Marina Francis

All Publications

• Novel Role for SMPDL3b in Radiation Nephropathy Francis, M. S., Ahmad, A., Bodgi, L., Fornoni, A., Marples, B., Zeidan, Y. ELSEVIER SCIENCE INC. 2024: E360

  View details for Web of Science ID 001325892301125

• SMPDL3b modulates radiation-induced DNA damage response in renal podocytes FASEB JOURNAL Francis, M., Ahmad, A., Bodgi, L., Azzam, P., Youssef, T., Abou Daher, A., Eid, A. A., Fornoni, A., Pollack, A., Marples, B., Zeidan, Y. H. 2022; 36 (10): e22545

  Abstract

  The kidneys are radiosensitive and dose-limiting organs for radiotherapy (RT) targeting abdominal and paraspinal tumors. Excessive radiation doses to the kidneys ultimately lead to radiation nephropathy. Our prior work unmasked a novel role for the lipid-modifying enzyme, sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b), in regulating the response of renal podocytes to radiation injury. In this study, we investigated the role of SMPDL3b in DNA double-strand breaks (DSBs) repair in vitro and in vivo. We assessed the kinetics of DSBs recognition and repair along with the ATM pathway and nuclear sphingolipid metabolism in wild-type (WT) and SMPDL3b overexpressing (OE) human podocytes. We also assessed the extent of DNA damage repair in SMPDL3b knock-down (KD) human podocytes, and C57BL6 WT and podocyte-specific SMPDL3b-knock out (KO) mice after radiation injury. We found that SMPDL3b overexpression enhanced DSBs recognition and repair through modulating ATM nuclear shuttling. OE podocytes were protected against radiation-induced apoptosis by increasing the phosphorylation of p53 at serine 15 and attenuating subsequent caspase-3 cleavage. SMPDL3b overexpression prevented radiation-induced alterations in nuclear ceramide-1-phosphate (C1P) and ceramide levels. Interestingly, exogenous C1P pretreatment radiosensitized OE podocytes by delaying ATM nuclear foci formation and DSBs repair. On the other hand, SMPDL3b knock-down, in vitro and in vivo, induced a significant delay in DSBs repair. Additionally, increased activation of apoptosis was induced in podocytes of SMPDL3b-KO mice compared to WT mice at 24 h post-irradiation. Together, our results unravel a novel role for SMPDL3b in radiation-induced DNA damage response. The current work suggests that SMPDL3b modulates nuclear sphingolipid metabolism, ATM nuclear shuttling, and DSBs repair.

  View details for DOI 10.1096/fj.202100186RR

  View details for Web of Science ID 000853121100001

  View details for PubMedID 36094323

  View details for PubMedCentralID PMC11934431

• Crosstalk Between SMPDL3b and NADPH Oxidases Mediates Radiation-Induced Damage of Renal Podocytes FRONTIERS IN MEDICINE Azzam, P., Francis, M., Youssef, T., Mroueh, M., Abou Daher, A., Eid, A. A., Fornoni, A., Marples, B., Zeidan, Y. H. 2021; 8: 732528

  Abstract

  Patients undergoing radiotherapy (RT) for various tumors localized in the abdomen or pelvis often suffer from radiation nephrotoxicity as collateral damage. Renal podocytes are vulnerable targets for ionizing radiation and contribute to radiation-induced nephropathies. Our prior work previously highlighted the importance of the lipid-modifying enzyme sphingomyelinase acid phosphodiesterase like 3b (SMPDL3b) in modulating the radiation response in podocytes and glomerular endothelial cells. Hereby, we investigated the interplay between SMPDL3b and oxidative stress in mediating radiation injury in podocytes. We demonstrated that the overexpression of SMPDL3b in cultured podocytes (OE) reduced superoxide anion generation and NADPH oxidase activity compared to wild-type cells (WT) post-irradiation. Furthermore, OE podocytes showed downregulated levels of NOX1 and NOX4 after RT. On the other hand, treatment with the NOX inhibitor GKT improved WTs' survival post-RT and restored SMPDL3b to basal levels. in vivo, the administration of GKT restored glomerular morphology and decreased proteinuria in 26-weeks irradiated mice. Taken together, these results suggest a novel role for NOX-derived reactive oxygen species (ROS) upstream of SMPDL3b in modulating the response of renal podocytes to radiation.

  View details for DOI 10.3389/fmed.2021.732528

  View details for Web of Science ID 000717244100001

  View details for PubMedID 34660640

  View details for PubMedCentralID PMC8511442

• Radiation-induced neuropathies in head and neck cancer: prevention and treatment modalities ECANCERMEDICALSCIENCE Azzam, P., Mroueh, M., Francis, M., Abou Daher, A., Zeidan, Y. H. 2020; 14: 1133

  Abstract

  Head and neck cancer (HNC) is the sixth most common human malignancy with a global incidence of 650,000 cases per year. Radiotherapy (RT) is commonly used as an effective therapy to treat tumours as a definitive or adjuvant treatment. Despite the substantial advances in RT contouring and dosage delivery, patients suffer from various radiation-induced complications, among which are toxicities to the nervous tissues in the head and neck area. Radiation-mediated neuropathies manifest as a result of increased oxidative stress-mediated apoptosis, neuroinflammation and altered cellular function in the nervous tissues. Eventually, molecular damage results in the formation of fibrotic tissues leading to susceptible loss of function of numerous neuronal substructures. Neuropathic sequelae following irradiation in the head and neck area include sensorineural hearing loss, alterations in taste and smell functions along with brachial plexopathy, and cranial nerves palsies. Numerous management options are available to relieve radiation-associated neurotoxicities notwithstanding treatment alternatives that remain restricted with limited benefits. In the scope of this review, we discuss the use of variable management and therapeutic modalities to palliate common radiation-induced neuropathies in head and neck cancers.

  View details for DOI 10.3332/ecancer.2020.1133

  View details for Web of Science ID 000587365900001

  View details for PubMedID 33281925

  View details for PubMedCentralID PMC7685771

• Modulation of DNA Damage Response by Sphingolipid Signaling: An Interplay that Shapes Cell Fate INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Francis, M., Abou Daher, A., Azzam, P., Mroueh, M., Zeidan, Y. H. 2020; 21 (12)

  Abstract

  Although once considered as structural components of eukaryotic biological membranes, research in the past few decades hints at a major role of bioactive sphingolipids in mediating an array of physiological processes including cell survival, proliferation, inflammation, senescence, and death. A large body of evidence points to a fundamental role for the sphingolipid metabolic pathway in modulating the DNA damage response (DDR). The interplay between these two elements of cell signaling determines cell fate when cells are exposed to metabolic stress or ionizing radiation among other genotoxic agents. In this review, we aim to dissect the mediators of the DDR and how these interact with the different sphingolipid metabolites to mount various cellular responses.

  View details for DOI 10.3390/ijms21124481

  View details for Web of Science ID 000549412000001

  View details for PubMedID 32599736

  View details for PubMedCentralID PMC7349968

• Modulation of radiation-induced damage of human glomerular endothelial cells by SMPDL3B FASEB JOURNAL Abou Daher, A., Francis, M., Azzam, P., Ahmad, A., Eid, A. A., Fornoni, A., Marples, B., Zeidan, Y. H. 2020; 34 (6): 7915-7926

  Abstract

  The intracellular molecular pathways involved in radiation-induced nephropathy are still poorly understood. Glomerular endothelial cells are key components of the structure and function of the glomerular filtration barrier but little is known about the mechanisms implicated in their injury and repair. The current study establishes the response of immortalized human glomerular endothelial cells (GEnC) to ionizing radiation (IR). We investigated the role of sphingolipids and the lipid-modifying enzyme sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b) in radiation-induced GEnC damage. After delivering a single dose of radiation, long and very-long-chain ceramide species, and the expression levels of SMPDL3b were elevated. In contrast, levels of ceramide-1-phosphate (C1P) dropped in a time-dependent manner although mRNA and protein levels of ceramide kinase (CERK) remained stable. Treatment with C1P or knocking down SMPDL3b partially restored cell survival and conferred radioprotection. We also report a novel role for the NADPH oxidase enzymes (NOXs), namely NOX1, and NOX-derived reactive oxygen species (ROS) in radiation-induced GEnC damage. Subjecting cultured endothelial cells to radiation was associated with increased NOX activity and superoxide anion generation. Silencing NOX1 using NOX1-specific siRNA mitigated radiation-induced oxidative stress and cellular injury. In addition, we report a novel connection between NOX and SMPDL3b. Treatment with the NOX inhibitor, GKT, decreased radiation-induced cellular injury and restored SMPDL3b basal levels of expression. Our findings indicate the importance of SMPDL3b as a potential therapeutic target in radiation-induced kidney damage.

  View details for DOI 10.1096/fj.201902179R

  View details for Web of Science ID 000526104200001

  View details for PubMedID 32293077

  View details for PubMedCentralID PMC11753461