Biology subjects

Baumel-Alterzon, S.

Publications and source records attributed to Baumel-Alterzon, S..

4 recordsLinked to original sources

bioRxiv2025

Mechanistic Link Between Glyoxalase 1 Expression and Methylglyoxal-Induced Oncogenic Stress in Prostate Cancer

Prostate cancer (PCa) is the second leading cause of cancer-related death in American men, with African American/Black (AA/B) men experiencing higher incidence and mortality than European American (EA) men. Obesity, which disproportionately affects AA/B men, is linked to increased PCa mortality, potentially through metabolic dysregulation. We hypothesize that methylglyoxal (MG), a reactive byproduct of glucose, lipid, and protein metabolism that is elevated in obesity, contributes to PCa progression. MG forms covalent adducts on DNA, RNA, and protein. We found that MG-adducts are elevated in AA/B men with PCa compared to EA men with PCa, as well as men without PCa. AA/B men with PCa had a higher frequency of SNP rs1049346 in glyoxalase 1 (GLO1), the primary MG detoxification enzyme. PCa cell lines from EA (C4-2) and AA/B (MDA-PCa-2b) men showed differential rs1049346 status, with C4-2 cells heterozygous and MDA-PCa-2b cells homozygous for the variant. This was associated with altered GLO1 expression and activity, with MDA-PCa-2b cells exhibiting reduced GLO1 function and increased MG-adducts compared to C4-2 cells. MG altered DNA repair and RNA processing pathways and induced distinct metabolic shifts in MDA-PCa-2b compared to C4-2 cells, including increased glycolysis and reduced oxidative phosphorylation. Transcriptomic analysis revealed unique MG-induced stress responses including a tenfold higher induction of TXNIP in MDA-PCa-2b vs. C4-2 cells, a gene inversely linked to GLO1 expression and activity. These findings suggest that MG stress may contribute to PCa progression in AA/B men through metabolic reprogramming and impaired detoxification, offering insight into potential precision medicine applications. Statement of SignificancePatients with obesity and diabetes have an elevated risk of cancer mortality. Defining how metabolic alterations contribute to this link is critical to understanding disease progression and identifying strategies to improve outcomes.

cancer biology↗

bioRxiv2025

Inflammatory Oxidative Stress Compounds Inhibit Insulin Secretion through Rapid Protein Carbonylation

Pancreatic {beta}-cells in pre-type 1 diabetes (T1D) experience stress due to islet inflammation, which accompanies early defects in insulin secretion that precede autoimmune destruction. One product of inflammatory stress is protein carbonylation (PC), brought on by reactive oxygen species (ROS) combining with lipids to produce reactive aldehydes such as 4-hydroxynonenal (4-HNE) that irreversibly modify Cys, His, and Lys sidechains. In this study, we used proteomics to measure patterns of PC in pancreatic islets from 10-week-old pre-diabetic NOD mice and in cultured insulin-secreting cells treated with either 4-HNE or pro-inflammatory cytokines. All three stress conditions increased carbonylation of proteins central to {beta}-cell function including Rab GTPases and other proteins that are essential for vesicle trafficking. Gene ontology analysis indicates that the affected proteins and pathways in pre-diabetic NOD islets reflect a combination of those impacted by 4-HNE and cytokine treatment. Furthermore, both 4-HNE and cytokines significantly inhibited insulin secretion by [~]50% in cultured MIN6 and INS-1-GRINCH cells. In particular, exposure to 4-HNE for as little as 5 minutes suppressed insulin secretion and increased the carbonylation of over 1000 proteins. Overall, the observed PC pattern in pre-T1D islets is consistent with a model in which {beta}-cells experience multiple sources of oxidative stress, including ROS generation within {beta}-cells themselves and reactive compounds released by infiltrating immune cells. The latter exogenous source may represent a novel rapid mechanism for inhibiting insulin secretion.

biochemistry↗

bioRxiv2023

NRF2 Dysregulation in Mice Leads to Inadequate Beta-Cell Mass Expansion during Pregnancy and Gestational Diabetes

The late stages of the mammalian pregnancy are accompanied with increased insulin resistance due to the increased glucose demand of the growing fetus. Therefore, as a compensatory response to maintain the maternal normal blood glucose levels, maternal beta-cell mass expands leading to increased insulin release. Defects in beta-cell adaptive expansion during pregnancy can lead to gestational diabetes mellitus (GDM). Although the exact mechanisms that promote GDM are poorly understood, GDM strongly associates with impaired beta-cell proliferation and with increased levels of reactive oxygen species (ROS). Here, we show that NRF2 levels are upregulated in mouse beta-cells at gestation day 15 (GD15) concomitant with increased beta-cell proliferation. Importantly, mice with tamoxifen-induced beta-cell-specific NRF2 deletion display inhibition of beta-cell proliferation, increased beta-cell oxidative stress and elevated levels of beta-cell death at GD15. This results in attenuated beta-cell mass expansion and disturbed glucose homeostasis towards the end of pregnancy. Collectively, these results highlight the importance of NRF2-oxidative stress regulation in beta-cell mass adaptation to pregnancy and suggest NRF2 as a potential therapeutic target for treating GDM.

molecular biology↗

bioRxiv2021

Nrf2 Regulates β-cell Mass by Suppressing Cell Death and Promoting Proliferation

Finding therapies that can protect and expand functional {beta}-cell mass is a major goal of diabetes research. Here we generated {beta}-cell-specific conditional knockout and gain-of-function mouse models and used human islet transplant experiments to examine how manipulating Nrf2 levels affects {beta}-cell survival, proliferation and mass. Depletion of Nrf2 in {beta}-cells resulted in decreased glucose-stimulated {beta}-cell proliferation ex vivo and decreased adaptive {beta}-cell proliferation and {beta}-cell mass expansion after a high fat diet in vivo. Nrf2 protects {beta}-cells from apoptosis after a high fat diet. Nrf2 loss-of-function decreases Pdx1 abundance and insulin content. Activating Nrf2 in a {beta}-cell-specific manner increases {beta}-cell proliferation and {beta}-cell mass. Human islets transplanted under the kidney capsule of immunocompromised mice and treated systemically with CDDO-Me, an Nrf2 activator, display increased {beta}-cell proliferation. Thus, Nrf2 regulates {beta}-cell mass and is an exciting therapeutic target for expanding {beta}-cell mass in diabetes.

physiology↗