Reperfusion Injury In Rats Research Articles

The key mediators involved in myocardial endoplasmic reticulum stress induced by ischaemia reperfusion injury in rats

Objective: Endoplasmic reticulum stress (ERS) occurs throughout the pathological process of myocardial ischaemia reperfusion injury (MIRI); however, the key mediators involved in the biological processes of ERS or that can influence the outcomes of ischaemia reperfusion injury (IRI) are unclear. To identify the differentially expressed genes (DEGs) encoding promising mediators in rat hearts in the context of MIRI, gene profiles were mined through transcriptome analysis. Methods: By searching the Gene Expression Omnibus (GEO) database, a suitable GEO dataset was identified in the context of MIRI with 24 h reperfusion after 45 min ischaemia in rats. DEGs were extracted and analysed with R studio, and the properties of those DEGs were elucidated by utilizing protein‒protein-interaction (PPI), Cytoscape, GO and KEGG bioinformatics techniques. The potential hub genes in the first cluster of the DEG dataset were retrieved and verified by basal experiments. Results: By searching the target dataset GSE122020, 1647 mRNAs, including 790 upregulated and 857 downregulated genes, were found in the datasets with criteria of | fold change ≥ 1.2 and p value <0.05. The upregulated and downregulated genes were primarily involved in the “positive regulation of cytokine production”, “regulation of inflammatory response” and “response to pheromone” biological processes. Most of them were mainly correlated with the MAPK, Ras and calcium signalling pathways. In particular, 15 DEGs were found to be involved in the ERS signalling pathways, including Bfar, Itpr1, Srpx, Hspa1b, Usp25, Jun, Casp12, Eif2ak2, Casp4, Trim25, Ifng, Atf3, Hspa1a, Ppp1r15a, and Creb3. Through analysis with the MCODE plugin in Cytoscape, six genes, Atf3, Ppp1r15a, Casp12, Eif2ak2, Ifng, and Hspa1a, were identified as hub genes by the K-means algorithm from Cluster 1. In the in vivo MIRI model, the six genes mentioned above exhibited significant mRNA overexpression in the left anterior descending coronary artery ligation (LAD) model in rats. Conclusions: Altogether, the present study identified six potential DEGs involved in ERS induced by MIRI, which could be therapeutic targets in dealing with IRI-related ERS.

Investigation of Protective Effects of Crocin in Experimentally Generated Lower Extremity Ischemia–Reperfusion Injury in Rats

Investigation of Protective Effects of Crocin in Experimentally Generated Lower Extremity Ischemia–Reperfusion Injury in Rats

Correction to: ERK/HIF-1α/VEGF pathway: a molecular target of ELABELA (ELA) peptide for attenuating cardiac ischemia–reperfusion injury in rats by promoting angiogenesis

Correction to: ERK/HIF-1α/VEGF pathway: a molecular target of ELABELA (ELA) peptide for attenuating cardiac ischemia–reperfusion injury in rats by promoting angiogenesis

The combination of astragaloside IV and Panax notoginseng saponins attenuates cerebral ischaemia-reperfusion injury in rats through ferroptosis and inflammation inhibition via activating Nrf2.

This study aimed to observe the effect of the combination of astragaloside IV (AST IV) and Panax notoginseng saponins (PNS) on cerebral ischaemia-reperfusion injury (CIRI) and explore the specific mechanism of the nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated combination of AST IV and PNS against CIRI based on ferroptosis and inflammatory response. The therapeutic effect and mechanism of AST IV and PNS were evaluated by constructing a Sprague-Dawley rat middle cerebral artery ischaemia-occlusion-reperfusion model. The specific mechanism of the combination of AST IV and PNS against CIRI was revealed through the combined intervention of the Nrf2-specific inhibitor brusatol. After AST IV and PNS treatment, the cerebral infarction area of the rats was reduced; behavioural performance was improved; Fe2+, malondialdehyde, lipid peroxidation, interleukin-6, interleukin-1β, tumour necrosis factor-α and myeloperoxidase levels were reduced; and glutathione and glutathione peroxidase 4 levels were increased. In addition, the expression of Nrf2 was significantly increased, the combined treatment was more effective than the single treatment, and the Nrf2 inhibitor brusatol could reverse the effects of the combined intervention of AST IV and PNS. The findings of this study suggest that combining AST IV and PNS attenuates CIRI by activating Nrf2 to inhibit ferroptosis and inflammatory responses.

Protective effects of anise in prevention of cerebral ischemia reperfusion injury in rats.

The aim of this study is to determine the protective efficacy of anise in cerebral ischemia and reperfusion injury in rats. In this study, 28 Wistar Albino rats, weighing 250-300 grams (g), were used. Four groups were formed with 7 rats in each group. Group 1 (n=7): Control group, Group 2 (n=7): Anise group, 5 mL/kg/day of anise aqueous extract prepared according to Gamberini's protocol was given orally by gavage for 30 days. Group 3 (n=7): Cerebral ischemia reperfusion (CIR) group, at the beginning of the experiment, 30 minutes of cerebral ischemia and 1 hour of reperfusion were induced and the animals were sacrificed by exanguination. Group 4 (n=7): Anise+ CIR group, After administering 30 days of anise's aqueous extract, CIR was induced and the study was terminated. TOS values of the Anise+ CIR group was significantly lower than that of the CIR group (p<0.05). Il-6 and TNF-α values of the CIR group were significantly higher than the Anise+ CIR group (p<0,05). Our study revealed that anise ameliorates oxidative damage and inflammation due to cerebral ischemia/reperfusion, by reducing the levels of inflammatory cytokines (TNF-α, Il-6).

Effects of Amantadine on Liver and Lung Tissue in Hepatic Ischemia Reperfusion Injury in Rats

Effects of Amantadine on Liver and Lung Tissue in Hepatic Ischemia Reperfusion Injury in Rats

The effects of tarantula cubensis extract on renal ischemia reperfusion injury in rats.

Renal ischemia-reperfusion (IR) related acute kidney injury (AKI) is an important health problem and has not yet been fully treated. Tarantula cubensis extract (TCE) is a homeopathic drug that has antiinflammatory and antioxidant effects. This study aimed to investigate the effects of TCE on renal ischemia-reperfusion injury in rats. This study was carried out on 48 Spraque-Dawley male rats, which were divided into six groups. The first, second, and third groups were control, sham, and IR groups, respectively. Group four received IR and 0.2 mL of 96% ethanol. Group five and six received ischemia and reperfusion and TCE 0.01 and 0.1 mg per rat (which correspond to approximately 0.04 mg/kg, and 0.4 mg/kg), respectively. Tumor necrosis factor alpha (TNF-α), interleukin-1beta (IL-1β), total antioxidant status (TAS), and total oxidant status (TOS) levels in renal tissue were measured by enzyme-linked immunosorbent assay (ELISA). Oxidative stress index (OSI) was obtained by proportioning TAS and TOS. Superoxide dismutase (SOD), myeloperoxidase (MPO) activities, and malondialdehyde (MDA) levels were determined by manual spectrophotometric methods. The histopathological changes were evaluated via hematoxylineosin and immunohistochemical staining. In IR group, renal tissue TNF-α and IL-1β levels were significantly higher than control group (p < 0.0001 for both), and low(p < 0.0001 for both) and high dose (p < 0.0001 for both) TCE administration decreased these markers. Low and high doses of TCE decreased OSI values compared with IR group (p = 0.04 and p = 0.001 respectively). Although TCE decreased MDA levels, it was not statistically significant. MPO levels significantly decreased. In addition, TCE has been found to prevent hemorrhage, cast formation, and dilatation caused by IR in renal tissues stained with hematoxylin-eosin. And also, the most intense nuclear factor kappa B (NFκB) and caspase-3 immunopositivity found in IR group was decreased in both of the TCE groups. Although TCE showed a protective effect by inhibiting inflammation against IR damage in renal tissues, there was no clear effect on oxidative stress. Larger and more detailed studies are needed to clarify the issue.

The effects of different doses of amantadine on lung tissue in lower extremity ischemia reperfusion injury in rats

Aim: Ischemia/reperfusion (I/R) injury is a common complication after abdominal aortic surgery. N-Methyl D-Aspartate (NMDA) antagonists protect many organs against to I/R injury. Therefore, in this study, we aimed to investigate the effects of 135 mg/kg and 90 mg/kg of amantadine, on lung tissue after lower extremity I/R injury in rats.&#x0D; Material and Methods: 36 wistar rats were randomly divided into 6 groups each containing six rats as follows; Sham group (Group S), Amantadine 90 group (Group A-90), Amantadine 135 group (Group A-135), Ischemia/Reperfusion group (Group I/R), Ischemia/Reperfusion + Amantadine 90 group (Group I/R-A 90), Ischemia/Reperfusion + Amantadine 135 group (Group I/R-A 135). At the end of procedure, all rats were sacrificed, and their lung tissues were obtained. Lung tissues were examined biochemical and histopathologically.&#x0D; Results: The lung tissue catalase, superoxide dismutase activities and malondialdehide levels were similar between the groups. Lung tissue neutrophil/lymphocyte infiltration score levels were higher in Group I/R than Group S, Group A-90 and Group A-135. Alveolar wall thickening score levels were higher in Group I/R than Group S, Group A-90, Group A-135 and Group I/R-A 135. &#x0D; Conclusion: Although we could not find a statistically significant difference between lung tissue biochemical values, we observed that lung tissue was histopathologically affected by I/R damage and the damage was less with amantadine use. In the reduction of I/R damage, 135 mg/kg administration of amantadine was more beneficial than 90 mg/kg.

Investigation of therapeutic effects of calcium dobesilate in cerebral hypoxia/ reperfusion injury in rats

ABSTRACT Objectives Cerebral stroke is a serious clinical condition in which oxidative stress, inflammation, necrosis, apoptosis, and autophagy play important roles in its pathogenesis. This study investigated the neuroprotective and healing effects of calcium dobesilate (CD) on cerebral hypoxia/reperfusion injury in rats. Methods Forty Wistar albino male rats, each weighing 300–350 g, were separated into the Control group (no surgery and no pharmacological agent was administered); Sham-A group (only surgery was performed); DBL-A group (surgery was performed and CD 100 mg/kg/day was administered intraperitoneally for 3 days); Sham-C group (only surgery was performed); and DBL-C group (surgery was performed and 100 mg/kg/day CD was administered intraperitoneally for 10 days). Under sedation anesthesia, the bilateral common carotid arteries of all rats except the Control group were clipped for 30 min. After 4 h, the CD was given to the relevant groups, and then, all subjects were euthanized at scheduled times. The brain of each animal was removed for histopathological (hematoxylin and eosin staining), immunohistochemical (beclin-1, anti-MHC class II and anti-CD-68 staining), and biochemical (TNF, IL-1β, IL-6, caspase-3, GSH/GSSG, malondialdehyde, protein carbonyl, LC3II/LC3I, and beclin-1 levels) evaluations. Results It was observed that CD could reduce necrosis and mitigate polarization of microglia to the M1 phenotype, autophagy, free oxygen radicals, protein carbonylation, lipid peroxidation, IL-1β, IL6, TNF, caspase-3, beclin-1, and LC3II/LC3I levels in acute and chronic periods of hypoxia/reperfusion injury. Conclusion From these results, it was observed that CD treatment could reduce neuronal necrosis and create anti-inflammatory, anti-edema, anti-oxidant, anti-apoptotic, and anti-autophagic effects in hypoxia/reperfusion injury in rats.

Sanwei sandalwood decoction ameliorates acute ischemia[sbnd]reperfusion injury in rats by modulating myocyte electrophysiological characteristics

Sanwei sandalwood decoction (SWTX) is a classical Chinese medicine formula and clinically effective treatment for coronary heart disease, including myocardial ischemia/reperfusion (I/R) injury. Because the treatment mechanism of SWTX in I/R injury remains obscure, we intended to analyze the potential cardioprotective effects of SWTX in rats with myocardial I/R injury. Our research revealed that SWTX prolonged ventricular conduction time in a dose-dependent manner. While SWTX significantly delayed left ventricular signal conduction velocity, it had no effect on left atrial conduction velocity. Under sinus conditions, low SWTX concentrations reduced left ventricular conduction dispersion, while high concentrations increased conduction dispersion. SWTX also prolonged the QRS interval, APD30/50/90, and ERP. In whole-cell patch clamp experiments on myocytes, Ito and Ikr were inhibited by SWTX. While SWTX had no effect on INa, the activation curve for Nav1.5 was left-shifted. Finally, SWTX reduced the probability of ventricular fibrillation and suppressed early and late depolarization in an acute I/R injury rat model. These findings shed light on the mechanism by which SWTX alleviates myocardial I/R injury.

Transcutaneous Electrical Acupoint Stimulation Pretreatment Alleviates Cerebral Ischemia-Reperfusion Injury in Rats by Modulating Microglia Polarization and Neuroinflammation Through Nrf2/HO-1 Signaling Pathway.

Cerebral ischemia-reperfusion injury (CIRI) may lead to severe disability even death, but the strategies for prevention and treatment are still limited. Transcutaneous electrical acupoint stimulation (TEAS) has been reported to have a significant neuroprotection against CIRI, but the underlying mechanisms remain obscure. In this study, we established a focal cerebral ischemia-reperfusion model in male Sprague-Dawley rats. TEAS pretreatment was applied to Baihui (GV20), Sanyinjiao (SP6) and Zusanli (ST36) acupoints for 5 consecutive days before CIRI. After 24h reperfusion, the brain damage was assessed using Zea-Longa score, brain water content (BWC) and infarct volume. Meanwhile, the number of activated microglia and the TNF-α were detected by immunofluorescence and ELISA respectively. Moreover, Western Blot and RT-qPCR were conducted to detect the proteins and mRNA expressions of Nrf2, HO-1, iNOS and Arg-1. We found that TEAS pretreatment significantly reduced Longa score, BWC, infarct volume and the number of activated microglia. Besides, TEAS pretreatment increased Nrf2 and HO-1 levels, while lowered the expression of TNF-α. Subsequently, we also discovered that the microglia M1 phenotype maker iNOS decreased and the M2 maker Arg-1 increased after TEAS pretreatment. However, these effects of TEAS pretreatment were markedly eliminated by brusatol. These findings clearly suggested that TEAS pretreatment exerted neuroprotection against CIRI, which might be related to modulating microglia polarization and neuroinflammation via Nrf2/HO-1 pathway.

Intervention effects of estradiol on myocardial ischemia- reperfusion injury of rat and its mechanisms

Objective: To study the effects of estradiol (E2) on alleviating myocardial ischemia/reperfusion(I/R) injury through estrogen receptorβ(ERβ) mediated extracellular regulated protein kinases(ERK) pathway activation. Methods: Eighty-four adult female SD rats were ovariectomized and randomly divided into control group, NC siRNA adeno-associated virus (AAV) group received sham operation, the myocardial I/R injury model was prepared by ligation of the left anterior descending coronary artery in I/R group, E2+I/R group, NC siRNA AAV+I/R group, NC siRNA AAV+E2+I/R group and ERβ-siRNA AAV+E2+I/R group. E2+I/R group, NC siRNA AAV+E2+I/R group and ERβ-siRNA AAV+E2+I/R group were treated with E2 0.8 mg/kg by gavage for 60 days before modeling. NC siRNA AAV+I/R group, NC siRNA AAV+E2+I/R group, and ERβ-siRNA AAV+E2+I/R group were treated with AAV by caudal vein injection 24 h before modeling. After 120 min of reperfusion, the contents of serum lactate dehydrogenase (LDH), phosphocreatine kinase (CK), phosphocreatine kinase isoenzyme (CK-MB), myocardial infarction area and the expressions of ERβ, p-ERK, the contents of tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1 β), malondialdehyde (MDA) and total antioxidant capacity (T-AOC) in myocardium were measured. Results: The contents of serum LDH, CK, CK-MB, myocardial infarction area and the contents of TNF-α, IL-1 β, MDA in myocardium of I/R group were higher than those of the control group, the expression levels of ERβ and p-ERK and the content of T-AOC were lower than those in the control group (P＜0.05). The contents of serum LDH, CK and CK-MB, myocardial infarction area and the contents of TNF-α, IL-1 β and MDA in myocardium of E2+I/R group were lower than those of the I/R group, the expression levels of ERβ and p-ERK and the content of T-AOC were higher than those of the I/R group(P＜0.05). After knockdown ERβ by caudal vein injection of ERβ-siRNA AAV, the contents of serum LDH, CK and CK-MB, myocardial infarction area and the contents of TNF-α, IL-1 β and MDA in myocardium of ERβ-siRNA AAV+E2+I/R group were higher than those of NC-siRNA AAV+E2+I/R, the expression levels of ERβ and p-ERK and the content of T-AOC were lower than those of NC-siRNA AAV+E2+I/R(P＜0.05). Conclusion: E2 has protective effects on myocardial I / R injury in ovariectomized rats, which are related to the promotion of ERβ mediating the activation of ERK pathway, reducing inflammatory and oxidative stress responses.

Mechanism of Huangqi–Honghua combination regulating the gut microbiota to affect bile acid metabolism towards preventing cerebral ischaemia–reperfusion injury in rats

Context Effective treatment of ischaemic stroke is required to combat its high prevalence and incidence. Although the combination of Astragalus membranaeus (Fisch.) Bge. (Fabaceae) and Carthamus tinctorius L. (Asteraceae) is used in traditional Chinese medicine for the treatment of stroke, its underlying mechanism remains unclear. Objective The objective of this study is to elucidate the mechanism underlying Huangqi-Honghua (HQ-HH) for the treatment of ischaemic stroke by gut microbiota analysis and metabonomics. Materials and methods Sprague–Dawley rats were randomly assigned to the sham, model, HQ-HH, and Naoxintong (NXT) groups. The middle cerebral artery occlusion-reperfusion model was established after 7 days of intragastric administration in the HQ-HH (4.5 g/kg, qd) and NXT (1.0 g/kg, qd) groups. The neurological examination, infarct volume, gut microbiota, bile acids, and inflammation markers were assessed after 72 h of reperfusion. Results Compared with the model group, HQ-HH significantly reduced the neurological deficit scores of the model rats (2.0 ± 0.2 vs. 3.16 ± 0.56), and reduced the cerebral infarct volume (27.83 ± 3.95 vs. 45.17 ± 2.75), and reduced the rate of necrotic neurons (26.35 ± 4.37 vs. 53.50 ± 9.61). HQ-HH regulating gut microbiota, activating the bile acid receptor FXR, maintaining the homeostasis of bile acid, reducing Th17 cells and increasing Treg cells in the rat brain, reducing the inflammatory response, and improving cerebral ischaemia–reperfusion injury. Conclusions These data indicate that HQ-HH combination can improve ischaemic stroke by regulating the gut microbiota to affect bile acid metabolism, providing experimental evidence for the wide application of HQ-HH in clinical practice of ischaemic stroke.

Organoprotective Properties of Argon (Review)

The history of studying the organoprotective properties of argon (Ar) began in 1998 when a group of Russian researchers investigated the effect of hypoxic gas mixtures on mammalian organisms. Over several decades, evidence of the cardio-, neuro-, and nephroprotective effects of argon in various diseases and conditions in experimental models in vivo and in vitro have been accumulated. However, the lack of clinical studies to date has prompted us to carry out a systematic review analyzing the results of preclinical studies revealing organoprotective properties of argon, which could provide a rationale for its future clinical studies.The aimof this review is to describe the mechanisms of organoprotective properties of argon determined in preclinical studies.Material and methods. The search yielded 266 articles. The search algorithm was developed in accordance with the requirements and reporting guidelines for systematic reviews and meta-analysis (PRISMA) in the PubMed and Google Scholar databases. The methodology included using search queries, keywords (including MeSH), and logical operators. The keywords used for the search in the PubMed and Google Scholar databases were «argon», «ar», «protection», and «mechanism». The review included in vivo and in vitro studies.Results.The following mechanisms of argon action were identified: activation of N-terminal c-Jun kinase(JNK), p38(ERK1/2), and ERK1/2 in models of airway epithelial cells, neuronal and astroglial cell cultures, as well as in models of retinal ischemia and reperfusion injury in rats and a rabbit model of ischemia-reperfusion myocardium. Significant neuroprotective effects of argon and its influence on apoptosis were shown using small rodent models.Conclusion.The results of preclinical studies of argon have proved both its safety and organoprotective properties in in vitro and in vivo models. Analysis of the data provides a rationale for the initiation of clinical studies of argon, which could significantly improve outcomes in patients after cerebrovascular accidents, particularly post ischemic stroke.

Loureirin C ameliorates ischemia and reperfusion injury in rats by inhibiting the activation of the TLR4/NF-κB pathway and promoting TLR4 degradation.

Ischemic stroke is a leading cause of death and disability worldwide. Post-ischemia, microglia respond immediately to the alternations in neuronal activity and mediate inflammation. Toll-like receptor 4 (TLR4) plays a key role in this phenomenon. To explore the effect of loureirin C, an effective compound from Chinese Dragon's blood, on ischemic stroke, Sprague-Dawley rats were subjected to middle cerebral artery occlusion/reperfusion (MCAO/R) with/without intragastric administration of loureirin C (7, 14, and 28 mg/kg). Loureirin C alleviated MCAO/R-induced brain impairment evaluated by neurological scores (p < 0.001), brain water content (p < 0.001), and cerebral infarct volume (p=0.001). The neuroprotective (p < 0.001) and inhibitory effects on microglial activation (p < 0.001) of loureirin C were revealed by immunofluorescence. Rescue studies with TLR4 overexpression in BV-2 microglia showed that the antiinflammatory effect of loureirin C was attributable to the inhibition of TLR4 protein expression. Moreover, co-immunoprecipitation assays showed that the binding of Triad3A, an E3 ubiquitin ligase of TLR4, was increased by loureirin C (p=0.003). Our study demonstrates that loureirin C could be a promising therapeutic agent for the management of ischemic stroke by inhibiting microglial activation, potentially by Triad3A-mediated promotion of TLR4 ubiquitination and degradation.

Urinary Proteome Analysis of Global Cerebral Ischemia–Reperfusion Injury Rat Model via Data-Independent Acquisition and Parallel Reaction Monitoring Proteomics

Cerebral ischemia–reperfusion (I/R) injury is the leading cause of death in severe hypotension caused by cardiac arrest, drowning, and excessive blood loss. Urine can sensitively reflect pathophysiological changes in the brain even at an early stage. In this study, a rat model of global cerebral I/R injury was established via Pulsinelli’s four-vessel occlusion (4-VO) method. Overall, 164 urinary proteins significantly changed in the 4-VO rat urine samples compared to the control samples by data-independent acquisition (DIA) proteomics technique (1.5-fold change, p < 0.05). Gene Ontology annotation showed that the acute-phase response, the ERK1 and ERK2 cascade, endopeptidase activity, blood coagulation, and angiogenesis were overrepresented. After parallel reaction monitoring (PRM) validation, 15 differential proteins having human orthologs were verified as the potential urinary markers associated with cerebral I/R injury. Of these potential biomarkers, 8 proteins were reported to be closely associated with cerebral I/R injury. Nine differential proteins changed even when there were no clinical manifestations or histopathological cerebral damage, including FGG, COMP, TFF2, HG2A, KNG1, CATZ, PTGDS, PRVA, and HEPC. These 9 proteins are potential biomarkers for early screening of cerebral I/R injury to prevent the development of cerebral injury. KNG1, CATZ, PTGDS, PRVA, and HEPC showed an overall trend of upregulation or downregulation at 12 and 48 h after I/R injury, reflecting the progression of cerebral I/R injury. These 5 proteins may serve as potential biomarkers for prognostic evaluation of cerebral I/R injury. These findings provide important clues to inform the monitoring of cerebral I/R injury and further the current understanding of its molecular biological mechanisms.

Intranasally administered melatonin core-shell polymeric nanocapsules: A promising treatment modality for cerebral ischemia

AimsThe neurohormone melatonin (MEL) has been reported as a promising neuroprotective molecule, however it suffers pharmaceutical limitations such as poor solubility and low bioavailability, which hinder its pharmacological and clinical potential. In the current work, MEL was loaded in core-shell nanocarrier system; polymeric nanocapsules (PNCs), and assessed for its potential in cerebral ischemia reperfusion injury rat model when administered intranasally. Key findingsAdopting a D-optimal factorial design, MEL-PNCs were successfully formulated using the nanoprecipitation technique. MEL-PNCs exhibited a particle size ranging from 143.5 to 444 nm, negative zeta potential values ranging from −24.2 to −38.7 mV, cumulative release % for MEL ranging from 36.79 to 41.31 % over 8 h period, with overall good storage properties. The selected MEL-PNCs formulation displayed 8-fold higher permeation than the drug solution across sheep nasal mucosa. MEL-PNCs administered intranasally decreased oxidative stress and hippocampal inflammation, and the histological examination revealed the significant restoration of hippocampal neurons. SignificanceMEL-PNCs administered intranasally could be a promising treatment modality in brain ischemia.

Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) Deletion but Not Inhibition of Extracellular PCSK9 Reduces Infarct Sizes Ex Vivo but Not In Vivo.

Hypoxia upregulates PCSK9 expression in the heart, and PCSK9 affects the function of myocytes. This study aimed to investigate the impact of PCSK9 on reperfusion injury in rats and mice fed normal or high-fat diets. Either the genetic knockout of PCSK9 (mice) or the antagonism of circulating PCSK9 via Pep2-8 (mice and rats) was used. Isolated perfused hearts were exposed to 45 min of ischemia followed by 120 min of reperfusion. In vivo, mice were fed normal or high-fat diets (2% cholesterol) for eight weeks prior to coronary artery occlusion (45 min of ischemia) and reperfusion (120 min). Ischemia/reperfusion upregulates PCSK9 expression (rats and mice) and releases it into the perfusate. The inhibition of extracellular PCSK9 does not affect infarct sizes or functional recovery. However, genetic deletion largely reduces infarct size and improves post-ischemic recovery in mice ex vivo but not in vivo. A high-fat diet reduced the survival rate during ischemia and reperfusion, but in a PCSK9-independent manner that was associated with increased plasma matrix metalloproteinase (MMP)9 activity. PCSK9 deletion, but not the inhibition of extracellular PCSK9, reduces infarct sizes in ex vivo hearts, but this effect is overridden in vivo by factors such as MMP9.

Creatine phosphate administration in cardiac ischemia-reperfusion injury in rats: focus on differences between preconditioning, perconditioning, and postconditioning protocols.

The aim of this study was to examine and compare the influence of preconditioning, perconditioning, and postconditioning with creatine phosphate (PCr) on functional recovery and production of prooxidants in isolated rat hearts subjected to ex vivo ischemic-reperfusion (I-R) injury on a Langendorff apparatus. Wistar albino rats (male, n=40) were divided into four groups: control and groups in which PCr (0.5mmol/L, 5 min) was perfused before (Pre group), after (Post group), or during (Per group) ex vivo induced ischemia. PCr application was associated with the great benefits of preserving cardiac contractility (in Pre group 100.96% for +(dP/dt max) and 97.61% for -(dP/dt max), in Per group 96.72% for +(dP/dt max) and 95.60% for -(dP/dt max), and in Post group 143.84% for +(dP/dt max) and 104.36% for -(dP/dt max) in relation to the stabilization). In addition, PCr application prevented the increase in prooxidative markers during I-R injury in all therapeutic modalities. The most intensive benefits in the current investigation were observed when PCr was applied during the period of ischemia because the lowest fluctuations in the parameters of cardiac function and oxidative stress were observed. Overall, the results of this study highlight PCr-induced cardioprotection with promising prospects for future clinical use.

Effect of electroacupuncture preconditioning on expression of Gasdermin D, Caspase-1 and IL-1β in rats with myocardial ischemia reperfusion injury

To observe the effect of electroacupuncture(EA) preconditioning on expression of Caspase-1, Gasdermin D(GSDMD) and interleukin-1β(IL-1β) in myocardial tissue of myocardial ischemia reperfusion injury (MIRI) rats in order to explore its underlying mechanisms in resisting MIRI. Forty male rats were randomly divided into 4 groups: normal control (normal), sham operation (sham), MIRI model and EA groups. The MIRI model was established by ligation of the left anterior descending branch of the left coronary artery for 30 min and perfusion. EA (2 Hz/100 Hz, 1 mA) was applied to bilateral "Neiguan" (PC6) for 20 min, once a day for 3 consecutive days. The echocardiography was used to analyze the left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic dimension (LVESD) and left ventricular ejection fraction (LVEF, by using Teichholz formula) 4 h after modeling. The myocardial TTC staining was used to observe the proportion of the infarct area, and Western blot was used to detect the expression levels of GSDMD, Caspase-1, IL-1β proteins in the myocardium. Compared with the normal group, the immunoactivity of GSDMD was increased in the sham group (P<0.05). Compared with the sham group, the LVEF was significantly decreased (P<0.000 1), while the myocardial infarction area, immunoactivity of GSDMD, and the expression levels of Caspase-1, GSDMD and IL-1β proteins were considerably increased in the model group (P<0.000 1, P<0.001). In comparison with the model group, the decreased ejection fraction and the increased myocardial infarction area, and Caspase-1, GSDMD and IL-1β expression were reversed in the EA group (P<0.001, P<0.000 1, P<0.01). EA preconditioning may ameliorate myocardial injury in MIRI rats which may be associated with its function in down-regulating the expression of myocardial Caspase-1 protein to reduce cardiomyocyte pyroptosis.