scholarly journals Transcriptomic analysis of equine chorioallantois reveals immune networks and molecular mechanisms involved in nocardioform placentitis

2021 ◽  
Vol 52 (1) ◽  
Author(s):  
Hossam El-Sheikh Ali ◽  
Shavahn C. Loux ◽  
Laura Kennedy ◽  
Kirsten E. Scoggin ◽  
Pouya Dini ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Glucose Transporter ◽  
Inflammasome Activation ◽  
Molecular Pathways ◽  
Toll Like Receptor ◽  
Inflammatory Signaling ◽  
Leukocytic Infiltration ◽  
Apoptosis Pathways ◽  
Placental Inflammation ◽  
First Time

AbstractNocardioform placentitis (NP) continues to result in episodic outbreaks of abortion and preterm birth in mares and remains a poorly understood disease. The objective of this study was to characterize the transcriptome of the chorioallantois (CA) of mares with NP. The CA were collected from mares with confirmed NP based upon histopathology, microbiological culture and PCR for Amycolatopsis spp. Samples were collected from the margin of the NP lesion (NPL, n = 4) and grossly normal region (NPN, n = 4). Additionally, CA samples were collected from normal postpartum mares (Control; CRL, n = 4). Transcriptome analysis identified 2892 differentially expressed genes (DEGs) in NPL vs. CRL and 2450 DEGs in NPL vs. NPN. Functional genomics analysis elucidated that inflammatory signaling, toll-like receptor signaling, inflammasome activation, chemotaxis, and apoptosis pathways are involved in NP. The increased leukocytic infiltration in NPL was associated with the upregulation of matrix metalloproteinase (MMP1, MMP3, and MMP8) and apoptosis-related genes, such as caspases (CASP3 and CASP7), which could explain placental separation associated with NP. Also, NP was associated with downregulation of several placenta-regulatory genes (ABCG2, GCM1, EPAS1, and NR3C1), angiogenesis-related genes (VEGFA, FLT1, KDR, and ANGPT2), and glucose transporter coding genes (GLUT1, GLUT10, and GLUT12), as well as upregulation of hypoxia-related genes (HIF1A and EGLN3), which could elucidate placental insufficiency accompanying NP. In conclusion, our findings revealed for the first time, the key regulators and mechanisms underlying placental inflammation, separation, and insufficiency during NP, which might lead to the development of efficacious therapies or diagnostic aids by targeting the key molecular pathways.

Transcriptomic analysis reveals the key regulators and molecular mechanisms underlying myometrial activation during equine placentitis†

2020 ◽  
Vol 102 (6) ◽  
pp. 1306-1325 ◽  
Author(s):  
H El-Sheikh Ali ◽  
Y L Boakari ◽  
S C Loux ◽  
P Dini ◽  
K E Scoggin ◽  
...  
Keyword(s):  
Preterm Labor ◽  
Molecular Mechanisms ◽  
Enrichment Analysis ◽  
Toll Like Receptor ◽  
Inflammatory Signaling ◽  
Transmembrane Receptors ◽  
Upstream Regulator ◽  
Apoptosis Pathways ◽  
Transcription Regulators ◽  
Upstream Regulators

Abstract The key event in placentitis-induced preterm labor is myometrial activation with the subsequent initiation of labor. However, the molecular mechanisms underlying myometrial activation are not fully understood in the mares. Therefore, the equine myometrial transcriptome was characterized during placentitis (290.0 ± 1.52 days of GA, n = 5) and the prepartum period (330 days of GA, n = 3) in comparison to normal pregnant mares (289.8 ± 2.18 days of GA, n = 4). Transcriptome analysis identified 596 and 290 DEGs in the myometrium during placentitis and the prepartum period, respectively, with 138 DEGs in common. The placentitis DEGs included eight genes (MMP1, MMP8, S100A9, S100A8, PI3, APOBEC3Z1B, RETN, and CXCL2) that are exclusively expressed in the inflamed myometrium. Pathway analysis elucidated that inflammatory signaling, Toll-like receptor signaling, and apoptosis pathways dominate myometrial activation during placentitis. The prepartum myometrium was associated with overexpression of inflammatory signaling, oxidative stress, and 5-hydroxytryptamine degradation. Gene ontology enrichment analysis identified several chemoattractant factors in the myometrium during placentitis and prepartum period, including CCL2, CXCL1, CXCL3, and CXCL6 in common. Upstream regulator analysis revealed 19 potential upstream regulators in placentitis dataset including transcription regulators (E2F1, FOXM1, HIF1A, JUNB, NFKB1A, and STAT1), transmembrane receptors (FAS, ICAM1, SELP, TLR2, and TYROBP), growth factors (HGF and TGFB3), enzymes (PTGS2 and PRKCP), and others (S100A8, S100A9, CD44, and C5AR1). Additionally, three upstream regulators (STAT3, EGR1, and F2R) were identified in the prepartum dataset. These findings revealed the key regulators and pathways underlying myometrial activation during placentitis, which aid in understanding the disease and facilitate the development of efficacious therapies.

Transcriptomic analysis of equine placenta reveals key regulators and pathways involved in ascending placentitis†

2020 ◽  
Author(s):  
Hossam El-Sheikh Ali ◽  
Pouya Dini ◽  
Kirsten Scoggin ◽  
Shavahn Loux ◽  
Carleigh Fedorka ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Immune Cell ◽  
Diagnostic Tools ◽  
Control Group ◽  
Aberrant Expression ◽  
Upstream Regulator ◽  
Placental Inflammation ◽  
First Time ◽  
Cell Chemotaxis

Abstract Improved understanding of the molecular mechanisms underlying ascending equine placentitis holds the potential for the development of new diagnostic tools and therapies to forestall placentitis-induced preterm labor. The current study characterized the equine placental transcriptome (chorioallantois [CA] and endometrium [EN]) during placentitis (placentitis group, n = 6) in comparison to gestationally-matched controls (control group, n = 6). Transcriptome analysis identified 2953 and 805 differentially expressed genes in CA and EN during placentitis, respectively. Upstream regulator analysis revealed the central role of toll-like receptors (TLRs) in triggering the inflammatory signaling, and consequent immune-cell chemotaxis. Placentitis was associated with the upregulation of matrix metalloproteinase (MMP1, MMP2, and MMP9) and apoptosis-related genes such as caspases (CASP3, CASP4, and CASP7) in CA. Also, placentitis was associated with downregulation of transcripts coding for proteins essential for placental steroidogenesis (SRD5A1 and AKR1C1), progestin signaling (PGRMC1 and PXR) angiogenesis (VEGFA, VEGFR2, and VEGFR3), and nutrient transport (GLUT12 and SLC1A4), as well as upregulation of hypoxia-related genes (HIF1A and EGLN3), which could explain placental insufficiency during placentitis. Placentitis was also associated with aberrant expression of several placenta-regulatory genes, such as PLAC8, PAPPA, LGALS1, ABCG2, GCM1, and TEPP, which could negatively affect placental functions. In conclusion, our findings revealed for the first time the key regulators and mechanisms underlying placental inflammation, separation, and insufficiency during equine placentitis, which might lead to the development of efficacious therapies or diagnostic aids by targeting the key molecular pathways.

scholarly journals Sirt1 restrains lung inflammasome activation in a murine model of sepsis

2015 ◽  
Vol 308 (8) ◽  
pp. L847-L853 ◽  
Author(s):  
Rong Gao ◽  
Zhongsen Ma ◽  
Yuxin Hu ◽  
Jiao Chen ◽  
Sreerama Shetty ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Cecal Ligation ◽  
High Mobility ◽  
The Elderly ◽  
Organ Injury ◽  
Inflammasome Activation ◽  
Acute Lung Inflammation ◽  
Inflammatory Signaling ◽  
Proinflammatory Mediators

Excessive inflammation is a major cause of organ damage during sepsis. The elderly are highly susceptible to sepsis-induced organ injury. Sirt1 expression is reduced during aging. In the present study, we investigated the role of Sirt1, a histone deacetylase, in controlling inflammatory responses in a murine sepsis model induced by cecal ligation and puncture (CLP). We examined lung inflammatory signaling in inducible Sirt1 knockout (Sirt1−/−) mice and wild-type littermates (Sirt1+/+) after CLP. Our results demonstrated that Sirt1 deficiency led to severe lung inflammatory injury. To further investigate molecular mechanisms of Sirt1 regulation of lung inflammatory responses in sepsis, we conducted a series of experiments to assess lung inflammasome activation after CLP. We detected increased lung inflammatory signaling including NF-κB, signal transducer and activator of transcription 3, and ERK1/2 activation in Sirt1−/− mice after CLP. Furthermore, inflammasome activity was increased in Sirt1−/− mice after CLP, as demonstrated by increased IL-1β and caspase-7 cleavage and activation. Aggravated inflammasome activation in Sirt1−/− mice was associated with the increased production of lung proinflammatory mediators, including ICAM-1 and high-mobility group box 1, and further disruption of tight junctions and adherens junctions, as demonstrated by dramatic reduction of lung claudin-1 and vascular endothelial-cadherin expression, which was associated with the upregulation of matrix metallopeptidase 9 expression. In summary, our results suggest that Sirt1 suppresses acute lung inflammation during sepsis by controlling inflammasome activation pathway.

scholarly journals COVID-19 patients upregulate toll-like receptor 4-mediated inflammatory signaling that mimics bacterial sepsis

2020 ◽  
Author(s):  
Kyung Mok Sohn ◽  
Sung-Gwon Lee ◽  
Hyeon Ji Kim ◽  
Shinhyea Cheon ◽  
Hyeongseok Jeong ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Mononuclear Cells ◽  
Severe Illness ◽  
Toll Like Receptor ◽  
Therapeutic Approaches ◽  
Bacterial Sepsis ◽  
Inflammatory Signaling ◽  
Toll Like Receptor 4 ◽  
Peripheral Blood Mononuclear ◽  
Tlr4 Ligand

AbstractObservational studies of the ongoing coronavirus disease 2019 (COVID-19) outbreak suggest that a cytokine storm is involved in the pathogenesis of severe illness. However, the molecular mechanisms underlying the altered pathological inflammation in COVID-19 are largely unknown. We report here that toll-like receptor (TLR) 4-mediated inflammatory signaling molecules are upregulated in peripheral blood mononuclear cells (PBMCs) from COVID-19 patients, compared with healthy controls. Among the most highly increased inflammatory mediators in severe/critically ill patients, S100A9, an alarmin and TLR4 ligand, was found as a noteworthy biomarker, because it inversely correlated with the serum albumin levels. These data support a link between TLR4 signaling and pathological inflammation during COVID-19 and contribute to develop therapeutic approaches through targeting TLR4-mediated inflammation.

scholarly journals A new organotypic model of synaptic competition reveals activity-dependent localization of C1q

2017 ◽  
Author(s):  
Ryuta Koyama ◽  
Yuwen Wu ◽  
Allison R. Bialas ◽  
Andrew Thompson ◽  
Christina A. Welsh ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Neural Circuits ◽  
Ex Vivo ◽  
Molecular Pathways ◽  
Synapse Elimination ◽  
Synaptic Competition ◽  
Coculture Model ◽  
First Time ◽  
Activity Dependent

AbstractImmature neural circuits undergo synaptic refinement, in which activity-dependent competition between synapses results in pruning of inappropriate connections and maintenance of appropriate ones. A longstanding question is how neuronal activity eliminates specific synapses based on their strength. The technical challenges of in vivo studies have made it difficult to identify a molecular link between decreased activity and synapse elimination. We developed an organotypic coculture model of the mouse retinogeniculate system that facilitates real-time imaging and elucidation of molecular mechanisms underlying the removal of less active synapses during synaptic competition. Using this model we show for the first time that complement component C1q is necessary for activity-dependent synaptic competition and preferentially localizes to less active, competing presynaptic inputs. In conjunction with classic in vivo and ex vivo models, this coculture model is a new tool to reveal molecular pathways underlying CNS circuit refinement.

TAMM HORSFALL PROTEIN: THE MEN BEHIND THE EPONYM

2019 ◽  
Vol 23 (2) ◽  
pp. 117-119 ◽  
Author(s):  
D. N. Paskalev ◽  
B. T. Galunska ◽  
D. Petkova-Valkova
Keyword(s):  
Viral Replication ◽  
Research Team ◽  
Molecular Mechanisms ◽  
Thick Ascending Limb ◽  
Rockefeller Institute ◽  
The Usa ◽  
Natural Inhibitor ◽  
Simplex Virus ◽  
First Time ◽  
New Protein

Tamm–Horsfall Protein (uromodulin) is named after Igor Tamm and Franc Horsfall Jr who described it for the first time in 1952. It is a glycoprotein, secreted by the cells in the thick ascending limb of the loop of Henle. This protein will perform a number of important pathophysiological functions, including protection against uroinfections, especially caused by E. Сoli, and protection against formation of calcium concernments in the kidney. Igor Tamm (1922-1995) is an outstanding cytologist, virologist and biochemist. He is one of the pioneers in the study of viral replication. He was born in Estonia and died in the USA. In 1964 he was elected for a professorship in Rockefeller Institute for Medical Research, where has been working continuously. Since 1959, he became a head of the virology lab established by his mentor and co-author Franc Horsfall. In the course of studies on the natural inhibitor of viral replication, Tamm and Horsfall isolated and characterized biochemically a new protein named after their names. Franc Lappin Horsfall Jr (1906-1971) was a well-known clinician and virologist with remarkable achievements in internal medicine. He was born and died in the USA. He worked in the Rockefeller Hospital from 1934 to 1960, then in the Center for Cancer Research at the Sloan-Kettering Institute. Here he was a leader of a research team studying the molecular mechanisms of immunity, the effects of chemotherapy with benzimidazole compounds (together with I. Tamm), coxsackie viruses, herpes simplex virus, etc. 

scholarly journals The correlation between lncRNAs and Helicobacter pylori in gastric cancer

2019 ◽  
Vol 77 (9) ◽  
Author(s):  
Narges Dastmalchi ◽  
Seyed Mahdi Banan Khojasteh ◽  
Mirsaed Miri Nargesi ◽  
Reza Safaralizadeh
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Molecular Mechanisms ◽  
Gastrointestinal Diseases ◽  
Mechanisms Of Action ◽  
Molecular Pathways ◽  
Gastric Diseases ◽  
Non Coding Rnas ◽  
H Pylori ◽  
The Relationship

ABSTRACT Helicobacter pylori infection performs a key role in gastric tumorigenesis. Long non-coding RNAs (lncRNAs) have demonstrated a great potential to be regarded as effective malignancy biomarkers for various gastrointestinal diseases including gastric cancer (GC). The present review highlights the relationship between lncRNAs and H. pylori in GC. Several studies have examined not only the involvement of lncRNAs in H. pylori-associated GC progression but also their molecular mechanisms of action. Among the pertinent studies, some have addressed the effects of H. pylori infection on modulatory networks of lncRNAs, while others have evaluated the effects of changes in the expression level of lncRNAs in H. pylori-associated gastric diseases, especially GC. The relationship between lncRNAs and H. pylori was found to be modulated by various molecular pathways.

scholarly journals ZBP1 promotes LPS-induced cell death and IL-1β release via RHIM-mediated interactions with RIPK1

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hayley I. Muendlein ◽  
Wilson M. Connolly ◽  
Zoie Magri ◽  
Irina Smirnova ◽  
Vladimir Ilyukha ◽  
...  
Keyword(s):  
Immune Response ◽  
Cell Death ◽  
Complex Formation ◽  
Complex I ◽  
Yersinia Pseudotuberculosis ◽  
Caspase 8 ◽  
Inflammasome Activation ◽  
Inflammatory Signaling ◽  
Complex Ii ◽  
Dependent Model

AbstractInflammation and cell death are closely linked arms of the host immune response to infection, which when carefully balanced ensure host survival. One example of this balance is the tightly regulated transition from TNFR1-associated pro-inflammatory complex I to pro-death complex II. By contrast, here we show that a TRIF-dependent complex containing FADD, RIPK1 and caspase-8 (that we have termed the TRIFosome) mediates cell death in response to Yersinia pseudotuberculosis and LPS. Furthermore, we show that constitutive binding between ZBP1 and RIPK1 is essential for the initiation of TRIFosome interactions, caspase-8-mediated cell death and inflammasome activation, thus positioning ZBP1 as an effector of cell death in the context of bacterial blockade of pro-inflammatory signaling. Additionally, our findings offer an alternative to the TNFR1-dependent model of complex II assembly, by demonstrating pro-death complex formation reliant on TRIF signaling.

scholarly journals Molecular Pathways Involved in the Development of Congenital Erythrocytosis

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1150
Author(s):  
Jana Tomc ◽  
Nataša Debeljak
Keyword(s):  
Signal Transduction ◽  
Iron Homeostasis ◽  
Molecular Mechanisms ◽  
Oxygen Affinity ◽  
Molecular Pathways ◽  
Disease Development ◽  
Post Translational Modifications ◽  
Hemoglobin Oxygen Affinity ◽  
Insight Into ◽  
Idiopathic Erythrocytosis

Patients with idiopathic erythrocytosis are directed to targeted genetic testing including nine genes involved in oxygen sensing pathway in kidneys, erythropoietin signal transduction in pre-erythrocytes and hemoglobin-oxygen affinity regulation in mature erythrocytes. However, in more than 60% of cases the genetic cause remains undiagnosed, suggesting that other genes and mechanisms must be involved in the disease development. This review aims to explore additional molecular mechanisms in recognized erythrocytosis pathways and propose new pathways associated with this rare hematological disorder. For this purpose, a comprehensive review of the literature was performed and different in silico tools were used. We identified genes involved in several mechanisms and molecular pathways, including mRNA transcriptional regulation, post-translational modifications, membrane transport, regulation of signal transduction, glucose metabolism and iron homeostasis, which have the potential to influence the main erythrocytosis-associated pathways. We provide valuable theoretical information for deeper insight into possible mechanisms of disease development. This information can be also helpful to improve the current diagnostic solutions for patients with idiopathic erythrocytosis.

scholarly journals Crosstalk between Long-Term Sublethal Oxidative Stress and Detrimental Inflammation as Potential Drivers for Age-Related Retinal Degeneration

Antioxidants ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 25
Author(s):  
Lara Macchioni ◽  
Davide Chiasserini ◽  
Letizia Mezzasoma ◽  
Magdalena Davidescu ◽  
Pier Luigi Orvietani ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Molecular Mechanisms ◽  
Age Related Macular Degeneration ◽  
Inflammasome Activation ◽  
Related Factor ◽  
Nuclear Factor ◽  
Rpe Cells ◽  
Age Related ◽  
Oxidative Insult

Age-related retinal degenerations, including age-related macular degeneration (AMD), are caused by the loss of retinal pigmented epithelial (RPE) cells and photoreceptors. The pathogenesis of AMD, deeply linked to the aging process, also involves oxidative stress and inflammatory responses. However, the molecular mechanisms contributing to the shift from healthy aging to AMD are still poorly understood. Since RPE cells in the retina are chronically exposed to a pro-oxidant microenvironment throughout life, we simulated in vivo conditions by growing ARPE-19 cells in the presence of 10 μM H2O2 for several passages. This long-term oxidative insult induced senescence in ARPE-19 cells without affecting cell proliferation. Global proteomic analysis revealed a dysregulated expression in proteins involved in antioxidant response, mitochondrial homeostasis, and extracellular matrix organization. The analyses of mitochondrial functionality showed increased mitochondrial biogenesis and ATP generation and improved response to oxidative stress. The latter, however, was linked to nuclear factor-κB (NF-κB) rather than nuclear factor erythroid 2–related factor 2 (Nrf2) activation. NF-κB hyperactivation also resulted in increased pro-inflammatory cytokines expression and inflammasome activation. Moreover, in response to additional pro-inflammatory insults, senescent ARPE-19 cells underwent an exaggerated inflammatory reaction. Our results indicate senescence as an important link between chronic oxidative insult and detrimental chronic inflammation, with possible future repercussions for therapeutic interventions.

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