bims-nurfca 2024-05-12 papers

Issue of 2024–05–12
seven papers selected by
Caner Geyik, Istinye University

bioRxiv. 2024 Apr 22. pii: 2024.04.18.590146. [Epub ahead of print]

Nrf2 regulates the activation-driven expansion of CD4 + T-cells by differentially modulating glucose and glutamine metabolism.

Aprajita Tripathi, Debolina Dasgupta, Anil Pant, Ashlyn Bugbee, Nanda Kumar Yellapu, Ben H Y Choi, Shailendra Giri, Kalyani Pyaram.

Upon antigenic stimulation, CD4 + T-cells undergo clonal expansion, elevating their bioenergetic demands and utilization of nutrients like glucose and glutamine. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a well-known regulator of oxidative stress, but its involvement in modulating the metabolism of CD4 + T-cells remains unexplored. Here, we elucidate the role of Nrf2 beyond the traditional antioxidation, in modulating activation-driven expansion of CD4 + T-cells by influencing their nutrient metabolism. T-cell-specific activation of Nrf2 enhances early activation and IL-2 secretion, upregulates TCR-signaling, and increases activation-driven proliferation of CD4 + T-cells. Mechanistically, high Nrf2 inhibits glucose metabolism through glycolysis but promotes glutamine metabolism via glutaminolysis to support increased T-cell proliferation. Further, Nrf2 expression is temporally regulated in activated CD4 + T-cells with elevated expression during the early activation, but decreased expression thereafter. Overall, our findings uncover a novel role of Nrf2 as a metabolic modulator of CD4 + T-cells, thus providing a framework for improving Nrf2-targeting therapies and T-cell immunotherapies.

DOI: https://doi.org/10.1101/2024.04.18.590146

Bull Exp Biol Med. 2024 May 09.

Modulators of the Nrf2 Signaling Pathway Enhance the Cytotoxic Effect of Standard Chemotherapeutic Drugs on Organoids of Metastatic Colorectal Cancer.

A V Razumovskaya, M O Silkina, S V Nikulin, A G Tonevitsky, B Ya Alekseev.

The activity of known modulators of the Nrf2 signaling pathway (bardoxolone and brusatol) was studied on cultures of tumor organoids of metastatic colorectal cancer previously obtained from three patients. The effect of modulators was studied both as monotherapy and in combination with standard chemotherapy drugs used to treat colorectal cancer. The Nrf2 inhibitor brusatol and the Nrf2 activator bardoxolone have antitumor activity. Moreover, bardoxolone and brusatol also significantly enhance the effect of the chemotherapy drugs 5-fluorouracil, oxaliplatin, and irinotecan metabolite SN-38. Thus, bardoxolone and brusatol can be considered promising candidates for further preclinical and clinical studies in the treatment of colorectal cancer.

Keywords: Nrf2 signaling pathway; bardoxolone; brusatol; colorectal cancer; tumor organoids

DOI: https://doi.org/10.1007/s10517-024-06093-0

Int J Biol Sci. 2024 ;20(7): 2592-2606

TAZ deficiency impairs the autophagy-lysosomal pathway through NRF2 dysregulation and lysosomal dysfunction.

Hyo Kyeong Kim, Hana Jeong, Mi Gyeong Jeong, Hee Yeon Won, Gibbeum Lee, Soo Han Bae, Miso Nam, Sung Hoon Lee, Geum-Sook Hwang, Eun Sook Hwang.

Transcriptional coactivator with a PDZ-binding motif (TAZ) plays a key role in normal tissue homeostasis and tumorigenesis through interaction with several transcription factors. In particular, TAZ deficiency causes abnormal alveolarization and emphysema, and persistent TAZ overexpression contributes to lung cancer and pulmonary fibrosis, suggesting the possibility of a complex mechanism of TAZ function. Recent studies suggest that nuclear factor erythroid 2-related factor 2 (NRF2), an antioxidant defense system, induces TAZ expression during tumorigenesis and that TAZ also activates the NRF2-mediated antioxidant pathway. We thus thought to elucidate the cross-regulation of TAZ and NRF2 and the underlying molecular mechanisms and functions. TAZ directly interacted with NRF2 through the N-terminal domain and suppressed the transcriptional activity of NRF2 by preventing NRF2 from binding to DNA. In addition, the return of NRF2 to basal levels after signaling was inhibited in TAZ deficiency, resulting in sustained nuclear NRF2 levels and aberrantly increased expression of NRF2 targets. TAZ deficiency failed to modulate optimal NRF2 signaling and concomitantly impaired lysosomal acidification and lysosomal enzyme function, accumulating the abnormal autophagy vesicles and reactive oxygen species and causing protein oxidation and cellular damage in the lungs. TAZ restoration to TAZ deficiency normalized dysregulated NRF2 signaling and aberrant lysosomal function and triggered the normal autophagy-lysosomal pathway. Therefore, TAZ is indispensable for the optimal regulation of NRF2-mediated autophagy-lysosomal pathways and for preventing pulmonary damage caused by oxidative stress and oxidized proteins.

Keywords: NRF2; TAZ; autophagy; lysosomal acidification; oxidative stress

DOI: https://doi.org/10.7150/ijbs.88897

Front Mol Biosci. 2023 ;10 1297826

Mechano-induced cell metabolism disrupts the oxidative stress homeostasis of SAOS-2 osteosarcoma cells.

Giuseppina Fanelli, Giulia Alloisio, Veronica Lelli, Stefano Marini, Sara Rinalducci, Magda Gioia.

There has been an increasing focus on cancer mechanobiology, determining the underlying-induced changes to unlock new avenues in the modulation of cell malignancy. Our study used LC-MS untargeted metabolomic approaches and real-time polymerase chain reaction (PCR) to characterize the molecular changes induced by a specific moderate uniaxial stretch regimen (i.e., 24 h-1 Hz, cyclic stretch 0,5% elongation) on SAOS-2 osteosarcoma cells. Differential metabolic pathway analysis revealed that the mechanical stimulation induces a downregulation of both glycolysis and the tricarboxylic acid (TCA) cycle. At the same time, the amino acid metabolism was found to be dysregulated, with the mechanical stimulation enhancing glutaminolysis and reducing the methionine cycle. Our findings showed that cell metabolism and oxidative defense are tightly intertwined in mechanically stimulated cells. On the one hand, the mechano-induced disruption of the energy cell metabolism was found correlated with an antioxidant glutathione (GSH) depletion and an accumulation of reactive oxygen species (ROS). On the other hand, we showed that a moderate stretch regimen could disrupt the cytoprotective gene transcription by altering the expression levels of manganese superoxide dismutase (SOD1), Sirtuin 1 (SIRT1), and NF-E2-related factor 2 (Nrf2) genes. Interestingly, the cyclic applied strain could induce a cytotoxic sensitization (to the doxorubicin-induced cell death), suggesting that mechanical signals are integral regulators of cell cytoprotection. Hence, focusing on the mechanosensitive system as a therapeutic approach could potentially result in more effective treatments for osteosarcoma in the future.

Keywords: cyclic stretch; mechanobiology; metabolomics (LC-MS); osteosarcoma; oxidative stress response

DOI: https://doi.org/10.3389/fmolb.2023.1297826

Bull Exp Biol Med. 2024 May 09.

Activation of Transcription Factor Nrf2 in HeLa Cells under the Action of Nitrosyl Iron Complex with N-Ethylthiourea.

A A Balakina, V I Amozova, N A Sanina.

We studied the effect of an NO donor, nitrosyl iron complex with N-ethylthiourea, on Nrf2-dependent antioxidant system activation of tumor cells in vitro. The complex increased intracellular accumulation of Nrf2 transcription factor and induced its nuclear translocation. It was shown that both heme oxygenase-1 gene and protein expression increased significantly under the influence of the complex. Nrf2 activation was accompanied by a decrease in the intracellular accumulation of proinflammatory transcription factor NF-κB p65 subunit and expression of its target genes. The cytotoxic effect of N-ethylthiourea leads to induction of Nrf2/HO-1 antioxidant response and suppression of NF-κB-dependent processes in tumor cells.

Keywords: Nrf2; heme oxygenase; iron nitrosyl complexes; nitrogen monoxide

DOI: https://doi.org/10.1007/s10517-024-06067-2

Colloids Surf B Biointerfaces. 2024 Apr 10. pii: S0927-7765(24)00170-X. [Epub ahead of print]239 113911

Photothermal and ferroptosis synergistic therapy for liver cancer using iron-doped polydopamine nanozymes.

Yunchun Li, Linqun Qian, Zhouping Yang, Siyu Li, Aimin Wu, Xianxiang Wang.

An innovative nanozyme, iron-doped polydopamine (Fe-PDA), which integrates iron ions into a PDA matrix, conferred peroxidase-mimetic activity and achieved a substantial photothermal conversion efficiency of 43.5 %. Fe-PDA mediated the catalysis of H2O2 to produce toxic hydroxyl radicals (•OH), thereby facilitating lipid peroxidation in tumour cells and inducing ferroptosis. Downregulation of solute carrier family 7 no. 11 (SLC7A11) and solute carrier family 3 no. 2 (SLC3A2) in System Xc- resulted in decreased intracellular glutathione (GSH) production and inactivation of the nuclear factor erythroid 2-related factor 2 (NRF2)-glutathione peroxidase 4 (GPX4) pathway, contributing to ferroptosis. Moreover, the application of photothermal therapy (PTT) enhanced the effectiveness of chemodynamic therapy (CDT), accelerating the Fenton reaction for targeted tumour eradication while sparing adjacent non-cancerous tissues. In vivo experiments revealed that Fe-PDA significantly hampered tumour progression in mice, emphasizing the potential of the dual-modality treatment combining CDT and PTT for future clinical oncology applications.

Keywords: Chemodynamic therapy (CDT); Fe-PDA nanozymes; Ferroptosis; Photothermal therapy (PTT); Tumour therapy

DOI: https://doi.org/10.1016/j.colsurfb.2024.113911

Int J Nanomedicine. 2024 ;19 3847-3859

Acidic Environment-Responsive Metal Organic Framework-Mediated Dihydroartemisinin Delivery for Triggering Production of Reactive Oxygen Species in Drug-Resistant Lung Cancer.

Xiaojie Yan, Xueying Zhao, Mingde Fan, Wenfu Zheng, Guanxiong Zhu, Bin Li, Le Wang.

Background: Dihydroartemisinin (DHA) has emerged as a promising candidate for anticancer therapy. However, the application of DHA in clinics has been hampered by several limitations including poor bioavailability, short circulation life, and low solubility, significantly restricting its therapeutic efficacy and leading to notable side effects during the treatment.
Purpose: We present DHA-loaded zeolitic imidazolate framework-8 (D-ZIF) with controllable and targeted DHA release properties, leading to enhanced antitumor effects while reducing potential side effects.
Methods: D-ZIF was prepared by one-pot synthesis method using methylimidazole (MIM), Zn(NO3)2•6H2O and DHA. We characterized the physical and chemical properties of D-ZIF by TEM, DLS, XRD, FT-IR, and TG. We measured the drug loading efficiency and the cumulative release of DHA in different pH conditions. We evaluated the cytotoxicity of D-ZIF on renal cell carcinoma (RCC786-O), glioma cells (U251), TAX-resistant human lung adenocarcinoma (A549-TAX) cells by CCK8 in vitro. We explored the possible antitumor mechanism of D-ZIF by Western blot. We evaluated the biocompatibility and hemolysis of D-ZIF and explored the in vivo antitumor efficiency in mice model by TUNEL testing and blood biomarker evaluations.
Results: D-ZIF showed rhombic dodecahedral morphology with size of 129±7.2 nm and possessed a noticeable DHA encapsulation efficiency (72.9%). After 48 hours, D-ZIF released a cumulative 70.0% of the loaded DHA at pH 6.5, and only 42.1% at pH 7.4. The pH-triggered programmed release behavior of D-ZIF could enhance anticancer effect of DHA while minimizing side effects under normal physiological conditions. Compared with the free DHA group with 31.75% of A549-TAX cell apoptosis, the percentage of apoptotic cells was approximately 76.67% in the D-ZIF group. D-ZIF inhibited tumor growth by inducing tumor cell apoptosis through the mechanism of ROS production and regulation of Nrf2/HO-1 and P38 MAPK signaling pathways. D-ZIF showed potent effects in treating tumors with high safety in vivo.
Conclusion: This pH-responsive release mechanism enhanced the targeting efficiency of DHA towards tumor cells, thereby increasing drug concentration in tumor sites with negligible side effects. Herein, D-ZIF holds great promise for curing cancers with minimal adverse effects.

Keywords: MOF; cancer therapy; controlled release; drug delivery

DOI: https://doi.org/10.2147/IJN.S451042