Biology subjects

Proschel, C.

Publications and source records attributed to Proschel, C..

5 recordsLinked to original sources

bioRxiv2024

Spinal Cord Injury Enhances Lung Inflammation and Exacerbates Immune Response After Acute Lung Injury

The severity of spinal cord injury (SCI) is closely tied to pulmonary function, especially in cases of higher SCI levels. Despite this connection, the underlying pathological mechanisms in the lungs post-SCI are not well understood. Previous research has established a connection between disrupted sympathetic regulation and splenocyte apoptosis in high thoracic SCI, leading to pulmonary dysfunction. The aim of this study was to investigate whether mice with low-level SCI exhibit increased susceptibility to acute lung injury by eliciting systemic inflammatory responses that operate independently of the sympathetic nervous system. Here, we employed T9 contusion SCI and exposed mice to aerosolized lipopolysaccharide (LPS) to simulate lung inflammation associated with acute respiratory distress syndrome (ARDS). Twenty-four hours post-LPS exposure, lung tissues and bronchoalveolar lavage (BAL) fluid were analyzed. LPS markedly induced proinflammatory gene expression (SAA3, IRG1, NLRP3, IL-1beta, MCP-1) and cytokine release (IL-1beta, IL-6, MCP-1) in SCI mice compared to controls, indicating an exaggerated inflammatory response. Infiltration of Ly6G/C positive neutrophils and macrophages was significantly higher in SCI mice lungs post-LPS exposure. Interestingly, spleen size and weight did not differ between control and SCI mice, suggesting that T9 SCI alone does not cause spleen atrophy. Notably, bone-marrow-derived macrophages (BMDMs) from SCI mice exhibited hyper-responsiveness to LPS. This study demonstrated an increase in lung inflammation and immune responses subsequent to low-level T9 SCI, underscoring the widespread influence of systemic inflammation post-SCI, especially pronounced in specific organs like the lungs. KEY POINTSO_LISpinal cord injury leads to increased lung permeability following LPS inhalation. C_LIO_LISpinal cord injury amplifies cytokine release after exposure to LPS. C_LIO_LISpinal cord injury affects bone marrow-derived macrophages, showing heightened glycolytic activity and inflammatory conditions. C_LI

immunology↗

bioRxiv2024

Drug-Induced p53 Activation Promotes Acinar Cell Identity and Prevents Pancreatic Cancer Initiation

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease, initiated predominantly by mutations in Kras, which induce acinar-to-ductal metaplasia (ADM) and subsequent formation of precursor lesions, such as pancreatic intraepithelial neoplasia (PanIN). Progression to PDAC is frequently associated with mutations in the tumor suppressor TP53, presumably via disrupting p53-mediated cellular senescence of PanINs. Whether TP53 also has tumor-suppressive activity in earlier phases of PDAC initiation has been less clear. In this study, we investigate the impact of pharmacological stabilization of the wild-type p53 protein on the formation of ADM in a KrasG12D-driven mouse model of PDAC. Our findings demonstrate that p53 stabilization via Nutlin-3a significantly reduces both ADM and PanIN formation by promoting the differentiation of ADM into acinar cells. This differentiation coincides with p53-dependent upregulation of the transcription factor Mist1 (Bhlha15), a critical inducer of acinar cell identity. Our results reveal a role for p53 in tissue repair and maintenance of homeostasis in tumor suppression and suggest pharmacological engagement of p53 as an intervention strategy to prevent PDAC initiation.

cancer biology↗

bioRxiv2023

Secondary structures that regulate mRNA translation provide insights for ASO-mediated modulation of cardiac hypertrophy

Translation of upstream open reading frames (uORFs) typically abrogates translation of main (m)ORFs. The molecular mechanism of uORF regulation in cells is not well understood. Here, we identified a double-stranded RNA (dsRNA) structure residing within the GATA4 uORF that augments uORF translation and inhibits mORF translation. Antisense oligonucleotides (ASOs) that disrupt this dsRNA structure promote mORF translation, while ASOs that base-pair immediately downstream (i.e., forming a bimolecular double-stranded region) of either the uORF or mORF start codon enhance uORF or mORF translation, respectively. Human cardiomyocytes and mice treated with a uORF-enhancing ASO showed reduced cardiac GATA4 protein levels and increased resistance to cardiomyocyte hypertrophy. We further show the general utility of uORF-dsRNA- or mORF- targeting ASO to regulate mORF translation for other mRNAs. Our work demonstrates a regulatory paradigm that controls translational efficiency and a useful strategy to alter protein expression and cellular phenotypes by targeting or generating dsRNA downstream of a uORF or mORF start codon. Bullet points for discoveriesO_LIdsRNA within GATA4 uORF activates uORF translation and inhibits mORF translation. C_LIO_LIASOs that target the dsRNA can either inhibit or enhance GATA4 mORF translation. C_LIO_LIASOs can be used to impede hypertrophy in human cardiomyocytes and mouse hearts. C_LIO_LIuORF- and mORF-targeting ASOs can be used to control translation of multiple mRNAs. C_LI

molecular biology↗

bioRxiv2021

Deletion or inhibition of astrocytic transglutaminase 2 promotes functional recovery after spinal cord injury

Following CNS injury astrocytes become "reactive" and exhibit pro-regenerative or harmful properties. However, the molecular mechanisms that cause astrocytes to adopt either phenotype are not well understood. Transglutaminase 2 (TG2) plays a key role in regulating the response of astrocytes to insults. Here we used mice in which TG2 was specifically deleted in astrocytes (Gfap-Cre+/-TG2fl/fl, referred to here as TG2-A-cKO) in a spinal cord contusion injury (SCI) model. Deletion of TG2 from astrocytes resulted in a significant improvement in motor function following SCI. GFAP and NG2 immunoreactivity, as well as number of SOX9 positive cells, were significantly reduced in TG2-A-cKO_mice. RNA-seq analysis of spinal cords from TG2-A-cKO and control mice 3 days postinjury identified thirty-seven differentially expressed genes, all of which were increased in TG2-A-cKO mice. Pathway analysis reveals a prevalence for fatty acid metabolism, lipid storage and energy pathways, which play essential roles in neuron-astrocyte metabolic coupling. Excitingly, treatment of wild type mice with the selective TG2 inhibitor VA4 significantly improved functional recovery after SCI, similar to what was observed using the genetic model. These findings indicate the use of TG2 inhibitors as a novel strategy for the treatment of SCI and other CNS injuries.

neuroscience↗

bioRxiv2021

Effect of knee joint loading on chondrocyte mechano-vulnerability and severity of post-traumatic osteoarthritis induced by ACL-injury in mice

ObjectiveThe objective of this study is to understand the role of altered in vivo mechanical environments in knee joints post anterior cruciate ligament (ACL)-injury in chondrocyte vulnerability against mechanical stimuli and in the progression of post-traumatic osteoarthritis (PT-OA). MethodsDifferential in vivo mechanical environments were induced by unilateral ACL-injury (uni-ACL-I) and bilateral ACL-injury (bi-ACL-I) in 8-week-old female C57BL/6 mice. The gait parameters, the mechano-vulnerability of in situ chondrocytes, Youngs moduli of cartilage extracellular matrix (ECM), and the histological assessment of OA severity (OARSI score) were compared between control and experimental groups at 0[~]8-weeks post-ACL-injury. ResultsWe found that bi-ACL-I mice experience higher joint-loading on their both injured limbs, but uni-ACL-I mice balance their joint-loading between injured and uninjured hind limbs resulting in a reduced joint-loading during gait. We also found that at 4- and 8-week post-injury the higher weight-bearing hind limbs (i.e., bi-ACL-I) had the increased area of chondrocyte death induced by impact loading and higher OARSI score than the lower weight-bearing limbs (uni-ACL-I). Additionally, we found that at 8-weeks post-injury the ECM became stiffer in bi-ACL-I joints and softer in uni-ACL-I joints. ConclusionsOur results show that ACL-injured limbs with lower in vivo joint-loading develops PT-OA significantly slower than injured limbs with higher joint-loading during gait. Our data also indicate that articular chondrocytes in severe PT-OA are more fragile from mechanical impacts than chondrocytes in healthy or mild PT-OA. Thus, preserving physiologic joint-loads on injured joints will reduce chondrocyte death post-injury and may delay PT-OA progression.

bioengineering↗