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Mitochondrion Sep 2023Mitochondrial transplantation is a promising solution for the heart following ischemia-reperfusion injury due to its capacity to replace damaged mitochondria and restore... (Review)
Review
Mitochondrial transplantation is a promising solution for the heart following ischemia-reperfusion injury due to its capacity to replace damaged mitochondria and restore cardiac function. However, many barriers (such as inadequate mitochondrial internalization, poor survival of transplanted mitochondria, few mitochondria colocalized with cardiac cells) compromise the replacement of injured mitochondria with transplanted mitochondria. Therefore, it is necessary to optimize mitochondrial transplantation therapy to improve clinical effectiveness. By analogy, myocardial ischemia-reperfusion injury is like a withered flower, it needs to absorb enough nutrients to recover and bloom. In this review, we present a comprehensive overview of "nutrients" (source of exogenous mitochondria and different techniques for mitochondrial isolation), "absorption" (mitochondrial transplantation approaches, mitochondrial transplantation dose and internalization mechanism), and "flowering" (the mechanism of mitochondrial transplantation in cardioprotection) for myocardial ischemia-reperfusion injury.
Topics: Humans; Myocardial Reperfusion Injury; Mitochondria, Heart; Heart
PubMed: 37549815
DOI: 10.1016/j.mito.2023.08.001 -
Journal of Cerebral Blood Flow and... Jul 2023Despite progress in reperfusion therapy, functional recovery remains suboptimal in many stroke patients, with oxidative stress, inflammation, dysbiosis, and secondary...
Despite progress in reperfusion therapy, functional recovery remains suboptimal in many stroke patients, with oxidative stress, inflammation, dysbiosis, and secondary neurodegeneration constituting the major hurdles to recovery. The essential trace element selenium is emerging as a promising therapeutic agent for stroke. However, although several rodent studies have shown that selenium can protect against cell loss following cerebral ischemia, no study has yet examined whether selenium can enhance long-term functional recovery. Moreover, published studies have typically reported a single mechanism of action underlying selenium-mediated stroke recovery. However, we propose that selenium is more likely to have multifaceted actions. Here, we show that selenomethionine confers a potent neuroprotective effect in a canonical filament-induced transient middle cerebral artery occlusion (tMCAO) mouse model. Post-tMCAO selenium treatment significantly reduces the cerebral infarct volume, oxidative stress, and ferroptosis and enhances post-tMCAO motor performance in the acute phase after stroke. Moreover, analysis of the gut microbiota reveals that acute selenium treatment reverses stroke-induced gut dysbiosis. Longer-term selenium supplementation activates intrinsic neuroprotective mechanisms, prevents secondary neurodegeneration, alleviates systemic inflammation, and diminishes gut microbe-derived circulating trimethylamine N-oxide. These findings demonstrate that selenium treatment even after cerebral ischemia has long-term and multifaceted neuroprotective effects, highlighting its clinical potential.
Topics: Mice; Animals; Selenium; Neuroprotection; Dysbiosis; Brain Ischemia; Stroke; Infarction, Middle Cerebral Artery; Neuroprotective Agents; Dietary Supplements; Reperfusion Injury
PubMed: 36756891
DOI: 10.1177/0271678X231156981 -
Journal of Clinical Medicine Jul 2023Acute myocardial infarction (MI) is the most common and dramatic complication of atherosclerosis, which, despite successful reperfusion therapy, can lead to incident... (Review)
Review
Acute myocardial infarction (MI) is the most common and dramatic complication of atherosclerosis, which, despite successful reperfusion therapy, can lead to incident heart failure (HF). HF occurs when the healing process is impaired due to adverse left ventricular remodelling, and can be the result of so-called ischaemia/reperfusion injury (IRI), visualised by the development of intramyocardial haemorrhage (IMH) or microvascular obstruction (MVO) in cardiac MRI. Thus far, translation of novel pharmacological strategies from preclinical studies to target either IRI or HF post MI have been largely unsuccessful. Anti-inflammatory therapies also carry the risk of affecting the immune system. Fractalkine (FKN, CXCL1) is a unique chemokine, present as a transmembrane protein on the endothelium, or following cleavage as a soluble ligand, attracting leukocyte subsets expressing the corresponding receptor CXCR1. We have shown previously that the fractalkine receptor CXCR1 is associated with MVO in patients undergoing primary PCI. Moreover, inhibition of CXCR1 with an allosteric small molecule antagonist (KAND567) in the rat MI model reduces acute infarct size, inflammation, and IMH. Here we review the cellular biology of fractalkine and its receptor, along with ongoing studies that introduce CXCR1 as a future target in coronary artery disease, specifically in patients with myocardial infarction.
PubMed: 37510939
DOI: 10.3390/jcm12144821 -
Biomedicine & Pharmacotherapy =... Sep 2023With the growing shortage of organs, improvements in donor organ protection are needed to meet the increasing demands for transplantation. Here, the aim was to...
With the growing shortage of organs, improvements in donor organ protection are needed to meet the increasing demands for transplantation. Here, the aim was to investigate the protective effect of cinnamaldehyde against ischemia-reperfusion injury (IRI) in donor hearts exposed to prolonged cold ischemia. Donor hearts were harvested from rats pretreated with or without cinnamaldehyde, then subjected to 24 h of cold preservation and 1 h of ex vivo perfusion. Hemodynamic changes, myocardial inflammation, oxidative stress, and myocardial apoptosis were evaluated. The PI3K/AKT/mTOR pathway involved in the cardioprotective effects of cinnamaldehyde was explored through RNA sequencing and western blot analysis. Intriguingly, cinnamaldehyde pretreatment remarkably improved cardiac function through increasing coronary flow, left ventricular systolic pressure, +dp/dt, and -dp/dt, decreasing coronary vascular resistance and left ventricular end-diastolic pressure. Moreover, our findings indicated that cinnamaldehyde pretreatment protected the heart from IRI by alleviating myocardial inflammation, attenuating oxidative stress, and reducing myocardial apoptosis. Further studies showed that the PI3K/AKT/mTOR pathway was activated after cinnamaldehyde treatment during IRI. The protective effects of cinnamaldehyde were abolished by LY294002. In conclusion, cinnamaldehyde pretreatment alleviated IRI in donor hearts suffering from prolonged cold ischemia. Cinnamaldehyde exerted cardioprotective effects through the activation of the PI3K/AKT/mTOR pathway.
Topics: Rats; Animals; Humans; Proto-Oncogene Proteins c-akt; Phosphatidylinositol 3-Kinases; Heart Transplantation; Rats, Sprague-Dawley; Myocardial Reperfusion Injury; Tissue Donors; TOR Serine-Threonine Kinases; Apoptosis; Inflammation
PubMed: 37385214
DOI: 10.1016/j.biopha.2023.114867 -
International Journal of Molecular... Nov 2023Ischemia is the main cause of cell death in retinal diseases such as vascular occlusions, diabetic retinopathy, glaucoma, or retinopathy of prematurity. Although...
Ischemia is the main cause of cell death in retinal diseases such as vascular occlusions, diabetic retinopathy, glaucoma, or retinopathy of prematurity. Although excitotoxicity is considered the primary mechanism of cell death during an ischemic event, antagonists of glutamatergic receptors have been unsuccessful in clinical trials with patients suffering ischemia or stroke. Our main purpose was to analyze if the transient receptor potential channel 7 (TRPM7) could contribute to retinal dysfunction in retinal pathologies associated with ischemia. By using an experimental model of acute retinal ischemia, we analyzed the changes in retinal function by electroretinography and the changes in retinal morphology by optical coherence tomography (OCT) and OCT-angiography (OCTA). Immunohistochemistry was performed to assess the pattern of TRPM7 and its expression level in the retina. Our results show that ischemia elicited a decrease in retinal responsiveness to light stimuli along with reactive gliosis and a significant increase in the expression of TRPM7 in Müller cells. TRPM7 could emerge as a new drug target to be explored in retinal pathologies associated with ischemia.
Topics: Animals; Humans; Infant, Newborn; Mice; Ischemia; Protein Serine-Threonine Kinases; Reperfusion; Retina; Retinal Diseases; Retinal Vessels; TRPM Cation Channels
PubMed: 38003256
DOI: 10.3390/ijms242216068 -
Frontiers in Neurology 2023The impact of COVID-19 on clinical outcomes in acute ischemic stroke patients receiving reperfusion therapy remains unclear. We therefore aimed to synthesize the... (Review)
Review
BACKGROUND
The impact of COVID-19 on clinical outcomes in acute ischemic stroke patients receiving reperfusion therapy remains unclear. We therefore aimed to synthesize the available evidence to investigate the safety and short-term efficacy of reperfusion therapy in this patient population.
METHODS
We searched the electronic databases MEDLINE, Embase and Cochrane Library Reviews for randomized controlled trials and observational studies that investigated the use of intravenous thrombolysis, endovascular therapy, or a combination of both in acute ischemic stroke patients with laboratory-confirmed COVID-19, compared to controls. Our primary safety outcomes included any intracerebral hemorrhage (ICH), symptomatic ICH and all-cause in-hospital mortality. Short-term favorable functional outcomes were assessed at discharge and at 3 months. We calculated pooled risk ratios (RR) and 95% confidence intervals (CI) using DerSimonian and Laird random-effects model. Heterogeneity was evaluated using Cochran's Q test and statistics.
RESULTS
We included 11 studies with a total of 477 COVID-19 positive and 8,092 COVID-19 negative ischemic stroke patients who underwent reperfusion therapy. COVID-19 positive patients exhibited a significantly higher risk of experiencing any ICH (RR 1.54, 95% CI 1.16-2.05, < 0.001), while the nominally increased risk of symptomatic ICH in these patients did not reach statistical significance (RR 2.04, 95% CI 0.97-4.31; = 0.06). COVID-19 positive stroke patients also had a significantly higher in-hospital mortality compared to COVID-19 negative stroke patients (RR 2.78, 95% CI 2.15-3.59, < 0.001). Moreover, COVID-19 positive stroke patients were less likely to achieve a favorable functional outcome at discharge (RR 0.66, 95% CI 0.51-0.86, < 0.001) compared to COVID-19 negative patients, but this difference was not observed at 3-month follow-up (RR 0.64, 95% CI 0.14-2.91, = 0.56).
CONCLUSION
COVID-19 appears to have an adverse impact on acute ischemic stroke patients who undergo reperfusion therapy, leading to an elevated risk of any ICH, higher mortality and lower likelihood of favorable functional outcome.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO, identifier CRD42022309785.
PubMed: 37681003
DOI: 10.3389/fneur.2023.1239953 -
Biomedicine & Pharmacotherapy =... Sep 2023The current study intended to delve into the mechanisms of dexmedetomidine (Dex) in regulating myocardial pyroptosis against myocardial ischemia/reperfusion injury...
The current study intended to delve into the mechanisms of dexmedetomidine (Dex) in regulating myocardial pyroptosis against myocardial ischemia/reperfusion injury (MIRI). The rat MIRI models were induced by ligation/release of the coronary artery in vivo and Langendorff perfusion ex vivo. Hemodynamic parameters, infarction sizes, and histopathological changes were assessed to understand the effects of Dex on MIRI. We explored the mechanisms through functional experiments on an H9c2 cell hypoxia/reoxygenation (H/R) model. Cell viability and apoptosis were evaluated using cell counting kit 8 (CCK-8) and AV/PI dual staining respectively. The expressions of miR-665 and MEF2D mRNA were detected by qRT-PCR. Western blot was employed to determine the expression levels of pyroptosis- and signaling pathway- related proteins. The interplays between miR-665 and MEF2D were validated by Dual-luciferase reporter assays. Our findings indicated that Dex preconditioning dramatically attenuated hemodynamic derangements, infarct size, and histopathological damage in rats undergoing MIRI. Dex markedly augmented cell viability, while suppressing cell apoptosis and expressions of NLRP3, cleaved-caspase-1, ASC, GSDMD, IL-1β, and IL-18 in H9c2 cells subjected to H/R injury. MiR-665 was significantly upregulated, MEF2D and Nrf2 downregulated following H/R, whereas Dex preconditioning reversed these changes. MEF2D was validated to be a target gene of miR-665. Overexpression of miR-665 decreased the expression of MEF2D and blunted the protective effects of Dex in H9c2 cells. Moreover, the functional rescue experiment further verified that Dex regulated MEF2D/Nrf2 pathway via miR-665. In conclusion, Dex mitigates MIRI through inhibiting pyroptosis via regulating miR-665/MEF2D/Nrf2 axis.
Topics: Rats; Animals; Myocardial Reperfusion Injury; Pyroptosis; Dexmedetomidine; NF-E2-Related Factor 2; Cell Line; MicroRNAs; Apoptosis; Myocytes, Cardiac; Reperfusion Injury; MEF2 Transcription Factors
PubMed: 37549462
DOI: 10.1016/j.biopha.2023.115255 -
Free Radical Biology & Medicine Aug 2023Myocardial ischemia-reperfusion (IR) injury may result in cardiomyocyte dysfunction. Mitochondria play a critical role in cardiomyocyte recovery after IR injury. The...
Myocardial ischemia-reperfusion (IR) injury may result in cardiomyocyte dysfunction. Mitochondria play a critical role in cardiomyocyte recovery after IR injury. The mitochondrial uncoupling protein 3 (UCP3) has been proposed to reduce mitochondrial reactive oxygen species (ROS) production and to facilitate fatty acid oxidation. As both mechanisms might be protective following IR injury, we investigated functional, mitochondrial structural, and metabolic cardiac remodeling in wild-type mice and in mice lacking UCP3 (UCP3-KO) after IR. Results showed that infarct size in isolated perfused hearts subjected to IR ex vivo was larger in adult and old UCP3-KO mice than in equivalent wild-type mice, and was accompanied by higher levels of creatine kinase in the effluent and by more pronounced mitochondrial structural changes. The greater myocardial damage in UCP3-KO hearts was confirmed in vivo after coronary artery occlusion followed by reperfusion. S1QEL, a suppressor of superoxide generation from site I in complex I, limited infarct size in UCP3-KO hearts, pointing to exacerbated superoxide production as a possible cause of the damage. Metabolomics analysis of isolated perfused hearts confirmed the reported accumulation of succinate, xanthine and hypoxanthine during ischemia, and a shift to anaerobic glucose utilization, which all recovered upon reoxygenation. The metabolic response to ischemia and IR was similar in UCP3-KO and wild-type hearts, being lipid and energy metabolism the most affected pathways. Fatty acid oxidation and complex I (but not complex II) activity were equally impaired after IR. Overall, our results indicate that UCP3 deficiency promotes enhanced superoxide generation and mitochondrial structural changes that increase the vulnerability of the myocardium to IR injury.
Topics: Mice; Animals; Superoxides; Myocardial Ischemia; Myocytes, Cardiac; Mitochondria; Oxidative Stress; Myocardial Reperfusion Injury; Coronary Artery Disease; Energy Metabolism; Ischemia; Reperfusion; Fatty Acids; Infarction
PubMed: 37295539
DOI: 10.1016/j.freeradbiomed.2023.05.014 -
Redox Biology Apr 2024Acute kidney injury (AKI) is a life-threatening health condition associated with increasing morbidity and mortality. Despite extensive research on the mechanisms...
Acute kidney injury (AKI) is a life-threatening health condition associated with increasing morbidity and mortality. Despite extensive research on the mechanisms underlying AKI, effective clinical tools for prediction and treatment remain scarce. Oxidative stress and mitochondrial damage play a critical role in AKI and dopamine D4 receptor (DRD4) has been confirmed to be associated with oxidative stress. In this study, we hypothesized that DRD4 could attenuate AKI through its antioxidative and antiapoptotic effects. In vivo, DRD4 was remarkably decreased in the kidneys of mice subjected to ischemia/reperfusion injury (IRI) or cisplatin treatment. Notably, DRD4 significantly attenuated nephrotoxicity by suppressing oxidative stress and enhancing mitochondrial bioenergetics through the downregulation of reactive oxygen species (ROS) generation and NADPH oxidase 4 (NOX4) expression. In vitro, DRD4 demonstrated the ability to ameliorate oxidative stress-induced apoptosis in HK-2 cells subjected to hypoxia/reoxygenation- or cisplatin treatment. Transcriptome sequencing revealed that, mechanistically, DRD4 reduced the expression of its downstream target, interferon-stimulated gene 15 (ISG15), suppressing NOX4 ISGylation, enhancing the ubiquitination of NOX4, leading to its degradation, and ultimately counteracting oxidative stress-induced AKI. Altogether, these findings underscore the significance of DRD4 in AKI and elucidate DRD4 as a potential protectant against IRI or cisplatin-induced nephrotoxicity.
Topics: Mice; Animals; Cisplatin; NADPH Oxidase 4; Interferons; Receptors, Dopamine D4; Cell Line; Oxidative Stress; Acute Kidney Injury; Kidney; Reactive Oxygen Species; Reperfusion Injury; Apoptosis
PubMed: 38354631
DOI: 10.1016/j.redox.2024.103078 -
IScience Sep 2023A major side effect of reperfusion therapy following myocardial infarction is myocardial ischemia-reperfusion injury (MIRI). Electroacupuncture preconditioning (EA-pre)...
A major side effect of reperfusion therapy following myocardial infarction is myocardial ischemia-reperfusion injury (MIRI). Electroacupuncture preconditioning (EA-pre) has a long history in the treatment of cardiovascular diseases. Here, we demonstrate how EA-pre attenuates MIRI by affecting the phagocytosis of neuronal dendritic spines of microglia of the fastigial nucleus (FN). We observed that EA-pre increased activity in FN and then improved myocardial injury by inhibiting abnormal activities of glutaminergic neurons of the FN (FN) during MIRI. Interestingly, we observed changes in the quantity and shape of FN microglia in mice treated with EA-pre and a decrease in the phagocytosis of FN neuronal dendritic spines by microglia. Furthermore, the effects of improving MIRI were reversed when EA-pre mice were chemically activated by intra-FN lipopolysaccharide injection. Overall, our results provide new insight indicating that EA-pre regulates microglial engulfment capacity, thus promoting the improvement of cardiac sympathetic nervous disorder during MIRI.
PubMed: 37670780
DOI: 10.1016/j.isci.2023.107645