-
Cancer Research Jan 2020Our understanding of intratumoral heterogeneity in cancer continues to evolve, with current models incorporating single-cell signatures to explore cell-cell interactions... (Review)
Review
Our understanding of intratumoral heterogeneity in cancer continues to evolve, with current models incorporating single-cell signatures to explore cell-cell interactions and differentiation state. The transition between stem and differentiation states in nonneoplastic cells requires metabolic plasticity, and this plasticity is increasingly recognized to play a central role in cancer biology. The insights from hematopoietic and neural stem cell differentiation pathways were used to identify cancer stem cells in leukemia and gliomas. Similarly, defining metabolic heterogeneity and fuel-switching signals in nonneoplastic stem cells may also give important insights into the corresponding molecular mechanisms controlling metabolic plasticity in cancer. These advances are important, because metabolic adaptation to anticancer therapeutics is rooted in this inherent metabolic plasticity and is a therapeutic challenge to be overcome.
Topics: Animals; Brain; Cell Differentiation; Cell Hypoxia; Cell Plasticity; Disease Models, Animal; Fatty Acids; Glycolysis; Hematopoietic Stem Cells; Humans; Neoplasms; Neoplastic Cells, Circulating; Neoplastic Stem Cells; Neural Stem Cells; Oxidation-Reduction; Oxygen
PubMed: 31575548
DOI: 10.1158/0008-5472.CAN-19-1169 -
Chronic Respiratory Disease 2021To synthesize evidence for prefrontal cortex (PFC), quadriceps, and respiratory muscle oxygenation using near-infrared spectroscopy (NIRS) during cycling in individuals... (Review)
Review
To synthesize evidence for prefrontal cortex (PFC), quadriceps, and respiratory muscle oxygenation using near-infrared spectroscopy (NIRS) during cycling in individuals with chronic obstructive pulmonary disease (COPD). A scoping review was performed searching databases (inception-August 2020): Ovid MEDLINE, EMBASE, Cochrane Systematic Reviews, Cochrane Central Register of Controlled Clinical Trials, CINAHL, SPORTDiscus and Pedro. The search focused on COPD, cycling, and NIRS outcomes. 29 studies (541 COPD participants) were included. Compared to healthy individuals (8 studies), COPD patients at lower cycling workloads had more rapid increases in vastus lateralis (VL) deoxygenated hemoglobin (HHb); lower increases in VL total hemoglobin (tHb) and blood flow; and lower muscle tissue saturation (StO). Heliox and bronchodilators were associated with smaller and slower increases in VL HHb. Heliox increased VL and intercostal blood flow compared to room air and supplemental oxygen in COPD patients (1 study). PFC oxygenated hemoglobin (OHb) increased in COPD individuals during cycling in 5 of 8 studies. Individuals with COPD and heart failure demonstrated worse VL and PFC NIRS outcomes compared to patients with only COPD-higher or more rapid increase in VL HHb and no change or decrease in PFC OHb. Individuals with COPD present with a mismatch between muscle oxygen delivery and utilization, characterized by more rapid increase in VL HHb, lower muscle OHb and lower muscle StO. PFC OHb increases or tends to increase in individuals with COPD during exercise, but this relationship warrants further investigation. NIRS can be used to identify key deoxygenation thresholds during exercise to inform PFC and muscle oxygenation.
Topics: Helium; Humans; Muscle, Skeletal; Oxygen; Oxygen Consumption; Pulmonary Disease, Chronic Obstructive; Quadriceps Muscle
PubMed: 33605155
DOI: 10.1177/1479973121993494 -
Artificial Organs Mar 2021Extreme prematurity, defined as a gestational age of fewer than 28 weeks, is a significant health problem worldwide. It carries a high burden of mortality and... (Review)
Review
Extreme prematurity, defined as a gestational age of fewer than 28 weeks, is a significant health problem worldwide. It carries a high burden of mortality and morbidity, in large part due to the immaturity of the lungs at this stage of development. The standard of care for these patients includes support with mechanical ventilation, which exacerbates lung pathology. Extracorporeal life support (ECLS), also called artificial placenta technology when applied to extremely preterm (EPT) infants, offers an intriguing solution. ECLS involves providing gas exchange via an extracorporeal device, thereby doing the work of the lungs and allowing them to develop without being subjected to injurious mechanical ventilation. While ECLS has been successfully used in respiratory failure in full-term neonates, children, and adults, it has not been applied effectively to the EPT patient population. In this review, we discuss the unique aspects of EPT infants and the challenges of applying ECLS to these patients. In addition, we review recent progress in artificial placenta technology development. We then offer analysis on design considerations for successful engineering of a membrane oxygenator for an artificial placenta circuit. Finally, we examine next-generation oxygenators that might advance the development of artificial placenta devices.
Topics: Artificial Organs; Equipment Design; Extracorporeal Membrane Oxygenation; Female; Humans; Infant, Extremely Premature; Oxygenators, Membrane; Placenta; Pregnancy
PubMed: 32979857
DOI: 10.1111/aor.13827 -
International Journal of Molecular... Aug 2021Every cell in the body requires oxygen for its functioning, in virtually every animal, and a tightly regulated system that balances oxygen supply and demand is therefore... (Review)
Review
Every cell in the body requires oxygen for its functioning, in virtually every animal, and a tightly regulated system that balances oxygen supply and demand is therefore fundamental. The vascular network is one of the first systems to sense oxygen, and deprived oxygen (hypoxia) conditions automatically lead to a cascade of cellular signals that serve to circumvent the negative effects of hypoxia, such as angiogenesis associated with inflammation, tumor development, or vascular disorders. This vascular signaling is driven by central transcription factors, namely the hypoxia inducible factors (HIFs), which determine the expression of a growing number of genes in endothelial cells and pericytes. HIF functions are tightly regulated by oxygen sensors known as the HIF-prolyl hydroxylase domain proteins (PHDs), which are enzymes that hydroxylate HIFs for eventual proteasomal degradation. HIFs, as well as PHDs, represent attractive therapeutic targets under various pathological settings, including those involving vascular (dys)function. We focus on the characteristics and mechanisms by which vascular cells respond to hypoxia under a variety of conditions.
Topics: Angiogenic Proteins; Animals; Blood Vessels; Cell Hypoxia; Gene Regulatory Networks; Humans; Hypoxia-Inducible Factor 1; Neovascularization, Physiologic; Oxygen
PubMed: 34502102
DOI: 10.3390/ijms22179191 -
Oxidative Medicine and Cellular... 2021Mitochondria are the main powerhouse of the cell, generating ATP through the tricarboxylic acid cycle (TCA) and oxidative phosphorylation (OXPHOS), which drives myriad... (Review)
Review
Mitochondria are the main powerhouse of the cell, generating ATP through the tricarboxylic acid cycle (TCA) and oxidative phosphorylation (OXPHOS), which drives myriad cellular processes. In addition to their role in maintaining bioenergetic homeostasis, changes in mitochondrial metabolism, permeability, and morphology are critical in cell fate decisions and determination. Notably, mitochondrial respiration coupled with the passage of electrons through the electron transport chain (ETC) set up a potential source of reactive oxygen species (ROS). While low to moderate increase in intracellular ROS serves as secondary messenger, an overwhelming increase as a result of either increased production and/or deficient antioxidant defenses is detrimental to biomolecules, cells, and tissues. Since ROS and mitochondria both regulate cell fate, attention has been drawn to their involvement in the various processes of carcinogenesis. To that end, the link between a prooxidant milieu and cell survival and proliferation as well as a switch to mitochondrial OXPHOS associated with recalcitrant cancers provide testimony for the remarkable metabolic plasticity as an important hallmark of cancers. In this review, the regulation of cell redox status by mitochondrial metabolism and its implications for cancer cell fate will be discussed followed by the significance of mitochondria-targeted therapies for cancer.
Topics: Animals; Cell Respiration; Cell Survival; Energy Metabolism; Humans; Mitochondria; Neoplasms; Oxidation-Reduction; Oxidative Phosphorylation; Reactive Oxygen Species
PubMed: 34777681
DOI: 10.1155/2021/1341604 -
Nature Communications Nov 2022It has been recently shown that electron transfer between mitochondrial cytochrome c and the cytochrome c subunit of the cytochrome bc can proceed at long-distance...
It has been recently shown that electron transfer between mitochondrial cytochrome c and the cytochrome c subunit of the cytochrome bc can proceed at long-distance through the aqueous solution. Cytochrome c is thought to adjust its activity by changing the affinity for its partners via Tyr48 phosphorylation, but it is unknown how it impacts the nanoscopic environment, interaction forces, and long-range electron transfer. Here, we constrain the orientation and separation between cytochrome c and cytochrome c or the phosphomimetic Y48pCMF cytochrome c, and deploy an array of single-molecule, bulk, and computational methods to investigate the molecular mechanism of electron transfer regulation by cytochrome c phosphorylation. We demonstrate that phosphorylation impairs long-range electron transfer, shortens the long-distance charge conduit between the partners, strengthens their interaction, and departs it from equilibrium. These results unveil a nanoscopic view of the interaction between redox protein partners in electron transport chains and its mechanisms of regulation.
Topics: Electron Transport; Cytochromes c; Phosphorylation; Oxidation-Reduction; Cell Respiration
PubMed: 36402842
DOI: 10.1038/s41467-022-34809-1 -
Cells Sep 2020Signal transducer and activator of transcription 3 (STAT3) functions as a major molecular switch that plays an important role in the communication between cytokines and... (Review)
Review
Signal transducer and activator of transcription 3 (STAT3) functions as a major molecular switch that plays an important role in the communication between cytokines and kinases. In this role, it regulates the transcription of genes involved in various biochemical processes, such as proliferation, migration, and metabolism of cancer cells. STAT3 undergoes diverse post-translational modifications, such as the oxidation of cysteine by oxidative stress, the acetylation of lysine, or the phosphorylation of serine/threonine. In particular, the redox modulation of critical cysteine residues present in the DNA-binding domain of STAT3 inhibits its DNA-binding activity, resulting in the inactivation of STAT3-mediated gene expression. Accumulating evidence supports that STAT3 is a key protein that acts as a mediator of metabolism and mitochondrial activity. In this review, we focus on the post-translational modifications of STAT3 by oxidative stress and how the modification of STAT3 regulates cell metabolism, particularly in the metabolic pathways in cancer cells.
Topics: Acetylation; Cell Respiration; Humans; Methylation; Mitochondria; Neoplasms; Oxidation-Reduction; Oxidative Stress; Peroxidases; Phosphorylation; Protein Processing, Post-Translational; STAT3 Transcription Factor
PubMed: 33003453
DOI: 10.3390/cells9102202 -
Cells Jun 2022Hypoxia in cancer is a thoroughly studied phenomenon, and the logical cause of the reduction in oxygen tension is tumor growth itself. While sustained hypoxia leads to... (Review)
Review
Hypoxia in cancer is a thoroughly studied phenomenon, and the logical cause of the reduction in oxygen tension is tumor growth itself. While sustained hypoxia leads to death by necrosis in cells, there is an exquisitely regulated mechanism that rescues hypoxic cells from their fatal fate. The accumulation in the cytoplasm of the transcription factor HIF-1α, which, under normoxic conditions, is marked for degradation by a group of oxygen-sensing proteins known as prolyl hydroxylases (PHDs) in association with the von Hippel-Lindau anti-oncogene (VHL) is critical for the cell, as it regulates different mechanisms through the genes it induces. A group of microRNAs whose expression is regulated by HIF, collectively called hypoxaMIRs, have been recognized. In this review, we deal with the hypoxaMIRs that have been shown to be expressed in colorectal cancer. Subsequently, using data mining, we analyze a panel of hypoxaMIRs expressed in both normal and tumor tissues obtained from TCGA. Finally, we assess the impact of these hypoxaMIRs on cancer hallmarks through their target genes.
Topics: Cell Hypoxia; Colorectal Neoplasms; Humans; Hypoxia; Oxygen; Transcription Factors; Von Hippel-Lindau Tumor Suppressor Protein
PubMed: 35741024
DOI: 10.3390/cells11121895 -
Cells Nov 2021Cardiorenal syndrome (CRS) is a pathological link between the kidneys and heart, in which an insult in a kidney or heart leads the other organ to incur damage. CRS is...
Cardiorenal syndrome (CRS) is a pathological link between the kidneys and heart, in which an insult in a kidney or heart leads the other organ to incur damage. CRS is classified into five subtypes, and type 3 (CRS3) is characterized by acute kidney injury as a precursor to subsequent cardiovascular changes. Mitochondrial dysfunction and oxidative and nitrosative stress have been reported in the pathophysiology of CRS3. It is known that vitamin C, an antioxidant, has proven protective capacity for cardiac, renal, and vascular endothelial tissues. Therefore, the present study aimed to assess whether vitamin C provides protection to heart and the kidneys in an in vivo CRS3 model. The unilateral renal ischemia and reperfusion (IR) protocol was performed for 60 min in the left kidney of adult mice, with and without vitamin C treatment, immediately after IR or 15 days after IR. Kidneys and hearts were subsequently collected, and the following analyses were conducted: renal morphometric evaluation, serum urea and creatinine levels, high-resolution respirometry, amperometry technique for NO measurement, gene expression of mitochondrial dynamic markers, and NOS. The analyses showed that the left kidney weight was reduced, urea and creatinine levels were increased, mitochondrial oxygen consumption was reduced, NO levels were elevated, and Mfn2 expression was reduced after 15 days of IR compared to the sham group. Oxygen consumption and NO levels in the heart were also reduced. The treatment with vitamin C preserved the left kidney weight, restored renal function, reduced NO levels, decreased iNOS expression, elevated constitutive NOS isoforms, and improved oxygen consumption. In the heart, oxygen consumption and NO levels were improved after vitamin C treatment, whereas the three NOS isoforms were overexpressed. These data indicate that vitamin C provides protection to the kidneys and some beneficial effects to the heart after IR, indicating it may be a preventive approach against cardiorenal insults.
Topics: Animals; Ascorbic Acid; Cardio-Renal Syndrome; Cell Respiration; Isoenzymes; Kidney; Male; Mice, Inbred C57BL; Mitochondria; Mitochondrial Dynamics; Models, Biological; Nitric Oxide; Nitric Oxide Synthase; Reperfusion Injury; Mice
PubMed: 34831251
DOI: 10.3390/cells10113029 -
International Journal of Molecular... Feb 2022Analysis of the function, structure, and intracellular organization of mitochondria is important for elucidating energy metabolism and intracellular energy transfer. In... (Review)
Review
Analysis of the function, structure, and intracellular organization of mitochondria is important for elucidating energy metabolism and intracellular energy transfer. In addition, basic and clinically oriented studies that investigate organ/tissue/cell dysfunction in various human diseases, including myopathies, cardiac/brain ischemia-reperfusion injuries, neurodegenerative diseases, cancer, and aging, require precise estimation of mitochondrial function. It should be noted that the main metabolic and functional characteristics of mitochondria obtained in situ (in permeabilized cells and tissue samples) and in vitro (in isolated organelles) are quite different, thereby compromising interpretations of experimental and clinical data. These differences are explained by the existence of the mitochondrial network, which possesses multiple interactions between the cytoplasm and other subcellular organelles. Metabolic and functional crosstalk between mitochondria and extra-mitochondrial cellular environments plays a crucial role in the regulation of mitochondrial metabolism and physiology. Therefore, it is important to analyze mitochondria in vivo or in situ without their isolation from the natural cellular environment. This review summarizes previous studies and discusses existing approaches and methods for the analysis of mitochondrial function, structure, and intracellular organization in situ.
Topics: Animals; Cell Respiration; Energy Metabolism; Humans; Mitochondria, Heart; Muscle, Skeletal; Myocytes, Cardiac
PubMed: 35216368
DOI: 10.3390/ijms23042252