Infarct Area Research Articles

Agmatine: An Emerging Approach for Neuroprotection in Recurrent Ischemic Stroke Events in a Murine Model.

This study investigates the effect of agmatine on reducing mortality, neurobehavioral alterations, infarct size, and expression of pro-inflammatory cytokines in mice subjected to bilateral carotid thrombosis. Under pentobarbital anesthesia, the left common carotid artery was exposed to 6% FeCl3. Thirty-two days later, the same procedure was performed on the right common carotid artery. Subsequently, Agmatine (100 mg/kg) was administered 15 min after the second procedure, and in another experimental group, the dose of Agmatine was repeated at 72 h. Administration of agmatine extended survival in ischemic animals up to 72 h for the single-dose group and up to 96 h for the repeated-dose group, without significant increases in neurological deficits or infarct area size. This neurobehavioral effect was also observed in sham animals treated with agmatine. In ischemic animals, agmatine administration improved digging behavior and reduced recovery times, consistently shorter in those animals treated with repeated doses. RT-PCR analyses revealed a positive regulation of the cytokine IL-1β in agmatine-treated animals, which has been associated with recovery stages. The results suggest that the observed effect may be attributed to the multiple interactions of agmatine with ischemic cascade events, highlighting its anti-inflammatory role.

MRPL41, as a target for acupuncture, promotes neuron apoptosis in models of ischemic stroke via activating p53 pathway

Neuronal death is the key cause of ischemic stroke. Acupuncture (Acu) is a recognized method for the treatment and amelioration of cerebral ischemia. However, the molecular mechanism of Acu for treating ischemic stroke has not yet been detailedly elucidated. Based our microarray analysis results, mitochondrial ribosomal protein L41 (MRPL41), which is related to apoptosis, was identified as the target of Acu. MRPL41 expression was increased in middle cerebral artery occlusion/reperfusion (MCAO/R) model and reduced after Acu treatment. Following, MCAO/R model and oxygen and glucose deprivation/reoxygenation (OGD/R) model were established to explore the effect of MRPL41. Knockdown of MRPL41 increased cell viability and ani-apoptotic protein (Bcl-2) expression, and reduced apoptosis intensity and pro-apoptotic protein (Bax and Cleaved caspase-3) of OGD/R neurons. In vivo, MRPL41 silencing decreased neurological severity score, shrank infarct area, reduced encephaledema and neuron apoptosis. In addition, reduction of MRPL41 caused loss of p53. Our data uncover that Acu targets MRPL41, following with inhibiting neuron apoptosis via p53 pathway, thereby ameliorating ischemic stroke.

Evaluation of 18F FOL a PET tracer targeting folate receptor beta in a rat model of myocardial infarction

Abstract Background Expression of folate receptor-β (FR-β) on the activated macrophages is associated with inflammatory diseases. However, the role of FR-β in the immune response following myocardial infarction (MI) remains unknown. Purpose To investigate FR-β-targeted positron emission tomography (PET) tracer aluminium fluoride-18-labeled 1,4,7,-triazacylononane-1,4,7-triacetic acid conjugated folate ([18F]FOL) for imaging immune response in a rat model of MI. Methods Rats underwent PET scan from 20 to 40 minutes after injection of 50±6 MBq of [18F]FOL on 3 (n=6), 7 (n=21), 15 (n=9), and 90 (n=11) days after surgical ligation of the left coronary artery. As controls, rats were studied on 3 (n=6), 7 (n=14), 15 (n=5), and 90 (n=8) days after sham-operation. [18F]FDG PET was performed a day before [18F]FOL injection in order to localize myocardium and area of MI. After [18F]FOL PET, autoradiography, histology, and staining of CD68 were performed 3 (n=6), 7 (n=6), and 90 (n=11) days after MI in order to detect [18F]FOL uptake and activated macrophages in myocardial tissue sections. A subgroup of rats (n=15) underwent serial [18F]FOL PET 7 and 90 days after MI together with echocardiography in order to evaluate left ventricular function. Results The presence of MI was confirmed by histology in all rats after coronary ligation. PET images showed increased uptake of [18F]FOL in the area of MI. The uptake was significantly higher (p<0.001) in the area of MI than in the myocardium of sham-operated rats on day 3 (SUV 2.04±0.25 vs. 0.74±0.12), and remained increased on day 7 (SUV 1.39±0.33 vs. 0.68±0.12), day 15 (SUV 1.24±0.20 vs. 0.59±0.07), and day 90 (SUV 1.39±0.25 vs. 0.69±0.11). On day 3, pre-treatment with folate glucosamine (n=3) reduced the [18F]FOL signal by 50% in the area of MI indicating specific binding to FR-β. Autoradiography confirmed focally increased uptake of [18F]FOL in the area of MI. A positive correlation was found between uptake of [18F]FOL in PET images and areal percentage of CD68-positivity in the area of MI (r2=0.447, p<0.001). Uptake of [18F]FOL on day 7 after MI was associated with decline in left ventricular ejection fraction (R=-0.665, p<0.01) and increase in left ventricular systolic volume (R=0.561, p=0.02) between 7 and 90 days after MI. Conclusion Cardiac [18F]FOL PET detects increased macrophage-associated FR-β expression after MI in a rat model. FR-β expression peaks early and remains elevated up to 3 months in the infarcted area. Increased FR-β expression early after MI is associated with worsening of left ventricular systolic function late after MI.

CT-perfusion quantitation of cardiac infarct size - a novel technique

Abstract Introduction Cardiac infarct size is associated with cardiac prognosis after AMI. Cardiac CT is able to delineate both coronary anatomy and myocardial pefusion. Thus far, CT identification of infarction has been qualitative. We describe a novel technique for quantitation of myocardial infarct size in CT-perfusion imaging. Methods Patient Population comprised 51 patients that were previously clinically diagnosed with myocardial infarction on the basis of clinical presentation, ECG findings and elevated cardiac enzymes. CTP Imaging All patients had undergone dynamic rest, vasodilator-stress, rest, delayed enhancement CT perfusion imaging performed on a dual-source, third generation scanner (FORCE, Siemens Healthcare). Image Analysis 2 trained investigators independently quantified the infarct volume in 51 patient studies using Siemens SmartSimulator software. Mean ± SD HU were taken from a 1cm² circular ROI of normal myocardium used in a thresholding method. The epicardium and endocardium of infarcted areas were manually contoured from apex to base. Volumetric measurements were obtained of the infarct and total myocardium. Interpolation of contours for segmentation objects was performed. Subtraction of left ventricle cavity from total left ventricle allowed volumetric measurements of total left ventricular myocardium. ROIs of the infarct were estimated using SDs above mean HU of normal myocardium (0.5, 1, 1.5 and 2 SDs) in delayed imaging. Selection of optimal threshold HU was based on visual assessment that best mapped the hyperenhanced infarct area. This allowed volumetric asessment of infarct and total myocardium. Inter-investigator variability was evaluated with Bland-Altman and Intra-Class Correlation Coefficient (ICC). Results Patient characteristics are follow: Age 60.20±11.35 years, 41(89%)male, BMI 25.41±4.17kg/m², Hypertension 23(50%), diabetes 10(22%), hyperlipidemia 40(87%), smoking 7(15%), family history of premature CAD 4(8.7%), previous PCI 45(97.8%). In 51 patients, 23(41%), 24 (46%) & 5(10%) of the infarctions were quantitated as being medium-sized (10%-20%), large (20% -30%) and very large (>30%). Thirty-seven (70%), 6 (11%) & 10(19%) involved the LAD, LCx and RCA territories respectively. 49 (94%) of infarctions were transmural. Identical thresholding was selected by both investigators for each SD above mean (mean 1.42; SD 0.46). 93% of the total cases were within a set threshold of 1 to 2 SDs above the mean HU for both. Interclass correlation coefficient was 0.95, CI range 0.90 – 0.97. Bland-Altman analysis did not demonstrate systemic variations or proportional bias from the plot. Conclusion The study suggests that a method of quantifying cardiac infarct size using a threshold technique and delayed hyperenhancement images with dynamic perfusion imaging is clinically feasible and consistent.Rest-Stress-Delayed Enhancement infarct

Early CSWT relieves myocardial fibrosis by inhibiting TGF-Smad2/3-MMP-9

Abstract Objective To investigate the correlation between the improvement of cardiac function and myocardial fibrosis and the TGF-β1-Smad2/3-MMP-9 signaling pathway in acute myocardial infarction (AMI) rats after early treatment with extracorporeal cardiac shock wave therapy (CSWT). Methods Thirty SD rats were randomly divided into five groups: sham group (6 rats), AMI group (6 rats), AMI+CSWT group (6 rats), AMI+SB431542 group (6 rats), and AMI+SB431542+CSWT group (6 rats). AMI was induced in all groups except the sham group. The AMI+CSWT group and AMI+SB431542+CSWT group received CSWT treatment. Echocardiography was performed at 4 days and 62 days postoperatively to assess left ventricular ejection fraction (LVEF) in all groups. Additionally, cardiac tissues were sampled and evaluated for pathological changes and degree of fibrosis by HE staining and Masson staining. The TGF-β1-Smad2/3-MMP-9 signaling pathway and protein expression of COL-I and COL-III were detected in the infarcted border area. Results (1) At 4 days postoperatively, EF and FS were significantly lower, and LVESV was enlarged in the AMI group, AMI+CSWT group, AMI+SB431542+CSWT group, and AMI+SB431542 group compared to the sham group (p < 0.05). (2) At 62 days postoperatively, EF and FS were significantly lower, and LVEDV and LVESV were significantly higher in the AMI group compared to the sham group (p < 0.05). EF and FS were significantly higher, and LVEDV and LVESV were significantly lower in the AMI+CSWT group compared to the AMI group (p < 0.05). There was no significant difference in EF, FS, LVEDV, and LVESV between the AMI+CSWT group and the AMI+SB431542+CSWT group (p > 0.05). (3) Histological analysis showed that the AMI group had more blue-stained areas compared to the sham group, while the AMI+CSWT group had fewer blue-stained areas and more neatly arranged red areas compared to the AMI group (p < 0.05). (4) Collagen volume fraction (CVF) was significantly higher in the AMI group compared to the sham group (p < 0.05). CVF was significantly lower in the AMI+CSWT group compared to the AMI group (p < 0.05). There was no significant difference in CVF between the AMI+CSWT group and the AMI+SB431542+CSWT group (p > 0.05). (5) The expression levels of TGF-β1, Smad3, MMP-9, COL-I, and COL-III were significantly higher in the AMI group compared to the sham group (p < 0.05). The expression levels of these proteins were significantly reduced in the AMI+CSWT group compared to the AMI group (p < 0.05). Conclusions Early CSWT improves cardiac function and inhibits myocardial fibrosis associated with the TGF-β1-Smad2/3-MMP-9 signaling pathway.pathological changesdegree of fibrosis

Nap1L1 Ubiquitination Degradation-dependent Protective Effects of Wnt2 on Cardiac Ischemia/Reperfusion Injury

Abstract Background Cardiomyocyte death during ischemia/reperfusion (I/R) injury occurs following the restoration of blood flow for obstructed coronary arteries, posing a challenge to timely reperfusion strategy for ischemic heart disease. This study aimed to investigate the potential protective role of Wnt2 against cardiomyocyte death after I/R injury. Methods Serum Wnt2 levels in patients with acute myocardial infarction (AMI) before and after percutaneous coronary intervention (PCI) and in mice subjected to I/R were measured by ELISA. Cardiomyocyte death, including apoptosis and ferroptosis, which were examined by TUNEL and thiobarbituric acid reactive substances (TBARs) assay, respectively. TMT6-based proteomics analysis was used to identify critical molecules mediating the effects of Wnt2. Results Serum Wnt2 level decreased after PCI in patients with MI and was negatively correlated with cTNT and CK-MB levels within the first 48 hours post-PCI. Wnt2 also decreased in I/R mice in compared with sham group.Supplement of rbWnt2 ameliorated I/R injury as characterized by the improved cardiac function and decreased infarct area and level of asynchronicity. Proteomics analysis KEGG Enrichment top 20 of differentially expressed proteins (DEPs) included reactive oxygen species (ROS). RbWnt2 inhibited cardiomyocytes apoptosis and ferroptosis by suppressed ROS level following I/R in vivo and in vitro. Based on proteomics analysis data, most of differentially expressed proteins (DEGs) were enriched in cytoplasm or nucleus. Among them, Nucleosome assembly protein-like 1(Nap1L1) was progressively increased in hearts following I/R, and showed a negative correlation with cardiac Wnt2 level during the I/R procedure. RbWnt2 treatment significantly attenuated the upregulation of Nap1L1 induced by I/R injury in vivo and in vitro. Hypoxia/Normoxia injury elicited Nap1L1 increased both in nucleus and cytoplasm, which was attenuated by rbWnt2 treatment in AMCMs. AAV9 mediated knockdown of Nap1l1 protects heart from apoptosis and ferroptosis while overexpression of Nap1l1 partly abolished the protective effects of Wnt2 in I/R mice. Mechanistically, Wnt2 upregulated anti-oxidative enzymes (Gpx1, Gpx4, Ucp3, Sod1, Sod2) by regulation of Nap1l1 to suppress ROS level and protect cardiomycoytes following I/R injury. Further analysis revealed that binding of Wnt2 and Lrp6 enhanced the expression of Tripartite motif 11 (TRIM11, a ubiquitin E3 ligase) and subsequently promoted the degradation of Nap1l1 in cardiomyocytes, which contributes to cardiac protection following I/R injury. Conclusions Wnt2 protects the heart against I/R-induced injury by inducing Nap1L1 degradation through Lrp6/Trim11 signaling, which was mediated by suppressing ROS levels via enhancing anti-oxidation enzymes to inhibits cardiomyocytes apoptosis and ferroptosis. These findings may offer new insights for developing therapeutic strategies to prevent I/R injury.Abstract GraphConclusion

A new free radical scavenger, resorcimoline, prevents ischaemia/reperfusion injury in the heart

Abstract Introduction Ischaemic heart disease remains the leading cause of death worldwide. Early coronary revascularisation is the most important treatment. Recent findings have revealed that reactive oxygen species (ROS) can lead to tissue damage following coronary artery revascularisation, known as ischaemia-reperfusion injury. In this study, we focused on resorcimoline, a new free radical scavenger that was generated during the synthesis of dimethylresveratrol and dimethylpiceatannol. Last year, we reported the scavenging activity in vitro against multiple ROS, confirmed by the electron spin resonance spectrometry (Ref. 1). Purpose This study aimed to assess the potential of resorcimoline as a novel therapeutic treatment for reducing the degree of infarction caused by myocardial ischaemia, by eliminating ROS generated during myocardial ischaemia-reperfusion. Methods Nine-to-eleven-week-old male Wistar rats were subjected to acute myocardial ischaemia induced by ligation of the left anterior descending coronary artery for 30 minutes, followed by reperfusion for 24 hours. Rats received intravenous injections of resorcimoline at 6 mg/kg before coronary ligation or saline as a control (n = 9 vs. n = 8). The heart sections were double-stained with Evans blue 1% and triphenyltetrazolium chloride 1% to assess infarct area and area-at-risk. For immunohistochemical study, the other ischaemia/reperfusion models were treated with resorcimoline and saline (n = 7 vs. n = 7) as above, and the middle parts of the hearts were embedded in optimal cutting temperature compound and quickly frozen. In the H＆E-stained section, the infarct border zone was defined as a 2-mm band surrounding the necrosis area. Troponin I levels in serum were measured using ELISA. Primary cultured cardiomyocytes were treated with 10 μM angiotensin II for 3.5 hours and then exposed to resorcimoline for 30 minutes at an increasing dosage. A cellular ROS assay kit was used to assess the levels of ROS in the cardiomyocytes and the number of cells was counted with DAPI stain using an image processing software. Results Infarct size in resorcimoline-treated animals was significantly smaller than in control animals (41.8±19.4% vs. 60.8±12.9%, p=0.03, Fig. 1A) and area-at-risk was not significantly different (58.0±27.8% vs. 51.9±18.5%, p=0.61). Apoptotic cells in the border zone were significantly reduced in resorcimoline-treated animals (32.0±11.7% vs. 55.1±16.9%, p=0.01, Fig. 1B). Troponin I levels in resorcimoline-treated animals were significantly lower than in control animals (4524±3596 vs. 7856±4653, p=0.04, Fig. 1C). resorcimoline significantly reduced angiotensin II-induced ROS in cardiomyocytes in a concentration-dependent manner (Fig. 2A,B). Conclusion This novel compound, resorcimoline, can reduce infarct size induced by coronary ischaemia-reperfusion injury by reducing the ROS damage to myocardiocytes in the border zone and cellular ROS levels in cardiomyocytes.

Dexmedetomidine Ameliorates Myocardial Ischemia-Reperfusion Injury by Inhibiting MDH2 Lactylation via Regulating Metabolic Reprogramming.

Myocardial ischemia-reperfusion injury (MIRI) significantly worsens the outcomes of patients with cardiovascular diseases. Dexmedetomidine (Dex) is recognized for its cardioprotective properties, but the related mechanisms, especially regarding metabolic reprogramming, have not been fully clarified. A total of 60 patients with heart valve disease are randomly assigned to Dex or control group. Blood samples are collected to analyze cardiac injury biomarkers and metabolomics. In vivo and vitro rat models of MIRI are utilized to assess the effects of Dex on cardiac function, lactate production, and mitochondrial function. It is found that postoperative CK-MB and cTNT levels are significantly lower in the Dex group. Metabolomics reveals that Dex regulates metabolic reprogramming and reduces lactate level. In Dex-treated rats, the myocardial infarction area is reduced, and myocardial contractility is improved. Dex inhibits glycolysis, reduces lactate, and improves mitochondrial function following MIRI. Lactylation proteomics identifies that Dex reduces the lactylation of Malate Dehydrogenase 2（MDH2), thus alleviating myocardial injury. Further studies reveal that MDH2 lactylation induces ferroptosis, leading to MIRI by impairing mitochondrial function. Mechanistic analyses reveal that Dex upregulates Nuclear Receptor Subfamily 3 Group C Member 1（NR3C1)phosphorylation, downregulates Pyruvate Dehydrogenase Kinase 4 (PDK4), and reduces lactate production and MDH2 lactylation. These findings provide new therapeutic targets and mechanisms for the treatment for MIRI.

Analysis of nerve excitability in the dentate gyrus of the hippocampus in cerebral ischaemia-reperfusion mice

Ischemic stroke often leads to cognitive dysfunction, which delays the recovery process of patients. However, its pathogenesis is not yet clear. In this study, the cerebral ischemia-reperfusion model was built as the experimental object, and the hippocampal dentate gyrus (DG) was the target brain area. TTC staining was used to evaluate the degree of cerebral infarction, and nerve cell membrane potentials and local field potentials (LFPs) signals were collected to explore the mechanism of cognitive impairment in ischemia-reperfusion mice. The results showed that the infarcted area on the right side of the brain of the mice in the model group was white. The resting membrane potential, the number of action potential discharges, the post-hyperpolarization potential and the maximum ascending slope of the hippocampal DG nerve cells in the model mice were significantly lower than those in the control group ( P < 0.01); the peak time, half-wave width, threshold and maximum descending slope of the action potential were significantly higher than those in the control group ( P < 0.01). The time-frequency energy values of LFPs signals in the θ and γ bands of mice in the ischemia and reperfusion groups were significantly reduced ( P < 0.01), and the time-frequency energy values in the reperfusion group were increased compared with the ischemia group ( P < 0.01). The signal complexity of LFPs in the ischemia and reperfusion group was significantly reduced ( P < 0.05), and the signal complexity in the reperfusion group was increased compared with the ischemia group ( P < 0.05). In summary, cerebral ischemia-reperfusion reduced the excitability of nerve cells in the DG area of the mouse hippocampus; cerebral ischemia reduced the discharge activity and signal complexity of nerve cells, and the electrophysiological indicators recovered after reperfusion, but it failed to reach the healthy state during the experiment period.

Successfully intravenous thrombolytic therapy in systemic lupus erythematosus-related ischemic stroke: A case report.

Stroke is a relatively frequent complication occurring in patients with systemic lupus erythematosus (SLE). The increasing number of patients with Ischemic Stroke secondary to SLE aroused the clinician's concern. SLE thrombosis markers, diagnostic high-resolution magnetic resonance image (HR-MRI), and therapeutic interventions for acute ischemic stroke were recently coming into focus perspectives from the field. A 42-year-old female with slurred speech and numbness in her left limb was admitted to our hospital. Magnetic resonance imaging (MRI) revealed right thalamic infarction with diffusion-weighted lesions. Prior to admission, the patient had a National Institute of Health Stroke Scale (NIHSS) score of 3. In light of the clinical manifestation, the American Heart Association/American Stroke Association (AHA/ASA) Guidelines for Intravenous Thrombolysis in Acute Ischemic Stroke (2019) should be referred to. The patient was treated with thrombolytic alteplase (rt-PA). The patient was hospitalized for 2 weeks and discharged after his symptoms improved. After thrombolysis, the NIHSS score of the patient decreased to zero. The computed tomography scan was reexamined 24 hours later, and no acute changes or hemorrhage were identified in the infarcted area. Subsequent imaging and serological analyses indicated that HR-MRI of the responsible vessel was negative, but the infarction in this patient was still regarded as being caused by vasculitis of the right posterior cerebral artery in the region supplying the thalamus. This is the first case of successful intravenous thrombolytic therapy with rt-PA in a patient with SLE secondary to stroke with an NIHSS score of 3. This provides further evidence for expanding the reference of indications with rt-PA intravenous thrombolysis.

APEX1 Knockdown Alleviates Inflammation and Fibrosis in Myocardial Infarction Through Promoting ZCCHC9 Expression and Blocking the p38 MAPK Signaling.

It was reported that serum apurinic/apyrimidinic endodeoxyribonuclease 1 (APEX1) level was higher in acute myocardial infarction (AMI) patients than in angina. This study aimed to investigate the role and mechanism of APEX1 in AMI progression. The mRNA and protein levels of APEX1 and zinc finger CCHC domain containing 9 (ZCCHC9) in blood specimens of AMI patients and normal controls were determined by RT-qPCR and Western blot assays, respectively. H9c2 cardiomyocytes were treated with angiotensin II (Ang II) to induce cardiomyocyte injury and then transfected with small interfering RNA against APEX1 (si-APEX1) or overexpression plasmids of ZCCHC9 (pcDNA-ZCCHC9). The cell viability, apoptosis, inflammatory cytokine levels, and fibrosis-associated protein expression in H9c2 cells were evaluated. ZCCHC9 promoter methylation were detected with methylation-specific PCR (MSP) assay. Then, rescue experiments were performed to explore whether APEX1 mediated cardiomyocyte functions by regulating ZCCHC9 expression. Furthermore, we explored whether the APEX1/ZCCHC9 axis regulated cardiomyocyte injury in AMI via the p38 MAPK signaling pathway. Additionally, an AMI rat model was established using the left anterior descending artery (LAD) ligation method and multipoint intramyocardial injection (5 points, 2 µL/point) of lentivirus (1 × 109 TU/mL) carrying scramble or si-APEX1 was conducted before modeling. The rats were euthanized four weeks after AMI modeling, and blood samples and myocardial tissues were harvested. The infarct area, cell apoptosis, inflammation, and fibrosis in myocardial tissues were detected. APEX1 was upregulated and ZCCHC9 was downregulated in blood samples of AMI patients compared with normal controls. APEX1 knockdown or ZCCHC9 overexpression attenuated Ang II-induced viability reduction, apoptosis, inflammation, and fibrosis in cardiomyocytes. APEX1 inhibited ZCCHC9 expression by promoting DNA methyltransferase 1 (DNMT1)-mediated ZCCHC9 promoter methylation. ZCCHC9 knockdown abolished the protective effects of APEX1 knockdown on Ang II-induced cardiomyocyte injury. APEX1 knockdown inhibited the p38 MAPK signal signaling, and anisomycin reversed the effect of APEX1 knockdown on cardiomyocyte functions. Additionally, APEX1 knockdown alleviated apoptosis, inflammation, and fibrosis in myocardial tissues of AMI rats. APEX1 knockdown attenuated Ang II-induced apoptosis, inflammation, and fibrosis in cardiomyocytes although promoting ZCCHC9 expression and inhibiting the p38 MAPK signaling pathway, thus relieving myocardial infarction, inflammation, and fibrosis in AMI rats.

Orexin A protects against cerebral ischemia-reperfusion injury by enhancing reperfusion in ischemic cortex via HIF-1α-ET-1/eNOS pathway

The purpose of this study was to investigate the protective effect and underlying mechanism of orexin A on cerebral ischemia-reperfusion injury, specifically through vasodilation mediated by the hypoxia inducible factor-1α (HIF-1α)-Endothelin-1(ET-1)/endothelial nitric oxide synthase (eNOS) pathway. A model of middle cerebral artery occlusion was established in both wild-type SD rats with exogenous orexin A intervention and in orexin A transgenic rats. Neurological deficit scores and cerebral infarction areas were assessed, and ischemic cortical blood flow was monitored. Gene and protein expression levels of HIF-1α, HIF-2α, ET-1, and three types of NOS were detected using real-time RT-qPCR and Western blot analysis, respectively. Additionally, nitric oxide (NO) levels in the cortex were analyzed through biochemical detection methods. Orexin A demonstrated a protective effect by reducing cerebral infarction and improving neurological deficits, which was achieved by increasing cortical blood flow during reperfusion. This protective mechanism was associated with upregulated HIF-1α expression, downregulated ET-1 expression, upregulated eNOS expression, and increased NO production. This study demonstrates the protective effect of orexin A on cerebral ischemia-reperfusion injury, achieved by regulating the release of vasomotor substances to enhance cortical blood flow during reperfusion. These findings suggest that orexin A may represent a potential therapeutic strategy for ischemic stroke.

Enhancing Ischemic Stroke Evaluation by a Model-Based Photoacoustic Tomography Algorithm.

Ischemic stroke (IS) is characterized by the sudden interruption of blood supply to the brain, resulting in neurological impairments and even mortality. Photoacoustic computed tomography (PACT) integrates the high contrast of optical imaging and the penetration of ultrasound imaging, enabling non-invasive IS evaluation. However, the image reconstruction quality significantly affects the oxyhemoglobin saturation (sO2) estimation. This study investigates a model-based with total variation minimized by augmented Lagrangian and alternating direction (MB-TVAL3) approach and compared it with the widely used back-projection (BP) and delay-and-sum (DAS) algorithms. Both simulations and invivo experiments are conducted to validate the performance of the MB-TVAL3 algorithm, showing a higher sO2 estimation accuracy and sensitivity in detecting infarct area compared to BP and DAS. The findings of this study emphasize the impact of acoustic inverse problem on the accuracy of sO2 estimation and the proposed approach offers valuable support for IS evaluation and cerebrovascular diagnosis.

Study on the Neuroprotective Mechanism of Salidroside Modified with Polydopamine Nanoparticles in Regulating Notch Pathway by Inhibiting Mir-155 in Stroke Rats

Background and Purpose Stroke threatens neurological function. Salidroside is widely used to treat neurological diseases such as stroke. Previous studies have shown that miR-155 plays an important regulatory role in the pathogenesis of stroke and that the Notch pathway plays an important role in nervous system development and regeneration. Methods PDA NPs-SAL complex was prepared, a stroke rat model was constructed, and the cerebral infarction area of rats was measured. Analyze the changes of PDA NPs-SAL on rat brain tissue and evaluate the neuroprotective effect. Detect the changes in miR-155 and Notch pathway-related proteins in stroke rat models to further understand the role of miR-155 and Notch pathway in the pathogenesis of stroke and their relationship. Results Salidroside had certain protective effects on the nerves of stroke rats, and the effect of PDA NPs-SAL was more prominent. At the same time, PDA NPs-SAL promotes the Notch pathway by inhibiting miR-155, thereby exerting a neuroprotective effect on stroke rats. Conclusion Under the intervention of PDA NPs-SAL, the neurological function scores of rats were reduced, and the effect of PDA NPs-SAL was more significant. In addition, PDA NPs-SAL inhibited miR-155 and activated the Notch pathway, thereby reducing the water content of rat brain tissue and cerebral infarction area, thereby exerting a neuroprotective effect on stroke rats.

Qingxin Jieyu Granule alleviates myocardial infarction through inhibiting neutrophil extracellular traps via activating ANXA1/FPR2 axis

BackgroundMyocardial infarction (MI), representing the most severe manifestation of coronary artery disease (CAD), stands as a primary concern in the prevention and management of cardiovascular diseases. Clinical evidence demonstrates that Qingxin Jieyu Granule (QXJYG) is efficacious in treatment of MI patients. However, the mechanisms underlying its therapeutic effects remain to be elucidated. PurposeThis study aimed to evaluate the effects of QXJYG on MI and investigate its underlying mechanisms. Materials and methodsThe MI model in rats was developed through ligating the left anterior descending (LAD) artery. The effect of QXJYG on cardiac function impairment in MI rats was assessed by echocardiography, while the improvement of cardiomyocyte morphology and myocardial fibrosis after treatment with QXJYG was evaluated through hematoxylin-eosin (H&E) staining and Masson staining. The chemical constituents of QXJYG in blood were identified by using the UPLC-Q-TOF/MS technique. Furthermore, the molecular mechanism underlying the QXJYG therapeutic effect in MI was postulated based on the disease gene-drug target network analysis. Other technical methods such as ELISA, immunohistochemical staining, Western Blot analysis and application of pharmacological inhibitors were employed to verify the effectiveness of QXJYG in treating MI and explore its potential molecular targets. ResultsThe cardiac function in experimental rats post-MI was significantly impaired, as evidenced by an enlarged infarction area, disordered arrangement of cardiomyocytes, and aggravated myocardial fibrosis. QXJYG treatment significantly enhanced the cardiac function and reduced the pathological damage of the cardiac tissue in MI rats. Through the network pharmacology analysis, we identified that FPR2 might be a potential target of QXJYG in its cardiac protection role. QXJYG markedly downregulated the level of neutrophil extracellular traps (NETs) in MI rats, specifically manifested as a significant reduction in the Histone-DNA level and expression of myeloperoxidase (MPO) and citrullinated histone H3 (CitH3) proteins. Furthermore, QXJYG upregulated the levels of ANXA1 and FPR2 proteins in MI rats. The level of FPR2 was markedly reduced in MI rats upon administration of WRW4, a specific inhibitor of FPR2, which was associated with exacerbated MI injury and an elevated level of NETs. When WRW4 was co-administered with QXJYG, the cardioprotective effects of QXJYG on MI were significantly diminished. However, the addition of DNase I did not result in significant changes of the outcomes in MI rats after QXJYG intervention. ConclusionQXJYG treatment alleviates cardiac tissue injury in MI rats by inhibiting NETs through activating the ANXA1/FPR2 axis. The findings extend our understanding of the therapeutic effectiveness of QXJYG and offer a scientific foundation for the clinical utilization of QXJYG.

Identification of 3-methyl-1-(3-methylpyridin-2-yl)-1H-pyrazol-5-ol as promising neuroprotective agent

Pyrazolol derivatives are gaining significant attention for their diverse pharmacological effects, such as analgesic, anti-inflammatory, antioxidant, and anticancer activities. In this study, 20 pyrazolol derivatives were designed and synthesized to develop an anti-ischemic stroke formulation with free radical scavenging activity. Most of these synthesized compounds demonstrated antioxidant capabilities in DPPH, ABTS radical scavenging, and ORACFL assays. The methyl-substituted compound Y12, in particular, showed exceptional antioxidant capacity. Additionally, these compounds showed excellent neurocytoprotective effects in the SH-SY5Y cell injury model subjected to oxygen-glucose deprivation/reoxygenation (OGD/R). Notably, Y12 exhibited significant metal chelating activity with Cu2+. In vivo studies confirmed that compound Y12 has neuroprotective effects and can significantly reduce the infarct area in a mouse model of focal cerebral ischemia induced by transient middle cerebral artery occlusion (tMCAO).

ECG data analysis to determine ST-segment elevation myocardial infarction and infarction territory type: an integrative approach of artificial intelligence and clinical guidelines.

Acute coronary syndrome (ACS) is one of the leading causes of death from cardiovascular diseases worldwide, with ST-segment elevation myocardial infarction (STEMI) representing a severe form of ACS that exhibits high prevalence and mortality rates. This study proposes a new method for accurately diagnosing STEMI and categorizing the infarction area in detail, based on 12-lead electrocardiogram (ECG) data using a deep learning-based artificial intelligence (AI) algorithm. Utilizing an ECG database consisting of 888 myocardial infarction (MI) patients, this study enhanced the generalization ability of the AI model through five-fold cross-validation. The developed ST-segment elevation (STE) detector accurately identified STE across all 12 leads, which is a crucial indicator for the clinical ECG diagnosis of STEMI. This detector was employed in the AI model to differentiate between STEMI and non-ST-segment elevation myocardial infarction (NSTEMI). In the process of distinguishing between STEMI and NSTEMI, the average area under the receiver operating characteristic curve (AUROC) was 0.939, and the area under the precision-recall curve (AUPRC) was 0.977, demonstrating significant results. Furthermore, this detector exhibited the ability to accurately differentiate between various infarction territories in the ECG, including anterior myocardial infarction (AMI), inferior myocardial infarction (IMI), lateral myocardial infarction (LMI), and suspected left main disease. These results suggest that integrating clinical domains into AI technology for ECG diagnosis can play a crucial role in the rapid treatment and improved prognosis of STEMI patients. This study provides an innovative approach for the diagnosis of cardiovascular diseases and contributes to enhancing the practical applicability of AI-based diagnostic tools in clinical settings.

Combining Quantitative Susceptibility Mapping With the Gray Matter Volume to Predict Neurological Deficits in Patients With Small Artery Occlusion.

Currently, there is still a lack of valuable neuroimaging markers to assess the clinical severity of stroke patients with small artery occlusion (SAO). Quantitative susceptibility mapping (QSM) is a quantitative processing method for neuroradiological diagnostics. Gray matter (GM) volume changes in stroke patients are also proved to be associated with neurological deficits. This study aims to explore the predictive value of QSM and GM volume in neurological deficits of patients with SAO. As neurological deficits, the National Institutes of Health Stroke Scale (NIHSS) was used. Sixty-six SAO participants within 24h of first onset were enrolled and divided into mild and moderate groups based on NIHSS. QSM values of infarct area and GM volume were calculated from magnetic resonance imaging (MRI) data. Two-sample t-tests were used to compare differences in QSM value and GM volume between the two groups, and the diagnostic efficacy of the combination of QSM value and GM volume was evaluated. The results revealed both the QSM value and GM volume within the infarct area of the moderate group were lower compared to the mild group. Moderate group exhibited lower GM volume in some specific gyrus compared with mild group in the case of voxel-wise GM volume on whole-brain voxel level. The support vector machine (SVM) classifier's analysis showed a high power for the combination of QSM value, GM volume within the infarct area, and voxel-wise GM volume. Our research first reported the combination of QSM value, GM volume within the infarct area, and voxel-wise GM volume could be used to predict neurological impairment of patients with SAO, which provides new insights for further understanding the SAO stroke.

Neuro- and vasoprotective potential of neuropeptide Y2 receptor agonist, NPY13-36, against transient focal cerebral ischemia in spontaneously hypertensive rats

Numerous in vitro and in vivo experimental studies indicate that neuropeptide Y Y2 receptors (Y2R) are potential targets for neuroprotective therapy, including neuroprotection against ischemic stroke in healthy rats. Since stroke in humans is typically associated with comorbidities and long-term hypertension is the most common comorbidity leading to stroke, this study aimed to assess the neuroprotective potential of the Y2R agonist NPY13–36 in the rats with essential hypertension (SHR) subjected to 90 min middle cerebral artery suture occlusion with subsequent reperfusion (MCAOR). The cerebrocortical microflow in the ischemic focus and penumbra was continuously monitored with a Laser-Doppler flowmeter. NPY13–36 (10 μg/6 μl physiological saline solution) was administered intracerebroventricularly (i.c.v.) during ischemia or early reperfusion. The infarct area (triphenyltetrazolium chloride staining), behavioral tests (gait, mobility, and sensorimotor functions), and the response of the cerebrocortical microcirculation in the penumbra to hypercapnia and to the inhibition of the synthesis of nitric oxide were studied. Our results demonstrate that administration of NPY13-36 reduces the size of the infarct, improves motor functions, and restores microcirculatory response to the blockade of nitric oxide synthase when administered during reperfusion. The novelty of this study is a finding of the vasoprotective effect of NPY13-36 in brain ischemia/reperfusion. Moreover, this study provides evidence of the beneficial effects of NPY13-36 in animals with essential hypertension and indicates that Y2R ligands may be promising candidates for treating the ischemic brain in the case of this disease.

Zinc sulfide nanoparticles serve as gas slow-release bioreactors for H2S therapy of ischemic stroke

Stroke is one of the leading causes of death and disability in the world. Ischemic stroke causes overproduction of reactive oxygen/nitrogen species (RONS) after reperfusion, triggering inflammatory responses that further leads to cell damage. In order to develop novel neuroprotective materials, we synthesized zinc sulfide nanoparticles (ZnS NPs) to function as gas slow-release bioreactors, showcasing stable and sustained H2S release while effectively removing RONS. In cultured cells, ZnS NPs can reduce the oxidative damage caused by oxygen-glucose deprivation and reoxygenation (OGD/R), promote the expression of p-AMPK, enhance microglia M2 polarization, decrease inflammatory factors and reduce neuronal apoptosis. Additionally, it increases the proliferation and migration of endothelial cells, promoting the formation of new neurovascular units by regulating the protein of p-AKT. In mice with ischemic stroke induced by middle cerebral artery occlusion/reperfusion (MCAO/R), ZnS NPs significantly reduce the infarct area and restore the mobility of mice owing to the slow release of H2S. In summary, our results indicate that ZnS NPs can be used as H2S slow-release bioreactors, offering a potentially innovative approach to treat ischemia-reperfusion injury caused by stroke.