Plasma cysteine is associated with human obesity, but it is unknown whether this is mediated by reduced, disulfide (cystine and mixed-disulfides) or protein-bound (bCys) fractions. We investigated which cysteine fractions are associated with adiposity in vivo and if a relevant fraction influences human adipogenesis in vitro. In the current study, plasma cysteine fractions were correlated with body fat mass in 35 adults. Strong positive correlations with fat mass were observed for cystine and mixed disulfides (r ≥ 0.61, P < 0.001), but not the quantitatively major form, bCys. Primary human preadipocytes were differentiated in media containing cystine concentrations varying from 10–50 μM, a range similar to that in plasma. Increasing extracellular cystine (10–50 μM) enhanced mRNA expression of PPARG2 (to sixfold), PPARG1, PLIN1, SCD1 and CDO1 (P = 0.042– < 0.001). Adipocyte lipid accumulation and lipid-droplet size showed dose-dependent increases from lowest to highest cystine concentrations (P < 0.001), and the malonedialdehyde/total antioxidant capacity increased, suggesting increased oxidative stress. In conclusion, increased cystine concentrations, within the physiological range, are positively associated with both fat mass in healthy adults and human adipogenic differentiation in vitro. The potential role of cystine as a modifiable factor regulating human adipocyte turnover and metabolism deserves further study.
The role of metabolic reprogramming in the coordination of the immune response has gained increasing consideration in recent years. Indeed, it has become clear that changes in the metabolic status of immune cells can alter their functional properties. During inflammation, T cells need to generate sufficient energy and biomolecules to support growth, proliferation, and effector functions. Therefore, T cells need to rearrange their metabolism to meet these demands. A similar metabolic reprogramming has been described in endothelial cells, which have the ability to interact with and modulate the function of immune cells. In this overview, we will discuss recent insights in the complex crosstalk between endothelial cells and T cells as well as their metabolic reprogramming following activation. We highlight key components of this metabolic switch that can lead to the development of new therapeutics against chronic inflammatory disorders.
Regenerative medicine is the field concerned with the repair and restoration of the integrity of damaged human tissues as well as whole organs. Since the inception of the field several decades ago, regenerative medicine therapies, namely stem cells, have received significant attention in preclinical studies and clinical trials. Apart from their known potential for differentiation into the various body cells, stem cells enhance the organ's intrinsic regenerative capacity by altering its environment, whether by exogenous injection or introducing their products that modulate endogenous stem cell function and fate for the sake of regeneration. Recently, research in cardiology has highlighted the evidence for the existence of cardiac stem and progenitor cells (CSCs/CPCs). The global burden of cardiovascular diseases’ morbidity and mortality has demanded an in-depth understanding of the biology of CSCs/CPCs aiming at improving the outcome for an innovative therapeutic strategy. This review will discuss the nature of each of the CSCs/CPCs, their environment, their interplay with other cells, and their metabolism. In addition, important issues are tackled concerning the potency of CSCs/CPCs in relation to their secretome for mediating the ability to influence other cells. Moreover, the review will throw the light on the clinical trials and the preclinical studies using CSCs/CPCs and combined therapy for cardiac regeneration. Finally, the novel role of nanotechnology in cardiac regeneration will be explored.
The present study explores the role of the cytosolic branched chain amino acid aminotransferase (BCAT1) in CD8+T cell activation, in general, and tumor immunity, in particular, and identifies a non-canonical function of the protein in iron homeostasis. Pharmacologic inhibition of BCAT1 using the novel drug ERG245 abrogates the effector functions of CD8+T cells in vitro and metabolically reprograms the cells towards increased OXPHOS. In vivo, it suppresses activation of CD8+T cells in DSS colitis leading to improved disease outcomes. Remarkably, withdrawal of BCAT1 inhibition further amplifies OXPHOS and gives rise to CD8+T cells with increased cytotoxicity in vitro and in vivo. When combined with an anti-PD-1 treatment, temporal BCAT1 inhibition dramatically increases anti-PD-1 efficacy inducing complete and durable tumor regressions in the moderately immunogenic CT26 tumor model. Single cell RNA-seq data link expression of Bcat genes to exhausted T cells within the tumor microenvironment of human cancer patients, whereas in vitro assays indicate that BCAT1 inhibition partially prevents the adoption of a terminally exhausted phenotype by CD8+ T cells. We propose BCAT1 as a target for cancer combinatory therapies.
BCAT1, the enzyme responsible for the reversible transamination of leucine in the cytosol, has recently been implicated in the development and growth of various types of cancer. The limited expression of BCAT1 in adult tissues under physiological conditions suggests that the enzyme is a sensible target for drug development. To better understand the role of BCAT1 in cancer, we examined its gene expression at the single cell level (scRNAseq) in specimens obtained from lung, colorectal, breast, and ovarian cancer patients (n=36; >200,000 single cells). In those samples, Bcat1 gene expression was primarily associated with myeloid cells and fibroblasts with the exception of ovarian cancer in which robust Bcat1 presence was also seen in cancer cells. In tumor infiltrating lymphocytes (TILs), enrichment in Bcat1 gene expression was observed in exhausted CD4+ and CD8+ T cells compared to other T cell subtypes; this was independent of the cancer type examined. We speculated that inhibition of BCAT1 in TILs reverses exhaustion and has a therapeutic impact in cancer. In the syngeneic CT26 colon cancer model, combination treatment of a BCAT1 inhibitor (ERG245; ip administration of 5 mg/kg, given at days 7, 8 and 9 after tumor cell inoculation) and an anti-PD1 antibody (ab) (clone RMP1-14; ip administration given at days 7, 11, 14, and 18) led to eradication of established tumors. In the same model, limited treatment of large tumors (average size of ~600 mm3) with ERG245+anti-PD1 ab suppressed tumor growth and increased the frequency of CD8+ T cells expressing Granzyme B and IFNγ by ~50% compared to anti-PD1 monotherapy. Mechanistically, in vitro treatment of newly activated hCD8+ T cells with ERG245 impaired translocation of the lactate transporter MCT1 to the cell surface and increased the levels of intracellular lactate within 30 min of activation leading to upregulation of transcription factor ATF3. ERG245-driven metabolic reprogramming of CD8+ T cells towards an oxidative phenotype (increased OXPHOS) was also observed at 24h of treatment. Withdrawal of ERG245 restored intracellular lactate levels without reversing the metabolic reprogramming of the cells. We propose that these are elements of a mechanism that links temporal inhibition of BCAT1 to the rise of highly energetic CD8+ T cells with increased cytotoxicity and proliferative capacity in vitro and in vivo. Citation Format: Adonia E. Papathanassiu, Francesca Lodi, Hagar Elkafrawy, Michelangelo Certo, Hong Vu, Jeong Hun Ko, Jacques Behmoaras, Claudio Mauro, Diether Lambrechts. BCAT1 as a druggable target in immuno-oncology [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3402.
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