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Objectives: We compared the cardioprotective capacity of Del Nido cardioplegia and warm Calafiore blood cardioplegia in an experimental setting during 90 min of ischaemia. Methods: 20 adult and 20 senescent rat hearts were isolated and mounted on a blood-perfused, pressure-controlled Langendorff apparatus. After a stabilization period, cardiac arrest (90 min) was induced by the administration of either Calafiore (Cala) or Del Nido solution (DNS). While Cala was given warm and intermittently, DNS was given as a cold single shot. During 90 min of reperfusion, cardiac function and metabolism were evaluated and biomarker levels were measured. After the end of the experiment, hearts were prepared for electronmicroscopic investigation. Results: Hearts exposed to Cala recovered faster during reperfusion compared with hearts administered DNS (Cala vs DNS at 30 min reperfusion: left ventricular developed pressure 72, SD: 22% of baseline (BL) versus 40, SD: 32% of BL, p <.001, and positive derived left ventricular pressure over time was better in both adult and senescent Cala groups (96, SD: 31% of BL) than in the DNS groups (39, SD: 27% of BL, p <.001). Ischaemic contractures were seen in the DNS groups starting after 30 min of ischaemia, whereas no rise in diastolic pressure was observed for the Cala groups. Accordingly, lactate production was higher after DNS (1.23 mg/dl (SD 0.87) than after Cala (0.33 mg/dl (SD 0.68), p =.015) at the beginning of reperfusion. Troponin I levels at the end of reperfusion were higher after DNS treatment in adult hearts (DNS: 287.9 SD: 147.7 ng/mL vs Cala 91.2: SD: 94.7 ng/mL, p =.02) and in senescent hearts (DNS: 376.5 (SD: 162.8) ng/ml versus Cala 104.7 (SD: 150.2) ng/ml, p =.025). Electron microscopy showed that the cellular oedema index was higher in adult DNS hearts (1.2 ± 0.2) than in adult Cala hearts (0.8 ± 0.1, p =.012), whereas the VS ratio was similar (0.18 ± 0.01 vs 0.17 ± 0.03). Conclusion: Calafiore cardioplegia offers better myocardial protection from ischaemia/reperfusion-related damage in isolated perfused adult and senescent rat hearts than Del Nido cardioplegia. [ABSTRACT FROM AUTHOR]

[Display omitted] • Ginsenoside fraction from Panax ginseng decreased the acetylated protein levels of spliceosome in cardiomyocytes. • Ginsenoside Rb2 inhibited SF3A2 acetylation at lysine 10 to promote mitochondrial function against myocardial ischemic/reperfusion injury. • Ginsenoside Rb2 promoted Fscn1 alternative splicing to enhance mitochondrial respiration. • The decreased acetylation of SF3A2 (K 10) by ginsenoside Rb2 was mediated by p300 inhibition. Ginsenosides (GS) derived from Panax ginseng can regulate protein acetylation to promote mitochondrial function for protecting cardiomyocytes. However, the potential mechanisms of GS for regulating acetylation modification are not yet clear. This study aimed to explore the potential mechanisms of GS in regulating protein acetylation and identify ginsenoside monomer for fighting myocardial ischemia-related diseases. The 4D-lable free acetylomic analysis was employed to gain the acetylated proteins regulated by GS pretreatment. The co-immunoprecipitation assay, immunofluorescent staining, and mitochondrial respiration measurement were performed to detect the effect of GS or ginsenoside monomer on acetylated protein level and mitochondrial function. RNA sequencing, site-specific mutation, and shRNA interference were used to explore the downstream targets of acetylation modificationby GS. Cellular thermal shift assay and surface plasmon resonance were used for identifying the binding of ginsenoside with target protein. In the cardiomyocytes of normal, oxygen glucose deprivation and/or reperfusion conditions, the acetylomic analysis identified that the acetylated levels of spliceosome proteins were inhibited by GS pretreatment and SF3A2 acetylation at lysine 10 (K 10) was significantly decreased as a potential target of GS. Ginsenoside Rb2 was identified as one of the active ginsenoside monomers for reducing the acetylation of SF3A2 (K 10), which enhanced mitochondrial respiration against myocardial ischemic injury in in vivo and in vitro experiments. RNA-seq analysis showed that ginsenoside Rb2 promoted alternative splicing of mitochondrial function-related genes and the level of fascin actin-bundling protein 1 (Fscn1) was obviously upregulated, which was dependent on SF3A2 acetylation. Critically, thermodynamic, kinetic and enzymatic experiments demonstrated that ginsenoside Rb2 directly interacted with p300 for inhibiting its activity. These findings provide a novel mechanism underlying cardiomyocyte protection of ginsenoside Rb2 by inhibiting p300-mediated SF3A2 acteylation for promoting Fscn1 expression, which might be a promising approach for the prevention and treatment of myocardial ischemic diseases. [ABSTRACT FROM AUTHOR]

Organic nanocrystals, particularly those composed of conjugated molecules, hold immense potential for various applications. However, their practical utility is often hindered by the challenge of achieving stable aqueous dispersions, which are essential for biological compatibility and effective delivery. This study introduces a novel and versatile strategy for preparing stable aqueous organic nanocrystals using a modified reprecipitation method. We demonstrate the broad applicability of this approach by successfully preparing a diverse library of nanocrystals from 27 conjugated molecules. Our findings reveal a charge-balanced aggregation mechanism for nanocrystal formation, highlighting the crucial role of surface charge in controlling particle size and stability. Based on this mechanism, we establish a comprehensive molecular combination strategy that directly links molecular properties to colloidal behaviour, enabling the straightforward prediction and preparation of stable aqueous dispersions without the need for excipients. This strategy provides a practical workflow for tailoring the functionality of these nanocrystals for a wide range of applications. To illustrate their therapeutic potential, we demonstrate the enhanced efficacy of these nanocrystals in treating acute ulcerative colitis, myocardial ischemia/reperfusion injury, and cancer in mouse models. This work paves the way for developing next-generation nanomaterials with tailored functionalities for diverse biomedical applications. [Display omitted] • Bridging Disciplines: This research bridges crystal engineering and colloid science by achieving aqueous stability of organic nanocrystals. • New Design Rules: Charge-balanced aggregation links molecular properties to colloidal behaviour for stable nanocrystals. • Predictive Strategy: A strategy for identifying suitable molecular combinations for aqueous organic nanocrystals. • Practical Workflow: A practical workflow for preparing diverse aqueous organic nanocrystals. • Functional Control & Applications: Diverse molecular combinations enable control over nanocrystal functionality for bioapplications. [ABSTRACT FROM AUTHOR]

Uremic cardiomyopathy (UC) represents a complex syndrome characterized by different cardiac complications, including systolic and diastolic dysfunction, left ventricular hypertrophy, and diffuse fibrosis, potentially culminating in myocardial infarction (MI). Revascularization procedures are often necessary for MI management and can induce ischemia reperfusion injury (IR). Despite this clinical relevance, the role of fine particulate matter (PM2.5) in UC pathology and the underlying subcellular mechanisms governing this pathology remains poorly understood. Hence, we investigate the impact of PM2.5 exposure on UC susceptibility to IR injury. Using a rat model of adenine-induced chronic kidney disease (CKD), the animals were exposed to PM2.5 at 250 µg/m3 for 3 h daily over 21 days. Subsequently, hearts were isolated and subjected to 30 min of ischemia followed by 60 min of reperfusion to induce IR injury. UC hearts exposed to PM2.5 followed by IR induction (Adenine + PM_IR) exhibited significantly impaired cardiac function and increased cardiac injury (increased infarct size and apoptosis). Analysis at the subcellular level revealed reduced mitochondrial copy number, impaired mitochondrial bioenergetics, decreased expression of PGC1-α (a key regulator of mitochondrial biogenesis), and compromised mitochondrial quality control mechanisms. Additionally, increased mitochondrial oxidative stress and perturbation of the PI3K/AKT/AMPK signaling axis were evident. Our findings therefore collectively indicate that UC myocardium when exposed to PM2.5 is more vulnerable to IR-induced injury, primarily due to severe mitochondrial impairment. [ABSTRACT FROM AUTHOR]

This research focused on investigating the effects of sevoflurane (Sev) on myocardial autophagy levels after myocardial ischemia reperfusion (I/R) injury via the microRNA-542-3p (miR-542-3p)/ADAM9 axis. Mice underwent 30 min occlusion of the left anterior descending coronary (LAD) followed by 2 h reperfusion. Cardiac infarction was determined by 2,3,5-triphenyltetrazolium chloride triazole (TTC) staining. Cardiac function was examined by echocardiography. Cardiac markers and oxidative stress factors were evaluated by ELISA. Autophagy-associated factors were detected by western blot. Relationship between miR-542-3p and ADAM9 was tested by dual-luciferase reporter gene assay, RT-qPCR, and western blot. Sev treatment ameliorated cardiac dysfunction, myocardial oxidative stress, and histopathological damages, decreased myocardial infarction size and myocardial apoptotic cells after myocardial I/R injury. Sev treatment elevated miR-542-3p expression and decreased ADAM9 expression in myocardial tissues after myocardial I/R injury. miR-542-3p overexpression could enhance the ameliorative effects of Sev on myocardial injury and myocardial autophagy in I/R mice. miR-542-3p targeted and negatively regulated ADAM9 expression. ADAM9 overexpression reversed the ameliorative effects of miR-542-3p up-regulation on myocardial injury and myocardial autophagy in Sev-treated I/R mice. Sev treatment could ameliorate myocardial injury and myocardial autophagy in I/R mice, mediated by mechanisms that include miR-542-3p up-regulation and ADAM9 down-regulation. [ABSTRACT FROM AUTHOR]

This study aimed to elucidate the role and underlying mechanisms of Peroxisome proliferator-activated receptor gamma (PPARγ) and its m6A methylation in renal ischemia-reperfusion (I/R) injury and ferroptosis of tubular epithelial cells (TECs). High-throughput transcriptome sequencing was performed on renal tissue samples from I/R injury models and sham-operated mice, complemented by in vivo and in vitro experiments focusing on the PPARγ activator Rosiglitazone and the manipulation of METTL14 and IGF2BP2 expression. Key evaluations included renal injury assessment, ferroptosis indicator measurement, and m6A methylation analysis of PPARγ. Our findings highlight the critical role of the PPARγ pathway and ferroptosis in renal I/R injury, with Rosiglitazone ameliorating renal damage and TEC ferroptosis. METTL14-mediated m6A methylation of PPARγ, dependent on IGF2BP2, emerged as a pivotal regulator of PPARγ expression, renal injury, and ferroptosis. This study reveals that PPARγ m6A methylation, orchestrated by METTL14 through an IGF2BP2-dependent mechanism, plays a crucial role in mitigating renal I/R injury and TEC ferroptosis. These insights offer promising avenues for therapeutic strategies targeting acute kidney injury. [ABSTRACT FROM AUTHOR]

Danshen formulation (GXDSF) is a traditional Chinese herbal recipe recorded in the Chinese Pharmacopeia since 1995 edition, which consists of Salviae miltiorrhizae Radix et Rhizoma, Notoginseng Radix et Rhizoma and Dalbergiae odoriferae Lignum. Our previous research suggested GXDSF had positive effect on cardiovascular disease. Therefore, the aim of this study was to elucidate the effects of GXDSF on myocardial ischemia reperfusion injury-induced left ventricular remodelling (MIRI-LVR). Methods: The effects of GXDSF on cardiac function were detected by haemodynamics and echocardiograms. The effects of GXDSF on biochemical parameters (AST, LDH and CK-MB) were analyzed. Histopathologic examinations were performed to evaluate the effect of GXDSF on cardiac structure. In addition, the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database was used to predict the main target of GXDSF. Target validation was conducted by using western blots and immunofluorescent double staining assays. Results: We found that Cdp/dt and LVSP were significantly elevated in the GXDSFtreated groups compared with the MIRI-LVR model group. Left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were increased in the GXDSF-treated groups compared with the model group. All biochemical parameters (AST, LDH and CK-MB) were considerably decreased in the GXDSF-treated groups compared with the model group. Fibrosis parameters (collagen I and III, a-SMA, and left ventricular fibrosis percentage) were decreased to different degrees in the GXDSFtreated groups compared with the model group, and the collagen III/I ratio was elevated by the same treatments. TCMSP database prediction and western blot results indicated that estrogen receptor b (ERb) could be the main target of GXDSF. PHTPP, a selective antagonist of ERb, could inhibit the expression of ERb and the phosphorylation of PI3K and Akt in myocardial tissue induced by GXDSF, and partly normalize the improving effects of GXDSF on Cdp/dt, LVEF, LVFS, LDH, CK-MB, a-SMA and myocardial fibrosis. Conclusion: Collectively, GXDSF showed therapeutic potential for use in the prevention and treatment of myocardial ischemia reperfusion injury-induced ventricular remodeling by upregulating ERb via PI3K/Akt signaling. Moreover, these findings may be valuable in understand the mechanism of disease and provide a potential therapy of MIRI-IVR. [ABSTRACT FROM AUTHOR]

Neutrophil polarization contributes to inflammation and its resolution, but the role of neutrophil polarization in myocardial ischemia/reperfusion (I/R) injury remains unknown. Cardiomyocytes (CMs) participate in cardiac inflammation by secreting extracellular vesicles (EVs). Therefore, we investigated the role of neutrophil polarization in myocardial I/R injury and the mechanism by which CM-derived EVs regulated neutrophil polarization. In the present study, our data showed that N1 neutrophil polarization enlarged cardiac infarct size and exacerbated cardiac dysfunction at the early stage of myocardial I/R. Further, CM-EV-derived miR-9-5p was identified as a mediator inducing neutrophils to the N1 phenotype. Mechanistically, miR-9-5p directly suppressed SOCS5 and SIRT1 expression, resulting in activating JAK2/STAT3 and NF-κB signaling pathways in neutrophils. Importantly, we confirmed that serum EV-derived miR-9-5p levels were independently associated with cardiovascular mortality in patients with ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention. These findings suggest neutrophil polarization is a promising therapeutic target against myocardial I/R-induced inflammation and injury, and serum EV-derived miR-9-5p is a promising prognostic biomarker for cardiovascular mortality in patients with ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention. [ABSTRACT FROM AUTHOR]

Objective: Calafiore and modified del Nido cardioplegic solutions are currently being used during coronary artery bypass surgery. This study aims to compare myocardial ischemic stress associated with both solutions by studying the changes in cardiac metabolites during cardioplegic ischemic arrest and early reperfusion. Methods: Biopsy specimens were taken from the left ventricles of 20 patients undergoing routine coronary artery bypass grafting using Calafiore or modified del Nido cardioplegic solutions. Biopsies were taken immediately after the beginning of extracorporeal circulation (basal biopsy), 30 min after application of the aortic cross‐clamp (ischemic biopsy), and 20 min following the removal of aortic cross‐clamp (reperfusion biopsy) and were analyzed for their amino acid and lactic acid contents using amino acid analyzer and appropriate kits. Peripheral blood samples were also collected for the determination of blood concentrations of cardiac proteins (CK‐MB and troponin I) using an immunofluorescence scanner. Results: Both CK‐MB and troponin I increased significantly 12 h postoperatively and were associated with an increase in myocardial lactic acid, but there were no significant differences in markers of myocardial injury between the two groups. Comparison of amino acid concentrations between the two groups according to sampling time showed that glutamic acid concentrations were significantly lower in the Calafiore cardioplegia group compared to the del Nido cardioplegia group, but there were no other significant differences in markers of metabolic stress (taurine and alanine/glutamate ratio) between the two groups. Moreover, there were no significant differences in changes in amino acid concentrations regardless of the type of cardioplegic solution used. Conclusions: Cardioplegic ischemic arrest and early reperfusion are associated with a rise in myocardial metabolic stress. Both Calafiore and modified del Nido cardioplegic solutions are effective in attenuating myocardial substrate derangements and confer equal myocardial protection during routine coronary artery bypass surgery. Trial Registration: ClinicalTrials.gov identifier: NCT06287372 [ABSTRACT FROM AUTHOR]

The antiarrhythmic and cardiac electrophysiological effects of SZV-2649 that contains a 2,6-diiodophenoxy moiety but lacks the benzofuran ring system present in amiodarone, were studied in mammalian cell line, rat and dog cardiac preparations. SZV-2649 exerted antiarrhythmic effects against coronary artery occlusion/reperfusion induced ventricular arrhythmias in rats and in acetylcholine- and burst stimulation induced atrial fibrillation in dogs. SZV-2649 inhibited hERG and GIRK currents in HEK cells (IC50: 342 and 529 nM, respectively). In canine ventricular myocytes, SZV-2649 (10 µM) decreased the densities of IKr, and Ito outward and INaL and ICaL inward currents. The compound (2.5–10 µM) elicited Class IB type Vmax reducing and Class III type action potential duration prolonging effects in dog right ventricular muscle preparations. In canine atrial muscle, SZV-2629 (2.5–10 µM) moderately prolonged action potential duration and this effect was greatly augmented in preparations pretreated with 1 µM carbachol. In conclusion, SZV-2649, has antiarrhythmic effects based on its multiple ion channel blocking properties. Since its chemical structure substantially differs from that of amiodarone, it is expected that SZV-2649 would exhibit fewer adverse effects than the currently used most effective multichannel inhibitor drug amiodarone and may be a promising molecule for further development. [ABSTRACT FROM AUTHOR]

Stroke is recognized as a leading cause of disability and mortality worldwide, posing a significant challenge, particularly in developing countries. The current study aimed to evaluate the neuroprotective effect of Ganoderic acid (GA) against focal ischemic stroke in rats. Material and methods.: Swiss Wistar rats were used for the current study. The rats were subjected to middle cerebral artery occlusion (MCAO) to simulate transient focal ischemia, followed by reperfusion. Various neurological parameters, including infarct size, neurological deficit score, brain water content, Evans blue leakage, nitric oxide (NO), inducible nitric oxide synthase (iNOS), lactate dehydrogenase (LDH), antioxidant levels, inflammatory cytokines, apoptosis markers, inflammatory parameters, and matrix metalloproteinases (MMP) levels, were estimated. Additionally, mRNA expressions were evaluated in the brain tissue. Results.: Dose dependently treatment of GA significantly (P < 0.001) suppressed the infarct size, neurological deflects score, brain water, evans blue leakage, NO, iNOS, LDH, C-X-C chemokine receptor type 4 (CXCR-4), monocyte chemoattractant protein-1 (MCP-1), S100 calcium-binding protein B (S-100β) and K+-Cl− cotransporter 1 (KCC1) positive cells. GA altered the level of oxidative stress parameters like Total antioxidant capacity (T-AOC), 8-hydroxy-2'-deoxyguanosine (8-OhdG), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione (GSH), malonaldehyde (MDA); cytokines viz., tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), IL-1β, IL-6, IL-9, IL-10; inflammatory parameters such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), prostaglandin (PGE2), Nuclear factor kappa B (NF-κB); apoptosis parameters like B-cell leukemia/lymphoma 2 protein (Bcl-2), Bcl-2-associated protein x (Bax), Caspase-3; matrix metallopeptidase (MMP) parameters like MMP-2, MMP-3, and MMP-9, respectively. GA remarkably suppressed the mRNA expression of TRL-4, Syndecan-1, CSF, Aquaporin-1, OCT3, and RFX1. Conclusion.: Ganoderic acid exhibited the protection against the cerebral ischemia reperfusion via multiple mechanism. [ABSTRACT FROM AUTHOR]

Background: Inflammation and oxidative stress are key players in lung injury stemming from cardiac ischemia (LISCI). Cannabidiol (CBD) demonstrates tissue-protective properties through its antioxidant, anti-inflammatory, and anti-apoptotic characteristics. This study aims to assess the preventive (p-CBD) and therapeutic (t-CBD) effects of CBD on LISCI. Methods: Forty male Wistar Albino rats were divided into four groups: control (CON), LISCI, p-CBD, and t-CBD. The left anterior descending coronary artery was ligated for 30 min of ischemia followed by 30 min of reperfusion. Lung tissues were then extracted for histopathological, immunohistochemical, genetic, and biochemical analyses. Results: Histopathologically, marked hyperemia, increased septal tissue thickness, and inflammatory cell infiltrations were observed in the lung tissues of the LISCI group. Spectrophotometrically, total oxidant status and oxidative stress index levels were elevated, while total antioxidant status levels were decreased. Immunohistochemically, expressions of cyclooxygenase-1 (COX1), granulocyte colony-stimulating factor (GCSF), interleukin-6 (IL6) were increased. In genetic analyses, PERK and CHOP expressions were increased, whereas Nuclear factor erythroid 2-related factor 2 (NRF2) and B-cell leukemia/lymphoma 2 protein (BCL2) expressions were decreased. These parameters were alleviated by both prophylactic and therapeutic CBD treatment protocols. Conclusion: In LISCI-induced damage, both endoplasmic reticulum and mitochondrial stress, along with oxidative and inflammatory markers, were triggered, resulting in lung cell damage. However, both p-CBD and t-CBD treatments effectively reversed these mechanisms, normalizing all histopathological, biochemical, and PCR parameters. [ABSTRACT FROM AUTHOR]

Successful reperfusion of myocardial tissue is the goal of primary percutaneous coronary intervention (pPCI) in patients with ST-segment elevation myocardial infarction (STEMI). We aimed to investigate the association between the De Ritis ratio (AST/ALT) and myocardial reperfusion in patients with STEMI who underwent pPCI. We retrospectively investigated 1236 consecutive patients who were hospitalized for STEMI and underwent pPCI. ST-segment resolution (STR) was defined as the return of the deviated ST-segment to baseline; poor myocardial reperfusion was defined as <70% STR. Patients were divided into 2 groups according to the median De Ritis ratio (.921); 618 patients (50%) were assigned to the De Ritis low group while 618 patients (50%) were assigned to the De Ritis high group. Stent size, neutrophil-to lymphocyte ratio (NLR), and the De Ritis ratio found to be associated with poor myocardial reperfusion (Odds ratio (OR) 1.45, 95% CI 1.07–1.98, P =.01, OR 1.22, 95% CI 1.01–1.48, P =.03 and OR 10.9, 95% CI 7.9–15, P <.001, respectively). A high De Ritis ratio was associated with poor myocardial reperfusion in STEMI patients who underwent pPCI. As an easily obtainable test in clinical practice, the De Ritis ratio may help identify patients at major risk for impaired myocardial perfusion. [ABSTRACT FROM AUTHOR]

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Background: Gasdermin D (GSDMD) mediated pyroptosis plays a significant role in the pathophysiology of myocardial ischemia/reperfusion (I/R) injury. However, the precise mechanisms regulating pyroptosis remain unclear. In the study, we aimed to investigate the underlying mechanism of pyroptosis in myocardial I/R injury. Methods: In the present study, we analyzed the effects of USP5 on the RIPK1 kinase activity mediated pyroptosis in vitro after H/R (hypoxia/reoxygenation) and in vivo in a MI/R mouse model. TTC and Evan's blue dye, Thioflavin S and immunohistochemistry staining were performed in wild-type, RIPK1flox/flox Cdh5-Cre and USP5 deficiency mice. CMEC cells were transfected with si-USP5. HEK293T cells were transfected with USP5 and RIPK1 overexpression plasmid or its mutants. The levels of USP5, RIPK1, Caspase-8, FADD and GSDMD were determined by Western blot. Protein interactions were evaluated by immunoprecipitation. The protein colocalization in cells was monitored using a confocal microscope. Results: In this study, our data demonstrate that RIPK1 is essential for limiting cardiac endothelial cell (CMEC) pyroptosis mediated by caspase-8 in response to myocardial I/R. Additionally, we investigate the role of ubiquitin-specific protease 5 (USP5) as a deubiquitinase for RIPK1. Mechanistically, USP5 interacts with RIPK1, leading to its deubiquitination and stabilization. Conclusions: These findings offer new insights into the role of USP5 in regulating RIPK1-induced pyroptosis. [ABSTRACT FROM AUTHOR]

Early revascularization for patients with acute myocardial infarction (AMI) is of outmost importance in limiting infarct size and associated complications, as well as for improving long-term survival and outcomes. However, reperfusion itself may further damage the myocardium and increase the infarct size, a condition commonly recognized as myocardial reperfusion injury. Several strategies have been developed for limiting the associated with reperfusion myocardial damage, including hypothermia. Hypothermia has been shown to limit the degree of infarct size increase, when started before reperfusion, in several animal models. Systemic hypothermia, however, failed to show any benefit, due to adverse events and potentially insufficient myocardial cooling. Recently, the novel technique of intracoronary selective hypothermia is being tested, with preclinical and clinical results being of particular interest. Therefore, in this review, we will describe the pathophysiology of myocardial reperfusion injury and the cardioprotective mechanics of hypothermia, report the animal and clinical evidence in both systemic and selective hypothermia and discuss the potential future directions and clinical perspectives in the context of cardioprotection for myocardial reperfusion injury. [ABSTRACT FROM AUTHOR]

The role of ferroptosis and iron metabolism dysregulation in the pathophysiology of cardiovascular diseases is increasingly recognized. Conditions such as hypertension, cardiomyopathy, atherosclerosis, myocardial ischemia/reperfusion injury, heart failure, and cardiovascular complications associated with COVID-19 have been linked to these processes. Inflammation is central to these conditions, prompting exploration into the inflammatory and immunoregulatory molecular pathways that mediate ferroptosis and its contribution to cardiovascular disease progression. Notably, emerging evidence highlights interleukin-37 as a protective cytokine with the ability to activate the nuclear factor erythroid 2-related factor 2 pathway, inhibit macrophage ferroptosis, and attenuate atherosclerosis progression in murine models. However, a comprehensive review focusing on interleukin-37 and its protective role against ferroptosis in CVD is currently lacking. This review aims to fill this gap by summarizing existing knowledge on interleukin-37, including its regulatory functions and impact on ferroptosis in conditions such as atherosclerosis and myocardial infarction. We also explore experimental strategies and propose that targeting interleukin-37 to modulate ferroptosis presents a promising therapeutic approach for the prevention and treatment of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

The identification of acute cardioprotective strategies against myocardial ischemia/reperfusion (I/R) injury that can be applied in the catheterization room is currently an unmet clinical need and several interventions evaluated in the past at the pre-clinical level have failed in translation. Autonomic imbalance, sustained by an abnormal afferent signalling, is a key component of I/R injury. Accordingly, there is a strong rationale for neuromodulation strategies, aimed at reducing sympathetic activity and/or increasing vagal tone, in this setting. In this review we focus on cervical vagal nerve stimulation (cVNS) and on transcutaneous auricular vagus nerve stimulation (taVNS); the latest has the potential to overcome several of the issues of invasive cVNS, including the possibility of being used in an acute setting, while retaining its beneficial effects. First, we discuss the pathophysiology of I/R injury, that is mostly a consequence of the overproduction of reactive oxygen species. Second, we describe the functional anatomy of the parasympathetic branch of the autonomic nervous system and the most relevant principles of bioelectronic medicine applied to electrical vagal modulation, with a particular focus on taVNS. Then, we provide a detailed and comprehensive summary of the most relevant pre-clinical studies of invasive and non-invasive VNS that support its strong cardioprotective effect whenever there is an acute or chronic cardiac injury and specifically in the setting of myocardial I/R injury. The potential benefit in the emerging field of post cardiac arrest syndrome (PCAS) is also mentioned. Indeed, electrical cVNS has a strong anti-adrenergic, anti-inflammatory, antioxidants, anti-apoptotic and pro-angiogenic effect; most of the involved molecular pathways were already directly confirmed to take place at the cardiac level for taVNS. Pre-clinical data clearly show that the sooner VNS is applied, the better the outcome, with the possibility of a marked infarct size reduction and almost complete left ventricular reverse remodelling when VNS is applied immediately before and during reperfusion. Finally, we describe in detail the limited but very promising clinical experience of taVNS in I/R injury available so far. [ABSTRACT FROM AUTHOR]

This research letter published in the journal Circulation discusses the potential cardioprotective activity of a retro-enantiomer peptide called Angiotensin-(1-9) [Ang-(1-9) RE]. The authors synthesized this peptide and found that it interacts with the angiotensin receptor type 2 (AT2R) and displays increased stability in serum compared to the original peptide Ang-(1-9). The study conducted on spontaneously hypertensive rats (SHRs) showed that Ang-(1-9) RE reduced systolic blood pressure and was more effective than Ang-(1-9) in reducing cardiac hypertrophy and collagen content in the hearts of SHRs. The study suggests that Ang-(1-9) RE has promising therapeutic applications for cardiovascular diseases. The text also briefly mentions the Iran Pasteur Institute, which has played a significant role in controlling infectious diseases in Iran and is considered a major component of Iran's healthcare and research infrastructure. [Extracted from the article]

AbstractObjectiveMaterials and methodsResultsDiscussion and conclusionThis study aimed to investigate the mechanism of emulsified isoflurane in reducing myocardial ischemia-reperfusion injury (MIRI).Forty-eight healthy male Sprague-Dawley rats were randomly divided into four groups (n = 12). In the sham group (group S) and ischemia-reperfusion group (group I/R), saline (4 ml/kg/h) was administered intravenously for 30 min. In intralipid group (group L), intralipid (4 ml/kg/h) was administered intravenously. In the emulsified isoflurane group (group EI), emulsified isoflurane (4 ml/kg/h) was administered intravenously. The infusion was then discontinued for 15 min during the washout period. Apart from group S, ischemia was produced by occlusion of the left anterior descending artery (LADA) for 30 min. After 30 min of occlusion, all groups received reperfusion for two hours.Creatine kinase MB (CK-MB), cardiac troponin I (cTnI), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) were measured by enzyme-linked immunosorbent assay (ELISA). Myocardial infarct size was measured using triphenyl tetrazolium chloride staining. According to the result, pretreatment with emulsified isoflurane attenuated CK-MB and cTnI concentrations (p < 0.05). And serum TNF-α and IL-6 levels and infarct size in the emulsified isoflurane group obviously decreased. An obvious decrease in the expression of the toll-like receptor-4 (TLR-4) mRNA in group EI was observed compared with group I/R.Emulsified isoflurane precondition had a potent cardioprotective effect against myocardial ischemia-reperfusion injury. The mechanisms involved may be related to the decrease in the expression of TLR-4 and the reduced inflammatory response. [ABSTRACT FROM AUTHOR]

Aim To investigate the effect and mechanism of hydrogen molecule on myocardial injury in severe traumatic brain injury (TBI) rats. Methods Using the fluid percussion injury (FPI)-induced TBI model. 72 SD rats were randomly divided into sham group, TBI group and hydrogen molecule-treated group, with 24 rats in each group, and the rats were executed at 48 h after the operation. HE staining was used to observe the myocardial injury and the infiltration of granulocytes, ELISA was used to detect the level of superoxide dismutase (SOD), Western blot was used to detect the expression of inflammation-related factors myeloperoxidase (MPO) and heme oxygenase-1 (HO-1) protein, RTqPCR was used to detect the levels of cardiac troponin T (cTnT), inhibitory factor-1 (IF-1), NADH/ubiquinone oxidoreductase core subunit S7 (NDUFS7), nicotinamide adenine dinucleotide phosphate (NADP) and reduced nicotinamide adenine dinucleotide phosphate (NADPH). The changes of post-traumatic echocardiography and the 7-day survival rate and body weight in the rats were observed and recorded. Results Compared with the sham group, rats in the TBI group had significantly higher troponin levels, and the echocardiographic results showed higher left ventricular end-diastolic diameter (LVEDD) and significantly lower left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), and the above pathologic changes were significantly improved after treatment with the hydrogen molecule. Myocardial tissue was disorganized with erythrocyte infiltration, and myocardial fibers were infiltrated with granulocytes in the section, which were improved in the hydrogen molecule-treated group. The body weight of the rats decreased dramatically after the operation, and about 5 days later dropped to the lowest level, and then showed a trend of slow recovery. mNSS scores showed that the neurological function of the rats was severely impaired after TBI, and the postoperative myocardial tissues showed an increase in the expression levels of MPO and HO-1 proteins and a decrease in the expression levels of SOD, and the above pathological changes were significantly improved by hydrogen molecule treatment. In the TBI group, the expression levels of NADPH, IF-1 and NDUFS7 were reduced, and the expression levels of the above indicators were significantly increased after hydrogen molecule treatment. Conclusion Hydrogen molecule may be able to increase mitochondrial energy metabolism in cardiomyocytes and reduce myocardial oxidative stress by synergistically enhancing the protein expression of IF-1 and NDUFS7 on the mitochondrial oxidative respiratory chain to increase cardiac function and survival rate in the acute phase of TBI. [ABSTRACT FROM AUTHOR]

Caveolae are intracellular vesicles with diameters ranging from 50 to 100 nm. The role of caveolins in mediating oxidative stress, autophagy, apoptosis, fibrosis, and vascular remodeling has attracted increasing attention in cardiovascular therapy. Several studies have suggested that caveolin could be a therapeutic target for the treatment of cardiac and/or vascular injury via several pathophysiological mechanisms. Despite substantial advances in our understanding of the basic biology of vesicles over the past decade, the relevance and specific role of these mechanisms in cardiovascular homeostasis remains ambiguous. Here, we review the macroscopic role of caveolins in protecting cardiac function and, at the microscopic level, examine possible cardioprotective caveolar mechanisms, including their antioxidative stress, antiapoptosis, autophagy‐regulatory, antifibrosis, and angiogenesis‐promoting properties. We believe that the role of caveolins in cardiac functioning has not been fully elucidated and is an important line of future research with several cardioprotective implications. [ABSTRACT FROM AUTHOR]

Myocardial reperfusion injury (MRI) accounts for up to 50% of the final size in acute myocardial infarction and other conditions associated with ischemia‐reperfusion. Currently, there is still no therapy to prevent MRI, but it is well known that oxidative stress has a key role in its mechanism. We previously reduced MRI in rats through a combined antioxidant therapy (CAT) of ascorbic acid, N‐acetylcysteine, and deferoxamine. This study determines the safety and pharmacokinetics of CAT in a Phase I clinical trial. Healthy subjects (n = 18) were randomized 2:1 to CAT or placebo (NaCl 0.9% i.v.). Two different doses/infusion rates of CATs were tested in a single 90‐minute intravenous infusion. Blood samples were collected at specific times for 180 minutes to measure plasma drug concentrations (ascorbic acid, N‐acetylcysteine, and deferoxamine) and oxidative stress biomarkers. Adverse events were registered during infusion and followed for 30 days. Both CAT1 and CAT2 significantly increased the CAT drug concentrations compared to placebo (P <.05). Most of the pharmacokinetic parameters were similar between CAT1 and CAT2. In total, 6 adverse events were reported, all nonserious and observed in CAT1. The ferric‐reducing ability of plasma (an antioxidant biomarker) increased in both CAT groups compared to placebo (P <.001). The CAT is safe in humans and a potential treatment for patients with acute myocardial infarction undergoing reperfusion therapy. [ABSTRACT FROM AUTHOR]

Acute myocardial infarction still represents the major cause of mortality in high-income countries. Therefore, considerable efforts have been focused on the treatment of myocardial infarctions in the acute and long-term phase, with special attention being paid to reperfusion strategies and adjunctive antithrombotic therapies. In fact, despite the successful mechanical recanalization of the epicardial conduit, a substantial percentage of patients still experience poor myocardial reperfusion or acute/subacute in-stent thrombosis. Due the delayed onset of action of currently available oral antiplatelet therapies, glycoprotein (GP) IIb–IIIa inhibitors could be expected to improve clinical outcomes, especially when administrated in the early phase of the infarction, due to the larger platelet composition of fresh thrombi, the dynamic nature of early thrombi, and the larger amount of viable myocardium existing in the early, as compared to a delayed, phase. Considerable evidence has accumulated regarding the benefits from GP IIb–IIIa inhibitors on mortality, especially among high-risk patients and when administered as an upstream strategy. Therefore, based on currently available data, GP IIb–IIIa inhibitors can be considered when the drug can be administered within the first 3 h of symptom onset and among high-risk patients (e.g., those with advanced Killip class or an anterior myocardial infarction). Even though it is not universally accepted, in our opinion, this strategy should be implemented in a pre-hospital setting (in an ambulance) or as soon as possible when arriving at the hospital (at the Emergency Room or Coronary Care Unit, irrespective of whether they are in spoke or hub hospitals). A new, second-generation GP IIb–IIIa inhibitor (zalunfiban) appears to be highly suitable as a pre-hospital pharmacological facilitation strategy at the time of first medical contact due to its favourable features, including its simple subcutaneous administration, rapid onset of action (15 min), and limited time of action (with a half-life of ~1 h), which is likely to minimize the risk of bleeding. The ongoing CELEBRATE trial, including 2499 STEMI patients, may potentially provide compelling data to support the upstream treatment of STEMI patients undergoing mechanical reperfusion. In fact, although the current therapeutic target of increased rates of timely reperfusion has been achieved, the future goal in myocardial infarction treatment should be to achieve the most rapid reperfusion prior to primary percutaneous coronary intervention, thus further minimizing myocardial damage, or, in some cases, even preventing it completely, and improving survival. [ABSTRACT FROM AUTHOR]

Ferroptosis is a regulatory cell death process pivotal in myocardial ischemia–reperfusion (I/R) injury. However, the precise mechanism underlying myocardial ferroptosis remains less known. In this study, we investigated the pathophysiological mechanisms of methylmalonic acid (MMA) associated with ferroptosis activation in cardiomyocytes after I/R. We found an increase level of MMA in patients with acute myocardial injury after reperfusion and AC16 cells under hypoxia/reoxygenation (H/R) condition. MMA treatment was found to be associated with excessive oxidative stress in cardiomyocytes, leading to ferroptosis-related myocardial injury. In mice with I/R injury, MMA treatment aggravated myocardial oxidative stress and ferroptosis, which amplified the myocardial infarct size and cardiac dysfunction. Mechanistically, MMA promoted NOX2/4 expression to increase reactive oxygen species (ROS) production in cardiomyocytes, aggravating myocardial injury. Notably, the increased ROS further activated ferroptosis by inhibiting solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) expression. In addition, MMA decreased the ectopic nuclear distribution of nuclear factor E2-related factor 2 (NRF2) by increasing the interaction between NRF2 and kelch-like ECH-associated protein 1 (KEAP1). This impeded the activation of GPX4/SLC7A11, downstream of NRF2, activating ferroptosis and aggravating myocardial cell injury. Collectively, our study indicates that MMA activates oxidative stress and ROS generation, which induces ferroptosis to exacerbate cardiomyocyte injury in an I/R model. These findings may provide a new perspective for the clinical treatment of I/R injury and warrant further investigation. [ABSTRACT FROM AUTHOR]

The kidney is vulnerable to ischemia and reperfusion (I/R) injury that can be fatal after major surgery. Currently, there are no effective treatments for I/R-induced kidney injury. Trimethylamine N-oxide (TMAO) is a gut-derived metabolite linked to many diseases, but its role in I/R-induced kidney injury remains unclear. Here, our clinical data reveals an association between preoperative systemic TMAO levels and postoperative kidney injury in patients after post-cardiopulmonary bypass surgery. By genetic deletion of TMAO-producing enzyme flavin-containing monooxygenase 3 (FMO3) and dietary supplementation of choline to modulate TMAO levels, we found that TMAO aggravated acute kidney injury through the triggering of endoplasmic reticulum (ER) stress and worsened subsequent renal fibrosis through TGFβ/Smad signaling activation. Together, our study underscores the negative role of TMAO in I/R-induced kidney injury and highlights the therapeutic potential through the modulation of TMAO levels by targeting FMO3, thereby mitigating acute kidney injury and preventing subsequent renal fibrosis. This study elucidates the potential of targeting FMO3 to modulate TMAO levels as a therapeutic approach for mitigating acute kidney injury and subsequent renal fibrosis. [ABSTRACT FROM AUTHOR]

Intestinal ischemia‒reperfusion (IIR) injury is a common complication of surgery, but clear molecular insights and valuable therapeutic targets are lacking. Mitochondrial calcium overload is an early sign of various diseases and is considered a vital factor in ischemia‒reperfusion injury. The mitochondrial calcium uniporter (MCU), which is located on the inner mitochondrial membrane, is the primary mediator of calcium ion entry into the mitochondria. However, the specific mechanism of MCU in IIR injury remains to be clarified. In this study, we generated an IIR model using C57BL/6 mice and Caco-2 cells and found increases in the calcium levels and MCU expression following IIR injury. The specific inhibition of MCU markedly attenuated IIR injury. Moreover, MCU knockdown alleviates mitochondrial dysfunction by reducing oxidative stress and apoptosis. Mechanistically, MCU knockdown substantially reduced the translocation of Drp1 and thus its binding to Fis1 receptors, resulting in decreased mitochondrial fission. Taken together, our findings demonstrated that MCU is a novel upstream regulator of Drp1 in ischemia‒reperfusion and represents a predictive and therapeutic target for IIR. [Display omitted] • MCU is upregulated after intestinal ischemia‒reperfusion. • MCU-specific inhibition markedly attenuated intestinal ischemia‒reperfusion injury. • Inhibition of MCU substantially reduced the translocation of Drp1. [ABSTRACT FROM AUTHOR]

Ischemia-reperfusion (I/R) injury, a multifaceted pathological process, occurs when the prolongation of reperfusion duration triggers ferroptosis-mediated myocardial damage. Isoliquiritigenin (ISL), a single flavonoid from licorice, exhibits a wide range of pharmacological impacts, but its function in ferroptosis caused by myocardial I/R injury remains unclear. This study delved into the protective effect of ISL on myocardial I/R injury-induced ferroptosis and its mechanism. Neonatal mouse cardiomyocytes (NMCM) underwent hypoxia/reoxygenation (H/R) to simulate the pathological process of myocardial I/R. ISL significantly attenuated H/R-triggered production of reactive oxygen species in NMCM, reduced the expression of malondialdehyde and the activity of lactate dehydrogenase, enhanced superoxide dismutase and catalase activity, and increased the expression of nuclear factor E2-related factor 2 (Nrf2) and its downstream heme oxygenase 1 (HO-1), thereby mitigating oxidative stress damage. CCK8 experiment revealed that the ferroptosis inhibitor Ferrostatin-1 significantly improved myocardial cell viability after 24 h of reoxygenation, and ISL treatment showed a similar effect. ISL reduced intracellular free iron accumulation, up-regulated glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) expression, and inhibited lipid peroxidation accumulation, thereby alleviating ferroptosis. The Nrf2-specific inhibitor ML385 counteracted ISL's defensive role against H/R-triggered oxidative stress damage and ferroptosis. In vivo experiments further confirmed that by regulating the translocation of Nrf2 into the nucleus, ISL treatment increased the levels of HO-1, GPX4, and SLC7A11, inhibited the expression of ACSL4, Drp1 to exert the antioxidant role, alleviated mitochondrial damage, and ferroptosis, ultimately reducing myocardial infarction area and injury induced by I/R. ML385 nearly abolished ISL's protective impact on the I/R model by inhibiting Nrf2 function. In summary, ISL is capable of mitigating oxidative stress, mitochondrial damage, and cardiomyocyte ferroptosis caused by I/R, thereby reducing myocardial injury. A key mechanism includes triggering the Nrf2/HO-1/SLC7A11/GPX4 pathway to prevent oxidative stress damage and cardiomyocyte ferroptosis caused by I/R. [Display omitted] • Isoliquiritigenin mitigates myocardial oxidative stress, and mitochondrial damage induced by I/R. • Cardiomyocyte ferroptosis has an essential role in mediating myocardial I/R injury. • Isoliquiritigenin activates the Nrf2/HO-1/SLC7A11/GPX4 pathway to reduce cardiomyocyte ferroptosis to protect hearts against myocardial I/R injury. [ABSTRACT FROM AUTHOR]

Alterations in zinc transporter expression in response to zinc loss protect cardiac cells from ischemia/reperfusion (I/R) injury. However, the underlying molecular mechanisms how cardiac cells sense zinc loss remains unclear. Here, we found that zinc deficiency induced ubiquitination and degradation of the protein inhibitor of activated STAT3 (PIAS3), which can alleviate myocardial I/R injury by activating STAT3 to promote the expression of ZIP family zinc transporter genes. The RING finger domain within PIAS3 is vital for PIAS3 degradation, as PIAS3-dRing (missing the RING domain) and PIAS3-Mut (zinc-binding site mutation) were resistant to degradation in the setting of zinc deficiency. Meanwhile, the RING finger domain within PIAS3 is critical for the inhibition of STAT3 activation. Moreover, PIAS3 knockdown increased cardiac Zn2+ levels and reduced myocardial infarction in mouse hearts subjected to I/R, whereas wild-type PIAS3 overexpression, but not PIAS3-Mut, reduced cardiac Zn2+ levels, and exacerbated myocardial infarction. These findings elucidate a unique mechanism of zinc sensing, showing that fast degradation of the zinc-binding regulatory protein PIAS3 during zinc deficiency can correct zinc dyshomeostasis and alleviate reperfusion injury. [Display omitted] • Zinc deficiency induces the activation of STAT3, which acts as a transcription factor to promote upregulation of ZIP family zinc transporter gene expression, thereby compensating for Zn2+ loss. • PIAS3 can sense intracellular Zn2+ deficiency through its ubiquitination-mediated degradation and regulate the activity of STAT3. • Ring finger domain plays a critical role in PIAS3's ubiquitination and degradation by releasing Zn2+ in response to Zn2+ deficiency. • Knockdown of PIAS3 protected mouse hearts from I/R injury, whereas overexpression of PIAS3 exacerbated injury. [ABSTRACT FROM AUTHOR]

Baicalin (BAN) has shown promise in alleviating myocardial ischemia/reperfusion (I/R) injury, yet its limited solubility and biocompatibility have hindered its application. Developing drug delivery systems is a promising strategy to enhance the therapeutic potential of BAN in the context of I/R injury. This study aims to prepare a BAN-loaded nanodrug system using polydopamine (PDA)-modified Zeolitic imidazolate framework-8 (ZIF-8) as a carrier, with the goal of improving BAN's mitigating effects on I/R injury. We prepared the BAN nanoparticles (NPs) system, PZB NPs, using ZIF-8 as the carrier. The system was characterized in terms of morphology, particle size, zeta potential, and X-ray diffraction (XRD). We assessed the cytotoxicity of PZB NPs in H9c2 cells, investigated its effects and mechanisms in H/R-induced H9c2 cells, and evaluated its ability to alleviate myocardial I/R injury in rats. PZB NPs exhibited good dispersion, with a BAN loading efficiency of 26.43 ± 1.55%, a hydrated particle size of 102.21 ± 1.19 nm, and a zeta potential of −24.84 ± 0.07 mV. It displayed slow and sustained drug release in an acidic environment (pH 5.5). In vitro studies revealed that PZB NPs was non-cytotoxic and significantly enhanced the recovery of H/R injury H9c2 cell viability. PZB NPs suppressed cell apoptosis, activated the Nrf2/HO-1 pathway, and cleared ROS. In vivo study demonstrated that PZB NPs significantly reduced infarct size, ameliorated fibrosis and improved heart function. The PZB NPs markedly enhances BAN's ability to alleviate I/R injury, both in vitro and in vivo, offering a promising drug delivery system for clinical applications. [ABSTRACT FROM AUTHOR]

Myocardial ischemia reperfusion injury (MIRI) is a common cardiovascular complications, which is a major problem for many clinical scholars. To improve the prognosis of MIRI, many scholars have devoted to the research of its mechanism, and founded that mitochondria are closely related to the occurrence of MIRI, where the function of mitochondrial respiratory chain enzyme complex is impaired, and energy metabolism disorders play a key role in the process of MIRI. The aim of this review is to describe the changes of mitochondrial respiratory chain enzyme complex in MIRI and its effect on MIRI, and to provide a basis for finding new and effective therapeutic targets for MIRI. [ABSTRACT FROM AUTHOR]

Background: Thyroid hormone (TH) appears to have a reparative action on the postinfarcted myocardium. This novel action was recently tested in a pilot, randomized, double-blind, placebo-controlled trial (ThyRepair). The present study performed a post-hoc analysis of data from the ThyRepair study to provide further insights into the novel actions of TH on the human postischemic myocardium. Methods: Data from 41 patients participating in the ThyRepair study (n = 20 placebo and n = 21 LT3) were included in the analysis. LT3 treatment started after stenting and continued intravenously for 48 h. All patients had cardiac magnetic resonance (CMR) at hospital discharge; left ventricular (LV) ejection fraction (LVEF%), LV end-diastolic volume index (LVEDVi;mL/m²), LV end-systolic volume index (LVESVi;mL/m²), infarct volume (IV), left ventricular mass index (LVMi) as edema index, and microvascular obstruction (MVO) were assessed. Patientswere divided into two groups based on the median value of the IV: patients with IV = 20% of the LV (group A) and patients with IV > 20% (group B). CMR measurements at discharge are expressed as mean ± SD. Results: In group A, the placebo and T3-treated groups had similar LVEF% (56.8 ± 10.2 vs. 52.2 ± 10.5), LVEDVi (90.9 ± 19.8 vs. 92.8 ± 14.5), and LVESVi (40.8 ± 18.2 vs. 44.9 ± 14.1) at discharge. In group B, LVEDVi and LVESVi were 112 ± 23.8 and 68.3 ± 21.5 for placebo vs. 91.8 ± 18.6 and 49.0 ± 14.0 for the T3-treated group, respectively, p < 0.05. LVEF% was significantly increased in the T3-treated group vs. placebo, 47.3 ± 6.5 vs. 39.9 ± 8.7, p < 0.05. In group B, CMR LVMi was lower in T3-treated patients vs. placebo but did not reach statistical significance (p = 0.1). MVO was 1.95 ± 2.2 in placebo vs. 0.84 ± 0.9 in the LT3-treated group, p = 0.15. Conclusion: The present study suggests that acute LT3 treatment may exert more favorable effects on the recovery of cardiac function in patients with large infarct size. Furthermore, it signals a potential effect of LT3 on myocardial edema andmicrovascular obstruction. These novel findings merit further investigation in large trials. [ABSTRACT FROM AUTHOR]

Background: Ischemia reperfusion (IR) causes impaired myocardial function, and autophagy activation ameliorates myocardial IR injury. Isoliquiritigenin (ISO) has been found to protect myocardial tissues via AMPK, with exerting anti-tumor property through autophagy activation. This study aims to investigate ISO capacity to attenuate myocardial IR through autophagy activation mediated by AMPK/mTOR/ULK1 signaling. Methods: ISO effects were explored by SD rats and H9c2 cells. IR rats and IR-induced H9c2 cell models were established by ligating left anterior descending (LAD) coronary artery and hypoxia/re-oxygenation, respectively, followed by low, medium and high dosages of ISO intervention (Rats: 10, 20, and 40 mg/kg; H9c2 cells: 1, 10, and 100 μmol/L). Myocardial tissue injury in rats was assessed by myocardial function-related index, HE staining, Masson trichrome staining, TTC staining, and ELISA. Autophagy of H9c2 cells was detected by transmission electron microscopy (TEM) and immunofluorescence. Autophagy-related and AMPK/mTOR/ULK1 pathway-related protein expressions were detected with western blot. Results: ISO treatment caused myocardial function improvement, and inhibition of myocardial inflammatory infiltration, fibrosis, infarct area, oxidative stress, CK-MB, cTnI, and cTnT expression in IR rats. In IR-modeled H9c2 cells, ISO treatment lowered apoptosis rate and activated autophagy and LC3 fluorescence expression. In vivo and in vitro, ISO intervention exhibited enhanced Beclin1, LC3II/LC3I, and p-AMPK/AMPK levels, whereas inhibited P62, p-mTOR/mTOR and p-ULK1(S757)/ULK1 protein expression, activating autophagy and protecting myocardial tissues from IR injury. Conclusion: ISO treatment may induce autophagy by regulating AMPK/mTOR/ULK1 signaling, thereby improving myocardial IR injury, as a potential candidate for treatment of myocardial IR injury. [ABSTRACT FROM AUTHOR]

Since the invention of cardiopulmonary bypass, cardioprotective strategies have been investigated to mitigate ischemic injury to the heart during aortic cross-clamping and reperfusion injury with cross-clamp release. With advances in cardiac surgical and percutaneous techniques and post-operative management strategies including mechanical circulatory support, cardiac surgeons are able to operate on more complex patients. Therefore, there is a growing need for improved cardioprotective strategies to optimize outcomes in these patients. This review provides an overview of the basic principles of cardioprotection in the setting of cardiac surgery, including mechanisms of cardiac injury in the context of cardiopulmonary bypass, followed by a discussion of the specific approaches to optimizing cardioprotection in cardiac surgery, including refinements in cardiopulmonary bypass and cardioplegia, ischemic conditioning, use of specific anesthetic and pharmaceutical agents, and novel mechanical circulatory support technologies. Finally, translational strategies that investigate cardioprotection in the setting of cardiac surgery will be reviewed, with a focus on promising research in the areas of cell-based and gene therapy. Advances in this area will help cardiologists and cardiac surgeons mitigate myocardial ischemic injury, improve functional post-operative recovery, and optimize clinical outcomes in patients undergoing cardiac surgery. [ABSTRACT FROM AUTHOR]

Objective: To investigate effect of Yiqi Huoxue Huazhuo Jiedu Prescription （YHHJP） on inflammatory factors of brain tissues, tight junction between brain and colon tissues, intestinal flora and bacterial metabolites in cerebral ischemia reperfusion injury （CIRI） rats based on brain-gut axis. Methods: Fifty male SD rats of SPF grade were randomly divided into sham-operation group （Sham）, model group （MCAO）, low, medium, high doses YHHJP groups （TCM-L/TCM-M/TCM-H）. Middle cerebral artery occlusion model was established according to Zea Longa methods. Neurological function defects were detected 3 days after administration. TTC staining was used to calculate infarct size of brain tissue. Pathological changes of brain tissue were observed by Nissl staining, and pathological changes of brain and colon tissues were observed by HE staining. IL-1β, IL-6, TNF-α in brain tissue and LPS content in serum were detected by ELISA, and D-LA content in serum was detected by biochemical method. Gene expressions of ZO-1 and Claudin-5 in brain tissue and gene expressions of ZO-1, Claudin-1 in colon tissue were studied by Real-time fluorescent quantitative PCR. Intestinal flora were detected by 16S rDNA high-throughput sequencing. Results: Compared with Sham group, pathological damage of brain and colon tissue were serious in MCAO group, intestinal flora structure was significantly different, neural function impairment was aggravated, infarct size was increased, IL-1β, IL-6, TNF-α contents in brain tissue, and LPS, D-LA contents in serum were increased, gene expressions of ZO-1 and Claudin-5 in brain tissue and gene expressions of ZO-1 and Claudin-1 in colon tissue were decreased significantly （P<0.05）. Compared with MCAO group, pathological damage of brain and colon tissue of rats were relieved in TCM-L, TCM-M, TCM-H groups, disturbance of intestinal microflora microecology was improved, neurological function impairment and infarct size were markedly decreased, IL-1β, IL-6, TNF-α contents in brain tissue were decreased, gene expressions of ZO-1 and Claudin-1 in colon tissue were increased significantly （P<0.05）; LPS and D-LA contents in serum were decreased in YHHJP medium and high doses groups, while gene expressions of ZO-1 and Claudin-5 in brain tissue were increased significantly （P< 0.05）. Conclusion: YHHJP has a good effect on improving CIRI, whose mechanism may be related to regulating diversity of intestinal flora, reducing release of intestinal bacterial metabolites LPS and D-LA, increasing gene expressions of tight junction proteins ZO-1, Claudin-5 and Claudin-1, and down-regulating secretion of proinflammatory cytokine. [ABSTRACT FROM AUTHOR]

OBJECTIVES Pharmacological postconditioning can protect against myocardial ischaemia-reperfusion injury during cardiac surgery with extracorporeal circulation. The aim of this study was to observe the protective effects of fructose-1,6-bisphosphate (FDP) postconditioning on myocardial ischaemia-reperfusion injury in patients undergoing cardiac valve replacement with extracorporeal circulation. METHODS Patients undergoing elective mitral valve replacement and/or aortic valve replacement were divided into normal saline postconditioning group (NS group) and FDP postconditioning group (FDP group). The primary outcome was the plasma concentration of creatine kinase-MB (CK-MB). The secondary outcomes were the plasma concentrations of lactate dehydrogenase, CK, high-sensitivity C-reactive protein, alpha-hydroxybutyrate dehydrogenase and cardiac troponin I, the spontaneous cardiac rhythm recovery profile, the extracorporeal circulation time and duration of surgery, intensive care unit and postoperative hospitalization. RESULTS Forty patients were randomly assigned to receive intervention and included in the analysis. The serum concentrations of CK-MB, lactate dehydrogenase, CK, cardiac troponin I, alpha-hydroxybutyrate dehydrogenase and high-sensitivity C-reactive protein at T1∼4 were lower in the FDP group than in the NS group (P  <   0.001). Compared with the NS group, the dosage of dopamine administered 1–90 min after cardiac resuscitation, the spontaneous cardiac rhythm recovery time and the incidence of ventricular fibrillation were lower in the FDP group (P  <   0.001, P  <   0.001 and P  =   0.040, respectively). The values of ST- changes were increased more significantly in the NS group than in the FDP group (median [standard deviation] 1.3 [0.3] mm vs 0.7 [0.2] mm; P  <   0.001). Compared with the NS group, the time of recovery of ST-segment deviations was shorter in the FDP group (50.3 [12.3] min vs 34.6 [6.9] min; P  <   0.001). CONCLUSIONS The FDP postconditioning could improve both myocardial ischaemia-reperfusion injury and the spontaneous cardiac rhythm recovery during cardiac valve surgery with extracorporeal circulation. [ABSTRACT FROM AUTHOR]

Background: Menopause is associated with elevated cardiovascular risk due to the loss of the cardioprotective effect of oestrogens. Postmenopausal women are often prescribed hormone replacement therapy (HRT) in order to control menopause symptoms and correct hormone imbalances; however, HRT can impact serum lipids' concentrations. At present, data on the effect of the administration of medroxyprogesterone acetate plus conjugated equine oestrogens (MPACEE) on the lipid profile in females are uncertain, as the investigations conducted so far have produced conflicting results. Thus, we aimed to clarify the impact of MPACEE prescription on the serum lipids' values in women by means of a systematic review and meta‐analysis of randomized controlled trials (RCTs). Methods: We employed a random‐effects model based on the DerSimonian and Laird method to determine the combined estimates of the intervention's impact on the lipid profile. The computation of the weighted mean difference (WMD) and its corresponding 95% confidence interval (CI) relied on the mean and standard deviation values from both the MPACEE and control group, respectively. Results: A total of 53 RCTs were included in the meta‐analysis with 68 RCT arms on total cholesterol (TC), 70 RCT arms on low‐density lipoprotein cholesterol (LDL‐C) and triglycerides (TG), and 69 RCT arms on high‐density lipoprotein cholesterol (HDL‐C). Administration of MPACEE resulted in a significant reduction of TC (WMD = −11.93 mg/dL; 95% CI: −13.42, −10.44; p <.001) and LDL‐C (WMD = −16.61 mg/dL; 95% CI: −17.97, −15.26; p <.001) levels, and a notable increase in HDL‐C (WMD = 3.40 mg/dL; 95% CI: 2.93, 3.86; p <.001) and TG (WMD = 10.28 mg/dL; 95% CI: 7.92, 12.64; p <.001) concentrations. Subgroup analysis revealed that changes in the lipid profile were influenced by several factors: body mass index (for TC, HDL‐C, TG), MPACEE dosages (for TC, LDL‐C, HDL‐C, TG), age (for TC, LDL‐C, HDL‐C, TG), durations of the intervention (for TC, LDL‐C, HDL‐C, TG), continuous/sequential administration of MPACEE (continuous for TC; sequential for LDL‐C, TG) administration of MPACEE and serum lipids' concentrations before enrolment in the RCT (for TC, LDL‐C, HDL‐C, TG). Conclusions: MPACEE administration can influence serum lipids' concentrations in females by raising HDL‐C and TG levels and reducing LDL‐C and TC values. Therefore, postmenopausal women who suffer from hypercholesterolaemia might benefit from this type of HRT. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the precise effects and mechanisms of bergamottin in heart failure. Oxygen-glucose deprivation and reperfusion was used to simulate H9C2 cell injury in heart failure. Cell Counting Kit-8 and lactate dehydrogenase kits were used to assess cell viability. JC-1 stain, reactive oxygen species, and adenosine triphosphate kits were utilized to probe mitochondrial status. In addition, oxidative stress indicators were analyzed by enzyme-linked immunosorbent assay. Bergamottin treatment reduced lactate dehydrogenase and enhanced cell survival. Furthermore, oxygen-glucose deprivation and reperfusion-induced mitochondrial function was recovered, and oxidative stress levels were decreased by bergamottin therapy. Finally, mechanistic research showed that the SIRT1/AMPK pathway was activated by bergamottin. Bergamottin could be a potential drug for the clinical treatment of heart disease. [ABSTRACT FROM AUTHOR]

Hypothermic ischemia-reperfusion arrhythmia is a common complication of cardiothoracic surgery under cardiopulmonary bypass, but few studies have focused on this type of arrhythmia. Our prior study discovered reduced myocardial Cx43 protein levels may be linked to hypothermic reperfusion arrhythmias. However, more detailed molecular mechanism research is required. The microRNA and mRNA expression levels in myocardial tissues were detected by real-time quantitative PCR (RT-qPCR). Besides, the occurrence of hypothermic reperfusion arrhythmias and changes in myocardial electrical conduction were assessed by electrocardiography and ventricular epicardial activation mapping. Furthermore, bioinformatics analysis, applying antagonists of miRNA, western blotting, immunohistochemistry, a dual luciferase assay, and pearson correlation analysis were performed to investigate the underlying molecular mechanisms. The expression level of novel-miR-17 was up-regulated in hypothermic ischemia-reperfusion myocardial tissues. Inhibition of novel-miR-17 upregulation ameliorated cardiomyocyte edema, reduced apoptosis, increased myocardial electrical conduction velocity, and shortened the duration of reperfusion arrhythmias. Mechanistic studies showed that novel-miR-17 reduced the expression of Cx43 by directly targeting Gja1 while mediating the activation of the PKC/c-Jun signaling pathway. Up-regulated novel-miR-17 is a newly discovered pro-arrhythmic microRNA that may serve as a potential therapeutic target and biomarker for hypothermic reperfusion arrhythmias. [Display omitted] • Upregulated novel-miR-17 aggravates myocardial hypothermic ischemia-reperfusion injury. • novel-miR-17 reduces electrical conduction velocity by targeting Gja1. • PKC/c-Jun signaling pathway activation in hypothermia reperfusion arrhythmia. • novel-miR-17 mediates the activation of the PKC/c-Jun signaling pathway. [ABSTRACT FROM AUTHOR]

• Anthracyclines may cause cancer therapy-related cardiovascular dysfunction. • Herein, we assessed the cardioprotective effects of statins in this setting. • Statins attenuated cancer therapy-related cardiovascular dysfunction. • Statins also improved left ventricular end-systolic volume. • Their benefits remain uncertain across the spectrum of dose of anthracyclines. Several interventions have been tested for cardio-protection against anthracycline-induced cancer therapy-related cardiovascular dysfunction (CTRCD). The role of statins in this setting remains unclear. We systematically searched PubMed, Embase, Cochrane Library, Clinicaltrials.gov, and Web of Science for randomized controlled trials (RCTs) comparing statins versus control (placebo or no intervention) for preventing anthracycline-induced CTRCD. We applied a random-effects model to pool risk ratios (RR) and mean differences (MD) with 95 % confidence intervals (CI). We included seven RCTs comprising 887 patients with planned chemotherapy with anthracycline-based regimens, of whom 49.8 % were randomized to statins. Relative to placebo, statins significantly reduced the incidence of cardiotoxicity/CTRCD (RR 0.46; 95 % CI 0.29 to 0.72; p < 0.001). The left ventricular end-systolic volume was also lower in patients treated with statin (MD -3.12 mL; 95 % CI -6.13 to -0.12 mL; p = 0.042). There was no significant difference between groups in post-anthracycline left ventricular ejection fraction (LVEF) overall. In this meta-analysis of RCTs, statins were significantly associated with a lower incidence of anthracycline-induced CTRCD and attenuated changes in the left ventricular end-systolic volume. Thus, our findings suggest that statins should be considered as a cardio-protection strategy for patients with planned anthracycline-based chemotherapy. [ABSTRACT FROM AUTHOR]

Ischemic heart disease, manifesting as myocardial infarction (MI), remains the leading cause of death in the western world. Both ischemia and reperfusion (I/R) cause myocardial injury and result in cardiac inflammatory responses. This sterile inflammation in the myocardium consists of multiple phases, involving cell death, tissue remodeling, healing, and scar formation, modulated by various cytokines, including the macrophage migration inhibitory factor (MIF). Meanwhile, different immune cells participate in these phases, with myeloid cells acting as first responders. They migrate to the injured myocardium and regulate the initial phase of inflammation. The MIF modulates the acute inflammatory response by affecting the metabolic profile and activity of myeloid cells. This review summarizes the role of the MIF in regulating myeloid cell subsets in MI and I/R injury and discusses emerging evidence of metabolism-directed cellular inflammatory responses. Based on the multifaceted role of the MIF affecting myeloid cells in MI or I/R, the MIF can be a therapeutic target to achieve metabolic balance under pathology and alleviate inflammation in the heart. [ABSTRACT FROM AUTHOR]

Background: Myocardial ischemia–reperfusion injury (MIRI) refers to severe damage to the ischemic myocardium following the restoration of blood flow, and it is a major complication of reperfusion therapy for myocardial infarction. Notably, drugs such as metoprolol have been utilized to reduce ischemia–reperfusion injury. Tanshinone IIA is a major constituent extracted from Salvia miltiorrhiza Bunge. Recently, tanshinone IIA has been studied extensively in animal models for controlling MIRI. Therefore, we conducted a meta-analysis on the application of tanshinone IIA in rat models with MIRI to evaluate the therapeutic effects of tanshinone IIA. Methods: A comprehensive search was conducted across PubMed, Web of Science, Embase, the Cochrane Library, the China National Knowledge Infrastructure database, the Wanfang database, and the Chinese Scientific Journal Database to gather studies on tanshinone IIA intervention in rat models with MIRI.We employed SYRCLE's risk of bias tool to assess study quality. The primary outcome indicators were superoxide dismutase (SOD) and malondialdehyde (MDA). Myocardial infarction area was a secondary outcome indicator. This study was registered at PROSPERO (registration number CRD 42022344447). Results: According to the inclusion and exclusion criteria, 15 eligible studies were selected from 295 initially identified studies. In rat models with MIRI, tanshinone IIA significantly increased SOD levels while reducing MDA levels and myocardial infarction area. Moreover, the duration of myocardial ischemia influenced the effectiveness of tanshinone IIA. However, additional high-quality research studies are needed to establish the efficacy and definitive guidelines for the use of tanshinone IIA. Animal studies demonstrated that tanshinone IIA exerted a significant therapeutic effect when the ischemia duration was less than 40 minutes. Tanshinone IIA was found to be more effective when administered via intravenous, intraperitoneal, and intragastric routes at doses above 5 mg/kg. Additionally, treatment with tanshinone IIA at all stages—prior to myocardial ischemia, after ischemia but before reperfusion, prior to ischemia and after reperfusion, and after reperfusion—showed satisfactory results. Conclusions: Tanshinone IIA enhanced SOD activity and reduced MDA levels, thereby ameliorating oxidative stress damage during MIRI. Additionally, it reduced the myocardial infarction area, indicating its effectiveness in mitigating MIRI-induced damage in rats and demonstrating a myocardial protective effect. These findings contribute valuable insights for developing MIRI treatment strategies. [ABSTRACT FROM AUTHOR]

Oxidative stress plays a significant role in the pathogenesis of cardiovascular diseases, such as myocardial ischemia/reperfusion injury, atherosclerosis, heart failure, and hypertension. This systematic review aims to integrate most relevant studies on oxidative stress management in cardiovascular diseases. We searched relevant literatures in the PubMed database using specific keywords. We put emphasis on those manuscripts that were published more recently and in higher impact journals. We reviewed a total of 200 articles. We examined current oxidative stress managements in cardiovascular diseases, including supplements like resveratrol, vitamins C and E, omega-3 fatty acids, flavonoids, and coenzyme-10, which have shown antioxidative properties and potential cardiovascular benefits. In addition, we reviewed the pharmacological treatments including newly discovered antioxidants and nanoparticles that show potential effects in targeting the specific oxidative stress pathways. Lastly, we examined biomarkers, such as soluble transferrin receptor, transthyretin, and cystatin C in evaluating antioxidant status and identifying cardiovascular risk. By addressing oxidative stress management and mechanisms, this paper emphasizes the importance of maintaining the balance between oxidants and antioxidants in the progression of cardiovascular diseases. This review paper is registered with the International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY), registration # INPLASY202470064. [ABSTRACT FROM AUTHOR]

Early invasive revascularization guided by moderate to severe ischemia did not improve outcomes over medical therapy alone, underlying the need to identify high-risk patients for a more effective invasive referral. CMR could determine the myocardial extent and matching locations of ischemia and infarction. This study sought to investigate if CMR peri-infarct ischemia is associated with adverse events incremental to known risk markers. Consecutive patients were included in an expanded cohort of the multicenter SPINS (Stress CMR Perfusion Imaging in the United States) study. Peri-infarct ischemia was defined by the presence of any ischemic segment neighboring an infarcted segment by late gadolinium enhancement imaging. Primary outcome events included acute myocardial infarction and cardiovascular death, whereas secondary events included any primary events, hospitalization for unstable angina, heart failure hospitalization, and late coronary artery bypass surgery. Among 3,915 patients (age: 61.0 ± 12.9 years; 54.7% male), ischemia, infarct, and peri-infarct ischemia were present in 752 (19.2%), 1,123 (28.8%), and 382 (9.8%) patients, respectively. At 5.3 years (Q1-Q3: 3.9-7.2 years) of median follow-up, primary and secondary events occurred in 406 (10.4%) and 745 (19.0%) patients, respectively. Peri-infarct ischemia was the strongest multivariable predictor for primary and secondary events (HR adjusted : 1.72 [95% CI: 1.23-2.41] and 1.71 [95% CI: 1.32-2.20], respectively; both P < 0.001), adjusted for clinical risk factors, left ventricular function, ischemia extent, and infarct size. The presence of peri-infarct ischemia portended to a >6-fold increased annualized primary event rate compared to those with no infarct and ischemia (6.5% vs 0.9%). Peri-infarct ischemia is a novel and robust prognostic marker of adverse cardiovascular events. [ABSTRACT FROM AUTHOR]

Due to the cancer therapy-related cardiovascular toxicity, heart failure following cancer therapy has a significant mortality rate. Gene-targeted therapy promotes the re-entry of existing cardiomyocytes into the cell cycle to achieve myocardial regeneration, which is a promising strategy for preventing and treating heart failure after myocardial infarction. Circular RNAs (circRNAs) are considered as potential targets for myocardial regeneration due to their strong stability, resistance to degradation, and potential role in heart development and cardiovascular diseases. By comparing the myocardial tissue of mice in the sham operation group and the Doxorubicin therapy group (DOX), we observed a significant decrease in Cirsorbs expression in the DOX group. Cirsorbs was predominantly localized in cardiomyocytes and exhibited high conservation. Subsequent investigations revealed that Cirsorbs could promote myocardial proliferation and inhibit myocardial apoptosis. Mechanistic studies further demonstrated that Cirsorbs could bind to miR99 and reduce its expression level. Meanwhile, miR99 was found to bind to GATA4 mRNA and decrease its expression level. The binding of Cirsorbs to miR99 alleviated the repression of miR99, thereby enhancing GATA4 expression and the transcription of downstream cyclin A2 and cyclin E1. This, in turn, increased cardiomyocyte proliferation and reduced apoptosis. In conclusion, Cirsorbs holds promise as an effective target for myocardial regeneration in reducing cancer therapy-related cardiovascular toxicity. [ABSTRACT FROM AUTHOR]

Background: Ischemia stroke is the leading cause of death and long-term disability. Sanhua Decoction (SHD), a classic Chinese herbal prescription, has been used for ischemic stroke for about thousands of years. Here, we aim to investigate the neuroprotective effects of SHD on cerebral ischemia/reperfusion (CIR) injury rat models. Methods: The male Sprague-Dawley rats (body weight, 250-280 g; age, 7-8 weeks) were randomly divided into sham group, CIR group, and SHD group and were further divided into subgroups according to different time points at 6 h, 1, 3, 7, 14, 21, and 28 d, respectively. The SHD group received intragastric administration of SHD at 10 g kg-1 d-1. The focal CIR models were induced by middle cerebral artery occlusion according to Longa's method, while sham group had the same operation without suture insertion. Neurological deficit score (NDS) was evaluated using the Longa's scale. BrdU, doublecortin (DCX), and glial fibrillary acidic protein (GFAP) were used to label proliferation, migration, and differentiation of nerve cells before being observed by immunofluorescence. The expression of reelin, total tau (t-tau), and phosphorylated tau (p-tau) were evaluated by western blot and RT-qPCR. Results: SHD can significantly improve NDS at 1, 3, 7, and 14 d (p < 0.05), increase the number of BrdU positive and BrdU/DCX positive cells in subventricular zone at 3, 7, and 14 d (p < 0.05), upregulate BrdU/GFAP positive cells in the ischemic penumbra at 28 d after CIR (p < 0.05), and reduce p-tau level at 1, 3, 7, and 14 d (p < 0.05). There was no significant difference on reelin and t-tau level between three groups at each time points after CIR. Conclusions: SHD exerts neuroprotection probably by regulating p-tau level and promoting the proliferation, migration, and differentiation of endogenous neural stem cells, accompanying with neurobehavioral recovery. [ABSTRACT FROM AUTHOR]

Epicardial epithelial-to-mesenchymal transition (EMT) plays a pivotal role in both heart development and injury response and involves dynamic cellular changes that are essential for cardiogenesis and myocardial repair. Specifically, epicardial EMT is a crucial process in which epicardial cells lose polarity, migrate into the myocardium, and differentiate into various cardiac cell types during development and repair. Importantly, following EMT, the epicardium becomes a source of paracrine factors that support cardiac growth at the last stages of cardiogenesis and contribute to cardiac remodeling after injury. As such, EMT seems to represent a fundamental step in cardiac repair. Nevertheless, endogenous EMT alone is insufficient to stimulate adequate repair. Redirecting and amplifying epicardial EMT pathways offers promising avenues for the development of innovative therapeutic strategies and treatment approaches for heart disease. In this review, we present a synthesis of recent literature highlighting the significance of epicardial EMT reactivation in adult heart disease patients. [ABSTRACT FROM AUTHOR]

Serum neurofilament light chain protein (sNfL) shows promise as a biomarker for infarct size in acute ischemic stroke and for monitoring cerebral small vessel disease (cSVD). However, distinguishing the cSVD contribution after stroke may not be possible due to post-stroke sNfL increase. Additionally, it remains unclear if etiologic subtype differences exist. We measured infarct and white matter hyperintensity (WMH) volumes using MRI at the index stroke in ischemic stroke patients (n = 316, mean age 53 years, 65% males) and at 7-year follow-up (n = 187). Serum NfL concentration was measured in the acute phase (n = 235), at 3-months (n = 288), and 7-years (n = 190) post stroke. In multivariable regression, acute and 3-month sNfL concentrations were associated with infarct volume and time since stroke, but not with stroke etiology or infarct location. Seven years post-stroke, sNfL was associated with WMHs and age, but not with stroke etiology. Nonlinear regression estimated that sNfL peaks around 1 month, and declines by 50% at 3 months, and 99% at 9 months. We conclude that sNfL can indicate infarct volume and time since brain injury in the acute and subacute phases after stroke. Due to the significant post-stroke sNfL increase, several months are needed for reliable assessment of cSVD activity. [ABSTRACT FROM AUTHOR]

Myocardial ischemia/reperfusion injury (MIRI) is the leading cause of irreversible myocardial damage. A pivotal pathogenic factor is ischemia/reperfusion (I/R)‐induced cardiomyocyte ferroptosis, marked by iron overload and lipid peroxidation. However, the impact of lipid droplet (LD) changes on I/R‐induced cardiomyocyte ferroptosis is unclear. In this study, an aggregation‐induced emission probe, TPABTBP is developed that is used for imaging dynamic changes in LD during myocardial I/R‐induced ferroptosis. TPABTBP exhibits excellent LD‐specificity, superior capability for monitoring lipophagy, and remarkable photostability. Molecular dynamics (MD) simulation and super‐resolution fluorescence imaging demonstrate that the TPABTBP is specifically localized to the phospholipid monolayer membrane of LDs. Imaging LDs in cardiomyocytes and myocardial tissue in model mice with MIRI reveals that the LD accumulation level increase in the early reperfusion stage (0–9 h) but decrease in the late reperfusion stage (>24 h) via lipophagy. The inhibition of LD breakdown significantly reduces the lipid peroxidation level in cardiomyocytes. Furthermore, it is demonstrated that chloroquine (CQ), an FDA‐approved autophagy modulator, can inhibit ferroptosis, thereby attenuating MIRI in mice. This study describes the dynamic changes in LD during myocardial ischemia injury and suggests a potential therapeutic target for early MIRI intervention. [ABSTRACT FROM AUTHOR]

BACKGROUND: The administration of intravenous cangrelor at reperfusion achieves faster onset of platelet P2Y12 inhibition than oral ticagrelor and has been shown to reduce myocardial infarction (MI) size in the preclinical setting. We hypothesized that the administration of cangrelor at reperfusion will reduce MI size and prevent microvascular obstruction in patients with ST-segment–elevation MI undergoing primary percutaneous coronary intervention. METHODS: This was a phase 2, multicenter, randomized, double-blind, placebo-controlled clinical trial conducted between November 2017 to November 2021 in 6 cardiac centers in Singapore. Patients were randomized to receive either cangrelor or placebo initiated before the primary percutaneous coronary intervention procedure on top of oral ticagrelor. The key exclusion criteria included presenting <6 hours of symptom onset; previous MI and stroke or transient ischemic attack; on concomitant oral anticoagulants; and a contraindication for cardiovascular magnetic resonance. The primary efficacy end point was acute MI size by cardiovascular magnetic resonance within the first week expressed as percentage of the left ventricle mass (%LVmass). Microvascular obstruction was identified as areas of dark core of hypoenhancement within areas of late gadolinium enhancement. The primary safety end point was Bleeding Academic Research Consortium–defined major bleeding in the first 48 hours. Continuous variables were compared by Mann-Whitney U test (reported as median [first quartile–third quartile]), and categorical variables were compared by Fisher exact test. A 2-sided P <0.05 was considered statistically significant. RESULTS: Of 209 recruited patients, 164 patients (78%) completed the acute cardiovascular magnetic resonance scan. There were no significant differences in acute MI size (placebo, 14.9% [7.3–22.6] %LVmass versus cangrelor, 16.3 [9.9–24.4] %LVmass; P =0.40) or the incidence (placebo, 48% versus cangrelor, 47%; P =0.99) and extent of microvascular obstruction (placebo, 1.63 [0.60–4.65] %LVmass versus cangrelor, 1.18 [0.53–3.37] %LVmass; P =0.46) between placebo and cangrelor despite a 2-fold decrease in platelet reactivity with cangrelor. There were no Bleeding Academic Research Consortium–defined major bleeding events in either group in the first 48 hours. CONCLUSIONS: Cangrelor administered at the time of primary percutaneous coronary intervention did not reduce acute MI size or prevent microvascular obstruction in patients with ST-segment–elevation MI given oral ticagrelor despite a significant reduction of platelet reactivity during the percutaneous coronary intervention procedure. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03102723. [ABSTRACT FROM AUTHOR]