Systems Approach to Integrating Preclinical Apolipoprotein E-Knockout Investigations Reveals Novel Etiologic Pathways and Master Atherosclerosis Network in Humans

2021 ◽  
Author(s):  
Megan M. Shuey ◽  
Rachel R. Xiang ◽  
M. Elizabeth Moss ◽  
Brigett V. Carvajal ◽  
Yihua Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Apolipoprotein E ◽  
Human Disease ◽  
Molecular Mechanisms ◽  
Systems Approach ◽  
Human Subjects ◽  
Strong Association ◽  
Human Study ◽  
Receptor Activation ◽  
Retinoid Receptor

Objective: Animal models of atherosclerosis are used extensively to interrogate molecular mechanisms in serial fashion. We tested whether a novel systems biology approach to integration of preclinical data identifies novel pathways and regulators in human disease. Approach and Results: Of 716 articles published in ATVB from 1995 to 2019 using the apolipoprotein E knockout mouse to study atherosclerosis, data were extracted from 360 unique studies in which a gene was experimentally perturbed to impact plaque size or composition and analyzed using Ingenuity Pathway Analysis software. TREM1 (triggering receptor expressed on myeloid cells) signaling and liver×receptor/retinoid×receptor activation were identified as the top atherosclerosis-associated pathways in mice (both P <1.93×10 − 4 , TREM1 implicated early and liver×receptor/retinoid×receptor in late atherogenesis). The top upstream regulatory network in mice (sc-58125, a COX2 inhibitor) linked 64.0% of the genes into a single network. The pathways and networks identified in mice were interrogated by testing for associations between the genetically predicted gene expression of each mouse pathway-identified human homolog with clinical atherosclerosis in a cohort of 88 660 human subjects. Homologous human pathways and networks were significantly enriched for gene-atherosclerosis associations (empirical P <0.01 for TREM1 and liver×receptor/retinoid×receptor pathways and COX2 network). This included 12(60.0%) TREM1 pathway genes, 15(53.6%) liver×receptor/retinoid×receptor pathway genes, and 67(49.3%) COX2 network genes. Mouse analyses predicted, and human study validated, the strong association of COX2 expression ( PTGS2 ) with increased likelihood of atherosclerosis (odds ratio, 1.68 per SD of genetically predicted gene expression; P =1.07×10 − 6 ). Conclusions: Preclinical Science Integration and Translation leverages published preclinical investigations to identify high-confidence pathways, networks, and regulators of human disease.

scholarly journals Jacob, a Synapto-Nuclear Protein Messenger Linking N-methyl-D-aspartate Receptor Activation to Nuclear Gene Expression

2021 ◽  
Vol 13 ◽  
Author(s):  
Katarzyna M. Grochowska ◽  
Julia Bär ◽  
Guilherme M. Gomes ◽  
Michael R. Kreutz ◽  
Anna Karpova
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Protein Transport ◽  
Pyramidal Neurons ◽  
Temporal Integration ◽  
Dendritic Tree ◽  
Nuclear Gene ◽  
Receptor Activation ◽  
Excitatory Input ◽  
Splice Isoforms

Pyramidal neurons exhibit a complex dendritic tree that is decorated by a huge number of spine synapses receiving excitatory input. Synaptic signals not only act locally but are also conveyed to the nucleus of the postsynaptic neuron to regulate gene expression. This raises the question of how the spatio-temporal integration of synaptic inputs is accomplished at the genomic level and which molecular mechanisms are involved. Protein transport from synapse to nucleus has been shown in several studies and has the potential to encode synaptic signals at the site of origin and decode them in the nucleus. In this review, we summarize the knowledge about the properties of the synapto-nuclear messenger protein Jacob with special emphasis on a putative role in hippocampal neuronal plasticity. We will elaborate on the interactome of Jacob, the signals that control synapto-nuclear trafficking, the mechanisms of transport, and the potential nuclear function. In addition, we will address the organization of the Jacob/NSMF gene, its origin and we will summarize the evidence for the existence of splice isoforms and their expression pattern.

scholarly journals The effect of alcohol and nicotine abuse on gene expression in the brain

2009 ◽  
Vol 22 (2) ◽  
pp. 148-162 ◽  
Author(s):  
Traute Flatscher-Bader ◽  
Peter A. Wilce
Keyword(s):  
Gene Expression ◽  
Drug Targets ◽  
Molecular Mechanisms ◽  
Drugs Of Abuse ◽  
Human Subjects ◽  
Common Mental Disorder ◽  
Tobacco Consumption ◽  
Western World ◽  
Mesocorticolimbic System ◽  
The Brain

Alcohol intake at levels posing an acute heath risk is common amongst teenagers. Alcohol abuse is the second most common mental disorder worldwide. The incidence of smoking is decreasing in the Western world but increasing in developing countries and is the leading cause of preventable death worldwide. Considering the longstanding history of alcohol and tobacco consumption in human societies, it might be surprising that the molecular mechanisms underlying alcohol and smoking dependence are still incompletely understood. Effective treatments against the risk of relapse are lacking. Drugs of abuse exert their effect manipulating the dopaminergic mesocorticolimbic system. In this brain region, alcohol has many potential targets including membranes and several ion channels, while other drugs, for example nicotine, act via specific receptors or binding proteins. Repeated consumption of drugs of abuse mediates adaptive changes within this region, resulting in addiction. The high incidence of alcohol and nicotine co-abuse complicates analysis of the molecular basis of the disease. Gene expression profiling is a useful approach to explore novel drug targets in the brain. Several groups have utilised this technology to reveal drug-sensitive pathways in the mesocorticolimbic system of animal models and in human subjects. These studies are the focus of the present review.

scholarly journals Investigating the in vitro steatotic mixture effects of similarly and dissimilarly acting test compounds using an adverse outcome pathway-based approach

2021 ◽  
Author(s):  
Jimmy Alarcan ◽  
Georges de Sousa ◽  
Efrosini S. Katsanou ◽  
Anastasia Spyropoulou ◽  
Petros Batakis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Adverse Outcome ◽  
Liver Steatosis ◽  
Receptor Activation ◽  
Adverse Outcome Pathway ◽  
Vitro Assay ◽  
Mixture Effects ◽  
Triglyceride Accumulation

AbstractWithin the EuroMix project, we have previously developed an adverse outcome pathway (AOP)-based in vitro assay toolbox to investigate the combined effects of liver steatosis-inducing compounds in human HepaRG hepatocarcinoma cells. In this study, we applied the toolbox to further investigate mixture effects of combinations, featuring either similarly acting or dissimilarly acting substances. The valproic acid structural analogs 2-propylheptanoic acid (PHP) and 2-propylhexanoic acid (PHX) were chosen for establishing mixtures of similarly acting substances, while a combination with the pesticidal active substance clothianidin (CTD) was chosen for establishing mixtures of dissimilarly acting compounds. We first determined relative potency factors (RPFs) for each compound based on triglyceride accumulation results. Thereafter, equipotent mixtures were tested for nuclear receptor activation in transfected HepG2 cells, while gene expression and triglyceride accumulation were investigated in HepaRG cells, following the proposed AOP for liver steatosis. Dose addition was observed for all combinations and endpoints tested, indicating the validity of the additivity assumption also in the case of the tested mixtures of dissimilarly acting substances. Gene expression results indicate that the existing steatosis AOP can still be refined with respect to the early key event (KE) of gene expression, in order to reflect the diversity of molecular mechanisms underlying the adverse outcome.

The Role of Free-Living Amoebae Occurring in Heated Effluents as Causative Agents of Human Disease

1983 ◽  
Vol 15 (10) ◽  
pp. 135-147
Author(s):  
Maurice A Shapiro ◽  
Meryl H Karol ◽  
Georg Keleti ◽  
Jan L Sykora ◽  
A J Martinez
Keyword(s):  
Human Disease ◽  
Power Plants ◽  
Elevated Temperatures ◽  
Human Subjects ◽  
Cooling Towers ◽  
Free Living ◽  
Cooling Systems ◽  
Delayed Onset ◽  
Source Of Infection ◽  
Causative Agents

It has been shown that several pathogenic organisms may be frequently found in thermal effluents and cooling systems of coal fired power plants. One of them is pathogenic Naegleria fowleri, the causative agent of an acute fatal human disease - primary amoebic meningoencephalitis (PAM). In our study two out of eight power plants investigated, harbored pathogenic N. fowleri in heated water or cooling towers. The occurrence of this organism was related to elevated temperatures. No significant correlation was found for other biological and chemical parameters. In addition, pathogenic Acanthamoeba which causes granulomatous amoebic encephalitis (GAE) was found in the tested heated effluents from coal fired power plants. Non-pathogenic strains of N. fowleri as well as other free-living and “harmless” amoebae were also very abundant in effluents from all investigated coal fired power plants and cooling towers. It has been reported that several species of nonpathogenic amoebae were isolated from humidifiers and air conditioning systems. Serological testing of symptomatic human subjects has indicated that these organisms may be one of the causative agents of hypersensitivity pneumonitis. An experimental study performed in our laboratory involved testing of guinea pigs sensitized by injection of axenic, non-pathogenic N. gruberi. Delayed onset skin reactivity was apparent in all animals injected with the antigen. Antibodies were detected in all sensitized animals. Bronchial provocation challenge employed to investigate pulmonary hypersensitivity was also used, and yielded positive results. All the sensitized animals displayed delayed onset respiratory responses. The results of this study indicate that not only pathogenic but also non-pathogenic free-living amoebae may be important causative agents of human disease. The occurrence of these organisms in cooling systems from coal fired power plants indicates that these facilities may be an important source of infection.

The Mechanisms Behind the Biological Activity of Flavonoids

2019 ◽  
Vol 26 (39) ◽  
pp. 6976-6990 ◽  
Author(s):  
Ana María González-Paramás ◽  
Begoña Ayuda-Durán ◽  
Sofía Martínez ◽  
Susana González-Manzano ◽  
Celestino Santos-Buelga
Keyword(s):  
Gene Expression ◽  
Biological Activity ◽  
Phenolic Compounds ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Radical Scavenging ◽  
Model Organism ◽  
Stress Theory ◽  
Radical Scavenging Properties

: Flavonoids are phenolic compounds widely distributed in the human diet. Their intake has been associated with a decreased risk of different diseases such as cancer, immune dysfunction or coronary heart disease. However, the knowledge about the mechanisms behind their in vivo activity is limited and still under discussion. For years, their bioactivity was associated with the direct antioxidant and radical scavenging properties of phenolic compounds, but nowadays this assumption is unlikely to explain their putative health effects, or at least to be the only explanation for them. New hypotheses about possible mechanisms have been postulated, including the influence of the interaction of polyphenols and gut microbiota and also the possibility that flavonoids or their metabolites could modify gene expression or act as potential modulators of intracellular signaling cascades. This paper reviews all these topics, from the classical view as antioxidants in the context of the Oxidative Stress theory to the most recent tendencies related with the modulation of redox signaling pathways, modification of gene expression or interactions with the intestinal microbiota. The use of C. elegans as a model organism for the study of the molecular mechanisms involved in biological activity of flavonoids is also discussed.

High Altitude hypoxia

2020 ◽  
Vol 17 ◽  
Author(s):  
Asma Babar ◽  
Kifayatullah Mengal ◽  
Abdul Hanan Babar ◽  
Shixin Wu ◽  
Mujahid Ali Shah ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
High Altitude ◽  
Molecular Mechanisms ◽  
Strong Association ◽  
Haemoglobin Concentration ◽  
Metabolic Reprogramming ◽  
Molecular Networks ◽  
Whole Genome ◽  
Gene Expressions ◽  
Transcriptional Responses

: The world highest and largest altitude area is called the Qinghai-Tibetan plateau (QTB), which harbors unique animal and plant species. Mammals that inhabit the higher altitude regions have adapted well to the hypoxic conditions. One of the main stressors at high altitude is hypoxia. Metabolic responses to hypoxia play important roles in cell survival strategies and some diseases. However, the homeostatic alterations that equilibrate variations in the demand and supply of energy to maintain organismal function in a prolonged low O2 environment persist partly understood, making it problematic to differentiate adaptive from maladaptive responses in hypoxia. Tibetans and yaks are two perfect examples innate to the plateau for high altitude adaptation. By the scan of the whole-genome, EPAS1 and EGLN1 were identified as key genes associated with sustained haemoglobin concentration in high altitude mammals for adaptation. The yak is a much more ancient mammal which has existed on QTB longer than humans, it is, therefore, possible that natural selection represented a diverse group of genes/pathways in yaks. Physiological characteristics are extremely informative in revealing molecular networks associated with inherited adaptation, in addition to the whole-genome adaptive changes at the DNA sequence level. Gene-expression can be changed by a variety of signals originating from the environment, and hypoxia is the main factor amongst them. The hypoxia-inducible factors (HIF-1α and EPAS1/HIF-2α) are the main regulators of oxygen in homeostasis which play a role as maestro regulators of adaptation in hypoxic reaction of molecular mechanisms. (Vague) The basis of this review is to present recent information regarding the molecular mechanism involved in hypoxia that regulates candidate genes and proteins. Many transcriptional responses toward hypoxia are facilitated by HIFs that change the number of gene expressions and help in angiogenesis, erythropoiesis, metabolic reprogramming and metastasis. HIFs also activate several signals highlighting a strong association between hypoxia, the misfolded proteins’ accumulation in the endoplasmic reticulum in stress and activation of unfolded protein response (UPR). It was observed that at high-altitude, pregnancies yield a low birth weight ∼100 g per1000 m of the climb. (Vague) It may involve variation in the events of energy-demanding, like protein synthesis. Prolonged hypobaric hypoxia causes placental ER stress, which in turn, moderates protein synthesis and reduces proliferation. Further, Cardiac hypertrophy by cytosolic Ca2+ raises and Ca2+/calmodulin, calcineurin stimulation, NF-AT3 pathway might be caused by an imbalance in Sarcoplasmic reticulum ER Ca2, might be adaptive in beginning but severe later.

Potential Therapeutic Targets of Curcumin, Most Abundant Active Compound of Turmeric Spice: Role in the Management of Various Types of Cancer

2020 ◽  
Vol 15 ◽  
Author(s):  
Saleh A. Almatroodi ◽  
Mansoor Ali Syed ◽  
Arshad Husain Rahmani
Keyword(s):  
Clinical Trials ◽  
Cancer Cells ◽  
Active Compound ◽  
Molecular Mechanisms ◽  
Human Subjects ◽  
Cell Signalling ◽  
Chemopreventive Agents ◽  
Signalling Molecules ◽  
Cancer Management ◽  
Induced Apoptosis

Background:: Curcumin, an active compound of turmeric spice is one of the most-studies natural compounds and have been widely recognized as chemopreventive agents. Several molecular mechanisms have been proven, curcumin and its analogs play a role in cancer prevention through modulating various cell signaling pathways as well as inhibition of carcinogenesis process. Objective:: To study the potential role of curcumin in the management of various types of cancer through modulating cell signalling molecules based on available literature and recent patents. Methods:: A wide-ranging literature survey was performed based on Scopus, PubMed, PubMed central and Google scholar for the implication of curcumin in cancer management along with special emphasis on human clinical trials. Moreover, patents were searched through www.google.com/patents, www.freepatentsonline.com and www.freshpatents.com. Result:: Recent studies based on cancer cells have proven that curcumin have potential effects against cancer cells, prevent the growth of cancer and act as cancer therapeutic agents. Besides, curcumin exerted anticancer effects through inducing apoptosis, activating tumor suppressor genes, cell cycle arrest, inhibiting tumor angiogenesis, initiation, promotion and progression stages of tumor. It was established that co-treatment of curcumin and anti-cancer drugs could induce apoptosis and also play a significant role in the suppression of the invasion and metastasis of cancer cells. Conclusion:: Accumulating evidences suggest that curcumin has potentiality to inhibit cancer growth, induced apoptosis and modulate various cell signalling pathways molecules. Well-designed clinical trials of curcumin based on human subjects are still needed to establish the bioavailability, mechanism of action, efficacy and safe dose in the management of various cancers.

scholarly journals The Integrated RNA Landscape of Renal Preconditioning against Ischemia-Reperfusion Injury

2020 ◽  
Vol 31 (4) ◽  
pp. 716-730 ◽  
Author(s):  
Marc Johnsen ◽  
Torsten Kubacki ◽  
Assa Yeroslaviz ◽  
Martin Richard Späth ◽  
Jannis Mörsdorf ◽  
...  
Keyword(s):  
Gene Expression ◽  
Reperfusion Injury ◽  
Caloric Restriction ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Hypoxic Preconditioning ◽  
Preventive Strategies ◽  
Gene Expression Signatures

BackgroundAlthough AKI lacks effective therapeutic approaches, preventive strategies using preconditioning protocols, including caloric restriction and hypoxic preconditioning, have been shown to prevent injury in animal models. A better understanding of the molecular mechanisms that underlie the enhanced resistance to AKI conferred by such approaches is needed to facilitate clinical use. We hypothesized that these preconditioning strategies use similar pathways to augment cellular stress resistance.MethodsTo identify genes and pathways shared by caloric restriction and hypoxic preconditioning, we used RNA-sequencing transcriptome profiling to compare the transcriptional response with both modes of preconditioning in mice before and after renal ischemia-reperfusion injury.ResultsThe gene expression signatures induced by both preconditioning strategies involve distinct common genes and pathways that overlap significantly with the transcriptional changes observed after ischemia-reperfusion injury. These changes primarily affect oxidation-reduction processes and have a major effect on mitochondrial processes. We found that 16 of the genes differentially regulated by both modes of preconditioning were strongly correlated with clinical outcome; most of these genes had not previously been directly linked to AKI.ConclusionsThis comparative analysis of the gene expression signatures in preconditioning strategies shows overlapping patterns in caloric restriction and hypoxic preconditioning, pointing toward common molecular mechanisms. Our analysis identified a limited set of target genes not previously known to be associated with AKI; further study of their potential to provide the basis for novel preventive strategies is warranted. To allow for optimal interactive usability of the data by the kidney research community, we provide an online interface for user-defined interrogation of the gene expression datasets (http://shiny.cecad.uni-koeln.de:3838/IRaP/).

scholarly journals Revising Endosomal Trafficking under Insulin Receptor Activation

2021 ◽  
Vol 22 (13) ◽  
pp. 6978
Author(s):  
Maria J. Iraburu ◽  
Tommy Garner ◽  
Cristina Montiel-Duarte
Keyword(s):  
Plasma Membrane ◽  
Tyrosine Kinase ◽  
Insulin Receptor ◽  
Molecular Mechanisms ◽  
Receptor Activation ◽  
Small Gtpases ◽  
Early Endosome ◽  
Tyrosine Kinase Receptors ◽  
Endosomal Trafficking ◽  
Cell Functions

The endocytosis of ligand-bound receptors and their eventual recycling to the plasma membrane (PM) are processes that have an influence on signalling activity and therefore on many cell functions, including migration and proliferation. Like other tyrosine kinase receptors (TKR), the insulin receptor (INSR) has been shown to be endocytosed by clathrin-dependent and -independent mechanisms. Once at the early endosome (EE), the sorting of the receptor, either to the late endosome (LE) for degradation or back to the PM through slow or fast recycling pathways, will determine the intensity and duration of insulin effects. Both the endocytic and the endosomic pathways are regulated by many proteins, the Arf and Rab families of small GTPases being some of the most relevant. Here, we argue for a specific role for the slow recycling route, whilst we review the main molecular mechanisms involved in INSR endocytosis, sorting and recycling, as well as their possible role in cell functions.

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