mTORC1-induced retinal progenitor cell overproliferation leads to accelerated mitotic aging and degeneration of descendent Müller glia

Retinal progenitor cells (RPCs) divide in limited numbers to generate the cells comprising vertebrate retina. The molecular mechanism that leads RPC to the division limit, however, remains elusive. Here, we find that the hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) in an RPC subset by deletion of tuberous sclerosis complex 1 (Tsc1) makes the RPCs arrive at the division limit precociously and produce Müller glia (MG) that degenerate from senescence-associated cell death. We further show the hyperproliferation of Tsc1-deficient RPCs and the degeneration of MG in the mouse retina disappear by concomitant deletion of hypoxia-induced factor 1-a (Hif1a), which induces glycolytic gene expression to support mTORC1-induced RPC proliferation. Collectively, our results suggest that, by having mTORC1 constitutively active, an RPC divides and exhausts mitotic capacity faster than neighboring RPCs, and thus produces retinal cells that degenerate with aging-related changes.

Development and Validation of a Combined Glycolysis and Immune Prognostic Model for Melanoma

BackgroundGlycolytic effects and immune microenvironments play important roles in the development of melanoma. However, reliable biomarkers for prognostic prediction of melanoma as based on glycolysis and immune status remain to be identified.MethodsGlycolysis-related genes (GRGs) were obtained from the Molecular Signatures database and immune-related genes (IRGs) were downloaded from the ImmPort dataset. Prognostic GRGs and IRGs in the TCGA (The Cancer Genome Atlas) and GSE65904 datasets were identified. Least absolute shrinkage and selection operator (LASSO) Cox regression and multivariate Cox regression were used for model construction. Glycolysis expression profiles and the infiltration of immune cells were analyzed and compared. Finally, in vitro experiments were performed to assess the expression and function of these CIGI genes.ResultsFour prognostic glycolysis- and immune-related signatures (SEMA4D, IFITM1, KIF20A and GPR87) were identified for use in constructing a comprehensive glycolysis and immune (CIGI) model. CIGI proved to be a stable, predictive method as determined from different datasets and subgroups of patients and served as an independent prognostic factor for melanoma patients. In addition, patients in the high-CIGI group showed increased levels of glycolytic gene expressions and exhibited immune-suppressive features. Finally, SEMA4D and IFITM1 may function as tumor suppressor genes, while KIF20A and GPR87 may function as oncogenes in melanoma as revealed from results of in vitro experiments.ConclusionIn this report we present our findings on the development and validation of a novel prognostic classifier for use in patients with melanoma as based on glycolysis and immune expression profiles.

Identification of subgroups along the glycolysis-cholesterol synthesis axis and the development of an associated prognostic risk model

Background Skin cutaneous melanoma (SKCM) is one of the most highly prevalent and complicated malignancies. Glycolysis and cholesterogenesis pathways both play important roles in cancer metabolic adaptations. The main aims of this study are to subtype SKCM based on glycolytic and cholesterogenic genes and to build a clinical outcome predictive algorithm based on the subtypes. Methods A dataset with 471 SKCM specimens was downloaded from The Cancer Genome Atlas (TCGA) database. We extracted and clustered genes from the Molecular Signatures Database v7.2 and acquired co-expressed glycolytic and cholesterogenic genes. We then subtyped the SKCM samples and validated the efficacy of subtypes with respect to simple nucleotide variations (SNVs), copy number variation (CNV), patients’ survival statuses, tumor microenvironment, and proliferation scores. We also constructed a risk score model based on metabolic subclassification and verified the model using validating datasets. Finally, we explored potential drugs for high-risk SKCM patients. Results SKCM patients were divided into four subtype groups: glycolytic, cholesterogenic, mixed, and quiescent subgroups. The glycolytic subtype had the worst prognosis and MGAM SNV extent. Compared with the cholesterogenic subgroup, the glycolytic subgroup had higher rates of DDR2 and TPR CNV and higher proliferation scores and MK167 expression levels, but a lower tumor purity proportion. We constructed a forty-four-gene predictive signature and identified MST-321, SB-743921, Neuronal Differentiation Inducer III, romidepsin, vindesine, and YM-155 as high-sensitive drugs for high-risk SKCM patients. Conclusions Subtyping SKCM patients via glycolytic and cholesterogenic genes was effective, and patients in the glycolytic-gene enriched group were found to have the worst outcome. A robust prognostic algorithm was developed to enhance clinical decisions in relation to drug administration.

Erythrocyte adenosine A2B receptor prevents cognitive and auditory dysfunction by promoting hypoxic and metabolic reprogramming

Hypoxia drives aging and promotes age-related cognition and hearing functional decline. Despite the role of erythrocytes in oxygen (O2) transport, their role in the onset of aging and age-related cognitive decline and hearing loss (HL) remains undetermined. Recent studies revealed that signaling through the erythrocyte adenosine A2B receptor (ADORA2B) promotes O2 release to counteract hypoxia at high altitude. However, nothing is known about a role for erythrocyte ADORA2B in age-related functional decline. Here, we report that loss of murine erythrocyte–specific ADORA2B (eAdora2b−/−) accelerates early onset of age-related impairments in spatial learning, memory, and hearing ability. eAdora2b-/- mice display the early aging-like cellular and molecular features including the proliferation and activation of microglia and macrophages, elevation of pro-inflammatory cytokines, and attenuation of hypoxia-induced glycolytic gene expression to counteract hypoxia in the hippocampus (HIP), cortex, or cochlea. Hypoxia sufficiently accelerates early onset of cognitive and cochlear functional decline and inflammatory response in eAdora2b−/− mice. Mechanistically, erythrocyte ADORA2B-mediated activation of AMP-activated protein kinase (AMPK) and bisphosphoglycerate mutase (BPGM) promotes hypoxic and metabolic reprogramming to enhance production of 2,3-bisphosphoglycerate (2,3-BPG), an erythrocyte-specific metabolite triggering O2 delivery. Significantly, this finding led us to further discover that murine erythroblast ADORA2B and BPGM mRNA levels and erythrocyte BPGM activity are reduced during normal aging. Overall, we determined that erythrocyte ADORA2B–BPGM axis is a key component for anti-aging and anti-age–related functional decline.

Correlations between glycolysis with clinical traits and immune function in bladder urothelial carcinoma

Background: Glycolysis was a representative hallmark in the tumor microenvironment (TME), and we aimed to explore the correlations between glycolysis with immune activity and clinical traits in bladder urothelial carcinoma (BLCA). Methods: Our study obtained glycolysis scores for each BLCA samples from TCGA by a single-sample gene set enrichment analysis (ssGSEA) algorithm, based on a glycolytic gene set. The relationship between glycolysis with prognosis, clinical characteristics, and immune function were investigated subsequently. Results: We found that enhanced glycolysis was associated with poor prognosis and metastasis in BLCA. Moreover, glycolysis had a close correlation with immune function, and enhanced glycolysis increased immune activities. In other words, glycolysis had a positive correlation with immune activities. Immune checkpoints such as IDO1, CD274, were up-regulated in high-glycolysis group as well. Conclusion: We speculated that in BLCA, elevated glycolysis enhanced immune function, which caused tumor cells to overexpress immune checkpoints to evade immune surveillance. Inhibition of glycolysis might be a promising assistant for immunotherapy in bladder cancer.

β-Catenin drives distinct transcriptional networks in proliferative and nonproliferative cardiomyocytes

ABSTRACTThe inability of the adult mammalian heart to regenerate represents a fundamental barrier in heart failure management. By contrast, the neonatal heart retains a transient regenerative capacity, but the underlying mechanisms for the developmental loss of cardiac regenerative capacity in mammals are not fully understood. Wnt/β-catenin signalling has been proposed as a key cardioregenerative pathway driving cardiomyocyte proliferation. Here, we show that Wnt/β-catenin signalling potentiates neonatal mouse cardiomyocyte proliferation in vivo and immature human pluripotent stem cell-derived cardiomyocyte (hPSC-CM) proliferation in vitro. By contrast, Wnt/β-catenin signalling in adult mice is cardioprotective but fails to induce cardiomyocyte proliferation. Transcriptional profiling and chromatin immunoprecipitation sequencing of neonatal mouse and hPSC-CMs revealed a core Wnt/β-catenin-dependent transcriptional network governing cardiomyocyte proliferation. By contrast, β-catenin failed to re-engage this neonatal proliferative gene network in the adult heart despite partial transcriptional re-activation of a neonatal glycolytic gene programme. These findings suggest that β-catenin might be repurposed from regenerative to protective functions in the adult heart in a developmental process dependent on the metabolic status of cardiomyocytes.

Hypoxia uncouples HIF gene transcription and metabolic flux in proliferating primary cells

Hypoxia is an important environmental stimulus that causes transcriptional and metabolic reprogramming in cells to facilitate their survival. Here, we performed stable isotope tracing and metabolic flux analyses of proliferating primary cells in hypoxia. Despite activation of the hypoxia-inducible factor (HIF) transcriptional program and up-regulation of glycolytic genes, glycolytic flux was decreased in hypoxic cells in our models. No evidence for increased glutaminolysis or reductive carboxylation was observed. While pharmacologic stabilization of HIF in normoxia with the prolyl hydroxylase inhibitor molidustat did increase glycolytic flux as expected, hypoxia abrogated this effect. Together, these data suggest that primary cell bioenergetic metabolism is closely coupled to cell proliferation rate and that other regulatory factors override the effects of HIF-dependent up-regulation of glycolytic gene expression on glycolytic flux.

The Apolipoprotein A-I Mimetic L-4F Attenuates Monocyte Activation and Adverse Cardiac Remodeling after Myocardial Infarction

Excessive inflammation after myocardial infarction (MI) can promote infarct expansion and adverse left ventricular (LV) remodeling. L-4F, a mimetic peptide of apolipoprotein A-I (apoA-I), exhibits anti-inflammatory and anti-atherogenic properties; however, whether L-4F imparts beneficial effects after myocardial infarction (MI) is unknown. Here we demonstrate that L-4F suppresses the expansion of blood, splenic, and myocardial pro-inflammatory monocytes and macrophages in a mouse model of reperfused MI. Changes in immune cell profiles were accompanied by alleviation of post-MI LV remodeling and dysfunction. In vitro, L-4F also inhibited pro-inflammatory and glycolytic gene expression in macrophages. In summary, L-4F treatment prevents prolonged and excessive inflammation after MI, in part through modulation of pro-inflammatory monocytes and macrophages, and improves post-MI LV remodeling. These data suggest that L-4F could be a used as a therapeutic adjunct in humans with MI to limit inflammation and alleviate the progression to heart failure.

The Warburg Effect and lactate signaling augment Fgf-MAPK to promote sensory-neural development in the otic vesicle

Recent studies indicate that many developing tissues modify glycolysis to favor lactate synthesis (Agathocleous et al., 2012; Bulusu et al., 2017; Gu et al., 2016; Oginuma et al., 2017; Sá et al., 2017; Wang et al., 2014; Zheng et al., 2016), but how this promotes development is unclear. Using forward and reverse genetics in zebrafish, we show that disrupting the glycolytic gene phosphoglycerate kinase-1 (pgk1) impairs Fgf-dependent development of hair cells and neurons in the otic vesicle and other neurons in the CNS/PNS. Fgf-MAPK signaling underperforms in pgk1- / - mutants even when Fgf is transiently overexpressed. Wild-type embryos treated with drugs that block synthesis or secretion of lactate mimic the pgk1- / - phenotype, whereas pgk1- / - mutants are rescued by treatment with exogenous lactate. Lactate treatment of wild-type embryos elevates expression of Etv5b/Erm even when Fgf signaling is blocked. However, lactate’s ability to stimulate neurogenesis is reversed by blocking MAPK. Thus, lactate raises basal levels of MAPK and Etv5b (a critical effector of the Fgf pathway), rendering cells more responsive to dynamic changes in Fgf signaling required by many developing tissues.