Myocardial Cells Research Articles

Ninerafaxstat in the Treatment of Cardiometabolic Disease: Shifting Metabolic Paradigms.

Cardiovascular disease (CVD) refers to a wide array of conditions that damage the heart muscle and impede its ability to effectively circulate blood throughout the body. In damaged or pathological states, the heart muscle might not function as effectively as it would have had there been no insult to it. Understanding this, certain CVDs can put the heart in a "metabolic disadvantage"-a state in which it cannot synthesize energy stores, in the form of adenosine triphosphate (ATP), as efficiently as it was once able to do. While the heart typically uses fatty acids for its ATP synthesis, the metabolic processes required to do so consume more oxygen per mole than the processes required to convert glucose (or carbohydrates) to ATP. In conditions when oxygen demand outweighs supply-such as angina, heart failure, and certain inherited CVDs-the myocardium can more efficiently run via glucose oxidation. Despite this knowledge, there are no currently approved therapeutics or interventions that encourage this "metabolic shift" in the myocardial cells. Currently in phase II clinical trials, however, is a novel medication called ninerafaxstat. This novel drug is a partial inhibitor of fatty acid oxidation and thus pushes the heart to convert glucose (instead of fatty acids) to ATP-ultimately cutting down on oxygen supply. While still completing clinical trials, ninerafaxstat must undergo further safety and efficacy evaluation before it can be used as a standard of care. If, however, the drug makes it to market, it might offer a unique way to improve both the symptoms and quality of life of the millions of Americans who suffer from CVDs.

Shexiang Tongxin Dropping Pill Promotes Angiogenesis through VEGF/eNOS Signaling Pathway on Diabetic Coronary Microcirculation Dysfunction.

To study the effect of Shexiang Tongxin Dropping Pill (STDP) on angiogenesis in diabetic cardiomyopathy mice with coronary microcirculation dysfunction (CMD). According to a random number table, 6 of 36 SPF male C57BL/6 mice were randomly selected as the control group, and the remaining 30 mice were injected with streptozotocin intraperitoneally to replicate the type 1 diabetes model. Mice successfully copied the diabetes model were randomly divided into the model group, STDP low-dose group [15 mg/(kg·d)], medium-dose group [30 mg/(kg·d)], high-dose group [60 mg/(kg·d)], and nicorandil group [15 mg/(kg·d)], 6 in each group. The drug was given by continuous gavage for 12 weeks. The cardiac function of mice in each group was detected at the end of the experiment, and coronary flow reserve (CFR) was detected by chest Doppler technique. Pathological changes of myocardium were observed by hematoxylin-eosin staining, collagen fiber deposition was detected by masson staining, the number of myocardial capillaries was detected by platelet endothelial cell adhesion molecule-1 staining, and the degree of myocardial hypertrophy was detected by wheat germ agglutinin staining. The expression of the vascular endothlial growth factor (VEGF)/endothelial nitric oxide synthase (eNOS) signaling pathway-related proteins in myocardial tissue was detected by Western blot. Compared with the model group, medium- and high-dose STDP significantly increased the left ventricular ejection fraction and left ventricular fraction shortening (P<0.01), obviously repaired the disordered cardiac muscle structure, reduced myocardial fibrosis, reduced myocardial cell area, increased capillary density, and increased CFR level (all P<0.01). Western blot showed that high-dose STDP could significantly increase the expression of VEGF and promote the phosphorylation of vascular endothelial growth factor receptor 2, phosphoinositide 3-kinase, protein kinase B, and eNOS (P<0.05 or P<0.01). STDP has a definite therapeutic effect on diabetic CMD, and its mechanism may be related to promoting angiogenesis through the VEGF/eNOS signaling pathway.

Clinical value of BRE-AS1 in myocardial infarction and its role in myocardial infarction-induced cardiac muscle cell apoptosis

Objectives. The aim of this study was to investigate the expression of long non-coding RNA (lncRNA) brain and reproductive organ-expressed protein (BRE) antisense RNA 1 (BRE-AS1) in patients with acute myocardial infarction (AMI) and its effect on ischemia/reperfusion (I/R)-induced oxidative stress and apoptosis of cardiomyocytes. Methods. Serum BRE-AS1 levels in patients with AMI was detected using quantitative real-time polymerase chain reaction (qRT-PCR). The diagnostic and prognostic values of BRE-AS1 were evaluated. H9c2 cells were treated with hypoxia/reoxygenation to establish an in vitro myocardial infarction cell model. The levels of inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 were detected by enzyme-linked immunosorbent assay (ELISA). Levels of lactate dehydrogenase (LDH), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) were determined by commercial kits. Cell counting kit-8 (CCK-8) and flow cytometry were used to evaluate the cell viability and cell apoptosis. Results. The expression of BRE-AS1 in serum of patients with AMI is upregulated, which shows the clinical diagnostic value for AMI. In the I/R injury cell model, the knockout of BRE-AS1 can significantly alleviate the increase in TNF-α, IL-1β, and IL-6 levels, inhibit the production of LDH and MDA, increase the activities of SOD and GSH-Px, promote the cell viability and suppress cell apoptosis. Conclusions. Abnormally elevated BRE-AS1 has a high diagnostic value for AMI as well as a prognostic value for major adverse cardiovascular events (MACEs). The elevation of BRE-AS1 promoted oxidative stress injury and cell apoptosis in vitro.

The cardiovascular toxicity of polystyrene microplastics in rats: based on untargeted metabolomics analysis

BackgroundPolystyrene microplastics (PS-MPs) exhibit multi-target, multi-dimensional, chronic, and low toxicity to the cardiovascular system. They enter the bloodstream through the gastrointestinal tract and respiratory system, altering blood parameters and conditions, inducing thrombotic diseases, and damaging myocardial tissue through the promotion of oxidative stress and inflammatory responses in myocardial cells. However, many of the links and mechanisms remain unclear.MethodsIn this study, 48 wistar rats were randomly divided into four groups and exposed to different concentrations of PS-MPs: control group (0 mg/kg/d), low dose group (0.5 mg/kg/d), middle dose group (5 mg/kg/d) and high dose group (50 mg/kg/d), with 12 rats in each group. After 90 consecutive days of intragastric administration of PS-MPs, biochemical markers in myocardium, aorta and blood were detected, and HE staining was performed to observe the toxic effects of PS-mps on cardiovascular system. Furthermore, non-targeted metabolomics methods were used to analyze the effect of PS-MPs exposure on the metabolism of cardiovascular system in rats, and to explore its potential molecular mechanism.ResultsThe results revealed no pathological changes in the heart and aorta following PS-MPs exposure. However, the myocardial enzyme levels in the high dose PS-MPs group of rats showed a significant increase. Moreover, exposure to polystyrene microplastics caused a disorder in lipid metabolism in rats, and led to an increase in indicators of inflammation and oxidative stress in myocardial and aortic tissues, but resulted in a decrease in the level of IL-6. Untargeted metabolomics results showed that metabolites with antioxidant and anti-inflammatory effects, including equol and 4-hydroxybenzoic acid, were significantly upregulated.ConclusionThese results suggest that long-term exposure to high concentrations of PS-MPs may lead to abnormal lipid metabolism and cardiovascular system damage. The mechanism may be related to oxidative stress and inflammatory response. Exogenous antioxidants and changes in own metabolites may have a protective effect on the injury. Therefore, understanding the toxicological mechanism of PS-MPs not only helps to elucidate its pathogenesis, but also provides new ideas for the treatment of chronic diseases.

Four-dimensional computed tomography is useful for detection of apical sparing of cardiac amyloidosis.

A 73-year-old male was admitted because of recurrent syncope. He was diagnosed with transient bradycardia caused by a 2:1 atrioventricular block, and he underwent cardiac computed tomography (CT) using 320 detector-row CT to screen for coronary artery disease. Significant coronary artery stenosis was not detected, but diffuse late iodinate enhancement was found on the epi-myocardium and endo-myocardium of the interventricular septum, and endo-myocardium of the anterior and lateral left ventricular (LV) myocardium (LVM) on CT. The ejection fraction and global longitudinal strain (LS) of LVM were 53.97% and - 9.87% on CT. Apical sparing was present, meaning the LS of LV apical segments were preserved compared with basal segments on CT. Pathological findings of LVM demonstrated loss of myocardial cells and extra-cellular amyloid deposition on the direct fast scarlet staining. He was finally diagnosed with transthyretin amyloidosis.

ZebraReg—a novel platform for discovering regulators of cardiac regeneration using zebrafish

Cardiovascular disease is the leading cause of death worldwide with myocardial infarction being the most prevalent. Currently, no cure is available to either prevent or revert the massive death of cardiomyocytes that occurs after a myocardial infarction. Adult mammalian hearts display a limited regeneration capacity, but it is insufficient to allow complete myocardial recovery. In contrast, the injured zebrafish heart muscle regenerates efficiently through robust proliferation of pre-existing myocardial cells. Thus, zebrafish allows its exploitation for studying the genetic programs behind cardiac regeneration, which may be present, albeit dormant, in the adult human heart. To this end, we have established ZebraReg, a novel and versatile automated platform for studying heart regeneration kinetics after the specific ablation of cardiomyocytes in zebrafish larvae. In combination with automated heart imaging, the platform can be integrated with genetic or pharmacological approaches and used for medium-throughput screening of presumed modulators of heart regeneration. We demonstrate the versatility of the platform by identifying both anti- and pro-regenerative effects of genes and drugs. In conclusion, we present a tool which may be utilised to streamline the process of target validation of novel gene regulators of regeneration, and the discovery of new drug therapies to regenerate the heart after myocardial infarction.

Isoliquiritigenin alleviates myocardial ischemia-reperfusion injury by regulating the Nrf2/HO-1/SLC7a11/GPX4 axis in mice

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.

New Insights into IGF-1 Signaling in the Heart.

Insulin-like growth factor (IGF)-1 signaling has multiple physiological roles in cellular growth, metabolism, and aging. Myocardial hypertrophy, cell death, senescence, fibrosis, and electrical remodeling are hallmarks of various heart disease and contributes to the progression of heart failure. This review highlights the critical role of IGF-1 and its cognate receptor in cardiac hypertrophy, aging and remodeling.

Overexpression of zinc-finger protein 418 inhibits pathological cardiac remodelling after acute myocardial infarction.

Zinc-finger protein 418 (ZNF418) has been confirmed to be expressed in myocardial tissue. However, the role and mechanism of ZNF418 in pathological myocardial remodelling after myocardial infarction (MI) have not been reported. This study was to elucidate the effect and mechanism of ZNF418 on ventricular remodelling after MI in mice. MI mice and H9c2 cardiomyocytes were used to conduct in vivo and in vitro experiments, respectively. ZNF418 expression was regulated by adeno-associated virus 9 and adenovirus vectors. Pathological analysis, echocardiography, and molecular analysis were performed. ZNF418 was down-regulated in the left ventricular tissues of post-MI mice. In contrast, ZNF418 overexpression decreased mortality and improved cardiac function in MI mice. The MI mice exhibited a significantly increased cross-sectional area of myocardial cells and elevated protein expression levels of myocardial hypertrophy markers ANP, BNP, and β-MHC (all P<0.05). Moreover, a significantly increased area of myocardial fibrosis and protein expression levels of myocardial fibrosis markers collagen I, collagen III, and CTGF were observed in MI mice (all P<0.05) in MI mice. All of the above negative effects in MI mice were ameliorated in ZNF418 overexpressed mice (all P<0.05). Mechanistically, ZNF418 overexpression inhibited the activation of the MAPK signalling pathway, as evidenced by the in vivo and in vitro experiments. Overexpression of ZNF418 could improve cardiac function and inhibit pathological cardiac remodelling by inhibiting the MAPK signalling pathway in post-MI mice.

Roles of O-GlcNAcylation in Mitochondrial Homeostasis and Cardiovascular Diseases

Protein posttranslational modifications are important factors that mediate the fine regulation of signaling molecules. O-linked β-N-acetylglucosamine-modification (O-GlcNAcylation) is a monosaccharide modification on N-acetylglucosamine linked to the hydroxyl terminus of serine and threonine of proteins. O-GlcNAcylation is responsive to cellular stress as a reversible and posttranslational modification of nuclear, mitochondrial and cytoplasmic proteins. Mitochondrial proteins are the main targets of O-GlcNAcylation and O-GlcNAcylation is a key regulator of mitochondrial homeostasis by directly regulating the mitochondrial proteome or protein activity and function. Disruption of O-GlcNAcylation is closely related to mitochondrial dysfunction. More importantly, the O-GlcNAcylation of cardiac proteins has been proven to be protective or harmful to cardiac function. Mitochondrial homeostasis is crucial for cardiac contractile function and myocardial cell metabolism, and the imbalance of mitochondrial homeostasis plays a crucial role in the pathogenesis of cardiovascular diseases (CVDs). In this review, we will focus on the interactions between protein O-GlcNAcylation and mitochondrial homeostasis and provide insights on the role of mitochondrial protein O-GlcNAcylation in CVDs.

Anthocyanin of Black Highland Barley Alleviates H2O2-Induced Cardiomyocyte Injury and Myocardial Infarction via Activating the Phosphatase and Tensin Homolog/Phosphatidylinositol 3-Kinase/Protein Kinase B Pathway.

Cardiovascular disease (CVD) represents a substantial global health challenge, with its impact on mortality and morbidity rates surpassing that of cancer. The present study was designed to explore the cardioprotective properties of anthocyanin (ACN), a compound derived from black barley, against oxidative stress-induced damage in myocardial cells and to uncover the molecular mechanisms at play. Utilizing both in vitro and in vivo experimental models, our findings indicate that ACN notably reduced cell damage caused by oxidative stress and effectively prevented apoptosis. High-throughput RNA sequencing analysis has shed light on the mechanism by which ACN achieves its antioxidative stress effects, implicating the PTEN-Akt signaling pathway. ACN was found to modulate PTEN expression levels, which in turn influences the Akt pathway, leading to a reduction in apoptotic processes. This novel insight lays the groundwork for the potential clinical utilization of ACN in the management of CVD. While this study has shed light on some of the functions of ACN, it is important to recognize that natural compounds often interact with multiple molecular targets and engage in intricate signaling cascades. Future research endeavors will concentrate on further elucidating the regulatory mechanisms by which ACN influences PTEN expression, with the goal of enhancing our comprehension and expanding the therapeutic potential of ACN in the treatment of cardiovascular conditions.

MiR-200b-3p relieved inflammation in patients with heart failure by regulating ZEB1 expression

BackgroundMicroRNA-200b-3p (miR-200b-3p) plays a pivotal role in inflammatory responses and is implicated in various inflammatory disorders. In this study, we aim to explore the role of miR-200b-3p in the inflammatory response in heart failure (HF).MethodsPatients diagnosed with heart failure and age-matched healthy controls were studied. Peripheral blood samples from participants were collected for RNA-seq analysis to explore the expression profile of miR-200b-3p. The predictive value of miR-200b-3p and ZEB1 in the prognosis of heart failure was evaluated by analyzing the receiver operating characteristic (ROC) curve. Bioinformatics analysis and double luciferase reporter gene analysis were used to confirm the interaction between miR-200b-3p and ZEB1. Real-time quantitative polymerase chain reaction (QRT-PCR) was used to detect the expression levels of miR-200b-3p and ZEB1 in cardiopulmonary bypass. Additionally, the effects of miR-200b-3p on myocardial cell line (H9c2) injury were evaluated by enzyme-linked immunosorbent assay (ELISA).ResultsIn the extracardiac circulation of HF patients, miR-200b-3p expression was significantly reduced, while ZEB1 levels were notably elevated. Analysis of the ROC curve revealed that miR-200b-3p and ZEB1 have predictive value in the prognosis of HF patients. The double luciferase reporter experiment demonstrated that miR-200b-3p binds to ZEB1 and inhibits its expression. Overexpression of miR-200b-3p demonstrated a remarkable ability to alleviate inflammation and inhibit the damage to myocardial cells in vivo.ConclusionMiR-200b-3p can target and inhibit ZEB1, reducing the inflammatory reaction of myocardial cells. The miR-200b-3p/ZEB1 network may be helpful in preventing and treating HF.

Protective Effect of Prunetin on Isoproterenol-Induced Myocardial Infarction in Wistar Rats via Biochemical Characterization.

The development of MI following ischemia damage is influenced by oxidative stress. Myocardial Infarction (MI) generates myocardial ischemia injury, which damages the cardiomyocytes. Ischemia builds up to a critical level over time in MI, causing permanent myocardial cell damage or death. The current study sought to determine whether Prunetin (PRU) could protect against Isoproterenol (ISO)-induced cardiac heart failure in rats by examining cardiac diagnostic markers, lipid peroxidation products, enzymatic and non-enzymatic antioxidant levels, and histological changes. PRU (20 mg/kg bwt) was orally administered for 19 days to rats, and after the treatment, ISO (85 mg/kg bwt) was subcutaneously administered with an intermission of 24 h for a couple of days to induce myocardial infarction on 20th and 21st days. ISO-treated rats exhibited considerable alterations in cardiac-sensitive markers in the serum. The levels of lipid peroxidation markers augmented drastically in the plasma and myocardium. Enzymatic antioxidant levels in erythrocytes and myocardium and the states of non-enzymatic antioxidants were diminished in the plasma and heart tissue of ISO-treated rats. The histopathological examination of heart tissue exhibited cardiac damage in ISO-induced rats. The oral administration of PRU significantly lowered the levels of lipid peroxidation and biochemical indicators, while significantly improving the antioxidant system function of ISO-interposed rats. In PRU-treated ISO-injected rats, histological examinations revealed suppressed myocardial destruction. Our research shows that oral pretreatment of PRU prevented ISO-induced oxidative stress in MI.

A biomimetic ion channel shortens the QT interval of type 2 long QT syndrome through efficient transmembrane transport of potassium ions

Potassium ion transport across myocardial cell membrane is essential for type 2 long QT syndrome (LQT2). However, the dysfunction of potassium ion transport due to genetic mutations limits the therapeutic effect in treating LQT2. Biomimetic ion channels that selectively and efficiently transport potassium ions across the cellular membranes are promising for the treatment of LQT2. To corroborate this, we synthesized a series of foldamer-based ion channels with different side chains, and found a biomimetic ion channel of K+ (BICK) with the highest transport activity among them. The selected BICK can restore potassium ion transport and increase transmembrane potassium ion current, thus shortening phase 3 of action potential (AP) repolarization and QT interval in LQT2. Moreover, BICK does not affect heart rate and cardiac rhythm in treating LQT2 model induced by E4031 in isolated heart as well as in guinea pigs. By restoring ion transmembrane transport tactic, biomimetic ion channels, such as BICK, will show great potential in treating diseases related to ion transport blockade. Statement of significanceType 2 long QT syndrome (LQT2) is a disease caused by K+ transport disorder, which can cause malignant arrhythmia and even death. There is currently no radical cure, so it is critical to explore ways to improve K+ transmembrane transport. In this study, we report that a small-molecule biomimetic ion channel BICK can efficiently simulate natural K+ channel proteins on the cardiomyocyte and cure E4031-induced LQT2 in guinea pig by restoring K+ transport function for the first time. This study found that the potassium transmembrane transport by BICK significantly reduced the QT interval, which provides a conceptually new strategy for the treatment of LQT2 disease.

Normothermic Ex Vivo Heart Perfusion With Exosomes From Human Umbilical Cord Mesenchymal Stem Cells Improves Graft Function in Donation After Circulatory Death Hearts.

This study aimed to investigate the cardioprotective effect of exosomes derived from human umbilical cord mesenchymal stem cells on donation after circulatory death (DCD) hearts preserved with normothermic ex vivo heart perfusion (EVHP) in a rat heart transplantation model. Thirty-two male Lewis rats were divided into 2 groups: the control group and the exosome group. The donor-heart rats were subjected to the DCD procedure by suffering a 15-min warm ischemia injury, subsequently preserved with EVHP for 90 min, and then transplanted into recipients via abdominal heterotopic heart transplantation. Vehicle or exosome was added into the perfusate of normothermic EVHP in the control or exosome group. We evaluated left ventricular graft function, myocardial inflammation, and myocardial apoptosis of the donor heart 1.5 h after heart transplantation. Furthermore, we investigate the alternation of myocardial gene expression in the donor hearts between both groups by transcriptome sequencing. The treatment with exosome significantly enhanced cardiac function through increasing left ventricular developed pressure, dp/dtmax, and dp/dtmin of DCD hearts at 90 min after heart transplantation compared with the control group. The myocardial cells in the exosome group exhibited an orderly arrangement without obvious edema. Furthermore, exosome added into perfusate in the exosome group significantly attenuated the level of inflammatory response and apoptosis. Transcriptome sequencing and RT-qPCR showed the phosphoinositide 3-kinase/protein kinase B pathway was activated after exosome treatment. Normothermic EVHP combined with exosome can be a promising and novel DCD heart preservation strategy, alleviating myocardial ischemia-reperfusion injury in the DCD heart.

A role of ROS-dependent defects in mitochondrial dynamic and autophagy in carbon black nanoparticle-mediated myocardial cell damage

Carbon black nanoparticles (CBNPs) are widely distributed in the environment and are increasingly recognized as a contributor in the development of cardiovascular disease.A variety of cardiac injuries and diseases result from structural and functional damage to cardiomyocytes. This study explored the mechanisms of CBNPs-mediated myocardial toxicity. CBNPs were given to mice through intra-tracheal instillation and it was demonstrated that the particles can be taken up into the cardiac tissue. Exposure to CBNPs induced cardiomyocyte inflammation and apoptosis. In combination with in vitro experiments, we showed that CBNPs increased the ROS and induced mitochondria fragmentation. Functionally, CBNPs-exposed cardiomyocyte exhibited depolarization of the mitochondrial membrane potential, release of cytochrome c, and activation of pro-apoptotic BAX, thereby initiating programmed cell death. On the other hand, CBNPs impaired autophagy, leading to the inadequate removal of dysfunctional mitochondria. The excess accumulation of damaged mitochondria further stimulated NF-κB activation and triggered the NLRP3 inflammasome pathway. Both the antioxidant N-acetylcysteine and the autophagy activator rapamycin were effective to attenuate the damage of CBNPs on cardiomyocytes. Taken together, this study elucidated the potential mechanism underlying CBNPs-induced myocardial injury and provided a scientific reference for the evaluation and prevention of the CBNPs-related heart risk.

Retracted] LncRNA TUG1 serves an important role in hypoxia‑induced myocardial cell injury by regulating the miR‑145‑5p‑Binp3 axis.

Following the publication of this article, a concerned reader drew to the Editor's attention that, for several of the figures showing the results of Transwell migration and invasion assay experiments, unexpected areas of similarity were identified in terms of cellular patterns comparing among data panels where the results from differently performed experiments were intended to have been shown, although the areas immediately surrounding these areas often featured comparatively different distributions of cells. Moreover, several of the figures contained invasion/migration assay data that were strikingly similar to data that had appeared in articles published previously by different authors at different research institutes. In addition, the western blots in this article were presented with atypical, unusually shaped and possibly anomalous protein bands in many cases. After having conducted an internal investigation, the Editor of Molecular Medicine Reports has reached the conclusion that the potentially anomalous data in this paper were unlikely to have arisen by coincidence. Therefore, on the grounds of a lack of confidence in the integrity of these data, and given the fact that some of the data were strikingly similar to that which had been published previously in other articles and journals, the Editor has decided that the article should be retracted from the publication. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused, and thanks the concerned reader for drawing this matter to our attention. [Molecular Medicine Reports 42: 2422‑2430, 2018; DOI: 10.3892/mmr.2017.8116].

Platycodin D Ameliorates Type 2 Diabetes-Induced Myocardial Injury by Activating the AMPK Signaling Pathway.

The current study aimed to assess the effectiveness of pharmacological intervention with Platycodin D (PD), a critically active compound isolated from the roots of Platycodon grandiflorum, in mitigating cardiotoxicity in a murine model of type 2 diabetes-induced cardiac injury and in H9c2 cells in vitro. Following oral administration for 4 weeks, PD (2.5 mg/kg) significantly suppressed the elevation of fasting blood glucose (FBG) levels, improved dyslipidemia, and effectively inhibited the rise of the cardiac injury markers creatine kinase isoenzyme MB (CK-MB) and cardiac troponin T (cTnT). PD treatment could ameliorate energy metabolism disorders induced by impaired glucose uptake by activating AMPK protein expression in the DCM mouse model, thereby promoting the GLUT4 transporter and further activating autophagy-related proteins. Furthermore, in vitro experiments demonstrated that PD exerted a concentration-dependent increase in cell viability while also inhibiting palmitic acid and glucose (HG-PA)-stimulated H9c2 cytotoxicity and activating AMPK protein expression. Notably, the AMPK activator AICAR (1 mM) was observed to upregulate the expression of AMPK in H9c2 cells after high-glucose and -fat exposure. Meanwhile, we used AMPK inhibitor Compound C (20 μM) to investigate the effect of PD activation of AMPK on cells. In addition, the molecular docking approach was employed to dock PD with AMPK, revealing a binding energy of -8.2 kcal/mol and indicating a tight interaction between the components and the target. PD could reduce the expression of autophagy-related protein p62, reduce the accumulation of autophagy products, promote the flow of autophagy, and improve myocardial cell injury. In conclusion, it has been demonstrated that PD effectively inhibits cardiac injury-induced type 2 diabetes in mice and enhances energy metabolism in HG-PA-stimulated H9c2 cells by activating the AMPK signaling pathway. These findings collectively unveil the potential cardioprotective effects of PD via modulation of the AMPK signaling pathway.

Synthesis of amide derivatives containing the imidazole moiety and evaluation of their anti-cardiac fibrosis activity.

Three series of N-{[4-([1,2,4]triazolo[1,5-α]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl]methyl}acetamides (14a-d, 15a-n, and 16a-f) were synthesized and evaluated for activin receptor-like kinase 5 (ALK5) inhibitory activities in an enzymatic assay. The target compounds showed high ALK5 inhibitory activity and selectivity. The half maximal inhibitory concentration (IC50) for phosphorylation of ALK5 of 16f (9.1 nM), the most potent compound, was 2.7 times that of the clinical candidate EW-7197 (vactosertib) and 14 times that of the clinical candidate LY-2157299. The selectivity index of 16f against p38α mitogen-activated protein kinase was >109, which was much higher than that of positive controls (EW-7197: >41, and LY-2157299: 4). Furthermore, a molecular docking study provided the interaction modes between the target compounds and ALK5. Compounds 14c, 14d, and 16f effectively inhibited the protein expression of α-smooth muscle actin (α-SMA), collagen I, and tissue inhibitor of metalloproteinase 1 (TIMP-1)/matrix metalloproteinase 13 (MMP-13) in transforming growth factor-β-induced human umbilical vein endothelial cells. Compounds 14c and 16f showed especially high activity at low concentrations, which suggests that these compounds could inhibit myocardial cell fibrosis. Compounds 14c, 14d, and 16f are potential preclinical candidates for the treatment of cardiac fibrosis.

Effects of High-Dose Cyclophosphamide on Ultrastructural Changes and Gene Expression Profiles in the Cardiomyocytes of C57BL/6J Mice

The pathogenesis of cyclophosphamide (CY)-induced cardiotoxicity remains unknown, and methods for its prevention have not been established. To elucidate the acute structural changes that take place in myocardial cells and the pathways leading to myocardial damage under high-dose CY treatments, we performed detailed pathological analyses of myocardial tissue obtained from C57BL/6J mice subjected to a high-dose CY treatment. Additionally, we analysed the genome-wide cardiomyocyte expression profiles of mice subjected to the high-dose CY treatment. Treatment with CY (400 mg/kg/day intraperitoneally for two days) caused marked ultrastructural aberrations, as observed using electron microscopy, although these aberrations could not be observed using optical microscopy. The expansion of the transverse tubule and sarcoplasmic reticulum, turbulence in myocardial fibre travel, and a low contractile protein density were observed in cardiomyocytes. The high-dose CY treatment altered the cardiomyocyte expression of 1210 genes (with 675 genes upregulated and 535 genes downregulated) associated with cell–cell junctions, inflammatory responses, cardiomyopathy, and cardiac muscle function, as determined using microarray analysis (|Z-score| &gt; 2.0). The expression of functionally important genes related to myocardial contraction and the regulation of calcium ion levels was validated using real-time polymerase chain reaction analysis. The results of the gene expression profiling, functional annotation clustering, and Kyoto Encyclopedia of Genes and Genomes pathway functional-classification analysis suggest that CY-induced cardiotoxicity is associated with the disruption of the Ca2+ signalling pathway.