Trends in Cell Biology, Journal Year: 2020, Volume and Issue: 30(3), P. 201 - 212
Published: Jan. 23, 2020
Language: Английский
Cell Death and Disease, Journal Year: 2022, Volume and Issue: 13(1)
Published: Jan. 10, 2022
Methylglyoxal (MGO) is an active metabolite of glucose and plays a prominent role in the pathogenesis diabetic vascular complications, including endothelial cell apoptosis induced by oxidative stress. Metformin (MET), widely prescribed antidiabetic agent, appears to reduce excessive reactive oxygen species (ROS) generation limit apoptosis. However, molecular mechanisms underlying this process are still not fully elucidated. We reported here that MET prevents MGO-induced suppressing stress vitro vivo. Protein expression protein phosphorylation were investigated using western blotting, ELISA, immunohistochemical staining, respectively. Cell viability assessed MTT assay, TUNEL Annexin V-FITC propidium iodide double staining. ROS mitochondrial membrane potential (MMP) measured with fluorescent probes. Our results revealed prevented HUVEC apoptosis, inhibited apoptosis-associated biochemical changes such as loss MMP, elevation Bax/Bcl-2 ratio, activation cleaved caspase-3, attenuated morphological alterations dose-dependent manner. pretreatment also significantly suppressed MGO-stimulated production, increased signaling through ROS-mediated PI3K/Akt Nrf2/HO-1 pathways, markedly elevated levels its downstream antioxidants. Finally, similar obtained vivo, we demonstrated damage, inflammation. As expected, reversed downregulation Nrf2 p-Akt. In addition, PI3K inhibitor (LY-294002) (ML385) observably protective effects on inhibiting while scavenger (NAC) permeability transition pores (CsA) completely these effects. Collectively, findings broaden our understanding mechanism which regulates MGO under conditions, important implications regarding application for treatment complications.
Language: Английский
Citations
83
Nature Metabolism, Journal Year: 2023, Volume and Issue: 5(4), P. 660 - 676
Published: April 6, 2023
Abstract Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is known to contain an active-site cysteine residue undergoing oxidation in response hydrogen peroxide, leading rapid inactivation of the enzyme. Here we show that human and mouse cells expressing a GAPDH mutant lacking this redox switch retain catalytic activity but are unable stimulate oxidative pentose phosphate pathway enhance their reductive capacity. Specifically, find anchorage-independent growth spheroids limited by elevation endogenous peroxide levels largely dependent on functional switch. Likewise, tumour vivo stress suppressed when disabled cells. The induction additional intratumoural chemo- or radiotherapy synergized with deactivation Mice exhibit altered fatty acid metabolism kidney heart, apparently compensation for lack Together, our findings demonstrate physiological pathophysiological relevance mammals.
Language: Английский
Citations
59
Redox Biology, Journal Year: 2023, Volume and Issue: 64, P. 102797 - 102797
Published: June 25, 2023
Mitochondria are highly dynamic organelles essential for cell metabolism, growth, and function. It is becoming increasingly clear that endothelial dysfunction significantly contributes to the pathogenesis vascular remodeling of various lung diseases, including pulmonary arterial hypertension (PAH), mitochondria at center this dysfunction. The more we uncover role play in disease, apparent it becomes multiple pathways involved. To achieve effective treatments, must understand how these dysregulated be able intervene therapeutically. We know nitric oxide signaling, glucose fatty acid oxidation, TCA cycle abnormal PAH, along with alterations mitochondrial membrane potential, proliferation, apoptosis. However, incompletely characterized especially cells, highlighting urgent need further research. This review summarizes what currently known about metabolism facilitates a metabolic shift cells induces during PAH.
Language: Английский
Citations
51
Nature Reviews Endocrinology, Journal Year: 2023, Volume and Issue: 19(12), P. 691 - 707
Published: Sept. 25, 2023
Language: Английский
Citations
42
Journal of Clinical Investigation, Journal Year: 2024, Volume and Issue: 134(4)
Published: Jan. 4, 2024
Blood vessels are continually exposed to circulating lipids and elevations of ApoB containing lipoproteins cause atherosclerosis. Lipoprotein metabolism is highly regulated by lipolysis, largely at the level capillary endothelium lining metabolically active tissues. How large blood vessels, site atherosclerotic vascular disease, regulate flux fatty acids (FA) into triglyceride (TG) rich lipid droplets (LD) not known. In this study, we showed that deletion enzyme, adipose lipase (ATGL) in endothelium, led neutral accumulation impaired endothelial dependent tone nitric oxide synthesis promote dysfunction. Mechanistically, loss ATGL endoplasmic reticulum stress-induced inflammation endothelium. Consistent with mechanism, markedly increased lesion size a model Together, these data demonstrate dynamics FA through LD impacts cell homeostasis consequently vessel function during normal physiology chronic disease state.
Language: Английский
Citations
22
Nature Reviews Nephrology, Journal Year: 2024, Volume and Issue: unknown
Published: Sept. 17, 2024
Language: Английский
Citations
18
Frontiers in Physiology, Journal Year: 2019, Volume and Issue: 10
Published: Dec. 17, 2019
Despite the decline in their proliferative potential, senescent cells display a high metabolic activity. Senescent have been shown to acquire more glycolytic state even presence of oxygen levels, way similar cancer cells. The diversion pyruvate, final product glycolysis, away from oxidative phosphorylation results an altered bioenergetic and may occur as response enhanced stress caused by accumulation dysfunctional mitochondria. This shift leads increased AMP/ATP ADP/ATP ratios, subsequent AMPK activation, ultimately p53-mediated growth arrest. Mounting evidences suggest that reprogramming is critical direct considerable amounts energy toward specific activities related state, including senescence-associated secretory phenotype (SASP) modulation immune responses within cell tissue microenvironment. Interestingly, despite relative abundance vascular compartment, healthy endothelial (ECs) produce most ATP content anaerobic conversion glucose lactate. Their rate further increases during senescence. Alterations EC metabolism identified age-related diseases (ARDs) associated with vasculature, atherosclerosis, type 2 diabetes cardiovascular diseases. In particular, higher production reactive species deriving variety enzymatic sources, uncoupled nitric oxide synthase electron transport chain, causes DNA damage activates NAD+-consuming enzymes polyADP-ribose polymerase 1 (PARP1). These non-physiological mechanisms drive impairment flux intermediates into many pathological pathways. Of note, ECs has reported context ARDs. Through pro-oxidant, pro-inflammatory, vasoconstrictor, prothrombotic activities, they negatively impact on physiology, promoting both onset development Here, we review current knowledge cellular senescence-related changes contribution underlying pathogenesis ARDs, particular focus ECs. Moreover, potential interventions aimed at modulating metabolism, order prevent or delay ARD onset, will be discussed.
Language: Английский
Citations
127
Theranostics, Journal Year: 2020, Volume and Issue: 10(16), P. 7053 - 7069
Published: Jan. 1, 2020
Lipids, the basic components of cell membrane, execute fundamental roles in almost all activities including cell-cell recognition, signalling transduction and energy supplies.Lipid metabolism is elementary for life sustentation that balances activity between synthesis degradation.An accumulating amount data has indicated abnormal lipid cancer stem cells (CSCs), alteration exerts a great impact on CSCs' properties such as capability self-renewal, differentiation, invasion, metastasis, drug sensitivity resistance.CSCs' formation maintenance cannot do without regulation fatty acids cholesterol.In normal embryonic development, cholesterol are regulated by some important pathways (such Hedgehog, Notch, Wnt pathways); these also play crucial initiating and/or maintaining properties, shown to be commonly modulated CSCs; other hand, altered turn modifies generates additional impacts CSCs.Metabolic rewiring considered an ideal hallmark CSCs, metabolic alterations would promising therapeutic targets CSCs aggressive tumors.In this review, we summarize most updated findings abnormalities prospect potential applications targeting anticancer treatment.
Language: Английский
Citations
118
Cell Reports, Journal Year: 2020, Volume and Issue: 33(8), P. 108421 - 108421
Published: Nov. 1, 2020
Emerging evidence indicates that non-mutational drug tolerance mechanisms underlie the survival of residual cancer "persister" cells. Here, we find BRAF(V600E) mutant melanoma persister cells tolerant to BRAF/MEK inhibitors switch their metabolism from glycolysis oxidative respiration supported by peroxisomal fatty acid β-oxidation (FAO) is transcriptionally regulated peroxisome proliferator-activated receptor alpha (PPARα). Knockdown key FAO enzyme, acyl-CoA oxidase 1 (ACOX1), as well treatment with inhibitor thioridazine, specifically suppresses and significantly decreases emergence. Consistently, a combination thioridazine in human-melanoma-bearing mice results durable anti-tumor response. In samples patients treated inhibitors, higher baseline expression FAO-related genes PPARα correlates patients' outcomes. These pave way for metabolic strategy overcome resistance.
Language: Английский
Citations
104
Nature Metabolism, Journal Year: 2019, Volume and Issue: 1(10), P. 937 - 946
Published: Sept. 30, 2019
Language: Английский
Citations
99