues of research toward new biological insights and applications to agriculture. Among these are the origins of the genome, characterization of genetic variants, and big data approaches to breeding. Key areas of research in molecular biology will include the control of flowering, fruit development, fruit quality, and plant–pathogen interactions. In order to realize this potential as a global community, investments in genome resources must be continually augmented.
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(2019)A genetic basis for otitis media is established, however, the role of rare variants in disease etiology is largely unknown. Previously a duplication variant within A2ML1 was identified as a significant risk factor for otitis media in an indigenous Filipino population and in US children. In this report exome and Sanger sequencing was performed using DNA samples from the indigenous Filipino population, Filipino cochlear implantees, US probands, Finnish, and Pakistani families with otitis media. Sixteen novel, damaging A2ML1 variants identified in otitis media patients were rare or low-frequency in population-matched controls. In the indigenous population, both gingivitis and A2ML1 variants including the known duplication variant and the novel splice variant c.4061 + 1 G>C were independently associated with otitis media. Sequencing of salivary RNA samples from indigenous Filipinos demonstrated lower A2ML1 expression according to the carriage of A2ML1 variants. Sequencing of additional salivary RNA samples from US patients with otitis media revealed differentially expressed genes that are highly correlated with A2ML1 expression levels. In particular, RND3 is upregulated in both A2ML1 variant carriers and high-A2ML1 expressors. These findings support a role for A2ML1 in keratinocyte differentiation within the middle ear as part of otitis media pathology and the potential application of ROCK inhibition in otitis media.
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(2010)Neuroblastoma has successfully served as a model system for the identification of neuroectoderm-derived oncogenes. However, in spite of various efforts, only a few clinically useful prognostic markers have been found. Here, we present a framework, which integrates DNA, RNA and tissue data to identify and prioritize genetic events that represent clinically relevant new therapeutic targets and prognostic biomarkers for neuroblastoma.
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(2019)Brain trauma triggers a cascade of deleterious events leading to enhanced incidence of drug resistant epilepsies, depression, and cognitive dysfunctions. The underlying mechanisms leading to these alterations are poorly understood and treatment that attenuates those sequels are not available. Using controlled-cortical impact as an experimental model of brain trauma in adult mice, we found a strong suppressive effect of the sodium-potassium-chloride importer (NKCC1) specific antagonist bumetanide on the appearance of depressive-like behavior. We demonstrate that this alteration in behavior is associated with an impairment of post-traumatic secondary neurogenesis within the dentate gyrus of the hippocampus. The mechanism mediating the effect of bumetanide involves early transient changes in the expression of chloride regulatory proteins and qualitative changes in GABA(A) mediated transmission from hyperpolarizing to depolarizing after brain trauma. This work opens new perspectives in the early treatment of human post-traumatic induced depression. Our results strongly suggest that bumetanide might constitute an efficient prophylactic treatment to reduce neurological and psychiatric consequences of brain trauma.
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(2020)Growth factors (GFs) hold considerable promise for disease modification in neurodegenerative disorders because they can protect and restore degenerating neurons and also enhance their functional activity. However, extensive efforts applied to utilize their therapeutic potential in humans have achieved limited success so far. Multiple clinical trials with GFs were performed in Parkinson's disease (PD) patients, in whom diagnostic symptoms of the disease are caused by advanced degeneration of nigrostriatal dopamine neurons (DNs), but the results of these trials are controversial. This review discusses recent developments in the field of therapeutic use of GFs, problems and obstacles related to this use, suggests the ways to overcome these issues, and alternative approaches that can be used to utilize the potential of GFs in PD management.
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(2020)Glial cell line-derived neurotrophic factor (GDNF) supports function and survival of dopamine neurons that degenerate in Parkinson's disease (PD). Ectopic delivery of GDNF in clinical trials to treat PD is safe but lacks significant therapeutic effect. In pre-clinical models, ectopic GDNF is effective but causes adverse effects, including downregulation of tyrosine hydroxylase, only a transient boost in dopamine metabolism, aberrant neuronal sprouting, and hyperactivity. Hindering development of GDNF mimetic increased signaling via GDNF receptor RET by activating mutations results in cancer. Safe and effective mode of action must be defined first in animal models to develop successful GDNF-based therapies. Previously we showed that about a 2-fold increase in endogenous GDNF expression is safe and results in increased motor and dopaminergic function and protection in a PD model in young animals. Recently, similar results were reported using a novel Gdnf mRNA-targeting strategy. Next, it is important to establish the safety of a long-term increase in endogenous GDNF expression. We report behavioral, dopamine system, and cancer analysis of five cohorts of aged mice with a 2-fold increase in endogenous GDNF. We found a sustained increase in dopamine levels, improvement in motor learning, and no side effects or cancer. These results support the rationale for further development of endogenous GDNF-based treatments and GDNF mimetic.
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(2015)Background: Ovarian granulosa cell tumors (GCTs) are the most frequent sex cord-stromal tumors. Several studies have shown that a somatic mutation leading to a C134W substitution in the transcription factor FOXL2 appears in more than 95% of adult-type GCTs. Its pervasive presence suggests that FOXL2 is the main cancer driver gene. However, other mutations and genomic changes might also contribute to tumor formation and/or progression. Methods: We have performed a combined comparative genomic hybridization and transcriptomic analyses of 10 adult-type GCTs to obtain a picture of the genomic landscape of this cancer type and to identify new candidate co-driver genes. Results: Our results, along with a review of previous molecular studies, show the existence of highly recurrent chromosomal imbalances (especially, trisomy 14 and monosomy 22) and preferential co-occurrences (i.e. trisomy 14/monosomy 22 and trisomy 7/monosomy 16q). In-depth analyses showed the presence of recurrently broken, amplified/duplicated or deleted genes. Many of these genes, such as AKT1, RUNX1 and LIMA1, are known to be involved in cancer and related processes. Further genomic explorations suggest that they are functionally related. Conclusions: Our combined analysis identifies potential candidate genes, whose alterations might contribute to adult-type GCT formation/progression together with the recurrent FOXL2 somatic mutation.
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(2016)Loss of podocytes is an early feature of diabetic nephropathy (DN) and predicts its progression. We found that treatment of podocytes with sera from normoalbuminuric type 1 diabetes patients with high lipopolysaccharide (LPS) activity, known to predict progression of DN, downregulated CDK2 (cyclin-dependent kinase 2). LPS-treatment of mice also reduced CDK2 expression. LPS-induced downregulation of CDK2 was prevented in vitro and in vivo by inhibiting the Toll-like receptor (TLR) pathway using immunomodulatory agent GIT27. We also observed that CDK2 is downregulated in the glomeruli of obese Zucker rats before the onset of proteinuria. Knockdown of CDK2, or inhibiting its activity with roscovitine in podocytes increased apoptosis. CDK2 knockdown also reduced expression of PDK1, an activator of the cell survival kinase Akt, and reduced Akt phosphorylation. This suggests that CDK2 regulates the activity of the cell survival pathway via PDK1. Furthermore, PDK1 knockdown reduced the expression of CDK2 suggesting a regulatory loop between CDK2 and PDK1. Collectively, our data show that CDK2 protects podocytes from apoptosis and that reduced expression of CDK2 associates with the development of DN. Preventing downregulation of CDK2 by blocking the TLR pathway with GIT27 may provide a means to prevent podocyte apoptosis and progression of DN.
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(2021)Parkinson's disease (PD) pathology involves progressive degeneration and death of vulnerable dopamine neurons in the substantia nigra. Extensive axonal arborization and distinct functions make this type of neurons particularly sensitive to homeostatic perturbations, such as protein misfolding and Ca2+ dysregulation. Endoplasmic reticulum (ER) is a cell compartment orchestrating protein synthesis and folding, as well as synthesis of lipids and maintenance of Ca2+ homeostasis in eukaryotic cells. When misfolded proteins start to accumulate in ER lumen the unfolded protein response (UPR) is activated. UPR is an adaptive signaling machinery aimed at relieving of protein folding load in the ER. When UPR is chronic, it can either boost neurodegeneration and apoptosis or cause neuronal dysfunctions. We have recently discovered that mesencephalic astrocyte-derived neurotrophic factor (MANF) exerts its prosurvival action in dopamine neurons and in an animal model of PD through the direct binding to UPR sensor inositol-requiring protein 1 alpha (IRE1) and attenuation of UPR. In line with this, UPR targeting resulted in neuroprotection and neurorestoration in various preclinical animal models of PD. Therefore, growth factors (GFs), possessing both neurorestorative activity and restoration of protein folding capacity are attractive as drug candidates for PD treatment especially their blood-brain barrier penetrating analogs and small molecule mimetics. In this review, we discuss ER stress as a therapeutic target to treat PD; we summarize the existing preclinical data on the regulation of ER stress for PD treatment. In addition, we point out the crucial aspects for successful clinical translation of UPR-regulating GFs and new prospective in GFs-based treatments of PD, focusing on ER stress regulation.
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(2022)Experimental evidence that nonstomatal limitations to photosynthesis (NSLs) correlate with leaf sugar and/or leaf water status suggests the possibility that stomata adjust to maximise photosynthesis through a trade-off between leaf CO2 supply and NSLs, potentially involving source-sink interactions. However, the mechanisms regulating NSLs and sink strength, as well as their implications for stomatal control, remain uncertain. We used an analytically solvable model to explore optimal stomatal control under alternative hypotheses for source and sink regulation. We assumed that either leaf sugar concentration or leaf water potential regulates NSLs, and that either phloem turgor pressure or phloem sugar concentration regulates sink phloem unloading. All hypotheses led to realistic stomatal responses to light, CO2 and air humidity, including conservative behaviour for the intercellular-to-atmospheric CO2 concentration ratio. Sugar-regulated and water-regulated NSLs are distinguished by the presence/absence of a stomatal closure response to changing sink strength. Turgor-regulated and sugar-regulated phloem unloading are distinguished by the presence/absence of stomatal closure under drought and avoidance/occurrence of negative phloem turgor. Results from girdling and drought experiments on Pinus sylvestris, Betula pendula, Populus tremula and Picea abies saplings are consistent with optimal stomatal control under sugar-regulated NSLs and turgor-regulated unloading. Our analytical results provide a simple representation of stomatal responses to above-ground and below-ground environmental factors and sink activity.
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Fascin promotes migration and invasion and is a prognostic marker for oral squamous cell carcinoma (2017)Oral squamous cell carcinoma (OSCC) prognosis is related to clinical stage and histological grade. However, this stratification needs to be refined. We conducted a comparative proteome study in microdissected samples from normal oral mucosa and OSCC to identify biomarkers for malignancy. Fascin and plectin were identified as differently expressed and both are implicated in several malignancies, but the clinical impacts of aberrant fascin and plectin expression in OSCCs remains largely unknown. Immunohistochemistry and real-time quantitative PCR were carried out in ex vivo OSCC samples and cell lines. A loss-of-function strategy using shRNA targeting fascin was employed to investigate in vitro and in vivo the fascin role on oral tumorigenesis. Transfections of microRNA mimics were performed to determine whether the fascin overexpression is regulated by miR-138 and miR-145. We found that fascin and plectin are frequently upregulated in OSCC samples and cell lines, but only fascin overexpression is an independent unfavorable prognostic indicator of disease-specific survival. In combination with advanced T stage, high fascin level is also an independent factor of disease-free survival. Knockdown of fascin in OSCC cells promoted cell adhesion and inhibited migration, invasion and EMT, and forced expression of miR-138 in OSCC cells significantly decreased the expression of fascin. In addition, fascin downregulation leads to reduced filopodia formation and decrease on paxillin expression. The subcutaneous xenograft model showed that tumors formed in the presence of low levels of fascin were significantly smaller compared to those formed with high fascin levels. Collectively, our findings suggest that fascin expression correlates with disease progression and may serve as a prognostic marker and therapeutic target for patients with OSCC.
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(2014)Concepts of epilepsy, based on a simple change in neuronal excitation/inhibition balance, have subsided in face of recent insights into the large diversity and context-dependence of signaling mechanisms at the molecular, cellular and neuronal network level. GABAergic transmission exerts both seizure-suppressing and seizure-promoting actions. These two roles are prone to short-term and long-term alterations, evident both during epileptogenesis and during individual epileptiform events. The driving force of GABAergic currents is controlled by ion-regulatory molecules such as the neuronal K-Cl cotransporter KCC2 and cytosolic carbonic anhydrases. Accumulating evidence suggests that neuronal ion regulation is highly plastic, thereby contributing to the multiple roles ascribed to GABAergic signaling during epileptogenesis and epilepsy.
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(2019)MicroRNAs are post-transcriptional regulators of gene expression, crucial for neuronal differentiation, survival, and activity. Age-related dysregulation of microRNA biogenesis increases neuronal vulnerability to cellular stress and may contribute to the development and progression of neurodegenerative diseases. All major neurodegenerative disorders are also associated with oxidative stress, which is widely recognized as a potential target for protective therapies. Albeit often considered separately, microRNA networks and oxidative stress are inextricably entwined in neurodegenerative processes. Oxidative stress affects expression levels of multiple microRNAs and, conversely, microRNAs regulate many genes involved in an oxidative stress response. Both oxidative stress and microRNA regulatory networks also influence other processes linked to neurodegeneration, such as mitochondrial dysfunction, deregulation of proteostasis, and increased neuroinflammation, which ultimately lead to neuronal death. Modulating the levels of a relatively small number of microRNAs may therefore alleviate pathological oxidative damage and have neuroprotective activity. Here, we review the role of individual microRNAs in oxidative stress and related pathways in four neurodegenerative conditions: Alzheimer's (AD), Parkinson's (PD), Huntington's (HD) disease, and amyotrophic lateral sclerosis (ALS). We also discuss the problems associated with the use of oversimplified cellular models and highlight perspectives of studying microRNA regulation and oxidative stress in human stem cell-derived neurons.
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(2019)BackgroundPrognostic markers specific to a particular cancer type can assist in the evaluation of survival probability of patients and help clinicians to assess the available treatment modalities.MethodsGene expression data was analyzed from three independent colon cancer microarray gene expression data sets (N=1052). Survival analysis was performed for the three data sets, stratified by the expression level of the LINE-1 type transposase domain containing 1 (L1TD1). Correlation analysis was performed to investigate the role of the interactome of L1TD1 in colon cancer patients.ResultsWe found L1TD1 as a novel positive prognostic marker for colon cancer. Increased expression of L1TD1 associated with longer disease-free survival in all the three data sets. Our results were in contrast to a previous study on medulloblastoma, where high expression of L1TD1 was linked with poor prognosis. Notably, in medulloblastoma L1TD1 was co-expressed with its interaction partners, whereas our analysis revealed lack of co-expression of L1TD1 with its interaction partners in colon cancer.ConclusionsOur results identify increased expression of L1TD1 as a prognostic marker predicting longer disease-free survival in colon cancer patients.
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(2017)Membrane-type matrix metalloproteases (MT-MMP) are pivotal regulators of cell invasion, growth and survival. Tethered to the cell membranes by a transmembrane domain or GPI-anchor, the six MT-MMPs can exert these functions via cell surface-associated extracellular matrix degradation or proteolytic protein processing, including shedding or release of signaling receptors, adhesion molecules, growth factors and other pericellular proteins. By interactions with signaling scaffold or cytoskeleton, the C-terminal cytoplasmic tail of the transmembrane MT-MMPs further extends their functionality to signaling or structural relay. MT-MMPs are differentially expressed in cancer. The most extensively studied MMP14/MT1-MMP is induced in various cancers along malignant transformation via pathways activated by mutations in tumor suppressors or proto-oncogenes and changes in tumor microenvironment including cellular heterogeneity, extracellular matrix composition, tissue oxygenation, and inflammation. Classically such induction involves transcriptional programs related to epithelial-to-mesenchymal transition. Besides inhibition by endogenous tissue inhibitors, MT-MMP activities are spatially and timely regulated at multiple levels by microtubular vesicular trafficking, dimerization/oligomerization, other interactions and localization in the actin-based invadosomes, in both tumor and the stroma. The functions of MT-MMPs are multifaceted within reciprocal cellular responses in the evolving tumor microenvironment, which poses the importance of these proteases beyond the central function as matrix scissors, and necessitates us to rethink MT-MMPs as dynamic signaling proteases of cancer. This article is part of a Special Issue entitled: Matrix Metalloproteinases edited by Rafael Fridman.
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(2020)The cytoskeleton is one of the most mobile and complex cell structures. It is involved in cellular transport, cell division, cell shape formation and adaptation in response to extra- and intracellular stimuli, endo- and exocytosis, migration, and invasion. These processes are crucial for normal cellular physiology and are affected in several pathological processes, including neurodegenerative diseases, and cancer. Some proteins, participating in clathrin-mediated endocytosis (CME), play an important role in actin cytoskeleton reorganization, and formation of invadopodia in cancer cells and are also deregulated in neurodegenerative disorders. However, there is still limited information about the factors contributing to the regulation of their expression. MicroRNAs are potent negative regulators of gene expression mediating crosstalk between different cellular pathways in cellular homeostasis and stress responses. These molecules regulate numerous genes involved in neuronal differentiation, plasticity, and degeneration. Growing evidence suggests the role of microRNAs in the regulation of endocytosis, cell motility, and invasiveness. By modulating the levels of such microRNAs, it may be possible to interfere with CME or other processes to normalize their function. In malignancy, the role of microRNAs is undoubtful, and therefore changing their levels can attenuate the carcinogenic process. Here we review the current advances in our understanding of microRNAs regulating actin cytoskeleton dynamics, CME and cell motility with a special focus on neurodegenerative diseases, and cancer. We investigate whether current literature provides an evidence that microRNA-mediated regulation of essential cellular processes, such as CME and cell motility, is conserved in neurons, and cancer cells. We argue that more research effort should be addressed to study the neuron-specific functions on microRNAs. Disease-associated microRNAs affecting essential cellular processes deserve special attention both from the view of fundamental science and as future neurorestorative or anti-cancer therapies.
