Glycogen synthase kinase-3ß: A multifaceted player in ischemia-reperfusion injury and its therapeutic prospects.

Ischemia-reperfusion injury (IRI) results in irreversible metabolic dysfunction and structural damage to tissues or organs, posing a formidable challenge in the field of organ implantation, cardiothoracic surgery, and general surgery. Glycogen synthase kinase-3ß (GSK-3ß) a multifunctional serine/threonine kinase, is involved in a variety of biological processes, including cell proliferation, apoptosis, and immune response. Phosphorylation of its tyrosine 216 and serine 9 sites positively and negatively regulates the activation and inactivation of the enzyme. Significantly, inhibition or inactivation of GSK-3ß provides protection against IRI, making it a viable target for drug development. Though numerous GSK-3ß inhibitors have been identified to date, the development of therapeutic treatments remains a considerable distance away. In light of this, this review summarizes the complicated network of GSK-3ß roles in IRI. First, we provide an overview of GSK-3ß's basic background. Subsequently, we briefly review the pathological mechanisms of GSK-3ß in accelerating IRI, and highlight the latest progress of GSK-3ß in multiorgan IRI, encompassing heart, brain, kidney, liver, and intestine. Finally, we discuss the current development of GSK-3ß inhibitors in various organ IRI, offering a thorough and insightful reference for GSK-3ß as a potential target for future IRI therapy.

FPR1: A critical gatekeeper of the heart and brain.

G protein-coupled receptors (GPCRs) are currently the most widely focused drug targets in the clinic, exerting their biological functions by binding to chemicals and activating a series of intracellular signaling pathways. Formyl-peptide receptor 1 (FPR1) has a typical seven-transmembrane structure of GPCRs and can be stimulated by a large number of endogenous or exogenous ligands with different chemical properties, the first of which was identified as formyl-methionine-leucyl-phenylalanine (fMLF). Through receptor-ligand interactions, FPR1 is involved in inflammatory response, immune cell recruitment, and cellular signaling regulation in key cell types, including neutrophils, neural stem cells (NSCs), and microglia. This review outlines the critical roles of FPR1 in a variety of heart and brain diseases, including myocardial infarction (MI), ischemia/reperfusion (I/R) injury, neurodegenerative diseases, and neurological tumors, with particular emphasis on the milestones of FPR1 agonists and antagonists. Therefore, an in-depth study of FPR1 contributes to the research of innovative biomarkers, therapeutic targets for heart and brain diseases, and clinical applications.

Risk prediction of preoperative acute ischemic stroke in acute type A aortic dissection.

OBJECTIVES: To predict preoperative acute ischemic stroke (AIS) in acute type A aortic dissection (ATAAD). METHODS: In this multi-center retrospective study, 508 consecutive patients diagnosed as ATAAD between April 2020 and March 2021 were considered for inclusion. The patients were divided into a development cohort and two validation cohorts based on time periods and centers. Clinical data and imaging findings obtained were analyzed. Univariable and multivariable logistic regression analyses were performed to identify predictors associated with preoperative AIS. The performance of resulting nomogram was evaluated in discrimination and calibration on all cohorts. RESULTS: A total of 224 patients were in the development cohort, 94 in the temporal validation cohort, and 118 in the geographical validation cohort. Six predictors were identified: age, syncope, D-dimer, moderate to severe aortic valve insufficiency, diameter ratio of true lumen in ascending aorta < 0.33, and common carotid artery dissection. The nomogram established showed good discrimination (area under the receiver operating characteristic curve [AUC], 0.803; 95% CI: 0.742, 0.864) and calibration (Hosmer-Lemeshow test p = 0.300) in the development cohort. External validation showed good discrimination and calibration abilities in both temporal (AUC, 0.778; 95% CI: 0.671, 0.885; Hosmer-Lemeshow test p = 0.161) and geographical cohort (AUC, 0.806; 95% CI: 0.717, 0.895; Hosmer-Lemeshow test p = 0.100). CONCLUSIONS: A nomogram, based on simple imaging and clinical variables collected on admission, showed good discrimination and calibration abilities in predicting preoperative AIS for ATAAD patients. KEY POINTS: • A nomogram based on simple imaging and clinical findings may predict preoperative acute ischemic stroke in patients with acute type A aortic dissection in emergencies. • The nomogram showed good discrimination and calibration abilities in validation cohorts.

Protection of melatonin treatment and combination with traditional antibiotics against septic myocardial injury.

BACKGROUND: Heart failure is a common complication of sepsis with a high mortality rate. It has been reported that melatonin can attenuate septic injury due to various properties. On the basis of previous reports, this study will further explore the effects and mechanisms of melatonin pretreatment, posttreatment, and combination with antibiotics in the treatment of sepsis and septic myocardial injury. METHODS AND RESULTS: Our results showed that melatonin pretreatment showed an obvious protective effect on sepsis and septic myocardial injury, which was related to the attenuation of inflammation and oxidative stress, the improvement of mitochondrial function, the regulation of endoplasmic reticulum stress (ERS), and the activation of the AMPK signaling pathway. In particular, AMPK serves as a key effector for melatonin-initiated myocardial benefits. In addition, melatonin posttreatment also had a certain degree of protection, while its effect was not as remarkable as that of pretreatment. The combination of melatonin and classical antibiotics had a slight but limited effect. RNA-seq detection clarified the cardioprotective mechanism of melatonin. CONCLUSION: Altogether, this study provides a theoretical basis for the application strategy and combination of melatonin in septic myocardial injury.

Prevalence of burnout among perfusionists in China: A nationwide survey.

BACKGROUND: Burnout has gained increasing attention worldwide as a phenomenon that affects health care professionals. However, there is a lack of relevant research about its impact on practitioners in the field of cardiovascular perfusion in China. This study investigated the prevalence of and the factors associated with the burnout affecting perfusionists in mainland China. METHODS: This national cross-sectional study included perfusionists from 31 provinces in mainland China. Participants were asked to complete a self-administered questionnaire, which included three parts: (1) demographic information, (2) work-related information, and (3) dissatisfaction with work and sources of pressure. The levels of burnout were calculated, and logistic regression was used to analyze the factors associated with burnout. RESULTS: The questionnaire, created by the survey program "Questionnaire Star", was sent to 2211 perfusionists in mainland China. A final sample of 1813 perfusionists participated in the survey, with a participation rate of 82.0% (1813/2211). The prevalence of burnout and severe burnout was 86.0% (1559/1813, 95%CI: 84.3%-87.5%) and 13.3% (241/1813, 95%CI: 11.8%-15.0%), respectively. The logistic regression analysis revealed that age [20-29 years, odds ratio (OR) = 1; 30-39 years, OR = 2.009; 40-49 years, OR = 2.220], educational background (bachelor and below, OR = 1; postgraduate, OR = 1.472), and professional background (others, OR = 1; surgery, OR = 1.283; anesthesiology, OR = 2.004) were associated with burnout. We also found that age (20-29 years, OR = 1; 30-39 years, OR = 1.928), professional background (others, OR = 1; surgery, OR = 1.734; anesthesiology, OR = 2.257), annual cardiopulmonary bypass (CPB) case load in the most recent 3 years (< 50, OR = 1; 50-100, OR = 1.613; 100-300, OR = 1.702; ≥300, OR = 2.637), and income level [< 5000 (RMB/month), OR = 1; 5000-10,000, OR = 0.587; 10,000-20,000, OR = 0.366] were associated with severe burnout among perfusionists. CONCLUSIONS: Cardiovascular perfusionists in mainland China experience high rates of burnout. Age, the professional background, annual CPB caseload in the most recent 3 years, and income level are independently associated with the burnout rates experienced by these health care professionals.

Novel role of sex-determining region Y-box 7 (SOX7) in tumor biology and cardiovascular developmental biology.

The sex-determining region Y-box 7 (Sox7) is an important member of the SOX F family, which is characterized by a high-mobility-group DNA-binding domain. Previous studies have demonstrated the role of SOX7 in cardiovascular development. SOX7 expression could be detected in normal adult tissues. Furthermore, the expression levels of SOX7 were different in different tumors. Most studies showed the downregulation of SOX7 in tumors, while some studies reported its upregulation in tumors. In this review, we first summarized the upstream regulators (including transcription factors, microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and some exogenous regulators) and downstream molecules (including factors in the Wnt/ß-catenin signaling pathway and some other signaling pathways) of SOX7. Then, the roles of SOX7 in multiple tumors were presented. Finally, the significance of divergent SOX7 expression during cardiovascular development was briefly discussed. The information compiled in this study characterized SOX7 during tumorigenesis and cardiovascular development, which should facilitate the design of future research and promote SOX7 as a therapeutic target.

The roles of liver X receptor α in inflammation and inflammation-associated diseases.

Liver X receptor α (LXRα; also known as NR1H3), an isoform of LXRs, is a member of the nuclear receptor family of transcription factors and plays essential roles in the transcriptional control of cholesterol homeostasis. Previous in-depth phenotypic analyses of mouse models with deficient LXRα have also demonstrated various physiological functions of this receptor within inflammatory responses. LXRα activation exerts a combination of metabolic and anti-inflammatory actions resulting in the modulation and the amelioration of inflammatory disorders. The tight "repercussions" between LXRα and inflammation, as well as cholesterol homeostasis, have suggested that LXRα could be pharmacologically targeted in pathologies such as atherosclerosis, acute lung injury, and Alzheimer's disease. This review gives an overview of the recent advances in understanding the roles of LXRα in inflammation and inflammation-associated diseases, which will help in the design of future experimental researches on the potential of LXRα and advance the investigation of LXRα as pharmacological inflammatory targets.

Melatonin protects against thoracic aortic aneurysm and dissection through SIRT1-dependent regulation of oxidative stress and vascular smooth muscle cell loss.

Melatonin functions as an endogenous protective molecule in multiple vascular diseases, whereas its effects on thoracic aortic aneurysm and dissection (TAAD) and underlying mechanisms have not been reported. In this study, TAAD mouse model was successfully induced by ß-aminopropionitrile fumarate (BAPN). We found that melatonin treatment remarkably prevented the deterioration of TAAD, evidenced by decreased incidence, ameliorated aneurysmal dilation and vascular stiffness, improved aortic morphology, and inhibited elastin degradation, macrophage infiltration, and matrix metalloproteinase expression. Moreover, melatonin blunted oxidative stress damage and vascular smooth muscle cell (VSMC) loss. Notably, BAPN induced a decrease in SIRT1 expression and activity of mouse aorta, whereas melatonin treatment reversed it. Further mechanistic study demonstrated that blocking SIRT1 signaling partially inhibited these beneficial effects of melatonin on TAAD. Additionally, the melatonin receptor was involved in this phenomenon. Our study is the first to report that melatonin exerts therapeutic effects against TAAD by reducing oxidative stress and VSMC loss via activation of SIRT1 signaling in a receptor-dependent manner, thus suggesting a novel therapeutic strategy for TAAD.

Endoplasmic reticulum stress and NLRP3 inflammasome: Crosstalk in cardiovascular and metabolic disorders.

When endoplasmic reticulum (ER) homeostasis is disrupted, known as ER stress (ERS), the ER generates an adaptive signaling pathway called the unfolded protein response to maintain the homeostasis of this organelle. However, if homeostasis is not restored, the ER initiates death signaling pathways, which contribute to the pathogenesis of various disorders. The activation of inflammatory mechanisms is also emerging as a crucial component of cardiovascular and metabolic disorders. Furthermore, the nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome has attracted more attention than others and is the best-characterized member of the NLR family of inflammasomes to date. ERS intersects with many different inflammatory pathways, particularly the NLRP3 inflammasome. In this review, we focus on the interactions between ERS and the NLRP3 inflammasome. The pharmacologic and nonpharmaceutical manipulation of these two processes may offer novel opportunities for the treatment of cardiovascular and metabolic disorders.

Nitric Oxide Decreases Acute Kidney Injury and Stage 3 Chronic Kidney Disease after Cardiac Surgery.

RATIONALE: No medical intervention has been identified that decreases acute kidney injury and improves renal outcome at 1 year after cardiac surgery. OBJECTIVES: To determine whether administration of nitric oxide reduces the incidence of postoperative acute kidney injury and improves long-term kidney outcomes after multiple cardiac valve replacement requiring prolonged cardiopulmonary bypass. METHODS: Two hundred and forty-four patients undergoing elective, multiple valve replacement surgery, mostly due to rheumatic fever, were randomized to receive either nitric oxide (treatment) or nitrogen (control). Nitric oxide and nitrogen were administered via the gas exchanger during cardiopulmonary bypass and by inhalation for 24 hours postoperatively. MEASUREMENTS AND MAIN RESULTS: The primary outcome was as follows: oxidation of ferrous plasma oxyhemoglobin to ferric methemoglobin was associated with reduced postoperative acute kidney injury from 64% (control group) to 50% (nitric oxide group) (relative risk [RR], 0.78; 95% confidence interval [CI], 0.62-0.97; P = 0.014). Secondary outcomes were as follows: at 90 days, transition to stage 3 chronic kidney disease was reduced from 33% in the control group to 21% in the treatment group (RR, 0.64; 95% CI, 0.41-0.99; P = 0.024) and at 1 year, from 31% to 18% (RR, 0.59; 95% CI, 0.36-0.96; P = 0.017). Nitric oxide treatment reduced the overall major adverse kidney events at 30 days (RR, 0.40; 95% CI, 0.18-0.92; P = 0.016), 90 days (RR, 0.40; 95% CI, 0.17-0.92; P = 0.015), and 1 year (RR, 0.47; 95% CI, 0.20-1.10; P = 0.041). CONCLUSIONS: In patients undergoing multiple valve replacement and prolonged cardiopulmonary bypass, administration of nitric oxide decreased the incidence of acute kidney injury, transition to stage 3 chronic kidney disease, and major adverse kidney events at 30 days, 90 days, and 1 year. Clinical trial registered with ClinicalTrials.gov (NCT01802619).

Snapshots: Endoplasmic Reticulum Stress in Lipid Metabolism and Cardiovascular Disease.

The endoplasmic reticulum (ER) is an organelle present in most eukaryotic cells and plays a pivotal role in lipid metabolism. ER dysfunction, specifically ER stress (ERS), is a pathophysiological response involved in lipid metabolism and cardiovascular lesions. Therefore, suppression of ERS may improve lipid metabolic disorders and reduce cardiovascular risk. Herein, we focus on novel breakthroughs regarding the roles of ERS in lipid metabolism and cardiovascular disease (CVD), as well as the internal mechanisms of ERS and its status as a potential therapeutic target. This review highlights recent advances in ERS, the regulation of which might be helpful for both basic research and clinical drug design for lipid metabolic disorders and CVD.

Noninvasive Cerebral Imaging and Monitoring Using Electrical Impedance Tomography During Total Aortic Arch Replacement.

OBJECTIVE: To explore the feasibility of using electrical impedance tomography (EIT) to provide noninvasive cerebral imaging and monitoring in total aortic arch replacement (TAAR). DESIGN: A prospective, observational study. SETTING: Department of cardiovascular surgery in a university hospital. PARTICIPANTS: Forty-two patients undergoing TAAR using hypothermic circulatory arrest and unilateral antegrade cerebral perfusion. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Cerebral impedances of the patients were monitored intraoperatively by an EIT system. The prognostic information of the patients, including postoperative neurological dysfunction, was collected during their hospitalizations. Eight (19.0%) subjects had at least 1 postoperative neurological dysfunction complication. The results show that cerebral impedance was related negatively to perfusion flow, and the gradual increase in cerebral resistivity might reflect the evolving process of brain tissue caused by hypoxia. Maximum resistivity asymmetry index was extracted from the reconstructed images to quantify the pathological changes of the brain. The area under the receiver operating characteristic curve of maximum resistivity asymmetry index for postoperative neurological dysfunction was 0.864. In multivariate logistic regression, maximum resistivity asymmetry index was the strongest independent predictor of neurological dysfunction with an odds ratio of 24.3. CONCLUSION: EIT is a promising technique to provide noninvasive cerebral imaging and monitoring in TAAR.

CaMKII inhibition mitigates ischemia/reperfusion-elicited calpain activation and the damage to membrane skeleton proteins in isolated rat hearts.

Ca2+/calmodulin-dependent protein kinase II (CaMKII) has been implicated in myocardial ischemia/reperfusion (IR) injury. The aim of this study was to determine the effect of CaMKII on the damage to membrane skeleton proteins, which is an important cause of IR injury. Isolated rat hearts were subjected to 45-min global ischemia/2-h reperfusion. Both KN-62 and KN-93 were used to inhibit CaMKII. Compared with controls, the hearts in the IR group exhibited remarkable myocardial injury area, LDH release, cell apoptosis and contractile dysfunction, along with an increase in the phosphorylation of CaMKII and its substrate phospholamban. Treatment with either KN-62 or KN-93 mitigated both the heart injury and the phosphorylation of CaMKII and phospholamban. The analysis of cell skeleton proteins revealed that IR injury resulted in an increase in the 150-kDa fragments resulting from the degradation of α-fodrin and dystrophin translocating from the sarcolemmal membrane to the cytosol and a decrease in the 220-kDa isoform of ankyrin-B. As expected, Evans blue dye staining showed an increase in membrane permeability or membrane rupture in the IR group. All of these alterations were alleviated by treatment with either KN-62 or KN-93. In addition, both KN-62 and KN-93 blocked the activity and membrane recruitment of calpain, a key protease responsible for destroying cell skeleton proteins during IR injury. In conclusion, our data provide evidence that damage to membrane skeleton proteins via calpain is a destructive downstream event of CaMKII activation in the setting of myocardial IR injury.

Melatonin ameliorates myocardial ischemia reperfusion injury through SIRT3-dependent regulation of oxidative stress and apoptosis.

Sirtuins are a family of highly evolutionarily conserved nicotinamide adenine nucleotide-dependent histone deacetylases. Sirtuin-3 (SIRT3) is a member of the sirtuin family that is localized primarily to the mitochondria and protects against oxidative stress-related diseases, including myocardial ischemia/reperfusion (MI/R) injury. Melatonin has a favorable effect in ameliorating MI/R injury. We hypothesized that melatonin protects against MI/R injury by activating the SIRT3 signaling pathway. In this study, mice were pretreated with or without a selective SIRT3 inhibitor and then subjected to MI/R operation. Melatonin was administered intraperitoneally (20 mg/kg) 10 minutes before reperfusion. Melatonin treatment improved postischemic cardiac contractile function, decreased infarct size, diminished lactate dehydrogenase release, reduced the apoptotic index, and ameliorated oxidative damage. Notably, MI/R induced a significant decrease in myocardial SIRT3 expression and activity, whereas the melatonin treatment upregulated SIRT3 expression and activity, and thus decreased the acetylation of superoxide dismutase 2 (SOD2). In addition, melatonin increased Bcl-2 expression and decreased Bax, Caspase-3, and cleaved Caspase-3 levels in response to MI/R. However, the cardioprotective effects of melatonin were largely abolished by the selective SIRT3 inhibitor 3-(1H-1,2,3-triazol-4-yl)pyridine (3-TYP), suggesting that SIRT3 plays an essential role in mediating the cardioprotective effects of melatonin. In vitro studies confirmed that melatonin also protected H9c2 cells against simulated ischemia/reperfusion injury (SIR) by attenuating oxidative stress and apoptosis, while SIRT3-targeted siRNA diminished these effects. Taken together, our results demonstrate for the first time that melatonin treatment ameliorates MI/R injury by reducing oxidative stress and apoptosis via activating the SIRT3 signaling pathway.

Melatonin protects against the pathological cardiac hypertrophy induced by transverse aortic constriction through activating PGC-1ß: In vivo and in vitro studies.

Melatonin, a circadian molecule secreted by the pineal gland, confers a protective role against cardiac hypertrophy induced by hyperthyroidism, chronic hypoxia, and isoproterenol. However, its role against pressure overload-induced cardiac hypertrophy and the underlying mechanisms remains elusive. In this study, we investigated the pharmacological effects of melatonin on pathological cardiac hypertrophy induced by transverse aortic constriction (TAC). Male C57BL/6 mice underwent TAC or sham surgery at day 0 and were then treated with melatonin (20 mg/kg/day, via drinking water) for 4 or 8 weeks. The 8-week survival rate following TAC surgery was significantly increased by melatonin. Melatonin treatment for 8 weeks markedly ameliorated cardiac hypertrophy. Compared with the TAC group, melatonin treatment for both 4 and 8 weeks reduced pulmonary congestion, upregulated the expression level of α-myosin heavy chain, downregulated the expression level of ß-myosin heavy chain and atrial natriuretic peptide, and attenuated the degree of cardiac fibrosis. In addition, melatonin treatment slowed the deterioration of cardiac contractile function caused by pressure overload. These effects of melatonin were accompanied by a significant upregulation in the expression of peroxisome proliferator-activated receptor-gamma co-activator-1 beta (PGC-1ß) and the inhibition of oxidative stress. In vitro studies showed that melatonin also protects against angiotensin II-induced cardiomyocyte hypertrophy and oxidative stress, which were largely abolished by knocking down the expression of PGC-1ß using small interfering RNA. In summary, our results demonstrate that melatonin protects against pathological cardiac hypertrophy induced by pressure overload through activating PGC-1ß.

2,3,5,4'-Tetrahydroxystilbene-2-O-ß-D-glucoside protects murine hearts against ischemia/reperfusion injury by activating Notch1/Hes1 signaling and attenuating endoplasmic reticulum stress.

2,3,5,4'-Tetrahydroxystilbene-2-O-ß-D-glucoside (TSG) is a water-soluble active component extracted from Polygonum multiflorum Thunb. A number of studies demonstrate that TSG exerts cardioprotective effects. Since endoplasmic reticulum (ER) stress plays a key role in myocardial ischemia/reperfusion (MI/R)-induced cell apoptosis, we sought to determine whether modulation of the ER stress during MI/R injury was involved in the cardioprotective action of TSG. Male mice were treated with TSG (60 mg·kg-1·d-1, ig) for 2 weeks and then were subjected to MI/R surgery. Pre-administration of TSG significantly improved post-operative cardiac function, and suppressed MI/R-induced myocardial apoptosis, evidenced by the reduction in the myocardial apoptotic index, serum levels of LDH and CK after 6 h of reperfusion. TSG (0.1-1000 µmol/L) did not affect the viability of cultured H9c2 cardiomyoblasts in vitro, but pretreatment with TSG dose-dependently decreased simulated ischemia/reperfusion (SIR)-induced cell apoptosis. Furthermore, both in vivo and in vitro studies revealed that TSG treatment activated the Notch1/Hes1 signaling pathway and suppressed ER stress, as evidenced by increasing Notch1, Notch1 intracellular domain (NICD), Hes1, and Bcl-2 expression levels and by decreasing p-PERK/PERK ratio, p-eIF2α/eIF2α ratio, and ATF4, CHOP, Bax, and caspase-3 expression levels. Moreover, the protective effects conferred by TSG on SIR-treated H9c2 cardiomyoblasts were abolished by co-administration of DAPT (the Notch1 signaling inhibitor). In summary, TSG ameliorates MI/R injury in vivo and in vitro by activating the Notch1/Hes1 signaling pathway and attenuating ER stress-induced apoptosis.

Melatonin reduces PERK-eIF2α-ATF4-mediated endoplasmic reticulum stress during myocardial ischemia-reperfusion injury: role of RISK and SAFE pathways interaction.

Recently, we demonstrated that melatonin reduced protein kinase RNA (PKR)-like ER kinase (PERK)-eukaryotic initiation factor 2 alpha (eIF2α)-activating transcription factor-4 (ATF4)-mediated myocardial endoplasmic reticulum (ER) stress and apoptosis during myocardial ischemia-reperfusion (MI/R) injury. However, the underlying mechanisms are still not clear. Myocardial reperfusion injury salvage kinase (RISK) pathway as well as survivor activating factor enhancement (SAFE) pathway are two pivotal intrinsic pro-survival signaling cascades. In this study, we performed in vivo and in vitro experiment to investigate the ameliorative effect of melatonin on ER stress with a focus on RISK and SAFE pathways interaction. Male C57Bl/6 mice received melatonin (300 µg/25 g/day, 3 days before MI/R surgery; 300 µg/25 g, 25 min before the onset of ischemia) pre-treatment with or without the administration of LY294002 (a PI3K/Akt inhibitor), U0126 (an ERK1/2 inhibitor) or AG490 (a STAT3 pathway inhibitor). H9c2 cells were pre-treated with melatonin (100 µM, 8 h) in the presence or absence of LY294002, U0126 or AG490. Compared with the I/R-injured group, melatonin effectively reduced myocardial apoptosis, oxidative stress and improved cardiac function. In addition, melatonin pre-treatment also increased the phosphorylation of Akt, GSK-3ß, ERK1/2 and STAT3 and reduced PERK-eIF2α-ATF4-mediated ER stress. However, these effects were blocked by LY294002, U0126 or AG490. Additionally, either LY294002 or U0126 treatment could inhibit STAT3 phosphorylation, whereas AG490 administration also reduced both Akt and ERK1/2 phosphorylation, indicating an interplay exists between RISK and SAFE pathways in melatonin's cardioprotective effect. In summary, our study demonstrates that RISK and SAFE pathways mediate the cardioprotective effect of melatonin against MI/R injury. Melatonin pre-treatment attenuates PERK-eIF2α-ATF4-mediated ER stress and apoptosis during MI/R injury via RISK and SAFE pathways interaction.

Bakuchiol attenuates myocardial ischemia reperfusion injury by maintaining mitochondrial function: the role of silent information regulator 1.

Ischemia reperfusion (IR) injury (IRI) is associated with poor prognoses in the settings of both cardiac surgery and ischemic heart disease and causes mitochondrial oxidative stress and cell death. Silent information regulator 1 (SIRT1), a member of the histone deacetylase family, exerts anti-IRI effects. Bakuchiol (BAK), an analog of resveratrol and a monoterpene phenol isolated from the seeds of Psoralea corylifolia (Leguminosae), protects tissues from injury. This study was designed to investigate the protective effects of BAK treatment in the setting of myocardial IRI and to elucidate the potential mechanism of those effects. Prior to induction of IR, isolated rat hearts or cardiomyocytes were exposed to BAK in either the absence or presence of the SIRT1 inhibitors Sirtinol and SIRT1 siRNA. BAK exerted cardioprotective effects, as evidenced by the improvements noted in cardiac function following ischemia, attenuated myocardial apoptosis, and changes in several biochemical parameters (including increases in the level of the anti-apoptotic protein Bcl2, decreases in the level of the pro-apoptotic protein Bax, and decreases in the cleaved Caspase 3 level). However, Sirtinol and SIRT1 siRNA each blocked BAK-induced cardioprotection by inhibiting SIRT1 signaling. Additionally, BAK significantly increased the activities of mitochondrial succinate dehydrogenase, cytochrome c oxidase, and mitochondrial superoxide dismutase and decreased the production of malondialdehyde. These findings suggested that BAK significantly attenuated IR-induced mitochondrial oxidative damage. However, Sirtinol and SIRT1 siRNA abolished BAK-dependent mitochondrial function. In summary, our results demonstrate that BAK treatment attenuates IRI by attenuating IR-induced mitochondrial oxidative damage via the activation of SIRT1/PGC-1α signaling.

Melatonin reverses flow shear stress-induced injury in bone marrow mesenchymal stem cells via activation of AMP-activated protein kinase signaling.

Tissue-engineered heart valves (TEHVs) are a promising treatment for valvular heart disease, although their application is limited by high flow shear stress (FSS). Melatonin has a wide range of physiological functions and is currently under clinical investigation for expanded applications; moreover, extensive protective effects on the cardiovascular system have been reported. In this study, we investigated the protection conferred by melatonin supplementation against FSS-induced injury in bone marrow mesenchymal stem cells (BMSCs) and elucidated the potential mechanism in this process. Melatonin markedly reduced BMSC apoptotic death in a concentration-dependent manner while increasing the levels of transforming growth factor ß (TGF-ß), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and B-cell lymphoma 2 (Bcl2), and decreasing those of Bcl-2-associated X protein (Bax), p53 upregulated modulator of apoptosis (PUMA), and caspase 3. Notably, melatonin exerted its protective effects by upregulating the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK), which promotes acetyl-CoA carboxylase (ACC) phosphorylation. Further molecular experiments revealed that luzindole, a nonselective antagonist of melatonin receptors, blocked the anti-FSS injury (anti-FSSI) effects of melatonin. Inhibition of AMPK by Compound C also counteracted the protective effects of melatonin, suggesting that melatonin reverses FSSI in BMSCs through the AMPK-dependent pathway. Overall, our findings indicate that melatonin contributes to the amelioration of FSS-induced BMSC injury by activating melatonin receptors and AMPK/ACC signaling. Our findings may provide a basis for the design of more effective strategies that promote the use of TEHCs in patients.

Berberine protects rat heart from ischemia/reperfusion injury via activating JAK2/STAT3 signaling and attenuating endoplasmic reticulum stress.

AIM: Berberine (BBR), an isoquinoline-derived alkaloid isolated from Rhizoma coptidis, exerts cardioprotective effects. Because endoplasmic reticulum (ER) stress plays a pivotal role in myocardial ischemia/reperfusion (MI/R)-induced apoptosis, it was interesting to examine whether the protective effects of BBR resulted from modulating ER stress levels during MI/R injury, and to define the signaling mechanisms in this process. METHODS: Male rats were treated with BBR (200 mg · kg(-1) · d(-1), ig) for 2 weeks, and then subjected to MI/R surgery. Cardiac dimensions and function were assessed using echocardiography. Myocardial infarct size and apoptosis was examined. Total serum LDH levels and CK activities, superoxide production, MDA levels and the antioxidant SOD activities in heart tissue were determined. An in vitro study was performed on cultured rat embryonic myocardium-derived cells H9C2 exposed to simulated ischemia/reperfusion (SIR). The expression of apoptotic, ER stress-related and signaling proteins were assessed using Western blot analyses. RESULTS: Pretreatment with BBR significantly reduced MI/R-induced myocardial infarct size, improved cardiac function, and suppressed myocardial apoptosis and oxidative damage. Furthermore, pretreatment with BBR suppressed MI/R-induced ER stress, evidenced by down-regulating the phosphorylation levels of myocardial PERK and eIF2α and the expression of ATF4 and CHOP in heart tissues. Pretreatment with BBR also activated the JAK2/STAT3 signaling pathway in heart tissues, and co-treatment with AG490, a specific JAK2/STAT3 inhibitor, blocked not only the protective effects of BBR, but also the inhibition of BBR on MI/R-induced ER stress. In H9C2 cells, treatment with BBR (50 µmol/L) markedly reduced SIR-induced cell apoptosis, oxidative stress and ER stress, which were abolished by transfection with JAK2 siRNA. CONCLUSION: BBR ameliorates MI/R injury in rats by activating the AK2/STAT3 signaling pathway and attenuating ER stress-induced apoptosis.