bims-noxint 2021-08-15 papers

Issue of 2021‒08‒15
four papers selected by
Laia Caja Puigsubira
Uppsala University

JCI Insight. 2021 Aug 10. pii: 149301. [Epub ahead of print]

Nox2-deficient Tregs improve heart transplant outcomes via their increased graft recruitment and enhanced potency.

Silvia C Trevelin, Anna Zampetaki, Greta Sawyer, Aleksandar Ivetic, Alison C Brewer, Lesley Ann Smyth, Federica Marelli-Berg, Robert Köchl, Robert I Lechler, Ajay M Shah, Giovanna Lombardi.

Nox2 is a ROS-generating enzyme, deficiency of which increases suppression by Tregs in vitro and in an in vivo model of cardiac remodelling. Since Tregs have emerged as a candidate therapy in autoimmunity and transplantation, we hypothesised that Nox2 deficiency in Tregs in recipient mice may improve outcomes in a heart transplant model. A novel B6129 mouse model with Treg-targeted Nox2 deletion (Nox2fl/flFoxP3Cre+) was generated and transplanted with hearts from CB6F1 donors. As compared to littermate controls, Nox2fl/flFoxP3Cre+ mice had lower plasma levels of alloantibodies and troponin-I, reduced levels of IFN-γ in heart allograft homogenates and diminished cardiomyocyte necrosis and allograft fibrosis. Single cell analyses of allografts revealed higher absolute numbers of Tregs and lower CD8+ T cell infiltration in Nox2-deficient recipients compared to Nox2-replete mice. Mechanistically, in addition to a greater suppression of CD8+CD25- T effector cell proliferation and IFN-γ production, Nox2-deficient Tregs expressed higher levels of CCR4 and CCR8, driving cell migration to allografts; this was associated with increased expression of miR214-3p. These data indicate that Nox2 deletion in Tregs enhances their suppressive ability and migration to heart allografts. Therefore, Nox2 inhibition in Tregs may be a useful approach to improve their therapeutic efficacy.

Keywords: Cardiology; Cell migration/adhesion; Heart failure; Immunology; Immunotherapy

DOI: https://doi.org/10.1172/jci.insight.149301

J Genet Genomics. 2021 Jul 15. pii: S1673-8527(21)00201-0. [Epub ahead of print]

Suppressed mitochondrial respiration via NOX5-mediated redox imbalance contributes to the antitumor activity of anlotinib in oral squamous cell carcinoma.

Zhexun Huang, Qiao Su, Wuguo Li, Hui Ren, Huiqiang Huang, Anxun Wang.

Anlotinib, a novel multitarget tyrosine kinase inhibitor, has shown promising results in the management of various carcinomas. This study aimed to investigate the antitumor activity of anlotinib in oral squamous cell carcinoma (OSCC) and the underlying molecular mechanism. A retrospective clinical study revealed that anlotinib improved the median progression-free survival (mPFS) and median overall survival (mOS) of patients with recurrent and metastatic (R/M) OSCC, respectively. Functional studies revealed that anlotinib markedly inhibited in vitro proliferation of OSCC cells and impeded in vivo tumor growth of OSCC patient-derived xenograft models. Mechanistically, RNA-sequencing identified that oxidative stress, oxidative phosphorylation and AKT/mTOR signaling were involved in anlotinib-treated OSCC cells. Anlotinib upregulated NADPH oxidase 5 (NOX5) expression, elevated reactive oxygen species (ROS) production, impaired mitochondrial respiration, and promoted apoptosis. Moreover, anlotinb also inhibited phospho-Akt (p-AKT) expression and elevated p-eIF2α expression in OSCC cells. NOX5 knockdown attenuated these inhibitory effects and cytotoxicity in anlotinib-treated OSCC cells. Collectively, we demonstrated that anlotinib monotherapy demonstrated favorable anticancer activity and manageable toxicities in patients with R/M OSCC. The antitumor activity of anlotinib in OSCC may be mainly involved in the suppression of mitochondrial respiration via NOX5-mediated redox imbalance and the AKT/eIF2α pathway.

Keywords: Anlotinib; Mitochondrial respiration function; NOX5; Oral squamous cell carcinoma; Oxidative phosphorylation; Oxidative stress

DOI: https://doi.org/10.1016/j.jgg.2021.06.014

Oncotarget. 2021 Aug 03. 12(16): 1629-1630

Glucose starvation induces NADPH collapse and disulfide stress in SLC7A11high cancer cells.

Xiaoguang Liu, Boyi Gan.

Keywords: NADPH; SLC7A11; cysteine; cystine; glucose starvation

DOI: https://doi.org/10.18632/oncotarget.27993

Redox Biol. 2021 Jul 27. pii: S2213-2317(21)00243-3. [Epub ahead of print]46 102084

PARP1 deficiency protects against hyperglycemia-induced neointimal hyperplasia by upregulating TFPI2 activity in diabetic mice.

Zhao-Yang Wang, Meng-Qi Guo, Qing-Ke Cui, Haitao Yuan, Shan-Ji Fu, Bin Liu, Fei Xie, Wen Qiao, Jie Cheng, Ying Wang, Ming-Xiang Zhang.

Diabetes mellitus (DM) promotes neointimal hyperplasia, characterized by dysregulated proliferation and accumulation of vascular smooth muscle cells (VSMCs), leading to occlusive disorders, such as atherosclerosis and stenosis. Poly (ADP-ribose) polymerase 1 (PARP1), reported as a crucial mediator in tumor proliferation and transformation, has a pivotal role in DM. Nonetheless, the function and potential mechanism of PARP1 in diabetic neointimal hyperplasia remain unclear. In this study, we constructed PARP1 conventional knockout (PARP1-/-) mice, and ligation of the left common carotid artery was performed to induce neointimal hyperplasia in Type I diabetes mellitus (T1DM) mouse models. PARP1 expression in the aorta arteries of T1DM mice increased significantly and genetic deletion of PARP1 showed an inhibitory effect on the neointimal hyperplasia. Furthermore, our results revealed that PARP1 enhanced diabetic neointimal hyperplasia via downregulating tissue factor pathway inhibitor (TFPI2), a suppressor of vascular smooth muscle cell proliferation and migration, in which PARP1 acts as a negative transcription factor augmenting TFPI2 promoter DNA methylation. In conclusion, these results suggested that PARP1 accelerates the process of hyperglycemia-induced neointimal hyperplasia via promoting VSMCs proliferation and migration in a TFPI2 dependent manner.

Keywords: Diabetes; Neointimal hyperplasia; PARP1; TFPI2

DOI: https://doi.org/10.1016/j.redox.2021.102084