Search

Objective: To study was to evaluate the potential modulatory impact of succinate/SUCNR1 signaling on the non-genomic immunosuppressive and gene-mediated inflammatory-degenerative effects of glucocorticoid receptor (GR) activation in the cerebral cortex (CC) of aging rats., Material and Methods: Using Western blot analysis, we assessed the expression level of pro-inflammatory (TNF-α, IL-1β), anti-inflammatory cytokines (IL-10, TGF-β1), mitochondriogenesis markers (PGC-1α, NDUFV2, SDHA, cyt c1, COX2, ATP5A), angiogenesis marker VEGF, neurotrophin BDNF, GR, succinate receptor SUCNR1 in the CC of 18-month-old rats with isolated administration of the highly specific GR ligand dexamethasone (1 mg/kg, i.p., daily, 10 days) and its combined administration with the succinate-containing drug Mexidol (100 mg/kg, i.p., daily, 10 days)., Results: Dexamethasone caused a decrease in the content of all detectable parameters in the CC of 18-month-old rats, including anti-inflammatory IL-10, TGF-β1, PGC-1α, VEGF, BDNF, which progressed by 10 days, amounting to 40-60%, which is consistent with the literature data on transrepression by GR of key pro-inflammatory (NFkB, AP1, STAT1), anti-inflammatory (PPARγ, ERRα), pro-anabolic transcription factors (estrogen, androgen receptors). The administration of Mexidol daily an hour after the injection of dexamethasone did not affect the dexamethasone-induced suppression of pro-inflammatory cytokines, but increased the expression levels of anti-inflammatory cytokines, protein markers of mitochondrio-, angio- and synaptogenesis., Conclusion: The study demonstrates for the first time the prospect and pathogenetic foundation of the combined use of dexamethasone and Mexidol in an aging body in order to minimize the activity of GC aimed at suppressing pro-anabolic programs and mechanisms for resolving inflammation.

Unlabelled: The mechanisms of the protective effect of oligonucleotides (OGN) during pathological processes are poorlyunderstood. The goal of this work was to study the effect of OGN on arrhythmias induced by myocardial ischemia and reperfusion, and the HSP70 level in the heart. As a source of OGN was used the drug "Derinat" ("Technomedservis", Russia). In male Wistar rats were pre-treated the drug for 7 days (i/m, 7.5 mg/kg).The intensity of the arrhythmias was assessed by ECG during 10 min occlusion of the left coronary artery and subsequent 5 min of reperfusion. Protein HSP70 determined in the left ventricle of the heart by Western-blot analysis. During ischemia, this drug reduced duration of extrasystolia by 13 times and the incidence of ventricular tachycardia by 1.5 times. During reperfusion the drug reduced the incidence of ventricular fibrillation, a more than 2-fold, as compared with the control (respectively 23% vs 56%) and by 5 times its duration (8,4 ± 2,3 48,1 ± sec vs 18 7 sec). "Derinat" increased the HSP70 level in the heart by 65% compared with control., Conclusion: These data support the fact that the activation of HSP70 synthesis, induced by OGN is one of the mechanisms that increases the heart resistance to the ischemic and reperfusion damages.

Previously we have shown that adaptation to hypoxia (AH) is cardio- and vasoprotective in myocardial ischemic and reperfusion injury and this protection is associated with restriction of nitrosative stress. The present study was focused on further elucidation of NO-dependent mechanisms of AH by identifying specific NO synthases (NOS) that could play the major role in AH protection. AH was performed in a normobaric hypoxic chamber by breathing hypoxic gas mixture (9.5-10% O2) for 5-10 min with intervening 4 min normoxia (5-8 cycles daily for 21 days). Expression of neuronal (nNOS), inducible (iNOS), and endothelial (eNOS) protein was measured in the left ventricular myocardium using Western blot analysis with respective antibodies. AH educed iNOS protein expression by 71% (p < 0.05) whereas eNOS protein expression tended to be reduced by 41% compared to control (p < 0.05). nNOS protein expression remained unchanged after AH. Selective iNOS inhibition can mimic the AH-induced protection. Therefore protective effects of AH could be at least partially due to restriction of iNOS and, probably, eNOS expression.

Alloxan diabetes was modeled in August rats with high activity of the NO system and in Wistar rats, and the effects of NO system blockade (by a course treatment with L-NNA) on Langerhans islet β cells were studied in 15 days. The toxic effects of diabetes on the rat β cells and islets were similar: the content of active β cells in the islets decreased to 15-20%, the number of islets to 24-29% of control. A course of L-NNA reduced the β cell and islet death, in August cells greater than in Wistar: the number of islets in August rats was restored to 81%, in Wistar rats to 60% of initial level; the activity of β cells remained at the control level in the former and 2-fold lower than in the control in the latter. It seems that a less pronounced protective effect of L-NNA in Wistar rats was explained by excessive reduction of NO level essential for β cell regeneration.

Studies have confirmed that hepatic iron overload is one of the important factors causing liver damage in the metabolic syndrome (MS). As a special form of autophagy, ferritinophagy is involved in the regulation of iron metabolism. Our previous studies have shown that chronic intermittent hypobaric hypoxia (CIHH) can improve the iron metabolism disorder. The aim of this study was to investigate how CIHH improves liver damage through ferritinophagy in MS rats. Male Sprague–Dawley rats aged 8–10 weeks were randomly divided into four groups: control (CON), CIHH (exposed to hypoxia at a simulated altitude of 5000 m for 28 days, 6 h daily), MS model (induced by a 16-week high-fat diet and 10% fructose water feeding), and MS + CIHH (exposed to CIHH after a 16-week MS inducement) groups. Liver index, liver function, iron content, tissue morphology, oxidative stress, ferritinophagy, ferroptosis, and iron metabolism-related protein expression were measured, and the ferritinophagy flux in the liver was further analyzed. Compared with CON rats, MS rats had an increased liver index, damaged liver tissue and function, increased iron content and iron deposition, disrupted iron metabolism, significantly increased oxidative stress indicators in the liver, significantly upregulated expression of ferroptosis-related proteins, and downregulated expression of nuclear receptor coactivator 4 (NCOA4) and ferritinophagy flux. After CIHH treatment, the degree of liver damage and various abnormal indicators in MS rats were significantly improved. CIHH may improve liver damage by promoting NCOA4-mediated ferritinophagy, reducing iron overload and oxidative stress, and thereby alleviating ferroptosis in MS rats. [ABSTRACT FROM AUTHOR]

The acute myocardial infarction (AMI) and sudden cardiac death (SCD), both associated with acute cardiac ischemia, are one of the leading causes of adult death in economically developed countries. The development of new approaches for the treatment and prevention of AMI and SCD remains the highest priority for medicine. A study on the cardiovascular effects of chronic hypoxia (CH) may contribute to the development of these methods. Chronic hypoxia exerts both positive and adverse effects. The positive effects are the infarct-reducing, vasoprotective, and antiarrhythmic effects, which can lead to the improvement of cardiac contractility in reperfusion. The adverse effects are pulmonary hypertension and right ventricular hypertrophy. This review presents a comprehensive overview of how CH enhances cardiac tolerance to ischemia/reperfusion. It is an indepth analysis of the published data on the underlying mechanisms, which can lead to future development of the cardioprotective effect of CH. A better understanding of the CH-activated protective signaling pathways may contribute to new therapeutic approaches in an increase of cardiac tolerance to ischemia/reperfusion. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) increases the risk of sudden cardiac death, which suggests the involvement of arrhythmogenic mechanisms. Among other changes, DM causes cardiac autonomic neuropathy (CAN), but its role in electrophysiological myocardial remodeling is unclear. The objective of the present study was to test the effects of β-adrenergic blockade regarding ventricular spatiotemporal electrophysiological properties in an experimental DM model. Epicardial mapping (64-lead sock electrode array) was done in 13 control and 11 alloxan-induced DM rabbits. Activation times (AT), end of repolarization times (RT), and activation-repolarization intervals (ARI) were determined as dV/dt min during QRS, dV/dt max during T-wave, and RT-AT difference, respectively. The β-adrenergic blockade was produced by esmolol infusion (0.5 mg/kg, i.v.). It was found that the early-stage DM in rabbits was characterized by relatively mild changes in ventricular myocardium, which did not involve ventricular activation and the average duration of repolarization. The signature of this stage was the local prolongation of repolarization, which pertained to the RV apical region. The blockade of β-adrenergic receptors in healthy animals produced a ventricular spatiotemporal repolarization pattern similar to that observed in diabetic rabbits with the local apical prolongation of repolarization. On the other hand, the blockade of β-adrenergic receptors in diabetics prolonged the relatively short basal repolarization. It can be concluded that β-adrenergic blockade in healthy animals reproduced the early-stage DM effects on the spatiotemporal electrophysiological properties of the ventricular myocardium. This demonstrated the role which CAN could play in the electrical remodeling of ventricular myocardium in early-stage DM. [ABSTRACT FROM AUTHOR]

Studies have confirmed that hepatic iron overload is one of the important factors causing liver damage in the metabolic syndrome (MS). As a special form of autophagy, ferritinophagy is involved in the regulation of iron metabolism. Our previous studies have shown that chronic intermittent hypobaric hypoxia (CIHH) can improve the iron metabolism disorder. The aim of this study was to investigate how CIHH improves liver damage through ferritinophagy in MS rats. Male Sprague-Dawley rats aged 8-10 weeks were randomly divided into four groups: control (CON), CIHH (exposed to hypoxia at a simulated altitude of 5000 m for 28 days, 6 h daily), MS model (induced by a 16-week high-fat diet and 10% fructose water feeding), and MS + CIHH (exposed to CIHH after a 16-week MS inducement) groups. Liver index, liver function, iron content, tissue morphology, oxidative stress, ferritinophagy, ferroptosis, and iron metabolism-related protein expression were measured, and the ferritinophagy flux in the liver was further analyzed. Compared with CON rats, MS rats had an increased liver index, damaged liver tissue and function, increased iron content and iron deposition, disrupted iron metabolism, significantly increased oxidative stress indicators in the liver, significantly upregulated expression of ferroptosis-related proteins, and downregulated expression of nuclear receptor coactivator 4 (NCOA4) and ferritinophagy flux. After CIHH treatment, the degree of liver damage and various abnormal indicators in MS rats were significantly improved. CIHH may improve liver damage by promoting NCOA4-mediated ferritinophagy, reducing iron overload and oxidative stress, and thereby alleviating ferroptosis in MS rats., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Previous studies suggest that sleep apnea hypopnea syndrome (SAHS) is an independent risk factor that contributes to certain cardiovascular events. However, there are studies arguing that patients with SAHS had lower peak troponin levels when suffering cardiovascular events compared to patients without SAHS, which indicates that there may potentially be a protective effect of SAHS. This meta-analysis aimed to assess the impact of SAHS on cardiovascular events. Methods: Databases were searched for studies that examined cardiac biomarkers or reported angiographic data when patients with SAHS experienced cardiovascular events. The data about peak cardiac biomarkers and angiographic coronary lesion were extracted and then used to compute the pooled standardized mean difference (SMD) and 95% confidence interval (95% CI). Results: Among 26 studies included in the meta-analysis, there was not a definite difference between the SAHS group and the control group for troponins (SMD, 0.05; 95% CI, [− 0.16, 0.26]), creatine kinase (SMD, − 0.08; 95% CI, [− 0.38, 0.22]), and CK-MB (SMD, − 0.11; 95% CI, [− 0.51, 0.29]). However, patients with SAHS revealed worse coronary lesion condition grading via both Gensini score (SMD, 0.63; 95% CI, [0.31, 0.95]) and SYNTAX score (SMD, 0.99; 95% CI, [0.31–1.67]). Conclusions: Ischemic preconditioning induced by the intermittent hypoxia at the early stage could generate a cardiac protection effect, which would then benefit SAHS patients encountering a major adverse cardiovascular event. [ABSTRACT FROM AUTHOR]

Ischemic preconditioning attenuates the reduction in brachial artery endothelial function following an ischemia-reperfusion injury. Brief bouts of systemic hypoxemia could similarly mitigate the blunted vasodilatory response induced by an ischemia-reperfusion injury. The aim of the present study was to determine whether an acute bout of intermittent hypoxia protects against an ischemia-reperfusion injury in young healthy individuals. Brachial artery endothelial function was assessed by flow-mediated dilation in 16 young healthy individuals before and after a 20-min upper arm blood flow occlusion to induce ischemia-reperfusion injury. Blood flow occlusion was preceded by either intermittent hypoxia or intermittent normoxia. Intermittent hypoxia consisted of three 4-min hypoxic cycles at an arterial oxygen saturation of 87 ± 3% separated by 4-min normoxic cycles. Intermittent hypoxia resulted in a lower arterial oxygen saturation than intermittent normoxia (hypoxia: 87 ± 3% vs. normoxia: 99 ± 1%, P < 0.01), which was equivalent to a lower fraction of inspired oxygen (hypoxia: 0.123 ± 0.013 and normoxia: 0.210 ± 0.003, P < 0.01). When preceded by intermittent normoxia, blood flow occlusion resulted in a blunted flow-mediated dilation. In contrast, the reduction in flow-mediated dilation following blood flow occlusion was attenuated by prior exposure to intermittent hypoxia (hypoxia: 6.4 ± 1.9 to 4.4 ± 2.3% and normoxia: 7.1 ± 2.5 to 4.0 ± 2.4%, time x condition interaction P = 0.048). Exposure to intermittent hypoxia did not affect mean arterial pressure (hypoxia: 92 ± 9mmHg and normoxia: 89 ± 8 mmHg, P = 0.19) or cardiac output (hypoxia: 5.8 ± 1.1 L·min-1 and normoxia: 5.3 ± 1.1 L·min-1, P = 0.29). In conclusion, hypoxic preconditioning attenuates the reduction in flow-mediated dilation induced by blood flow occlusion in young healthy individuals. Intermittent hypoxia represents a potential strategy to mitigate the effect of ischemia-reperfusion injury associated with ischemic events. [ABSTRACT FROM AUTHOR]

Although intermittent hypoxia training (IHT) has proven effective against various clinical disorders, its impact on mild cognitive impairment (MCI) is unknown. This pilot study examined IHT's safety and therapeutic efficacy in elderly patients with amnestic MCI (aMCI). Seven patients with aMCI (age 69 ± 3 years) alternately breathed 10% O2 and room-air, each 5 minutes, for 8 cycles/session, 3 sessions/wk for 8 weeks. The patients' resting arterial pressures fell by 5 to 7 mm Hg (P <.05) and cerebral tissue oxygenation increased (P <.05) following IHT. Intermittent hypoxia training enhanced hypoxemia-induced cerebral vasodilation (P <.05) and improved mini-mental state examination and digit span scores from 25.7 ± 0.4 to 27.7 ± 0.6 (P =.038) and from 24.7 ± 1.2 to 26.1 ± 1.3 (P =.047), respectively. California verbal learning test score tended to increase (P =.102), but trail making test-B and controlled oral word association test scores were unchanged. Adaptation to moderate IHT may enhance cerebral oxygenation and hypoxia-induced cerebrovasodilation while improving short-term memory and attention in elderly patients with aMCI. [ABSTRACT FROM AUTHOR]

We studied the role of NO synthase in the infarct-limiting effect of short-term (SNH) and chronic continuous normobaric hypoxia (CNH). In male Wistar rats, SNH (6 sessions of 10-min hypoxia 8% O2 and 10-min reoxygenation) or CNH (12% O2 for 21 days) was modeled. In 30 min after SNH or 24 h after CNH, the rats were subjected to coronary artery occlusion (45 min) and reperfusion (2 h). The following drugs were administered to rats: non-selective NO synthase inhibitor L-NAME (10 mg/kg), inhibitor of inducible NO synthase S-methylthiourea (3 mg/kg), and inhibitor of neuronal NO-synthase 7-nitroindazole (50 mg/kg). NO donor diethylenetriamine was administered intravenously in a dose 2 mg/kg. It was found that L-NAME and S-methylthiourea abolished the infarct-limiting effect of SNH and CNH. Diethylenetriamine increased cardiac tolerance to ischemia/reperfusion. It is believed that inducible NO synthase plays an important role in the cardioprotective effect of normobaric hypoxia., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature.)

The calibrated application of limited-duration, cyclic, moderately intense hypoxia-reoxygenation increases cardiac resistance to ischemia-reperfusion stress. These intermittent hypoxic conditioning (IHC) programs consistently produce striking reductions in myocardial infarction and ventricular tachyarrhythmias after coronary artery occlusion and reperfusion and, in many cases, improve contractile function and coronary blood flow. These IHC protocols are fundamentally different from those used to simulate sleep apnea, a recognized cardiovascular risk factor. In clinical studies, IHC improved exercise capacity and decreased arrhythmias in patients with coronary artery or pulmonary disease and produced robust, persistent, antihypertensive effects in patients with essential hypertension. The protection afforded by IHC develops gradually and depends on β-adrenergic, δ-opioidergic, and reactive oxygen-nitrogen signaling pathways that use protein kinases and adaptive transcription factors. In summary, adaptation to intermittent hypoxia offers a practical, largely unrecognized means of protecting myocardium from impending ischemia. The myocardial and perhaps broader systemic protection provided by IHC clearly merits further evaluation as a discrete intervention and as a potential complement to conventional pharmaceutical and surgical interventions. [ABSTRACT FROM AUTHOR]

Delta sleep-inducing peptide (DSIP) is an endogenous peptide that is constantly present in several different brain regions. Lindane is used as a pesticide and scabicide, but it also induces seizures refractory to conventional antiepileptics. The aim of this paper was to determine whether DSIP modulates lindane-induced seizures in rats in a behavioral and electroencephalographic (EEG) study. DSIP (1 mg/kg, i.p.) or dimethyl-sulfoxide (DMSO, 0.5 ml/kg, intraperitoneally (i.p.)) were injected 30 min before lindane (8 mg/kg, i.p.) to adult male rats with previously implanted electrodes for EEG registration. During the following 30 min, the EEG was registered, and the following behavioral characteristics of seizures were observed: incidence, latency and intensity. A descriptive scale with grades from 0 to 4 provided an estimate of seizure intensity. In the EEG, the number and duration of ictal periods were analyzed using NeuroSciLaBG (Belgrade, Serbia) software. The lethality rate was also analyzed. DSIP-treated animals showed significantly modified characteristics of lindane-induced seizures when compared to the group without DSIP pretreatment (i.e. a reduced seizure intensity and a prolonged seizure latency period). However, no significant effects of DSIP on seizure incidence and lindane-induced lethality were observed. EEG analyses showed a significantly decreased number of lindane-induced EEG ictal periods in DSIP-treated animals, but with unaltered duration. These results show that DSIP favorably modulates lindane-induced seizures in rats, showing a potential to be an adjuvant component of antiepileptic treatment strategy for refractory seizures. [ABSTRACT FROM AUTHOR]

The article focused on understanding the pathophysiological impact of severe intermittent hypoxia in an effort to better understand the negative impact of obstructive sleep apnea. Topics include positive clinical outcomes are impacted by notable heterogeneity in the intermittent hypoxia protocols used, as well as various patient populations; and impact of carbon dioxide when combined with mild intermittent hypoxia warrants consideration when exploring the positive outcomes.

The article informs about the treatment approach for patients mild intermittent hypoxia (MIH) elicits beneficial cardiovascular and autonomic outcomes in males with obstructive sleep apnea (OSA) and concurrent hypertension. Topics include a controlled intermittent hypoxia conditioning program is a safe and effective way to prevent and treat hypertension; and sustained increases in motor neuron, nerve, and muscle activity that contribute to ventilation and maintain upper airway patency.

Context:Alcea roseaL. (Malvaceae) has various medicinal uses including anticancer, anti-inflammatory and analgesic properties. However, there is no report on its antidiabetic activity. Objective:Alcea roseaseed extracts were evaluated for antihyperglycaemic and antioxidative potential in diabetic rats. Materials and methods:Single intra-peritoneal injection of alloxan (130 mg/kg b.w.) was used for induction of diabetes in Albino Wistar rats. Antihyperglycaemic and antioxidant activities of methanol and aqueous extracts ofAlcea roseaseed (100 and 300 mg/kg b.w.), administered orally on daily basis for 15 days, were assessedin vivofor fasting blood glucose level and antioxidant status of liver and pancreas. Metformin was used as a positive control. Results:Aqueous and methanol extracts (300 mg/kg b.w.) decreased blood glucose level in diabetic rats by 24% and 46%, respectively. Administration of aqueous and methanol extracts at 300 mg/kg b.w. significantly (p < 0.01) modulated the antioxidant status of liver in diabetic rats by increasing levels of GR (22.5 ± 1.0, 24.4 ± 1.02 μg GSSG utilized/min/mg of protein), GPx (20.7 ± 1.2, 23.6 ± 2.04 μg GSH utilized/min/mg of protein), SOD (36.1 ± 1.7, 39.05 ± 1.5 units/mg of protein) and CAT (1744.5 ± 132.5, 1956.6 ± 125.2 nmol H2O2decomposed/min/mg of protein), respectively. Similar results were observed for pancreas. Discussion and conclusions:Antihyperglycaemic and antioxidative potentials ofAlcea roseaseeds suggest its usefulness in management of diabetes and its complications. This is the first report on antidiabetic activity of this plant. [ABSTRACT FROM PUBLISHER]

Aims Vagal nerve stimulation ( VNS) protects from myocardial and vascular injury following myocardial ischaemia and reperfusion ( IR) via a mechanism involving activation of alpha-7 nicotinic acetylcholine receptor (α7 n AChR) and reduced inflammation. Arginase is involved in development of myocardial IR injury driven by inflammatory mediators. The aim of the study was to clarify whether VNS downregulates myocardial and vascular arginase via a mechanism involving activation of α7 n AChR following myocardial IR. Methods Anaesthetized rats were randomized to (i) sham-operated, (ii) control IR (30-min ischaemia and 2-h reperfusion, (iii) VNS throughout IR, (iv) the arginase inhibitor nor- NOHA+ IR, (v) nor- NOHA+ VNS+ IR, (vi) selective α7 n AChR blockade by methyllycaconitine ( MLA) followed by VNS throughout IR and (vii) MLA+IR. Results Infarct size was reduced by VNS compared to control IR (41 ± 3% vs. 67 ± 2% of the myocardium at risk, P < 0.001). Myocardial IR increased myocardial and aortic arginase activity 1.7- and 3.1-fold respectively ( P < 0.05). VNS attenuated the increase in arginase activity compared to control IR both in the myocardium and aorta ( P < 0.05). MLA partially abolished the cardioprotective effect of VNS and completely abrogated the effect of VNS on arginase activity. Arginase inhibition combined with VNS did not further reduce infarct size. Conclusion Vagal nerve stimulation reduced infarct size and reversed the upregulation of arginase induced by IR both in the myocardium and aorta via a mechanism depending on α7 n AChR activation. The data suggest that the cardioprotective effect of VNS is mediated via reduction in arginase activity. [ABSTRACT FROM AUTHOR]

Background: To determine whether intermittent hypoxia (IH) can reduce the infarct size (IS) after acute myocardial infarction (AMI) in rats.Methods: Articles were identified in PubMed, EMBASE and the Web of Science and were included if they evaluated the effect of IH on the changes in the infarcted area after AMI in rats.Results: A preliminary search identified 3633 articles and 29 data sets from 23 articles (12 in vivo, 16 in vitro). The IS decreased after AMI in IH rats both in vitro (SMD -1.46, 95% CI [- 2.37, - 0.55]; I2 = 85.6%, P = 0.000) and in vivo (SMD -1.43, 95% CI [- 2.05, - 0.82], I2 = 73.6%, P = 0.000). Sensitivity analysis indicated that IH had a strong protective effect against myocardial infarction, and the hypoxia concentration was significantly correlated with the change in IS after AMI.Conclusion: IH can reduce IS after AMI in rats. This effect of IH may be related to the dose of hypoxia, and the oxygen concentration may be one of the most important influencing factors. [ABSTRACT FROM AUTHOR]