Biology subjects

Pascal, Q.

Publications and source records attributed to Pascal, Q..

3 recordsLinked to original sources

bioRxiv2026

Medical diagnostic radiation promotes murine Apc/Kras-driven colon carcinogenesis

Computed tomography (CT) is one of the most widely used diagnostic imaging modalities worldwide, yet the biological risks associated with such exposures remain incompletely understood. Here, we investigated the effects of clinically relevant low (25 mGy) and moderate (250 mGy) dose radiation exposures on colon carcinogenesis using in vivo KPC:APC transgenic mice and an ex vivo organoid system carrying inducible Apc and Kras driver mutations. While medical diagnostic radiation did not initiate carcinogenesis in wild-type and did not alter carcinogenesis in Apc-mutant tissues, it significantly promoted the progression of precancerous lesions in the presence of both mutations, especially when exposure occurred during early tumor initiation. Organoids derived from mice harboring both Apc and Kras mutations mirrored this susceptibility, exhibiting radiation-induced enlargement and activation of transcriptomic and proteomic programs associated with colorectal cancer, including cell-cycle dysregulation and mTORC1 pathway activation. These findings show that radiation doses within the range delivered by routine abdominal CT imaging can potentiate the carcinogenic processes in genetically predisposed cells, underscoring the need to consider individual susceptibility when evaluating the benefit-risk balance of medical diagnostic exposures.

Cancer Biology↗

bioRxiv2025

Disease progression is associated with differential neutrophil maturation in Mycobacterium tuberculosis-infected macaques

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is associated with clinical diversity and outcomes ranging from latent TB to active TB with distinct pathophysiologies. However, our understanding of the innate immune mechanisms related to the protection or progression of TB is limited. Among innate immune cells, the role of neutrophils is not fully elucidated, as they have been shown to exhibit both protective and harmful capacities in TB. This duality suggests possible differences in the nature and type of neutrophils present during the infection, generating different effects. We hypothesized that Mtb infection induces changes in neutrophil phenotype and function, influencing the infection outcomes. In order to decipher the link between neutrophils and disease progression, we used a cynomolgus macaque model of human TB. Based on clinical, bacteriological, and positron emission tomography with X-ray computed tomography (PET/CT) scan parameters, animals were stratified into two categories: animals that rapidly progressed to an active form of TB, designated as "fast progressors", and "slow progressors", which include low symptomatic or asymptomatic animals. In this study, we identified transcriptomic signatures of type I interferons and neutrophil degranulation in macaques with fast progression to active TB, which were not observed in animals with slow TB progression. Unsuppervised mass cytometry analysis showed the emergence of blood immature neutrophils (CD101+ CD10-) in fast progressing animals. In addition, circulating neutrophils from infected animals displayed capacities to modulate TNF- production and cytotoxic function of CD8 T cells in a contact-dependent mechanism. In the lungs, neutrophils infiltration in granuloma was higher in fast progressors and specifically located in the lymphocyte-rich region in lesions. These data suggest that specific neutrophil subpopulations are associated with disease progression. Furthermore, these data suggest that neutrophils may modulate CD8 T cells functions, which in turn contribute to the loss of Mtb control and fuel inflammation. AUTHORS SUMMARYMycobacterium tuberculosis (Mtb) infection in humans is associated with a wide range of disease progression, ranging from latent tuberculosis (TB) to active TB. Understanding immune factors leading to the control of the infection or disease progression is essential to identify new biomarkers and targets for host-directed therapies. Innate immunity plays an important role in inflammatory imbalance observed in active TB, among which neutrophils have both beneficial and detrimental roles. Using a macaque model developing a broad range of clinical forms of TB, we seek to understand the links between neutrophils and disease progression. We found that rapid progression to active TB leads to type I interferon signalling and neutrophil activation. In the blood, immature neutrophils were enriched when the disease progressed. In case of severe TB, Neutrophils also infiltrate a specific region of lung TB lesions rich in T lymphocytes, whereas they could modulate CD8 T cells. Our study provides new insights into the role of neutrophils in TB progression.

immunology↗

bioRxiv2023

Multi-target mode of action of Sulfodyne(R), a stabilized Sulforaphane, against pathogenic effects of SARS-CoV-2 infection

The coronavirus disease 2019 (COVID-19) due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has shown that, except vaccination, few therapeutics options for its treatment or prevention are available. Among the pathways that can be targeted for COVID-19 treatment, the Keap1/Nrf2 pathway seems of high interest as it regulates redox homeostasis and inflammation that are altered during SARS-CoV-2 infection. Here, we use three potent activators of the Keap1/Nrf2 pathway and showed that Sulfodyne(R), a stabilized natural Sulforaphane preparation with optimal bioavailability, had the highest antiviral activity in pulmonary or colonic epithelial cell lines even when added late after SARS-CoV-2 infection. This antiviral activity was not dependent on NRF2 activity but associated with action on ER stress and mTOR signaling that are activated during SARS-CoV-2 infection. Sulfodyne(R) also decreased the inflammatory response of epithelial cell lines infected by SARS-CoV-2 independently of SARS-CoV-2 replication and reduced the activation of human monocytes that are recruited after infection of epithelial cells by SARS-CoV-2. Administration of Sulfodyne(R) had little effects on SARS-CoV-2 replication in mice and hamsters infected with SARS-CoV-2 but significantly reduced weight loss and disease severity. Altogether, these results pinpoint the natural compound Sulfodyne(R) as a potent therapeutic agent of COVID-19 symptomatology. Author SummaryAccumulating evidence shows that oxidative stress coupled with the systemic inflammation contribute to COVID-19 pathogenesis. As the Keap1/Nrf2 pathway is the major regulator of redox homeostasis and promotes resolution of inflammation and as lung biopsies from COVID-19 patients showed a decreased NRF2 target gene signature, pharmacological agents that are known to activate NRF2 are good candidates for COVID-19 treatment. We show herein that Sulfodyne(R), an NRF2 activator that consists in a stabilized Sulforaphane preparation with optimal bioavailability, impairs SARS-CoV-2 replication in colonic or pulmonary epithelial cells. We show that this antiviral activity of Sulfodyne(R) is not dependent of NRF2 activation, characterize the pathways associated with the Sulfodyne(R) antiviral activity and show that Sulfodyne(R) displays multiple actions that result in a decrease of the inflammation associated with SARS-CoV-2 infection. Finally, we show that Sulfodyne(R) decreases the pathogenesis of mice or hamster infected with SARS-CoV-2. Overall, this study provides mechanistic explanations of the action of Sulfodyne(R) during SARS-CoV-2 infection and suggests that Sulfodyne(R) is a potential therapeutic agent of COVID-19 pathogenesis.

cell biology↗