Biology subjects

Russo, I.

Publications and source records attributed to Russo, I..

4 recordsLinked to original sources

bioRxiv2025

Functional Impact of CYFIP2 RNA Editing on Actin Regulation, Axon Growth, and Spinogenesis

Cytoplasmic FMRP Interacting Protein 2 (CYFIP2) a component of the Wave Regulatory Complex (WRC), one of the most important players in regulating cellular actin dynamics. Interestingly, CYFIP2 transcript undergoes RNA editing, an epitranscriptomic modification catalysed by ADAR enzymes, that leads adenosine (A) to inosine (I) deamination. CYFIP2 editing in the coding sequence results in a K/E substitution at amino acid 320. The functional meaning of this regulation is still unknown. In this study, we aim at investigating the potential implication of CYFIP2 RNA editing related to actin dynamics during cell differentiation, axon development and synaptogenesis in neural cells. We have generated SH-SY5Y neuroblastoma cell lines in which CYFIP2 gene has been functionally inactivated by CRISPR-Cas9 technology. CYFIP2 KO cells showed profound actin filaments disorganisation and loss of the capability to differentiate into a neuronal-like phenotype. Overexpression of both CYFIP2 unedited (K) and edited (E) isoforms rescued normal capability. Finally, we took advantage of primary neuronal culture where endogenous CYFIP2 was knocked down by shRNA technology and CYFIP2 editing variants were overexpressed. While CYFIP2 KD cells reported a decrease in axon development and spine frequency, CYFIP2-E variants increase the number of axon branches, total axon length and dendritic spine frequency compared to either CYFIP2 KD cells or CYFIP-K variants. Overall, our work reveals for the first time a functional significance of the CYFIP2 K/E RNA editing process in regulating the spreading of neuronal axons during the initial stages of in-vitro development and the process of spinogenesis.

cell biology↗

bioRxiv2024

Extracellular Matrix Instability and Chronic Inflammation Underlie Maladaptive Right Ventricular Pressure Overload Remodeling and Failure in Male Mice

BackgroundRight ventricular dysfunction (RVD) portends increased death risk for heart failure (HF) and pulmonary arterial hypertension (PAH) patients, regardless of left ventricular function or etiology. In both, RVD arises from the chronic RV pressure overload, and represents advanced cardiopulmonary disease. RV remodeling responses and survival rates of HF and PAH patients, however, differ by sex. Men develop more severe RVD and die at younger ages than do women. Mechanistic details of this sexual dimorphism in RV remodeling are incompletely understood. We sought to elucidate the cardiac pathophysiology underlying the sex-specific RV remodeling phenotypes, RV failure (RVF) versus compensated RVD. MethodsWe subjected male (M-) and female (F-) adult mice to moderate pulmonary artery banding (PAB) for 9wks. Mice underwent serial echocardiography, cardiac MRI, RV pressure-volume loop recordings, histologic and molecular analyses. ResultsM-PAB developed severe RVD with RVF, increased RV collagen deposition and degradation, extracellular matrix (ECM) instability, and activation and recruitment of macrophages. Despite the same severity and chronicity of RV pressure overload, F-PAB had more stable ECM, lacked chronic inflammation, and developed mild RVD without RVF. ConclusionsECM destabilization and chronic activation of recruited macrophages are associated with maladaptive RV remodeling and RVF in male PAB mice. Adaptive RV remodeling of female PAB mice lacked these histopathologic changes. Our findings suggest that these two pathophysiologic processes likely contribute to the sexual dimorphism of RV pressure overload remodeling. Further mechanistic studies are needed to assess their pathogenic roles and potential as targets for RVD therapy and RVF prevention. CLINICAL PERSPECTIVE What is new?O_LIIn a mouse model of pure PH, males but not females showed an association between ECM instability, chronic inflammation with activation of recruited macrophages, and severe RV dysfunction and failure. C_LI What are the clinical implications?O_LIIn male HF and PH patients, enhancing ECM stability and countering the recruitment and activation of macrophages may help preserve RV function such that RVF can be prevented or delayed. Further preclinical mechanistic studies are needed to assess the therapeutic potential of such approaches. C_LI RESEARCH PERSPECTIVE What new question does this study raise? What question should be addressed next?O_LIWhat mechanisms regulate RV ECM stability and macrophage recruitment and activation in response to chronic RV pressure overload? Are these regulatory mechanisms dependent upon or independent of sex hormone signaling? C_LI

physiology↗

bioRxiv2021

Molecular Pathophysiology of Cardiac Injury and Cardiac Microthrombi in Fatal COVID-19: Insights from Clinico-histopathologic and Single Nuclei RNA Sequencing Analyses

Cardiac injury is associated with critical COVID-19, yet its etiology remains debated. To elucidate the pathogenic mechanisms of COVID-19-associated cardiac injury, we conducted a single-center prospective cohort study of 69 COVID-19 decedents. Of six cardiac histopathologic features, microthrombi was the most commonly detected (n=48, 70%). We tested associations of cardiac microthrombi with biomarkers of inflammation, cardiac injury, and fibrinolysis and with in-hospital antiplatelet therapy, therapeutic anticoagulation, and corticosteroid treatment, while adjusting for multiple clinical factors, including COVID-19 therapies. Higher peak ESR and CRP during hospitalization were independently associated with higher odds of microthrombi. Using single nuclei RNA-sequence analysis, we discovered an enrichment of pro-thrombotic/anti-fibrinolytic, extracellular matrix remodeling, and immune-potentiating signaling amongst cardiac fibroblasts in microthrombi-positive COVID-19 hearts relative to microthrombi-negative COVID-19. Non-COVID-19 non-failing hearts were used as reference controls. Our cumulative findings identify the specific transcriptomic changes in cardiac fibroblasts as salient features of COVID-19-associated cardiac microthrombi.

pathology↗

bioRxiv2017

Plasmodium falciparum dipeptidyl aminopeptidase 3 activity is important for efficient erythrocyte invasion.

Parasite egress from infected erythrocytes and invasion of new erythrocytes are essential for the exponential asexual replication of the malaria parasite, and both processes are regulated and mediated by proteases. The putative cysteine protease dipeptidyl aminopeptidase 3 (DPAP3) was previously suggested to be essential for parasite egress, but little is known about its biological function. Here, we demonstrate that DPAP3 has proteolytic activity, but contrary to previously studied DPAPs, removal of its prodomain is not required for activation. Interestingly, P. falciparum DPAP3 localizes to merozoite apical organelles from which it is secreted immediately before egress. Using a conditional knock out approach coupled to complementation studies with wild type or mutant DPAP3, we show that DPAP3 activity is critical for efficient RBC invasion and overall parasite replication, and demonstrate that it does not play a role in parasite egress. Overall, this study establishes DPAP3 as a key regulator of erythrocyte invasion.

microbiology↗