microRNA‐mRNA network model in patients with achalasia

Palmieri, Orazio; Mazza, Tommaso; Bassotti, Gabrio; Merla, Antonio; Tolone, Salvatore; Biagini, Tommaso; Cuttitta, Antonello; Bossa, Fabrizio; Martino, Giuseppina; Latiano, Tiziana Pia; Corritore, Giuseppe; Gioffreda, Domenica; Palumbo, Orazio; Carella, Massimo; Panza, Anna; Andriulli, Angelo

doi:10.1111/nmo.13764

Cited by 14 publications

(11 citation statements)

References 36 publications

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“…It has been proven that IRAG1 has an important role in the pathophysiological function of the gastrointestinal tract. MRVI1—the human homologue of IRAG1—exhibits a role in the development of achalasia, which can cause injuries of the mucous membrane [ 13 , 14 ]. Therefore, it is possible that a loss of IRAG1 results in gastrointestinal lesions or microbleeding because no duodenal ulcerations—as described in global Prkg1 mutants—were detected in Irag1 -deficient mice ( Figure S9 ).…”

Section: Discussionmentioning

confidence: 99%

Loss of PKGIβ/IRAG1 Signaling Causes Anemia-Associated Splenomegaly

Majer

Prueschenk

Schlossmann

2021

IJMS

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Inositol 1,4,5triphosphate receptorassociated cGMP kinase substrate 1 (IRAG1) is a substrate protein of the NO/cGMP-signaling pathway and forms a ternary complex with the cGMPdependent protein kinase Iβ (PKGIβ) and the inositol triphosphate receptor I (IP3RI). Functional studies about IRAG1 exhibited that IRAG1 is specifically phosphorylated by the PKGIβ, regulating cGMPmediated IP3dependent Ca2+release. IRAG1 is widely distributed in murine tissues, e.g., in large amounts in smooth muscle-containing tissues and platelets, but also in lower amounts, e.g., in the spleen. The NO/cGMP/PKGI signaling pathway is important in several organ systems. A loss of PKGI causes gastrointestinal disorders, anemia and splenomegaly. Due to the similar tissue distribution of the PKGIβ to IRAG1, we investigated the pathophysiological functions of IRAG1 in this context. Global IRAG1KO mice developed gastrointestinal bleeding, anemiaassociated splenomegaly and iron deficiency. Additionally, Irag1deficiency altered the protein levels of some cGMP/PKGI signaling proteins—particularly a strong decrease in the PKGIβ—in the colon, spleen and stomach but did not change mRNAexpression of the corresponding genes. The present work showed that a loss of IRAG1 and the PKGIβ/IRAG1 signaling has a crucial function in the development of gastrointestinal disorders and anemia-associated splenomegaly. Furthermore, global Irag1deficient mice are possible in vivo model to investigate PKGIβ protein functions.

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Section: Discussionmentioning

confidence: 99%

Loss of PKGIβ/IRAG1 Signaling Causes Anemia-Associated Splenomegaly

Majer

Prueschenk

Schlossmann

2021

IJMS

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“…Creating network-based methods to model molecular systems is a rich area of study that capitalizes on several research fields, mainly transcriptomics, proteomics, and ecology, as well as in computer science applied to biological sciences ( Mazza et al, 2016 ; Piepoli et al, 2012 ; Mazzoccoli et al, 2016 ; Palmieri et al, 2020 ; Mazza et al, 2017 ; Capocefalo et al, 2018 ; Ballarini et al, 2009 ; Franco et al, 2006 ). However, these methods become especially fascinating when they are made to handle the massive amounts of data produced by enhanced or long-timescale MD simulations where, thanks to their vast potential, could help answer a variety of different questions, e.g., putative allosteric mechanism or protein-ligand interaction pathway, or also could be useful for challenging tasks like the identification of epistatic mutant sites ( Castellana et al, 2015 ; Castellana et al, 2017 ; 2021 ).…”

Section: Final Thoughts and Future Plansmentioning

confidence: 99%

Connecting the dots: A practical evaluation of web-tools for describing protein dynamics as networks

Petrizzelli

Biagini²,

Bianco³

et al. 2022

Front. Bioinform.

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Protein Structure Networks (PSNs) are a well-known mathematical model for estimation and analysis of the three-dimensional protein structure. Investigating the topological architecture of PSNs may help identify the crucial amino acid residues for protein stability and protein-protein interactions, as well as deduce any possible mutational effects. But because proteins go through conformational changes to give rise to essential biological functions, this has to be done dynamically over time. The most effective method to describe protein dynamics is molecular dynamics simulation, with the most popular software programs for manipulating simulations to infer interaction networks being RING, MD-TASK, and NAPS. Here, we compare the computational approaches used by these three tools—all of which are accessible as web servers—to understand the pathogenicity of missense mutations and talk about their potential applications as well as their advantages and disadvantages.

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“…Whole-exome sequencing studies and genetic association studies have found susceptibility genes (rs1705003, rs1126511, and rs28688207) for achalasia [ 23 , 24 ]. Transcriptomic studies in LES muscle found that molecules involved in immunity, skeletal, and muscular system development and nervous system development macro-processes were over-represented in achalasia patients [ 25 , 26 ]. However, there is still a lack of protein evidence that is more pronounced in this disease due to its direct functionality.…”

Section: Introductionmentioning

confidence: 99%

The molecular pathogenesis of achalasia: a paired lower esophageal sphincter muscle and serum 4D label-free proteomic study

Chen

Xing

et al. 2022

Gastroenterology Report

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Background Achalasia is a primary esophageal motility disorder with potential molecular pathogenesis remaining uncertain. This study aimed to identify the differentially expressed proteins and potential pathways among achalasia subtypes and controls to further reveal the molecular pathogenesis of achalasia. Methods Paired lower esophageal sphincter (LES) muscle and serum samples from 24 achalasia patients were collected. We also collected 10 normal serum samples from healthy controls and 10 normal LES muscle samples from esophageal cancer patients. The 4D label-free proteomic analysis was performed to identify the potential proteins and pathways involved in achalasia. Results Analysis of Similarities showed distinct proteomic patterns of serum and muscle samples between achalasia patients and controls (both P < 0.05). Functional enrichment analysis suggested that these differentially expressed proteins were immunity-, infection-, inflammation-, and neurodegeneration-associated. The mfuzz analysis in LES specimens showed that proteins involved in the extracellular matrix–receptor interaction increased sequentially between the control group, type III, type II, and type I achalasia. Only 26 proteins altered in the same directions in serum and muscle samples. Conclusions This first 4D label-free proteomic study of achalasia indicated that there were specific protein alterations in both the serum and muscle of achalasia, involving immunity, inflammation, infection, and neurodegeneration pathways. Distinct protein clusters between types I, II, and III revealed the potential molecular pathways associated with different disease stages. Analysis of proteins changed in both muscle and serum samples highlighted the importance of further studies on LES muscle and revealed potential autoantibodies.

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microRNA‐mRNA network model in patients with achalasia

Cited by 14 publications

References 36 publications

Loss of PKGIβ/IRAG1 Signaling Causes Anemia-Associated Splenomegaly

Loss of PKGIβ/IRAG1 Signaling Causes Anemia-Associated Splenomegaly

Connecting the dots: A practical evaluation of web-tools for describing protein dynamics as networks

The molecular pathogenesis of achalasia: a paired lower esophageal sphincter muscle and serum 4D label-free proteomic study

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