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Cold Spring Harbor Perspectives in... May 2021
Review
Topics: Adenosine Triphosphate; Aerobiosis; Animals; Glycolysis; Humans; NAD; Pyruvic Acid; Warburg Effect, Oncologic
PubMed: 33941515
DOI: 10.1101/cshperspect.a040535 -
Journal of Experimental & Clinical... Jul 2020Liver cancer has become the sixth most diagnosed cancer and the fourth leading cause of cancer death worldwide. Hepatocellular carcinoma (HCC) is responsible for up to... (Review)
Review
Liver cancer has become the sixth most diagnosed cancer and the fourth leading cause of cancer death worldwide. Hepatocellular carcinoma (HCC) is responsible for up to 75-85% of primary liver cancers, and sorafenib is the first targeted drug for advanced HCC treatment. However, sorafenib resistance is common because of the resultant enhancement of aerobic glycolysis and other molecular mechanisms. Aerobic glycolysis was firstly found in HCC, acts as a hallmark of liver cancer and is responsible for the regulation of proliferation, immune evasion, invasion, metastasis, angiogenesis, and drug resistance in HCC. The three rate-limiting enzymes in the glycolytic pathway, including hexokinase 2 (HK2), phosphofructokinase 1 (PFK1), and pyruvate kinases type M2 (PKM2) play an important role in the regulation of aerobic glycolysis in HCC and can be regulated by many mechanisms, such as the AMPK, PI3K/Akt pathway, HIF-1α, c-Myc and noncoding RNAs. Because of the importance of aerobic glycolysis in the progression of HCC, targeting key factors in its pathway such as the inhibition of HK2, PFK or PKM2, represent potential new therapeutic approaches for the treatment of HCC.
Topics: Aerobiosis; Carcinoma, Hepatocellular; Glycolysis; Humans; Liver Neoplasms; Signal Transduction
PubMed: 32631382
DOI: 10.1186/s13046-020-01629-4 -
Theranostics 2019Angiogenesis is a fundamental process that involves in tumor progression and metastasis. Vascular endothelial growth factor (VEGF) family and their receptors are...
Angiogenesis is a fundamental process that involves in tumor progression and metastasis. Vascular endothelial growth factor (VEGF) family and their receptors are identified as the most prominent regulators of angiogenesis. However, the clinical efficacy of anti-VEGF/VEGFR therapy is not ideal, prompting the needs to further understand mechanisms behind tumor angiogenesis. Here, we found that Dickkopf associated protein 2 (DKK2), a secretory protein highly expressed in metastatic colorectal cancer tissues, could stimulate angiogenesis via a classic VEGF/VEGFR independent pathway. : DKK2 was screened out from microarray data analyzing gene expression profiles of eight pairs of non-metastatic and metastatic human colorectal cancer (CRC) tissues. Immunofluorescence histochemical staining (IHC) was used to detect the expression of DKK2 and angiogenesis in CRC tissues. Chicken chorioallantoic membrane (CAM) assay and Human umbilical vein endothelial cells (HUVEC) tubule formation assay was used for and in angiogenesis study, respectively. Lactate and glucose concentration in the culture medium was measured by enzyme-linked immunosorbent assay (ELISA). Luciferase reporter assay was used to verify the interaction between miR-493-5p and the 3'UTR of DKK2. : DKK2 could stimulate angiogenesis via accelerating the aerobic glycolysis of CRC cells, through which lactate is produced from glucose and accumulated in tumor microenvironment. Lactate functions as the final executor of DDK2 to stimulate tube formation of endothelial cells, and blockage of lactate secretion by lactate transporter (MCT) inhibitors dramatically neutralize the progression and metastasis of CRC both and . DKK2 could cooperate with lipoprotein receptor-related protein 6, which is required for glucose uptake, and activated the downstream mTOR signal pathway to accelerate lactate secretion. In addition, the expression of DKK2 is switched on via the demethylation of miR-493-5p, which allows the dissociated of miR-493-5p from the 3'-UTRs of DKK2 and initiates its stimulatory role on CRC progression in an autocrine or paracrine manner. : DKK2 promotes tumor metastasis and angiogenesis through a novel VEGF-independent, but energy metabolism related pathway. DKK2 might be a potential anti-angiogenic target in clinical treatment for the advanced CRC patients.
Topics: Aerobiosis; Colorectal Neoplasms; Gene Expression Profiling; Glycolysis; Histocytochemistry; Humans; Intercellular Signaling Peptides and Proteins; Microarray Analysis; Microscopy, Fluorescence; Neovascularization, Pathologic
PubMed: 30867812
DOI: 10.7150/thno.30056 -
Cancer Metastasis Reviews Jun 2019
Topics: Aerobiosis; Glycolysis; Humans; Hydrogen-Ion Concentration; Neoplasms
PubMed: 31069573
DOI: 10.1007/s10555-019-09798-1 -
Nutrients May 2020Nitric oxide related ergogenic aids such as arginine (Arg) have shown to impact positively on sport performance through several physiological and metabolic mechanisms.... (Meta-Analysis)
Meta-Analysis
Nitric oxide related ergogenic aids such as arginine (Arg) have shown to impact positively on sport performance through several physiological and metabolic mechanisms. However, research results have shown to be controversial. The great differences regarding required metabolic pathways and physiological demands between aerobic and anaerobic sport disciplines could be the reasons. The aim of this systematic review and meta-analysis was to evaluate the effects of Arg supplementation on aerobic (≤VOmax) and anaerobic (>VOmax) performance. Likewise, to show the effective dose and timing of this supplementation. A structured search was carried out in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement and PICOS guidelines in PubMed/MEDLINE, Web of Science (WOS), and Scopus databases from inception to January 2020. Eighteen studies were included which compare Arg supplementation with placebo in an identical situation and testing its effects on aerobic and anaerobic performance tests. Trials analyzing supplementation with other supplements were removed and there was not athlete's level, gender, ethnicity, or age filters. The performed meta-analysis included 15 studies and random effects model and pooled standardized mean differences (SMD) were used according to Hedges' g. Results revealed that Arg supplementation could improve aerobic (SMD, 0.84; 95% CI, 0.12 to 1.56; magnitude of SMD (MSMD), large; I2, 89%; = 0.02) and anaerobic (SMD, 0.24; 95% CI, 0.05 to 0.43; MSMD, small; I2, 0%; = 0.01) performance tests. In conclusion, acute Arg supplementation protocols to improve aerobic and anaerobic performance should be adjusted to 0.15 g/kg of body weight ingested between 60-90 min before. Moreover, chronic Arg supplementation should include 1.5-2 g/day for 4-7 weeks in order to improve aerobic performance, and 10-12 g/day for 8 weeks to enhance anaerobic performance.
Topics: Aerobiosis; Anaerobiosis; Arginine; Athletic Performance; Body Weight; Dietary Supplements; Energy Metabolism; Female; Humans; Male; Nitric Oxide; Performance-Enhancing Substances
PubMed: 32370176
DOI: 10.3390/nu12051300 -
Theranostics 2019Emerging evidence indicates that reprogramming of energy metabolism involving disturbances in energy production from a defect in cellular respiration with a shift to...
Endocytosis-mediated mitochondrial transplantation: Transferring normal human astrocytic mitochondria into glioma cells rescues aerobic respiration and enhances radiosensitivity.
Emerging evidence indicates that reprogramming of energy metabolism involving disturbances in energy production from a defect in cellular respiration with a shift to glycolysis is a core hallmark of cancer. Alterations in cancer cell energy metabolism are linked to abnormalities in mitochondrial function. Mitochondrial dysfunction of cancer cells includes increased glycolysis, decreased apoptosis, and resistance to radiotherapy. The study was designed for two main points: firstly, to investigate whether exogenous functional mitochondria can transfer into glioma cells and explore the underlying molecular mechanisms from the perspective of endocytosis; secondly, to further verify whether the mitochondrial transplantation is able to rescue aerobic respiration, attenuate the Warburg effect and enhance the radiosensitivity of gliomas. Mitochondria were isolated from normal human astrocytes (HA) and immediately co-incubated with starved human glioma cells (U87). Confocal microscopy and gene sequencing were performed to evaluate the ability of isolated mitochondria internalization into U87 cells. The interaction between endocytosis and isolated mitochondria transfer were captured by 3D tomographic microscopy and transmission electron microscopy. NAD, CD38, cADPR and Ca release were determined by commercial kits, western blot, HLPC-MS and Fluo-3 AM respectively. PCR array expression profiling and Seahorse XF analysis were used to evaluate the effect of mitochondrial transplantation on energy phenotypes of U87 cells. U87 cells and U87 xenografts were both treated with mitochondrial transplantation, radiation, or a combination of mitochondrial transplantation and radiation. Apoptosis and were detected by cytochrome C, cleaved caspase 9 and TUNEL staining. We found that mitochondria from HA could be transferred into starved U87 cells by simple co-incubation. Starvation treatment slowed the rate of glycolysis and decreased the transformation of NAD to NADH in U87 cells. A large amount of accumulated NAD was released into the extracellular space. CD38 is a member of the NAD glycohydrolase family that catalyzes the cyclization of extracellular NAD to intracellular cADPR. cADPR triggered release of Ca to promote cytoskeleton remodeling and plasma membrane invagination. Thus, endocytosis involving isolated mitochondria internalization was mediated by NAD-CD38-cADPR-Ca signaling. Mitochondrial transfer enhanced gene and protein expression related to the tricarboxylic acid (TCA) cycle, increased aerobic respiration, attenuated glycolysis, reactivated the mitochondrial apoptotic pathway, inhibited malignant proliferation of U87 cells. Isolated mitochondria injected into U87 xenograft tumors also entered cells, and inhibited glioma growth in nude mice. Mitochondrial transplantation could enhance the radiosensitivity of gliomas and . These findings suggested that starvation-induced endocytosis via NAD-CD38-cADPR-Ca signaling could be a new mechanism of mitochondrial transplantation to rescue aerobic respiration and attenuate the Warburg effect. This mechanism could be a promising approach for radiosensitization.
Topics: Aerobiosis; Animals; Astrocytes; Cell Line, Tumor; Cell Respiration; Cellular Reprogramming; Disease Models, Animal; Endocytosis; Glioma; Humans; Mice, Nude; Mitochondria; Models, Biological; Neoplasm Transplantation; Radiation Tolerance; Transplantation, Heterologous
PubMed: 31281500
DOI: 10.7150/thno.33100 -
Nutrients Aug 2020Beta-alanine supplementation (BA) has a positive impact on physical performance. However, evidence showing a benefit of this amino acid in aerobic-anaerobic transition... (Meta-Analysis)
Meta-Analysis
Beta-alanine supplementation (BA) has a positive impact on physical performance. However, evidence showing a benefit of this amino acid in aerobic-anaerobic transition zones is scarce and the results controversial. The aim of this systematic review and meta-analysis is to analyze the effects of BA supplementation on physical performance in aerobic-anaerobic transition zones. At the same time, the effect of different dosages and durations of BA supplementation were identified. The search was designed in accordance with the PRISMA guidelines for systematic reviews and meta-analyses and performed in Web of Science (WOS), Scopus, SPORTDiscus, PubMed, and MEDLINE between 2010 and 2020. The methodological quality and risk of bias were evaluated with the Cochrane Collaboration tool. The main variables were the Time Trial Test (TTT) and Time to Exhaustion (TTE) tests, the latter separated into the Limited Time Test (LTT) and Limited Distance Test (LDT). The analysis was carried out with a pooled standardized mean difference (SMD) through Hedges' g test (95% CI). Nineteen studies were included in the systematic review and meta-analysis, revealing a small effect for time in the TTT (SMD, -0.36; 95% CI, -0.87-0.16; I = 59%; = 0.010), a small effect for LTT (SMD, 0.25; 95% CI, -0.01-0.51; I = 0%; = 0.53), and a large effect for LDT (SMD, 4.27; 95% CI, -0.25-8.79; I = 94%; = 0.00001). BA supplementation showed small effects on physical performance in aerobic-anaerobic transition zones. Evidence on acute supplementation is scarce (one study); therefore, exploration of acute supplementation with different dosages and formats on physical performance in aerobic-anaerobic transition zones is needed.
Topics: Aerobiosis; Anaerobiosis; Dietary Supplements; Humans; Physical Functional Performance; Sports Nutritional Physiological Phenomena; beta-Alanine
PubMed: 32824885
DOI: 10.3390/nu12092490 -
International Journal of Molecular... Dec 2021Glycolysis is considered a main metabolic pathway in highly proliferative cells, including endothelial, epithelial, immune, and cancer cells. Although oxidative... (Review)
Review
Glycolysis is considered a main metabolic pathway in highly proliferative cells, including endothelial, epithelial, immune, and cancer cells. Although oxidative phosphorylation (OXPHOS) is more efficient in ATP production per mole of glucose, proliferative cells rely predominantly on aerobic glycolysis, which generates ATP faster compared to OXPHOS and provides anabolic substrates to support cell proliferation and migration. Cellular metabolism, including glucose metabolism, is under strong circadian control. Circadian clocks control a wide array of metabolic processes, including glycolysis, which exhibits a distinct circadian pattern. In this review, we discuss circadian regulations during metabolic reprogramming and key steps of glycolysis in activated, highly proliferative cells. We suggest that the inhibition of metabolic reprogramming in the circadian manner can provide some advantages in the inhibition of oxidative glycolysis and a chronopharmacological approach is a promising way to treat diseases associated with up-regulated glycolysis.
Topics: Adenosine Triphosphate; Aerobiosis; Cell Proliferation; Circadian Clocks; Glucose; Glycolysis; Humans; Oxidative Phosphorylation
PubMed: 34948470
DOI: 10.3390/ijms222413666 -
Biochimica Et Biophysica Acta.... Jan 2021The cyclic tetrapyrrole heme is used as a prosthetic group in a broad variety of different proteins in almost all organisms. Often, it is essential for vital biochemical... (Review)
Review
The cyclic tetrapyrrole heme is used as a prosthetic group in a broad variety of different proteins in almost all organisms. Often, it is essential for vital biochemical processes such as aerobic and anaerobic respiration as well as photosynthesis. In Nature, heme is made from the common tetrapyrrole precursor 5-aminolevulinic acid, and for a long time it was assumed that heme is biosynthesized by a single, common pathway in all organisms. However, although this is indeed the case in eukaryotes, heme biosynthesis is more diverse in the prokaryotic world, where two additional pathways exist. The final elucidation of the two 'alternative' heme biosynthesis routes operating in some bacteria and archaea was achieved within the last decade. This review summarizes the three different heme biosynthesis pathways with a special emphasis on the two 'new' prokaryotic routes.
Topics: Aerobiosis; Aminolevulinic Acid; Anaerobiosis; Archaea; Bacteria; Heme; Photosynthesis; Prokaryotic Cells; Tetrapyrroles
PubMed: 32976912
DOI: 10.1016/j.bbamcr.2020.118861 -
Trends in Microbiology May 2021Ancient microbes invented biochemical mechanisms and assembled core metabolic pathways on an anoxic Earth. Molecular oxygen appeared far later, forcing microbes to... (Review)
Review
Ancient microbes invented biochemical mechanisms and assembled core metabolic pathways on an anoxic Earth. Molecular oxygen appeared far later, forcing microbes to devise layers of defensive tactics that fend off the destructive actions of both reactive oxygen species (ROS) and oxygen itself. Recent work has pinpointed the enzymes that ROS attack, plus an array of clever protective strategies that abet the well known scavenging systems. Oxygen also directly damages the low-potential metal centers and radical-based mechanisms that optimize anaerobic metabolism; therefore, committed anaerobes have evolved customized tactics that defend these various enzymes from occasional oxygen exposure. Thus a more comprehensive, detailed, and surprising view of oxygen toxicity is coming into view.
Topics: Aerobiosis; Anaerobiosis; Bacteria; Biological Evolution; Oxidative Stress; Oxygen; Reactive Oxygen Species
PubMed: 33109411
DOI: 10.1016/j.tim.2020.10.001