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Effect of Sirolimus/Metformin Co-Treatment on Hyperglycemia and Cellular Respiration in BALB/c Mice.International Journal of Molecular... Jan 2023Sirolimus (SRL) is widely used as an immunosuppressant to prevent graft rejection, despite the risk of impairing glucose metabolism. Metformin (MET) can reduce the...
Sirolimus (SRL) is widely used as an immunosuppressant to prevent graft rejection, despite the risk of impairing glucose metabolism. Metformin (MET) can reduce the detrimental effects of SRL in many patients, including diabetes and renal transplant recipients. Limited in vivo studies have reported on SRL and MET therapy, particularly in relation to cellular bioenergetics, glucose metabolism, and insulin resistance. Herein, we investigated the efficacy of SRL and MET co-treatment in BALB/c mice over 4 weeks. Balb/c mice (4-6 weeks old) were divided into four groups and injected intraperitoneally (i.p.) with water (control, CTRL), MET (200 µg/g), SRL (5 µg/g), or MET (200 µg/g) +SRL (5 µg/g) over a period of one month. We evaluated the body weight, food consumption rate, random blood glucose (BG), insulin levels, serum biochemistry parameters (ALT, Albumin, BUN, Creatinine), and histomorphology in all groups using standardized techniques and assays. All drug-treated groups showed a statistically significant decrease in weight gain compared to the CTRL group, despite normal food intake. Treatment with SRL caused elevated BG and insulin levels, which were restored with SRL + MET combination. Serum biochemical parameters were within the normal range in all the studied groups. SRL+ MET co-treatment decreased liver cellular respiration and increased cellular ATP levels in the liver. In the pancreas, co-treatment resulted in increased cellular respiration and decreased cellular ATP levels. Liver and pancreatic histology were unchanged in all groups. This study showed that co-treatment of SRL with MET alleviates hyperglycemia induced by SRL without any deleterious effects. These results provide initial insights into the potential use of SRL + MET therapy in various settings.
Topics: Animals; Mice; Sirolimus; Metformin; Mice, Inbred BALB C; Immunosuppressive Agents; Hyperglycemia; Cell Respiration; Glucose; Insulins; Adenosine Triphosphate; Graft Rejection
PubMed: 36674739
DOI: 10.3390/ijms24021223 -
Oncotarget May 2023While glycolysis is abundant in malignancies, mitochondrial metabolism is significant as well. Mitochondria harbor the enzymes relevant for cellular respiration, which...
While glycolysis is abundant in malignancies, mitochondrial metabolism is significant as well. Mitochondria harbor the enzymes relevant for cellular respiration, which is a critical pathway for both regeneration of reduction equivalents and energy production in the form of ATP. The oxidation of NADH and FADH are fundamental since NAD and FAD are the key components of the TCA-cycle that is critical to entertain biosynthesis in cancer cells. The TCA-cycle itself is predominantly fueled through carbons from glucose, glutamine, fatty acids and lactate. Targeting mitochondrial energy metabolism appears feasible through several drug compounds that activate the CLPP protein or interfere with NADH-dehydrogenase, pyruvate-dehydrogenase, enzymes of the TCA-cycle and mitochondrial matrix chaperones. While these compounds have demonstrated anti-cancer effects , recent research suggests which patients most likely benefit from such treatments. Here, we provide a brief overview of the status quo of targeting mitochondrial energy metabolism in glioblastoma and highlight a novel combination therapy.
Topics: Humans; Glioblastoma; NAD; Citric Acid Cycle; Energy Metabolism; Cell Respiration; Glycolysis; Glucose; Oxidoreductases
PubMed: 37141415
DOI: 10.18632/oncotarget.28424 -
Cell Reports Apr 2023The mitochondrial response to changes in cellular energy demand is necessary for cellular adaptation and organ function. Many genes are essential in orchestrating this...
The mitochondrial response to changes in cellular energy demand is necessary for cellular adaptation and organ function. Many genes are essential in orchestrating this response, including the transforming growth factor (TGF)-β1 target gene Mss51, an inhibitor of skeletal muscle mitochondrial respiration. Although Mss51 is implicated in the pathophysiology of obesity and musculoskeletal disease, how Mss51 is regulated is not entirely understood. Site-1 protease (S1P) is a key activator of several transcription factors required for cellular adaptation. However, the role of S1P in muscle is unknown. Here, we identify S1P as a negative regulator of muscle mass and mitochondrial respiration. S1P disruption in mouse skeletal muscle reduces Mss51 expression and increases muscle mass and mitochondrial respiration. The effects of S1P deficiency on mitochondrial activity are counteracted by overexpressing Mss51, suggesting that one way S1P inhibits respiration is by regulating Mss51. These discoveries expand our understanding of TGF-β signaling and S1P function.
Topics: Animals; Mice; Cell Respiration; Mitochondria; Muscle, Skeletal; Signal Transduction; Transforming Growth Factor beta
PubMed: 37002920
DOI: 10.1016/j.celrep.2023.112336 -
Frontiers in Bioscience (Landmark... Jul 2022This report aims to detail the use of the phosphorescence oxygen analyzer for investigation of thymic responses to pharmaceutical agents, in particular...
BACKGROUND
This report aims to detail the use of the phosphorescence oxygen analyzer for investigation of thymic responses to pharmaceutical agents, in particular immunosuppressants and immunomodulators. Sirolimus (a highly specific inhibitor of the 'molecular target of rapamycin', mTOR) and ozanimod (an agonist of the sphingosine 1-phosphate receptor, recently approved for treatment of multiple sclerosis and ulcerative colitis) are used for this purpose.
METHODS
Thymic fragments from mice were placed in glass vials containing phosphate-buffered saline, bovine albumin, and Pd(II) meso-tetra (sulfophenyl) tetrabenzoporphyrin. The vials were sealed from air, and the cellular oxygen consumption was monitored as function of time.
RESULTS
The decline of dissolved oxygen concentration with time (d[O2]/d) was linear; thus, its rate (thymocyte respiration) was expressed as μM O2 min-1. Cyanide inhibited respiration, confirming the oxygen consumption was in cytochrome oxidase. In age-matched mice, the rate of thymocyte respiration (mean ± SD, in μM O2 min-1 mg-1) was 0.046 ± 0.011 (median = 0.043, range = 0.028 to 0.062, n = 10). In thymic fragments from littermates, this rate was inhibited in the presence of sirolimus (16% lower) or ozanimod (29% lower).
CONCLUSIONS
Thymocyte respiration can serve as a surrogate biomarker for studying the mode-of-action and the cytotoxicity of immunotoxins and immunosuppressants.
Topics: Animals; Cattle; Cell Respiration; Immunosuppressive Agents; Mice; Oxygen; Oxygen Consumption; Sirolimus
PubMed: 36042174
DOI: 10.31083/j.fbl2708230 -
Journal of Molecular Endocrinology Apr 2018Many physiological processes are regulated with a 24-h periodicity to anticipate the environmental changes of daytime to nighttime and vice versa. These 24-h... (Review)
Review
Many physiological processes are regulated with a 24-h periodicity to anticipate the environmental changes of daytime to nighttime and vice versa. These 24-h regulations, commonly termed circadian rhythms, among others control the sleep-wake cycle, locomotor activity and preparation for food availability during the active phase (daytime for humans and nighttime for nocturnal animals). Disturbing circadian rhythms at the organ or whole-body level by social jetlag or shift work, increases the risk to develop chronic metabolic diseases such as type 2 diabetes mellitus. The molecular basis of this risk is a topic of increasing interest. Mitochondria are essential organelles that produce the majority of energy in eukaryotes by converting lipids and carbohydrates into ATP through oxidative phosphorylation. To adapt to the ever-changing environment, mitochondria are highly dynamic in form and function and a loss of this flexibility is linked to metabolic diseases. Interestingly, recent studies have indicated that changes in mitochondrial morphology (i.e., fusion and fission) as well as generation of new mitochondria are dependent on a viable circadian clock. In addition, fission and fusion processes display diurnal changes that are aligned to the light/darkness cycle. Besides morphological changes, mitochondrial respiration also displays diurnal changes. Disturbing the molecular clock in animal models leads to abrogated mitochondrial rhythmicity and altered respiration. Moreover, mitochondrial-dependent production of reactive oxygen species, which plays a role in cellular signaling, has also been linked to the circadian clock. In this review, we will summarize recent advances in the study of circadian rhythms of mitochondria and how this is linked to the molecular circadian clock.
Topics: Animals; Cell Respiration; Circadian Rhythm; Humans; Mitochondria; Mitophagy; Models, Biological; Reactive Oxygen Species
PubMed: 29378772
DOI: 10.1530/JME-17-0196 -
Experimental Biology and Medicine... Jul 2020Hypoxia contributes to tumor aggressiveness and promotes growth of many solid tumors that are often resistant to conventional therapies. In order to achieve successful... (Review)
Review
Hypoxia contributes to tumor aggressiveness and promotes growth of many solid tumors that are often resistant to conventional therapies. In order to achieve successful therapeutic strategies targeting different cancer types, it is necessary to understand the molecular mechanisms and signaling pathways that are induced by hypoxia. Aberrant tumor vasculature and alterations in cellular metabolism and drug resistance due to hypoxia further confound this problem. This review focuses on the implications of hypoxia in an inflammatory TME and its impact on the signaling and metabolic pathways regulating growth and progression of cancer, along with changes in lymphangiogenic and angiogenic mechanisms. Finally, the overarching role of hypoxia in mediating therapeutic resistance in cancers is discussed.
Topics: Cell Hypoxia; Cell Respiration; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Mitochondria; Neoplasms; Tumor Microenvironment
PubMed: 32594767
DOI: 10.1177/1535370220934038 -
Biochemical Society Transactions Dec 2023SLC25A51 is the primary mitochondrial NAD+ transporter in humans and controls many local reactions by mediating the influx of oxidized NAD+. Intriguingly, SLC25A51 lacks... (Review)
Review
SLC25A51 is the primary mitochondrial NAD+ transporter in humans and controls many local reactions by mediating the influx of oxidized NAD+. Intriguingly, SLC25A51 lacks several key features compared with other members in the mitochondrial carrier family, thus its molecular mechanism has been unclear. A deeper understanding would shed light on the control of cellular respiration, the citric acid cycle, and free NAD+ concentrations in mammalian mitochondria. This review discusses recent insights into the transport mechanism of SLC25A51, and in the process highlights a multitiered regulation that governs NAD+ transport. The aspects regulating SLC25A51 import activity can be categorized as contributions from (1) structural characteristics of the transporter itself, (2) its microenvironment, and (3) distinctive properties of the transported ligand. These unique mechanisms further evoke compelling new ideas for modulating the activity of this transporter, as well as new mechanistic models for the mitochondrial carrier family.
Topics: Animals; Humans; Biological Transport; Cell Respiration; Mammals; Mitochondria; Mitochondrial Membrane Transport Proteins; NAD
PubMed: 38108469
DOI: 10.1042/BST20220318 -
Biomolecules Jan 2021Inflammatory response plays an essential role in the resolution of infections. However, inflammation can be detrimental to an organism and cause irreparable damage. For...
Inflammatory response plays an essential role in the resolution of infections. However, inflammation can be detrimental to an organism and cause irreparable damage. For example, during sepsis, a cytokine storm can lead to multiple organ failures and often results in death. One of the strongest triggers of the inflammatory response is bacterial lipopolysaccharides (LPS), acting mostly through Toll-like receptor 4 (TLR4). Paradoxically, while exposure to LPS triggers a robust inflammatory response, repeated or prolonged exposure to LPS can induce a state of endotoxin tolerance, a phenomenon where macrophages and monocytes do not respond to new endotoxin challenges, and it is often associated with secondary infections and negative outcomes. The cellular mechanisms regulating this phenomenon remain elusive. We used metabolic measurements to confirm differences in the cellular metabolism of naïve macrophages and that of macrophages responding to LPS stimulation or those in the LPS-tolerant state. In parallel, we performed an unbiased secretome survey using quantitative mass spectrometry during the induction of LPS tolerance, creating the first comprehensive secretome profile of endotoxin-tolerant cells. The secretome changes confirmed that LPS-tolerant macrophages have significantly decreased cellular metabolism and that the proteins secreted by LPS-tolerant macrophages have a strong association with cell survival, protein metabolism, and the metabolism of reactive oxygen species.
Topics: Animals; Cell Respiration; Cytokines; Humans; Immune Tolerance; Inflammation; Macrophages; Mass Spectrometry; Mice; Monocytes; RAW 264.7 Cells; Signal Transduction; Toll-Like Receptor 4
PubMed: 33513762
DOI: 10.3390/biom11020164 -
Plant Physiology Apr 2023Plant respiration is a foundational biological process with the potential to be optimized to improve crop yield. To understand and manipulate the outputs of respiration,... (Review)
Review
Plant respiration is a foundational biological process with the potential to be optimized to improve crop yield. To understand and manipulate the outputs of respiration, the inputs of respiration-respiratory substrates-need to be probed in detail. Mitochondria house substrate catabolic pathways and respiratory machinery, so transport into and out of these organelles plays an important role in committing substrates to respiration. The large number of mitochondrial carriers and catabolic pathways that remain unidentified hinder this process and lead to confusion about the identity of direct and indirect respiratory substrates in plants. The sources and usage of respiratory substrates vary and are increasing found to be highly regulated based on cellular processes and environmental factors. This review covers the use of direct respiratory substrates following transport through mitochondrial carriers and catabolism under normal and stressed conditions. We suggest the introduction of enzymes not currently found in plant mitochondria to enable serine and acetate to be direct respiratory substrates in plants. We also compare respiratory substrates by assessing energetic yields, availability in cells, and their full or partial oxidation during cell catabolism. This information can assist in decisions to use synthetic biology approaches to alter the range of respiratory substrates in plants. As a result, respiration could be optimized by introducing, improving, or controlling specific mitochondrial transporters and mitochondrial catabolic pathways.
Topics: Mitochondria; Cell Respiration; Oxidation-Reduction; Energy Metabolism; Plants; Respiration
PubMed: 36573332
DOI: 10.1093/plphys/kiac599 -
Plant & Cell Physiology Nov 2021Oxygen is essential for multicellular aerobic life due to its central role in energy metabolism. The availability of oxygen can drop below the level to sustain oxidative... (Review)
Review
Oxygen is essential for multicellular aerobic life due to its central role in energy metabolism. The availability of oxygen can drop below the level to sustain oxidative phosphorylation when plants are flooded, posing a severe threat to survival. However, under non-stressful conditions, the internal oxygen concentration of most plant tissue is not in equilibrium with the environment, which is attributed to cellular respiration and diffusion constrains imposed by O2 barriers and bulky tissue. This is exemplified by the observations of steep oxygen gradients in roots, fruits, tubers, anthers and meristems. To adapt to a varying availability of oxygen, plants sense O2 via the conditional proteolysis of transcriptional regulators. This mechanism acts to switch oxidative metabolism to anaerobic fermentation, but it was also shown to play a role in plant development and pathogen defense. To investigate how dynamic and spatial distribution of O2 impacts on these processes, accurate mapping of its concentration in plants is essential. Physical oxygen sensors have been employed for decades to profile internal oxygen concentrations in plants, while genetically encoded oxygen biosensors have only recently started to see use. Driven by the critical role of hypoxia in human pathology and development, several novel oxygen-sensing devices have also been characterized in cell lines and animal model organisms. This review aims to provide an overview of available oxygen biosensors and to discuss their potential application to image oxygen levels in plants.
Topics: Biosensing Techniques; Cell Respiration; Intravital Microscopy; Oxygen; Plant Cells
PubMed: 33725087
DOI: 10.1093/pcp/pcab039