scholarly journals Normalizing HIF-1α Signaling Improves Cellular Glucose Metabolism and Blocks the Pathological Pathways of Hyperglycemic Damage

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1139
Author(s):  
Carla Iacobini ◽  
Martina Vitale ◽  
Giuseppe Pugliese ◽  
Stefano Menini
Keyword(s):  
Diabetic Complications ◽  
Oxidative Metabolism ◽  
Cell Injury ◽  
Hypoxia Inducible Factor ◽  
Biochemical Changes ◽  
Glyoxalase 1 ◽  
Mitochondrial Superoxide ◽  
Monocyte Cell ◽  
Intracellular Metabolism ◽  
Excess Glucose

Intracellular metabolism of excess glucose induces mitochondrial dysfunction and diversion of glycolytic intermediates into branch pathways, leading to cell injury and inflammation. Hyperglycemia-driven overproduction of mitochondrial superoxide was thought to be the initiator of these biochemical changes, but accumulating evidence indicates that mitochondrial superoxide generation is dispensable for diabetic complications development. Here we tested the hypothesis that hypoxia inducible factor (HIF)-1α and related bioenergetic changes (Warburg effect) play an initiating role in glucotoxicity. By using human endothelial cells and macrophages, we demonstrate that high glucose (HG) induces HIF-1α activity and a switch from oxidative metabolism to glycolysis and its principal branches. HIF1-α silencing, the carbonyl-trapping and anti-glycating agent ʟ-carnosine, and the glyoxalase-1 inducer trans-resveratrol reversed HG-induced bioenergetics/biochemical changes and endothelial-monocyte cell inflammation, pointing to methylglyoxal (MGO) as the non-hypoxic stimulus for HIF1-α induction. Consistently, MGO mimicked the effects of HG on HIF-1α induction and was able to induce a switch from oxidative metabolism to glycolysis. Mechanistically, methylglyoxal causes HIF1-α stabilization by inhibiting prolyl 4-hydroxylase domain 2 enzyme activity through post-translational glycation. These findings introduce a paradigm shift in the pathogenesis and prevention of diabetic complications by identifying HIF-1α as essential mediator of glucotoxicity, targetable with carbonyl-trapping agents and glyoxalase-1 inducers.

HIF-1α in endurance training: suppression of oxidative metabolism

2007 ◽  
Vol 293 (5) ◽  
pp. R2059-R2069 ◽  
Author(s):  
Steven D. Mason ◽  
Helene Rundqvist ◽  
Ioanna Papandreou ◽  
Roger Duh ◽  
Wayne J. McNulty ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Endurance Training ◽  
Oxidative Metabolism ◽  
Hypoxia Inducible Factor ◽  
Transcriptional Response ◽  
Oxidative Capacity ◽  
Pyruvate Dehydrogenase Kinase ◽  
Amp Activated Protein Kinase ◽  
Training Protocol

During endurance training, exercising skeletal muscle experiences severe and repetitive oxygen stress. The primary transcriptional response factor for acclimation to hypoxic stress is hypoxia-inducible factor-1α (HIF-1α), which upregulates glycolysis and angiogenesis in response to low levels of tissue oxygenation. To examine the role of HIF-1α in endurance training, we have created mice specifically lacking skeletal muscle HIF-1α and subjected them to an endurance training protocol. We found that only wild-type mice improve their oxidative capacity, as measured by the respiratory exchange ratio; surprisingly, we found that HIF-1α null mice have already upregulated this parameter without training. Furthermore, untrained HIF-1α null mice have an increased capillary to fiber ratio and elevated oxidative enzyme activities. These changes correlate with constitutively activated AMP-activated protein kinase in the HIF-1α null muscles. Additionally, HIF-1α null muscles have decreased expression of pyruvate dehydrogenase kinase I, a HIF-1α target that inhibits oxidative metabolism. These data demonstrate that removal of HIF-1α causes an adaptive response in skeletal muscle akin to endurance training and provides evidence for the suppression of mitochondrial biogenesis by HIF-1α in normal tissue.

scholarly journals HIF-1-mediated production of exosomes during hypoxia is protective in renal tubular cells

2017 ◽  
Vol 313 (4) ◽  
pp. F906-F913 ◽  
Author(s):  
Wei Zhang ◽  
Xiangjun Zhou ◽  
Qisheng Yao ◽  
Yutao Liu ◽  
Hao Zhang ◽  
...  
Keyword(s):  
Cell Injury ◽  
Hypoxia Inducible Factor ◽  
Atp Depletion ◽  
Tubular Cell ◽  
Renal Tubular Cell ◽  
Dependent Manner ◽  
Protective Effects ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Renal Tubular

Exosomes are nano-sized vesicles produced and secreted by cells to mediate intercellular communication. The production and function of exosomes in kidney tissues and cells remain largely unclear. Hypoxia is a common pathophysiological condition in kidneys. This study was designed to characterize exosome production during hypoxia of rat renal proximal tubular cells (RPTCs), investigate the regulation by hypoxia-inducible factor-1 (HIF-1), and determine the effect of the exosomes on ATP-depletion-induced tubular cell injury. Hypoxia did not change the average sizes of exosomes secreted by RPTCs, but it significantly increased exosome production in a time-dependent manner. HIF-1 induction with dimethyloxalylglycine also promoted exosome secretion, whereas pharmacological and genetic suppression of HIF-1 abrogated the increase of exosome secretion under hypoxia. The exosomes from hypoxic RPTCs had inhibitory effects on apoptosis of RPTCs following ATP depletion. The protective effects were lost in the exosomes from HIF-1α knockdown cells. It is concluded that hypoxia stimulates exosome production and secretion in renal tubular cells. The exosomes from hypoxic cells are protective against renal tubular cell injury. HIF-1 mediates exosome production during hypoxia and contributes to the cytoprotective effect of the exosomes.

Hepatocarcinogenesis by Thioacetamide: Correlations of Histological and Biochemical Changes, and Possible Role of Cell Injury

Pathobiology ◽  
1977 ◽  
Vol 45 (1-2) ◽  
pp. 34-47 ◽  
Author(s):  
L.J. Anghileri ◽  
M. Heidbreder ◽  
G. Weiler ◽  
R. Dermietzel
Keyword(s):  
Cell Injury ◽  
Biochemical Changes

Differential effects of respiratory inhibitors on glycolysis in proximal tubules

1990 ◽  
Vol 258 (6) ◽  
pp. F1608-F1615 ◽  
Author(s):  
K. G. Dickman ◽  
L. J. Mandel
Keyword(s):  
Oxidative Metabolism ◽  
Cell Injury ◽  
Lactate Production ◽  
Proximal Tubules ◽  
Antimycin A ◽  
Transport Function ◽  
Atp Production ◽  
Rotenone Treatment ◽  
Glycolytic Atp ◽  
Ldh Release

The effects of inhibition of mitochondrial energy production at various points along the respiratory chain on glycolytic lactate production and transport function were examined in a suspension of purified rabbit renal proximal tubules. Paradoxically, partial blockage at site 3 by hypoxia (1% O2) induced lactate production, whereas total site 3 blockage by anoxia (0% O2) failed to stimulate glycolysis. Compared with anoxia, hypoxic tubules exhibited greater preservation of ATP and K+ contents during O2 deprivation and more fully recovered oxidative metabolism and transport function during reoxygenation. The mitochondrial site 1 inhibitor rotenone and the uncoupler carbonyl cyanide-p-trifluorome-thoxyphenylhydrazone (FCCP) were equipotent stimuli for lactate production, whereas the site 2 inhibitor antimycin A failed to stimulate glycolysis despite a 90% inhibition of O2 consumption. Compared with antimycin A, treatment with rotenone or FCCP resulted in less cell injury [measured by lactate dehydrogenase (LDH) release] and greater preservation of cell K+ and ATP contents. 2-Deoxyglucose blocked lactate production by 50% in the presence of rotenone and increased LDH release, suggesting that glycolytic ATP is partially protective. Addition of ouabain during rotenone treatment reduced lactate production by 50%, indicating that glycolytic ATP can be used to fuel the Na pump when mitochondrial ATP production is inhibited. We conclude that 1) proximal tubules can generate lactate during inhibition of oxidative metabolism by hypoxia, rotenone, or FCCP; 2) mitochondrial inhibition is not obligatorily linked to activation of glycolysis, since neither anoxia nor antimycin A stimulate lactate production; 3) when ATP can be produced through anaerobic glycolysis it serves to protect cell viability and transport function during respiratory inhibition.

Nox as a target for diabetic complications

2013 ◽  
Vol 125 (8) ◽  
pp. 361-382 ◽  
Author(s):  
Yves Gorin ◽  
Karen Block
Keyword(s):  
Diabetic Complications ◽  
Cell Injury ◽  
Transforming Growth Factor ◽  
Current Knowledge ◽  
Critical Role ◽  
Control Cell ◽  
Renin Angiotensin System ◽  
Present Review ◽  
Nadph Oxidases ◽  
Complications Of Diabetes

Oxidative stress has been linked to the pathogenesis of the major complications of diabetes in the kidney, the heart, the eye or the vasculature. NADPH oxidases of the Nox family are a major source of ROS (reactive oxygen species) and are critical mediators of redox signalling in cells from different organs afflicted by the diabetic milieu. In the present review, we provide an overview of the current knowledge related to the understanding of the role of Nox in the processes that control cell injury induced by hyperglycaemia and other predominant factors enhanced in diabetes, including the renin–angiotensin system, TGF-β (transforming growth factor-β) and AGEs (advanced glycation end-products). These observations support a critical role for Nox homologues in diabetic complications and indicate that NADPH oxidases are an important therapeutic target. Therefore the design and development of small-molecule inhibitors that selectively block Nox oxidases appears to be a reasonable approach to prevent or retard the complications of diabetes in target organs. The bioefficacy of these agents in experimental animal models is also discussed in the present review.

scholarly journals Metabolic Heterogeneity of Cancer Cells: An Interplay between Reprogrammed and Oxidative Metabolism and Roles of HIF-1, GLUTs and AMPK

2020 ◽  
Author(s):  
Nurbubu T. Moldogazieva ◽  
Innokenty M. Mokhosoev ◽  
Alexander A. Terentiev
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Oxidative Metabolism ◽  
Cell Metabolism ◽  
Hypoxia Inducible Factor ◽  
Metabolic Plasticity ◽  
Anti Cancer ◽  
Cancer Cell Metabolism ◽  
Metabolic Heterogeneity ◽  
Amp Activated Protein Kinase

It has been long recognized that under hypoxia conditions cancer cells reprogram their metabolism through shift from oxidative phosphorylation (OXPHOS) to glycolysis to meet elevated requirements in energy and nutrients for proliferation, migration and survival. However, data accumulated over the last years increasingly evidence that cancer cells can revert from glycolysis to OXPHOS and maintain both reprogrammed and oxidative metabolism even in the same tumor. The phenomenon denoted as cancer cell metabolic plasticity or hybrid metabolism depends on a tumor micro-environment, which is highly heterogeneous and influenced by intensity of vasculature and blood flow, oxygen concentration, nutrient and energy supply, and requires regulatory interplay between multiple oncogenes, transcription factors, growth factors, reactive oxygen species (ROS), etc. Hypoxia-inducible factor-1 (HIF-1) and AMP-activated protein kinase (AMPK) represent key modulators of switch between reprogrammed and oxidative metabolism. The present review focuses on cross-talks between HIF-1, GLUTs, and AMPK and other regulatory proteins including oncogenes such as c-Myc, p53 and KRAS, growth factor-initiated PKB/Akt, PI3K and mTOR signaling pathways and tumor suppressors such as LKB1 and TSC1 in controlling cancer cell metabolism. The multiple switches between metabolic pathways can underlie chemo-resistance to conventional anti-cancer therapy and should be taken into account in choosing molecular targets to discovery novel anti-cancer drugs.

scholarly journals Diabetes, Immunity and Defense System: A Paradox in Treatment

2020 ◽  
Vol 2 (3) ◽  
pp. 79-84
Author(s):  
Gupta BL ◽  
Prasad G
Keyword(s):  
Immune System ◽  
Diabetic Complications ◽  
Herbal Medicines ◽  
Black Pepper ◽  
Pentose Phosphate ◽  
The Body ◽  
Defense System ◽  
System A ◽  
Bacteria And Fungi ◽  
Excess Glucose

Hyperglycemia has been the primary metabolic condition for the origin of diabetic complications. The glucose in the cell is underutilized due to diminished entry of glucose into the cell and down-regulation of the Pentose Phosphate Pathway. The PPP is the potential pathway in maintaining the defense of the cell through GPx, GR, GSH, and GSSG. Particularly, GPx and GSH levels diminish in diabetes. Constipation in diabetes also plays an important role in decreasing the immune system as the excess glucose in the gut lining enhances the number of gut bacteria and fungi. Antioxidants have not been proved to enhance the immune and defense of cells in diabetes but the exhibitory roles of herbal medicines have been potential in exaggerating the immune and defense system by their unknown modulators and enhancers molecules. Turmeric and black pepper have been proven to enhance the immune and defense of the body in diabetics.

scholarly journals The role of DJ-1 in human primary alveolar type II cell injury induced by e-cigarette aerosol

2019 ◽  
Vol 317 (4) ◽  
pp. L475-L485 ◽  
Author(s):  
Karim Bahmed ◽  
Chih-Ru Lin ◽  
Hannah Simborio ◽  
Loukmane Karim ◽  
Mark Aksoy ◽  
...  
Keyword(s):  
Lung Injury ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Cell Injury ◽  
Electronic Cigarettes ◽  
Alveolar Epithelial Cells ◽  
Alveolar Type ◽  
Type Ii ◽  
Mitochondrial Superoxide ◽  
Atii Cell

The alveolus participates in gas exchange, which can be impaired by environmental factors and toxins. There is an increase in using electronic cigarettes (e-cigarettes); however, their effect on human primary alveolar epithelial cells is unknown. Human lungs were obtained from nonsmoker organ donors to isolate alveolar type II (ATII) cells. ATII cells produce and secrete pulmonary surfactant and restore the epithelium after damage, and mitochondrial function is important for their metabolism. Our data indicate that human ATII cell exposure to e-cigarette aerosol increased IL-8 levels and induced DNA damage and apoptosis. We also studied the cytoprotective effect of DJ-1 against ATII cell injury. DJ-1 knockdown in human primary ATII cells sensitized cells to mitochondrial dysfunction as detected by high mitochondrial superoxide production, decreased mitochondrial membrane potential, and calcium elevation. DJ-1 knockout (KO) mice were more susceptible to ATII cell apoptosis and lung injury induced by e-cigarette aerosol compared with wild-type mice. Regulation of the oxidative phosphorylation (OXPHOS) is important for mitochondrial function and protection against oxidative stress. Major subunits of the OXPHOS system are encoded by both nuclear and mitochondrial DNA. We found dysregulation of OXPHOS complexes in DJ-1 KO mice after exposure to e-cigarette aerosol, which could disrupt the nuclear/mitochondrial stoichiometry, resulting in mitochondrial dysfunction. Together, our results indicate that DJ-1 deficiency sensitizes ATII cells to damage induced by e-cigarette aerosol leading to lung injury.

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