Abstract:Aim To investigate the effect of alfentanil on myocardial ischemia-reperfusion injury (MIRI) in rats and its regulatory mechanism on the sphingosine kinase 1 (SphK1)/sphingosine-1-phosphate (S1P) signaling pathway during this process. Methods SPF grade SD male rats were randomly divided into sham surgery group, model group, positive drug group (compound salvia miltiorrhiza group), low dose alfentanil group, high dose alfentanil group, and high alfentanil+SphK1 agonist group (alfentanil+PMA group), with 20 rats in each group. Except the sham operation group, the MIRI model was reproduced by ligating the left anterior descending coronary artery and reperfusion. The activities of serum lactate dehydrogenase (LDH), creatine kinase (CK) and aspartate aminotransferase (AST) were detected by automatic biochemical analyzer; TTC was applied to detect the size of myocardial infarction in rats; HE staining was applied to observe the morphological characteristics of rat myocardial tissue; TUNEL staining was applied to detect myocardial cell apoptosis in rats; ELISA was applied to detect the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), and S1P; kits were applied to detect content of malondialdehyde (MDA) and activity of superoxide dismutase (SOD) in myocardial tissue; Western blot was applied to detect the expression level of SphK1 protein in myocardial tissue. Results Compared with the sham surgery group, the pathological damage to the myocardial tissue of rats was severe in the model group, the activities of serum central muscle injury markers LDH, CK, and AST, myocardial infarction area, myocardial cell apoptosis rate, the levels of TNF-α, IL-6, IL-1β, MDA, S1P and the expression of SphK1 protein all increased, the activity of SOD decreased (P＜0.05). Compared with the model group, the myocardial tissue damage of rats was reduced in the positive drug group and the low and high dose alfentanil groups, the activities of serum central muscle injury markers LDH, CK, and AST, myocardial infarction area, myocardial cell apoptosis rate, the levels of TNF-α, IL-6, IL-1β, MDA, S1P and the expression of SphK1 protein all decreased, the activity of SOD increased (P＜0.05). The SphK1 agonist was able to reverse the impact of high-dose alfentanil on the above indicators (P＜0.05). Conclusion Alfentanil has protective effect on MIRI rats, and its mechanism may be related to the inhibition of SphK1/S1P signaling pathway.

Abstract:Damage to organelles plays a significant role in myocardial ischemia/reperfusion injury, which results in the dysfunction of mitochondria and other related organelles. The communication between mitochondria and other organelles can also affect the development of myocardial ischemia/reperfusion injury. For instance, the mitochondria-associated endoplasmic reticulum membrane provides a “seamless connection” and regulates the exchange of organelles and metabolites (such as ions, lipids and proteins) between the mitochondria and the endoplasmic reticulum, which subsequently affects myocardial ischemia/reperfusion injury. However, there is a lack of studies regarding the interaction between mitochondria and related organelles, which is a critical component in triggering myocardial ischemia/reperfusion injury. Therefore, this article describes the role of mitochondrial crosstalk with endoplasmic reticulum, lysosomes and nuclei in myocardial ischemia/reperfusion injury, and aims to provide a theoretical basis for targeting mitochondrial crosstalk with other organelles in the treatment of myocardial ischemia/reperfusion injury.

Abstract:Myocardial ischemia/reperfusion injury (MIRI) occurs after cardiopulmonary bypass open heart surgery, cardiovascular intervention and thrombolytic therapy, which is the most important cause of cardiac insufficiency, heart failure, and even death in patients after treatment. In recent years, studies have found that the release of endogenous active peptides can alleviate the production of MIRI, and regulating the function and action of endogenous peptides may be one of the most effective ways to treat MIRI. Dipeptidyl peptidase 4 (DPP4) is an important serine protease in mammals, with enzymatic activity to hydrolyze endogenous peptides. Its primary physiological function is to metabolize short peptides, including growth factors, hormones, etc. This review aims to better understand and search for effective therapeutic targets by elucidating the impact of DPP4 on the hydrolysis of endogenous peptides in MIRI, and ultimately provide new ideas for the therapeutic effects of MIRI.

Abstract:Aim Investigating the effects of exercise during pregnancy on blood pressure and brain ischemia-reperfusion injury in 1-month-old (1M) and 3-month-old (3M) offspring of spontaneously hypertensive rat (SHR). Methods SHR and Wistar Kyoto rats (WKY) were selected, they were paired in a 1∶1 male-to-female ratio within the same strain, and the first day of pregnancy was confirmed by the presence of copulatory plugs and sperm on a vaginal smear. Pregnant rats were randomly divided into pregnancy sedentary group (p-WKY-SED, p-SHR-SED) and pregnancy exercise group (p-WKY-EX, p-SHR-EX). The rats in the exercise group were performed non-weight-bearing swimming for 60 minutes per day, 6 days per week, in water 40 cm deep at a temperature of 34～35 ℃, until the 20th day of pregnancy. The body weight of the pregnant rats, as well as physiological indicators such as fetal weight, body length, and placental efficiency were monitored to reflect the growth and development of the fetus. 1M and 3M offspring were selected as research subjects, non-invasive blood pressure was measured in the tail artery, a rat middle cerebral artery occlusion (MCAO) model was prepared by using the thread embolism method, and the area of cerebral infarction was observed 24 hours after reperfusion. Results (1) Compared with p-WKY-SED group, the body weight of p-SHR-SED pregnant rats was significantly decreased (P＜0.01); there was no significant difference in the litter size among all groups of pregnant rats (P＞0.05). (2) Compared with p-SHR-SED group, exercise during pregnancy can significantly increase the body weight and placental efficiency of both female and male fetal rats in the p-SHR-EX group (P＜0.05), and decrease the weight of the placenta (P＜0.05). (3) Compared with p-WKY-SED group, the body weight of both female and male offspring rats at 1M and 3M was significantly decreased in the p-SHR-SED group, and their blood pressure was significantly increased (P＜0.01); Compared with p-SHR-SED group, exercise during pregnancy had no significant effect on the body weight and blood pressure of 1M offspring in the p-SHR-EX group (P＞0.05), but it could significantly reduce the blood pressure of 3M male offspring in the p-SHR-EX group (P＜0.01); The body weight and blood pressure of 3M male offspring were significantly higher in p-WKY-SED group and p-SHR-SED group than those of female in the same group (P＜0.01). (4) Compared with p-WKY-SED group, the infarct area of MCAO injury in both female and male offspring rats at 1M and 3M was significantly increased in the p-SHR-SED group (P＜0.01); Compared with p-SHR-SED group, exercise during pregnancy can significantly reduce the infarct area of MCAO injury in both female and male offspring at 1M and 3M in the p-SHR-EX group (P＜0.05). Conclusion Aerobic exercise during pregnancy can significantly improve blood pressure in the offspring of hypertensive rats, and reduce their susceptibility to ischemic reperfusion injury in the brain as adults.

Abstract:Timely restoration of blood supply after myocardial infarction is crucial for saving the infarcted myocardium. So far, the most effective method is to restore myocardial oxygenation and coronary blood flow through coronary interventional therapy. However, reperfusion may also lead to greater heart damage due to the reintroduction of molecular oxygen. New treatments are needed to protect the heart from myocardial ischemia-reperfusion injury (MIRI) to improve clinical outcomes in patients with acute myocardial infarction and heart failure (HF). A deeper understanding of the mechanisms of MIRI and the search for new treatments could provide key evidence to mitigate myocardial damage and improve patient survival. At present, it has been found that copper, as a trace element in human body, can have a significant protective effect on MIRI. Copper can reduce apoptosis in cardiomyocytes, that is, control the self-destruction process of cell, so as to reduce the degree of myocardial injury. However, the potential relationship between abnormal copper ion metabolism as well as cuproptosis and MIRI as well as HF has not been explored. In this review, we focus on potential therapeutic strategies for MIRI and understand the metabolic pathways of copper in the human body, so as to provide more options and hope for the treatment of cardiovascular diseases.

Abstract:Myocardial ischemia-reperfusion injury (MIRI) is one of the reasons for the high mortality in patients with acute myocardial infarction after percutaneous coronary intervention, which is regulated by several cell death pathways including apoptosis, autophagy, and pyroptosis. Recently, it has been found that ferroptosis, a unique programmed cell death, appears to be a therapeutic target for MIRI. However, the mechanisms remain incompletely elucidated. This review summarizes the latest research progress on the role of ferroptosis in MIRI, including mitochondrial dysfunction, endoplasmic reticulum stress (ERS), oxidative stress, calcium overload, epigenetic modification, apoptosis, autophagy, etc. Moreover, the signaling pathways between ferroptosis and MIRI are elaborated, which will provide new insights for the prevention and treatment of MIRI.

Abstract:Aim To investigate the effects of tissue factor pathway inhibitor (TFPI) on cardiomyocyte apoptosis following ischemia/reperfusion (I/R) injury. Methods I/R model was established by ligating the anterior descending coronary artery in vivo. Rats were randomly divided into three groups:the control, I/R, and I/R+rTFPI groups. HE staining was used to evaluate the morphological changes of rats myocardial tissue after reperfusion for 3 days. TTC staining was used to detect the myocardial infarct size. Ultrastructural damage in cardiomyocytes was measured by transmission electron microscopy. The expression levels of Bcl-2, Bax and cleaved Caspase-3 in rats myocardial tissue were detected by Western blot analysis. Cardiomyocytes of Sprague Dawley (SD) rats were cultured by enzyme digestion and differential adherent method in vitro experiments. Cardiomyocytes I/R injury in vitro model was established by 2 h of hypoxia and 12 h of reoxygenation using MIC101 system. Cardiomyocytes were divided into control group, H/R group, and H/R+rTFPI group (10 μg/L). Cell viability was detected by CCK-8 assay. Detection of cardiomyocytes apoptosis was performed by TUNEL technique. Western blot analysis was used to detect the expression of Bax, Bcl-2 and cleaved Caspase-3. Results A myocardial I/R model was successfully established in vivo. HE staining showed myocardiumin exhibited a higher degree of necrosis than that in control group, which was milder in I/R+rTFPI group than that in I/R group (P＜0.05). TTC staining showed that, compared with I/R group, myocardial infarct size reduced 39.76% in I/R+rTFPI group (P＜0.05). The data of transmission electron microscopy showed that the degree of apoptosis and injury was severer in I/R group than that in control group, whereas it was milder in I/R+rTFPI group than that in I/R group. Western blot detection results showed that compared with control group, the expression of Bcl-2 decreased 53.43% in I/R group(P＜0.05), but the expression of Bax and cleaved Caspase-3 increased 29.05% and 73.25% respectively (P＜0.05). After adding rTFPI, the expression of Bax and cleaved Caspase-3 in myocardial tissue decreased 13.77% and 24.25% respectively compared with I/R group(P＜0.05), whereas the expression of Bcl-2 increased 55.01% compared with I/R group (P＜0.05). In in vitro experiment, the CCK-8 results showed the cell viability of H/R group decreased 29.70% compared with control group(P＜0.05), but it increased 19.77% after adding rTFPI compared with H/R group(P＜0.05). The TUNEL detection showed that the apoptotic rate of H/R group increased 56.76% compared with control group, whereas the apoptotic rate of H/R+rTFPI group decreased 24.55% compared with H/R group(P＜0.05). Western blot results showed that compared with control group, the expression of Bcl-2 in cardiomyocytes decreased 46.92% in H/R group (P＜0.05), but the expression of Bax increased 41.90%(P＜0.05) and the expression of cleaved Caspase-3 increased 2.68 fold (P＜0.05). After adding rTFPI, the expressions of Bax and cleaved Caspase-3 in the cardiomyocytes decreased 26.34% and 57.60% respectively when compared with H/R group(P＜0.05), whereas the expression of Bcl-2 increased 28.24% compared with H/R group (P＜0.05). Conclusion TFPI served a protective role against I/R and H/R-induced cardiomyocyte injury by inhibiting apoptosis.

Abstract:Aim To observe the effect of edaravone dexborneol (EDDE) on neuronal apoptosis in rats with cerebral ischemia-reperfusion, and to explore its mechanism. Methods SD rats were randomly divided into sham group, middle cerebral artery occlusion (MCAO) group, low-dose EDDE group (EDDE-L group, 3 mg/kg), and high-dose EDDE group (EDDE-H group, 6 mg/kg), chelerythrine (CHE, PKC inhibitor) group (5 mg/kg CHE), EDDE＋CHE group (6 mg/kg EDDE＋5 mg/kg CHE), with 15 rats in each group. Except for the sham group, the rats in the other groups were given the suture method to construct the MCAO model. The rats in each group were scored for neurological deficits; after 24 hours of reperfusion, TTC staining was used to detect the cerebral infarct volume of rats; HE staining was used to observe the pathological damage of cortical nerve cells; TUNEL staining was used to detect cortical nerve cells apoptosis; immunohistochemical method was used to detect the expression of Bcl-2 and Bax in the cortex nerve cells; Western blot was used to detect the expression of Caspase-3, cleaved Caspase-3 and protein kinase C (PKC)/extracellular signal-regulated kinase (ERK) pathway related proteins (PKC, p-PKC, ERK1/2 and p-ERK1/2) in brain tissue. ResultsCompared with sham group, the neurological deficit score, the percentage of cerebral infarction volume and the apoptosis rate of nerve cells increased, the positive expression of Bax increased and the ratio of cleaved Caspase-3/Caspase-3 increased (all P＜0.05), the positive expression of Bcl-2 decreased, the ratio of Bcl-2/Bax, p-PKC/PKC and p-ERK1/2/ERK1/2 decreased in brain tissue (all P＜0.05), the cerebral cortex cells were sparsely arranged, swelling and vacuolar degeneration of nerve cells were obvious, the nucleus shrank and the tissue becomes necrotic in MCAO group. Compared with MCAO group, the neurological deficit score, cerebral infarction volume percentage and apoptosis rate of nerve cells decreased, the positive expression of Bax decreased, the ratio of cleaved Caspase-3/Caspase-3 decreased (all P＜0.05), the positive expression of Bcl-2 increased, the ratio of Bcl-2/Bax, p-PKC/PKC and the ratio of p-ERK1/2/ERK1/2 increased in brain tissue (P＜0.05) in the EDDE-L group and EDDE-H group, the pathological damage of the cerebral cortex was improved to varying degrees, the number of nerve cells increased, the vacuolar degeneration was reduced, the nucleus was clearer, and the EDDE-H group was better than the EDDE-L group. CHE could eliminate the neuroprotective effect of EDDE. Conclusion EDDE cloud inhibit neuronal apoptosis and reduce cerebral ischemia/reperfusion injury, and its mechanism may be related to the activation of PKC/ERK pathway.

Abstract:Long non-coding RNA (lncRNA) is a class of RNA more than 200 nucleotides long and has no protein-coding capacity, but it plays a very important role in regulating various biological processes such as proliferation, apoptosis, migration, invasion and differentiation. It has found that lncRNA is closely related to the development of myocardial ischemia/reperfusion (I/R) injury. This review discusses the advances in the reduction of myocardial I/R injury and its possible mechanisms by lncRNA.

Abstract:Abnormalities in lipid metabolism induce myocardial structural and functional disorders, leading to the development of diabetic cardiomyopathy (DCM), which has become a hotspot in current DCM research. The transmembrane glycoprotein CD36 is a multifunctional membrane protein that facilitates fatty acid transport, which is involved in the regulation of cardiac lipid metabolism. CD36 signaling plays a key role in the pathogenesis of DCM mediated cardiac injuries. This article summarizes the structure of CD36 and its role in specific cell types, and further explores the pathophysiological role of CD36 in DCM, proposing that targeting CD36 may prove to be a potential pharmacological strategy in the prevention and treatment of DCM.