scholarly journals New data on well-known drug: focus on meldonium

2021 ◽  
pp. 110-117
Author(s):  
M. E. Statsenko ◽  
S. V. Turkina ◽  
Yu. E. Lopushkova
Keyword(s):  
Immune Response ◽  
Fatty Acid ◽  
Mitochondrial Dysfunction ◽  
Krebs Cycle ◽  
Acid Oxidation ◽  
Chronic Obstructive ◽  
Positive Trend ◽  
Beta Oxidation ◽  
Obstructive Pulmonary Disease ◽  
Response Increase

The article reviews the efficacy of meldonium in patients with various diseases, which are based on secondary mitochondrial dysfunction. Mitochondria are complex cellular organelles that control many metabolic processes, including fatty acid oxidation, the Krebs cycle, oxidative phosphorylation in the electron transport chain, and many other processes. Many conditions can lead to secondary mitochondrial dysfunction and affect other diseases. Damage to mitochondria can promote the activation of free radical processes and the  initiation of  the  mechanisms of  programmed cell death, mitochondrial dysfunction decrease in the immune response, increase in the activity of the body’s inflammatory response in various infections. Mitochondria appear to be important in COVID-19 pathogenesis because of its role in innate antiviral immunity, as well as inflammation. The article presents data on the effectiveness of using meldonium as a drug that helps to arrest pathological processes in mitochondria. The main mechanism of action of meldonium is based on a decrease in L-carnitine levels and increase of peroxisomes activity in the cytosol Meldonium was designed as a inhibitor of carnitine biosynthesis aimed to prevent accumulation of cytotoxic intermediate products of fatty acid beta- oxidation in ischemic tissues and to block this highly oxygen- consuming process. It is based on the correction of the energy metabolism of the cell. There was a positive trend in the use of meldonium in patients with diseases of the cardiovascular system (chronic ischemic diseases, chronic heart failure, arterial hypertension, etc.), neurological disorders (stroke, cerebrovascular insufficiency, etc.), respiratory diseases. The data on the beneficial effect of meldonium on the immune response in patients with coronavirus, bronchial asthma, chronic obstructive pulmonary disease, during vaccination with anti-influenza serum are presented. A decrease in asthenia was noted against the background of the use of meldonium in patients who had undergone coronavirus infection.

scholarly journals Elevated CO2 Levels Delay Skeletal Muscle Repair by Increasing Fatty Acid Oxidation

2021 ◽  
Vol 11 ◽  
Author(s):  
Ermelinda Ceco ◽  
Diego Celli ◽  
Samuel Weinberg ◽  
Masahiko Shigemura ◽  
Lynn C. Welch ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Muscle Regeneration ◽  
Skeletal Muscle Regeneration ◽  
Acid Oxidation ◽  
Chronic Obstructive ◽  
C2c12 Myoblasts ◽  
Delayed Differentiation ◽  
Chronic Obstructive Pulmonary Diseases

Muscle dysfunction often occurs in patients with chronic obstructive pulmonary diseases (COPD) and affects ventilatory and non-ventilatory skeletal muscles. We have previously reported that hypercapnia (elevated CO2 levels) causes muscle atrophy through the activation of the AMPKα2-FoxO3a-MuRF1 pathway. In the present study, we investigated the effect of normoxic hypercapnia on skeletal muscle regeneration. We found that mouse C2C12 myoblasts exposed to elevated CO2 levels had decreased fusion index compared to myoblasts exposed to normal CO2. Metabolic analyses of C2C12 myoblasts exposed to high CO2 showed increased oxidative phosphorylation due to increased fatty acid oxidation. We utilized the cardiotoxin-induced muscle injury model in mice exposed to normoxia and 10% CO2 for 21 days and observed that muscle regeneration was delayed. High CO2-delayed differentiation in both mouse C2C12 myoblasts and skeletal muscle after injury and was restored to control levels when cells or mice were treated with a carnitine palmitoyltransfearse-1 (CPT1) inhibitor. Taken together, our data suggest that hypercapnia leads to changes in the metabolic activity of skeletal muscle cells, which results in impaired muscle regeneration and recovery after injury.

scholarly journals Alteration of fatty acid oxidation by increased CPT1A on replicative senescence of placenta-derived mesenchymal stem cells

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Jin Seok ◽  
Hyun Sook Jung ◽  
Sohae Park ◽  
Jung Ok Lee ◽  
Chong Jai Kim ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Fatty Acid ◽  
Mitochondrial Dysfunction ◽  
Fatty Acid Oxidation ◽  
Replicative Senescence ◽  
Acid Oxidation ◽  
Differentiation Potential ◽  
Passage Number

Abstract Background Human placenta-derived mesenchymal stem cells (PD-MSCs) are powerful sources for cell therapy in regenerative medicine. However, a limited lifespan by senescence through mechanisms that are well unknown is the greatest obstacle. In the present study, we first demonstrated the characterization of replicative senescent PD-MSCs and their possible mitochondrial functional alterations. Methods Human PD-MSCs were cultured to senescent cells for a long period of time. The cells of before passage number 8 were early cells and after passage number 14 were late cells. Also, immortalized cells of PD-MSCs (overexpressed hTERT gene into PD-MSCs) after passage number 14 were positive control of non-senescent cells. The characterization and mitochondria analysis of PD-MSCs were explored with long-term cultivation. Results Long-term cultivation of PD-MSCs exhibited increases of senescent markers such as SA-β-gal and p21 including apoptotic factor, and decreases of proliferation, differentiation potential, and survival factor. Mitochondrial dysfunction was also observed in membrane potential and metabolic flexibility with enlarged mitochondrial mass. Interestingly, we founded that fatty acid oxidation (FAO) is an important metabolism in PD-MSCs, and carnitine palmitoyltransferase1A (CPT1A) overexpressed in senescent PD-MSCs. The inhibition of CPT1A induced a change of energy metabolism and reversed senescence of PD-MSCs. Conclusions These findings suggest that alteration of FAO by increased CPT1A plays an important role in mitochondrial dysfunction and senescence of PD-MSCs during long-term cultivation.

scholarly journals 2-Mercaptoacetate administration depresses the β-oxidation pathway through an inhibition of long-chain acyl-CoA dehydrogenase activity

1981 ◽  
Vol 196 (3) ◽  
pp. 803-809 ◽  
Author(s):  
F Bauché ◽  
D Sabourault ◽  
Y Giudicelli ◽  
J Nordmann ◽  
R Nordmann
Keyword(s):  
Fatty Acid ◽  
Dehydrogenase Activity ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Beta Oxidation ◽  
Oxidation Pathway ◽  
Respiration Rates ◽  
Chain Acyl ◽  
The One ◽  
Mitochondrial Defect

To elucidate the mechanisms through which 2-mercaptoacetate administration inhibits fatty acid oxidation in the liver, the respiration rates induced by different substrates were studied polarographically in rat hepatic mitochondria isolated 3 h after 2-mercaptoacetate administration. Palmitoyl-L-carnitine oxidation was almost completely inhibited in either the absence or presence of malonate. Octanoate oxidation was also inhibited, and the intramitochondrial acyl-CoA content was markedly increased. The oxidation rate of pyruvate and 2-oxoglutarate on the one hand and of 3-hydroxybutyrate, succinate and glutamate on the other was either normal or only slightly decreased. In the presence of 2,4-dinitrophenol, the extent of the inhibition of palmitoyl-L-carnitine oxidation was unchanged. All these results are consistent with the hypothesis that the 2-mercaptoacetate inhibition of fatty acid oxidation is due to an inhibition of the beta-oxidation pathway itself. Finally, the mitochondrial defect responsible for this inhibition was shown to be an inhibition of palmitoyl-CoA dehydrogenase activity (EC 1.3.99.3).

Role of fatty acid oxidation in mechanism of action of gastric secretagogues

1980 ◽  
Vol 238 (3) ◽  
pp. G255-G262
Author(s):  
J. Chacin ◽  
G. Martinez ◽  
E. Severin
Keyword(s):  
Fatty Acid ◽  
Gastric Mucosa ◽  
Acid Secretion ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Primary Role ◽  
Dependent Manner ◽  
Beta Oxidation

The role of beta-oxidation in the mechanism of stimulation of acid secretion was examined in toad gastric mucosa in vitro. The incubation with 4-pentenoate selectively inhibited in a dose-dependent manner the rate of 14CO2 formation from [1-14C]octanoate. Pretreatment with 20 mM 4-pentenoate sharply reduced the respiratory and secretory responses to theophylline and histamine. Tracer studies showed a major utilization of exogenous octanoate over glucose and pyruvate by the in vitro toad gastric mucosa. Theophylline and histamine stimulated by 69% the rate of octanoate oxidation. Over 60% of the increments in oxygen uptake produced by theophylline and histamine accounted for the increments in octanoate oxidation, whereas glucose and pyruvate together accounted for less than 25%. Octanoate-dependent respiration was shown to correlate with octanoate oxidation under both inhibition with 4-pentenoate and stimulation with theophylline. Theophylline stimulated by 25% the rate of octanoate oxidation in Cl--free glucuronate-nutrient solutions. The present work provides further evidence for the primary role of fatty acid oxidation in the mechanism of acid secretion in amphibian.

scholarly journals Impact of aging on inflammatory and immune responses during elastin peptide-induced murine emphysema

2019 ◽  
Vol 316 (4) ◽  
pp. L608-L620 ◽  
Author(s):  
Alexandre Pierre ◽  
Flora Lemaire ◽  
Aïda Meghraoui-Kheddar ◽  
Sandra Audonnet ◽  
Stéphanie Héry-Huynh ◽  
...  
Keyword(s):  
Immune Response ◽  
Structural Changes ◽  
Interferon Γ ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Specific Memory ◽  
Cell Clones ◽  
The Matrix ◽  
Key Factor ◽  
Lymphocytic Infiltrates

Deterioration of lung functions and degradation of elastin fibers with age are accelerated during chronic obstructive pulmonary disease (COPD). Excessive genesis of soluble elastin peptides (EP) is a key factor in the pathophysiology of COPD. We have previously demonstrated that 6-wk-old mice exhibited emphysematous structural changes associated with proinflammatory immune response after EP instillation. In this study, we investigated the consequences of aging on inflammatory, immune, and histological criteria associated with murine emphysema progression after EP exposure. Young (6 wk old) and elderly (15 mo old) C57BL/6J mice were endotracheally instilled with EP, and, at various time points after treatment, the inflammatory cell profiles from bronchoalveolar lavage fluids (BALF) and the T-lymphocyte phenotypes, at local and systemic levels, were analyzed by flow cytometry. Lungs were also prepared to allow morphological and histological analysis by confocal microscopy. Elderly mice exhibited an earlier development of pulmonary emphysema, characterized by an increase of the inflammatory and lymphocytic infiltrates, extracellular matrix breakdown, and airspace enlargement compared with young mice. This age-dependent parenchymal tissue remodeling was associated with an increase of the matrix metalloproteinase expressions and desmosine levels in BALF and/or sera of EP-treated mice. In addition, both the proportion of CD4+CD28− and CD8+CD28− T cells in the tissues of EP-treated mice and the interferon-γ levels in the EP-specific memory T-cell clones were significantly higher in elderly versus younger mice. This study demonstrates that aging accelerates emphysema development and that this effect is linked to increased EP production and their effects on inflammatory and immune response.

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