Uridine as a protector against hypoxia-induced lung injury

Rozova, E. V.; Mankovskaya, I. N.; Belosludtseva, Natalia V.; Khmil, Natalya; Mironova, Galina D.

doi:10.1038/s41598-019-45979-2

Cited by 14 publications

(11 citation statements)

References 27 publications

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“…Currently available data indicate that the activation of mitoK ATP is able to prevent the development of oxidative stress in the myocardium, the decomposition of ATP and creatine phosphate, reduces the generation of ROS and blocks the oxidation of glutathione [7,8]. Moreover, it was shown, including our data, that mitoK ATP is involved in the adaptation of animals to hypoxia, exerting a positive effect not only in the myocardium, but also in the lungs [12,13], which is of particular importance in P, which is accompanied by the formation of a hypoxic state in the organism, at least of the respiratory type [14].…”

Section: Introductionsupporting

confidence: 66%

Peculiarities of the influence of mitochondrial ATP-dependent K+ channels activation on the function of external respiration under experimental pneumonia

Tsapenko¹,

Shapovalova²,

Timchenko³

et al. 2021

Fiziol Zh

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The studies were performed on male Wistar rats weighing 250-270 with experimental pneumonia (EP) induced by the method of A.M. Kulik. The animals were divided into the following groups: 1 – control; 2 - experimental pneumonia; 3 (first experimental group) - animals, which in parallel with the simulation of pneumonia were intraperitoneally administered uridine at a dose of 0.3 mg/100 g of body weight (daily within 1 week); 4 (second experimental group) - animals in which uridine was administered daily starting from day 4 (at the peak of pneumonia). Animals with EP were examined at 5th (n = 10), 9th (n = 8) and 12th (n = 6) days of the disease development, as well as 1 (n = 5) and 2 (n = 5) months after EP modeling. It was shown that in the first experimental group on the 5th day of EP development, an isoventilator restructuring of respiration was observed. In this group, from day 12 to the end of the study, there was a stenoventilator restructuring of breathing, which was characterized by an increase in tidal volume, alveolar ventilation, oxygen consumption and, accordingly, an increase in oxygen extraction from the alveoli and in the oxygen effect of the respiratory cycle. It can be assumed that in this group, an increase in the intensity of metabolism is provided by the effective activity of the respiratory system. In the second experimental group, isoventilator changes in respiration were observed with a gradual decrease in oxygen consumption and other indicators of the respiratory system efficiency. After 2 months, these changes became significant. Thus, we can talk about significant differences in the effect of uridine on the function of external respiration (i.e., apparently, on the activity of the mitochondrial ATP-dependent K+ channel) during EP, which depended on the period of onset of uridine administration. Application of uridine immediately (1st experimental group) looks more effective and even has a stimulating effect on the respiratory function over a long period of experiment. The administration of uridine starting from the 4 partially normalizes the respiration parameters. However, after 1 month there is a depression of the functions of the respiratory system, which, probably, may further worsen. The reasons for the differences in the identified dynamics require further investigation.

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Section: Introductionsupporting

confidence: 66%

Peculiarities of the influence of mitochondrial ATP-dependent K+ channels activation on the function of external respiration under experimental pneumonia

Tsapenko¹,

Shapovalova²,

Timchenko³

et al. 2021

Fiziol Zh

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“…In agreement with this hypothesis, it has been recently reported that the CDA-dependent deoxyuridine salvage may function as anti-oxidant to protect pancreatic cancer cells against ROS [ 54 ]. Specifically, it has been suggested that uridine has an activating effect on the mitochondrial ATP-dependent potassium channel (mitoKATP) thereby reducing H 2 O 2 levels in the mitochondria and thus the development of oxidative stress [ 55 ]. Indeed, it has been shown that CDA-dependent deoxyuridine can relieve ROS-induced endoplasmic reticulum stress to promote cancer cell survival [ 54 ].…”

Section: Discussionmentioning

confidence: 99%

Chemotherapy-induced CDA expression renders resistant non-small cell lung cancer cells sensitive to 5′-deoxy-5-fluorocytidine (5′-DFCR)

Gao

Zens

et al. 2021

J Exp Clin Cancer Res

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Background Pemetrexed (MTA) plus cisplatin combination therapy is considered the standard of care for patients with advanced non-small-cell lung cancer (NSCLC). However, in advanced NSCLC, the 5-year survival rate is below 10%, mainly due to resistance to therapy. We have previously shown that the fraction of mesenchymal-like, chemotherapy-resistant paraclone cells increased after MTA and cisplatin combination therapy in the NSCLC cell line A549. Cytidine deaminase (CDA) and thymidine phosphorylase (TYMP) are key enzymes of the pyrimidine salvage pathway. 5′-deoxy-5-fluorocytidine (5′-DFCR) is a cytidine analogue (metabolite of capecitabine), which is converted by CDA and subsequently by TYMP into 5-fluorouracil, a chemotherapeutic agent frequently used to treat solid tumors. The aim of this study was to identify and exploit chemotherapy-induced metabolic adaptations to target resistant cancer cells. Methods Cell viability and colony formation assays were used to quantify the efficacy of MTA and cisplatin treatment in combination with schedule-dependent addition of 5′-DFCR on growth and survival of A549 paraclone cells and NSCLC cell lines. CDA and TYMP protein expression were monitored by Western blot. Finally, flow cytometry was used to analyze the EMT phenotype, DNA damage response activation and cell cycle distribution over time after treatment. CDA expression was measured by immunohistochemistry in tumor tissues of patients before and after neoadjuvant chemotherapy. Results We performed a small-scale screen of mitochondrial metabolism inhibitors, which revealed that 5′-DFCR selectively targets chemotherapy-resistant A549 paraclone cells characterized by high CDA and TYMP expression. In the cell line A549, CDA and TYMP expression was further increased by chemotherapy in a time-dependent manner, which was also observed in the KRAS-addicted NSCLC cell lines H358 and H411. The addition of 5′-DFCR on the second day after MTA and cisplatin combination therapy was the most efficient treatment to eradicate chemotherapy-resistant NSCLC cells. Moreover, recovery from treatment-induced DNA damage was delayed and accompanied by senescence induction and acquisition of a hybrid-EMT phenotype. In a subset of patient tumors, CDA expression was also increased after treatment with neoadjuvant chemotherapy. Conclusions Chemotherapy increases CDA and TYMP expression thereby rendering resistant lung cancer cells susceptible to subsequent 5′-DFCR treatment.

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“…The exact mechanism of action of H 2 S on KATP-channels remains unclear, but it is suggested that hydrogen sulfide exerts its influence through the K+ conductivity feature, and specific KATP-channel inhibitors completely inhibit H 2 S effects on it [1]. We are inclined to take this view, since it is precisely such dynamics of changes of the mitochondrial apparatus in different tissues of the body that promotes not only the ultrastructure but also the function of the mitochondria [16,19].…”

Section: Discussionmentioning

confidence: 99%

“…Another of our findings is the activation of autophagy in hypertension. As autophagy is thought to be a process that contributes not only to the death of damaged cells but also to their preservation (by preventing apoptosis by mitochondrial pathways) [4,19], it can be assumed that in hypertension regardless of patients' age, such a mechanism is activated at least in blood cells. Addition to the traditional therapy of AH donor H 2 S did not lead to significant changes in the intensity of mitochondrial autophagy, although in the literature there are isolated data on the reduction of the process under the influence of endogenous H 2 S [15,22].…”

Section: Discussionmentioning

confidence: 99%

The influence of hydrogen sulfide on the structural characteristics of leukocytes mitochondrial apparatus in patients with arterial hypertension

Kravchuk

Rozova

2019

Rep. of Morph.

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One of the leading causes of arterial hypertension (AH) is mitochondrial dysfunction (MD) – moreover, disorders in regulation of blood pressure occur on the background of progressive energy deficiency. At the same time, the cardioprotective effect of H2S has been proven. In particular, the inhibition of mitochondrial pore opening by hydrogen sulfide plays an important role, and H2S should affect the structural component of MD, namely, the ultrastructure of mitochondria. However, at present, the question of structural changes in the mitochondrial apparatus in patients with hypertension is extremely insufficiently studied. For the study of MD in healthy people and patients with pathology, almost the only objects (in the absence of surgical intervention) are blood cells, in particular leukocytes. Based on the above, the aim of the study was to investigate the effect of a hydrogen sulfide donor on the ultrastructure of the mitochondrial apparatus of leukocytes in patients with arterial hypertension. The effect of a hydrogen sulfide donor on some ultrastructural characteristics of the leukocyte mitochondrial apparatus in patients with hypertension was studied. The examination involved patients (men) with arterial hypertension aged 30-60 years, who were divided into 2 age groups: 30-40 and 40-60 years. Control groups (healthy men without signs of hypertension) were randomized by age. An electron microscopic and morphometric assessment of the structure of mitochondria revealed that under hypertension it undergoes significant changes that depend on the age of the patients. It has been established that the addition of a hydrogen sulfide donor (Full Spectrum Garlic phytopreparation (Swanson Health Products, USA) at a dose of 400 mg per day) to the traditional therapy of hypertension leads to positive changes in the mitochondrial ultrastructure of the studied cells aimed at increasing the energy capacity of the mitochondrial apparatus – the quantity reduction of structurally damaged mitochondria, and with an increase in the duration of treatment – the increase their total number in people of the younger age group (by 57.5%), and in the older age group – by 53.7%. Thus, the indicated effect of H2S significantly depends both on the age of the patients (young people respond more intensively) and on the duration of the hydrogen sulfide donor using (long-term use is accompanied by a more pronounced positive dynamics of changes).

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Uridine as a protector against hypoxia-induced lung injury

Cited by 14 publications

References 27 publications

Peculiarities of the influence of mitochondrial ATP-dependent K+ channels activation on the function of external respiration under experimental pneumonia

Peculiarities of the influence of mitochondrial ATP-dependent K+ channels activation on the function of external respiration under experimental pneumonia

Chemotherapy-induced CDA expression renders resistant non-small cell lung cancer cells sensitive to 5′-deoxy-5-fluorocytidine (5′-DFCR)

The influence of hydrogen sulfide on the structural characteristics of leukocytes mitochondrial apparatus in patients with arterial hypertension

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