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. 2023 Jul 7;15(13):3533.
doi: 10.3390/cancers15133533.

Divergent Oxidative Stress in Normal Tissues and Inflammatory Cells in Hodgkin and Non-Hodgkin Lymphoma

Cecilia Marini  1   2 , Vanessa Cossu  3 , Francesco Lanfranchi  4 , Sonia Carta  2 , Francesca Vitale  2 , Francesca D'Amico  4 , Matteo Bauckneht  2   4 , Silvia Morbelli  2   4 , Maria Isabella Donegani  2 , Silvia Chiola  2 , Stefano Raffa  2 , Luca Sofia  4 , Tania Di Raimondo  4 , Filippo Ballerini  2   5 , Chiara Ghiggi  2 , Paolo Durando  4 , Silvia Ravera  3 , Mattia Riondato  2 , Anna Maria Orengo  2 , Silvia Bruno  3 , Sabrina Chiesa  2 , Gianmario Sambuceti  2   4
Affiliations

Divergent Oxidative Stress in Normal Tissues and Inflammatory Cells in Hodgkin and Non-Hodgkin Lymphoma

Cecilia Marini et al. Cancers (Basel). .

Abstract

Background: Previous studies reported mitochondrial and endoplasmic reticulum redox stress in peripheral blood mononucleated cells (PBMCs) of treatment-naïve Hodgkin lymphoma (HL) patients. Here, we assessed whether this response also applies to non-HL (NHL) patients, and whether the oxidative damage is a selective feature of PBMCs or, rather, also affects tissues not directly involved in the inflammatory response.

Methods: Isolated PBMCs of 28 HL, 9 diffuse large B cell lymphoma, 8 less aggressive-NHL, and 45 controls underwent flow cytometry to evaluate redox stress and uptake of the glucose analogue 2-NBDG. This analysis was complemented with the assay of malondialdehyde (MDA) levels and enzymatic activity of glucose-6P-dehydrogenase and hexose-6P-dehydrogenase (H6PD). In all lymphoma patients, 18F-fluoro-deoxyglucose uptake was estimated in the myocardium and skeletal muscles.

Results: Mitochondrial reactive oxygen species generation and MDA levels were increased only in HL patients as well as H6PD activity and 2-NBDG uptake. Similarly, myocardial FDG retention was higher in HL than in other groups as opposed to a similar tracer uptake in the skeletal muscle.

Conclusions: Redox stress of PBMCs is more pronounced in HL with respect to both NHL groups. This phenomenon is coherent with an increased activity of H6PD that also extends to the myocardium.

Keywords: 2-NBDG; FDG-PET/CT; endoplasmic reticulum; lymphoma; mitochondria; pentose phosphate pathway; redox stress.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
PBMCs cell culture, oxidative stress, and antioxidant response. Representative flow cytometry dot plots of forward- and side-scatter features (FSC, x-axis and SSC, y-axis) of PBMCs showing the recovery of lymphocytes and monocytes in the expected gates of controls (A), HL (B), DLBCL (C), and LA-NHL patients (D). Percentage of recovered viable PBMCs (E), lymphocytes (F), and monocytes (G) of controls (green), HL (red), DLBCL (blue), and LA-NHL patients (orange). Mean fluorescence intensity (MFI) of DCF (H) of lymphocytes (on the left) and monocytes (on the right). Percentage of MitoSOX-positive (I) and mean fluorescence intensity (MFI) of MitoSOX (J) of lymphocytes (on the left) and monocytes (on the right). Malondialdehyde content evaluated in lysed PBMCs (K). Data are expressed as mean ± SD. * = p < 0.05, ** = p < 0.01, *** = p < 0.001 vs. controls. # = p < 0.05, ## = p < 0.01 vs. HL group.
Figure 2
Figure 2
Mitochondrial energetic function and enzymatic activity in PBMCs. Glucose consumption through glycolysis in PBMCs (A) of controls (green), HL patients (red), DLBCL (blue), and LA-NHL patients (orange) at the Seahorse XFp analysis. Lactate dehydrogenase (LDH) activity of PBMCs (B). Mitochondrial ATP-linked OCR (solid-pattern) and OXPHOS–uncoupled OCR (dashed–pattern) (C). Extramitochondrial OCR, expressed as the percentage of the corresponding total OCR (D). Catalytic function of H6PD (E) and G6PD (F), measured by enzymatic assay in lysed PBMCs. Percentage of 2-NBDG-positive (G) and mean fluorescence intensity (MFI) of 2-NBDG (H) of lymphocytes (on the left) and monocytes (on the right). Data are expressed as mean ± SD. * = p < 0.05, ** = p < 0.01, *** = p < 0.001 vs. controls. # = p < 0.05, ## = p < 0.01, ### = p < 0.001 vs. HL group.
Figure 3
Figure 3
FDG uptake of the myocardium and the skeletal muscle in association with ER redox stress of PBMCs. Representative transaxial (above) and maximum intensity projection (below) images of two FDG-PET/CT scans performed in a patient with HL (A), in a patient with DLBCL (B), and in a patient with LA-NHL (C). Myocardial average (D) and maximal (E) standardized uptake value (SUV) in HL (red), DLBCL (blue), and LA-NHL patients (orange). Correlation between average (F) and maximal (G) SUV of the myocardium and H6PD activity in circulating PBMCs. Psoas muscle average (H) and maximal (I) SUV. Lack of correlation between average (J) and maximal (K) SUV of the myocardium and H6PD activity in circulating PBMCs. # = p < 0.05 vs. HL group.
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