Pharmacokinetics and molecular docking of the cardioprotective flavonoids in Dalbergia odorifera.

The purpose of this research was to investigate the cardioprotective effects and pharmacokinetics of Dalbergia odorifera flavonoids. The cardioprotective effects were detected by hematoxylin-eosin staining histopathological observations and the detection of myocardial enzymes by kits in serum, peroxidation and antioxidant levels and ATPase activities by kits in the homogenate supernatant, and antioxidant and apoptosis-related protein expression in heart tissue by immunohistochemistry. The pharmacokinetics parameters of the flavonoids in rat plasma were investigated by ultra-high-performance liquid chromatography coupled with tandem mass spectrometry. Molecular docking of the compounds absorbed by the blood with specific proteins was carried out. D. odorifera flavonoids significantly reduced the levels of creatinine kinase, alanine transaminase, nitric oxide, and Hydrogen peroxide, elevated the levels of glutathione, superoxide dismutase, and ATPase, significantly reduced the pathological degree of heart tissue and had obvious anti-myocardial ischemia efficacy. Nine out of the 17 flavonoids were detected in rat plasma. The peak concentration and the area under the plasma concentration-time curve values of 3'-O-methylviolanone and sativanone were significantly higher than those of other ingredients. The peak time of most flavonoids (except for Genistein and Pruneion) was lower than 2 h, while the half-life of elimination of the nine flavonoids ranged from 3.32 to 21.5 h. The molecular docking results showed that daidzein, dalbergin, formononetin, and genistein had the potential to bind to the target proteins. The results of the study provide an important basis for understanding the cardioprotective effects and clinical application of D. odorifera.

IGF Signaling in the Heart in Health and Disease.

One of the most vital processes of the body is the cardiovascular system's proper operation. Physiological processes in the heart are regulated by the balance of cardioprotective and pathological mechanisms. The insulin-like growth factor system (IGF system, IGF signaling pathway) plays a pivotal role in regulating growth and development of various cells and tissues. In myocardium, the IGF system provides cardioprotective effects as well as participates in pathological processes. This review summarizes recent data on the role of IGF signaling in cardioprotection and pathogenesis of various cardiovascular diseases, as well as analyzes severity of these effects in various scenarios.

[Discrimination of anti-tumor and cardioprotective effect quality markers from Aidi Injection based on "spider web" mode].

Chinese medicinal preparations play an equally important role in reducing toxicity and treating tumors. Few studies discriminate the quality markers(Q-markers) conferring different therapeutic effects of traditional Chinese medicine preparations. Therefore, we take Aidi Injection(AD) as an example to comprehensively identify the Q-markers of anti-tumor and cardioprotective effects based on the "spider web" mode. Firstly, based on the principle of measurability, the chemical components in the prescription were qualitatively analyzed, and then the components with high content and capable to be measured were quantitatively analyzed as measurable evaluation indexes. Based on the principle of stability, the effects of light and temperature on the content of each component of AD were investigated as indicators of stability. Based on the principle of compatibility, the compounds were classified according to the law of compatibility of sovereign, minister, assistant, and guide medicinal materials in the prescription. Based on the principle of efficacy, the anti-tumor and antiangiogenic activities of the Q-markers were evaluated, and their synergistic effects with doxorubicin(DOX) in inhibiting tumorigenesis and angiogenesis and lowering cardiotoxicity were evaluated as the evaluation indexes of effectiveness. The seven-dimensional spider web of "compatibility-content-stability-antitumor activity-synergistic anti-tumor activity with DOX-antiangiogenic activity-synergistic anti-angiogenic activity with DOX" and the four-dimensional spider web of "compatibility-content-stability-protective effects against DOX-induced myocardial toxicity" were established, on the basis of which the Q-markers of anti-tumor and cardioprotective effects of AD were comprehensively analyzed. The results showed that 12 components were selected as the Q-markers of AD, among which cantharidin, ginsenoside Re, ginsenoside Rb_1, astragaloside Ⅱ, cryptochlorogenic acid, and ginsenoside Rg_2 were the anti-tumor Q-markers of AD. Ginsenoside Rd, isofraxidin, syringin, eleutheroside E, calycosin-7-O-ß-D-glucoside, and azelaic acid were the cardioprotective Q-markers of AD. Taking into account both the anti-tumor and cardioprotective effects, these Q-markers could cover the four herbs constituting the prescription. The findings provides a scientific basis for the quality control of AD and an effective method for identifying comprehensive and reasonable Q-markers for the two effects of Chinese medicinal preparations.

Disturbance of suprachiasmatic nucleus function improves cardiac repair after myocardial infarction by IGF2-mediated macrophage transition.

Suprachiasmatic nucleus (SCN) in mammals functions as the master circadian pacemaker that coordinates temporal organization of physiological processes with the environmental light/dark cycles. But the causative links between SCN and cardiovascular diseases, specifically the reparative responses after myocardial infarction (MI), remain largely unknown. In this study we disrupted mouse SCN function to investigate the role of SCN in cardiac dysfunction post-MI. Bilateral ablation of the SCN (SCNx) was generated in mice by electrical lesion; myocardial infarction was induced via ligation of the mid-left anterior descending artery (LAD); cardiac function was assessed using echocardiography. We showed that SCN ablation significantly alleviated MI-induced cardiac dysfunction and cardiac fibrosis, and promoted angiogenesis. RNA sequencing revealed differentially expressed genes in the heart of SCNx mice from D0 to D3 post-MI, which were functionally associated with the inflammatory response and cytokine-cytokine receptor interaction. Notably, the expression levels of insulin-like growth factor 2 (Igf2) in the heart and serum IGF2 concentration were significantly elevated in SCNx mice on D3 post-MI. Stimulation of murine peritoneal macrophages in vitro with serum isolated from SCNx mice on D3 post-MI accelerated the transition of anti-inflammatory macrophages, while antibody-mediated neutralization of IGF2 receptor blocked the macrophage transition toward the anti-inflammatory phenotype in vitro as well as the corresponding cardioprotective effects observed in SCNx mice post-MI. In addition, disruption of mouse SCN function by exposure to a desynchronizing condition (constant light) caused similar protective effects accompanied by elevated IGF2 expression on D3 post-MI. Finally, mice deficient in the circadian core clock genes (Ckm-cre; Bmal1f/f mice or Per1/2 double knockout) did not lead to increased serum IGF2 concentration and showed no protective roles in post-MI, suggesting that the cardioprotective effect observed in this study was mediated particularly by the SCN itself, but not by self-sustained molecular clock. Together, we demonstrate that inhibition of SCN function promotes Igf2 expression, which leads to macrophage transition and improves cardiac repair post-MI.

Discovery of New D-Ring Modified Isosteviol Derivatives as Potent Cardioprotective Agents against Oxidative Stress-Trigged Damage.

Cardiovascular diseases (CVDs) are a major global health concern, and oxidative stress is known to play a central role in their pathogenesis. The identification of new agents capable of inhibiting oxidative stress presents a promising strategy for preventing and treating CVDs. Natural products and their derivatives offer a valuable source for drug discovery, and isosteviol, a readily available natural product, is known to exhibit cardioprotective effects. In this study, 22 new D-ring modified isosteviol derivatives were synthesized and evaluated for their cardioprotective effect in vivo using the zebrafish cardiomyopathy model. The findings revealed that derivative 4e exhibited the most potent cardioprotective effect, surpassing its parent compound isosteviol and the positive drug levosimendan. At 1 µM, derivative 4e significantly protected the cardiomyocytes from injury, while at 10 µM it effectively maintained normal heart phenotypes, preventing cardiac dysfunction in zebrafish. Further investigation demonstrated that 4e protected cardiomyocytes from oxidative stress-induced damage by inhibiting reactive oxygen species overaccumulation, activating superoxide dismutase 2 expression, and enhancing the endogenous antioxidant defense system. These results suggest that isosteviol derivatives, particularly 4e, have the potential to serve as a novel class of cardioprotective agents for the prevention and treatment of CVDs.

Alpha-Linolenic Acid and Cardiovascular Events: A Narrative Review.

Cardiovascular diseases (CVDs) represent the leading cause of global mortality with 1.7 million deaths a year. One of the alternative systems to drug therapy to minimize the risk of CVDs is represented by alpha-linolenic acid (ALA), an essential fatty acid of the omega-3 series, known for its cholesterol-lowering effect. The main purpose of this review is to analyze the effects of ALA and investigate the relevant omega-6/omega-3 ratio in order to maintain functionally beneficial effects. Concerning the lipid-lowering preventive effects, ALA may favorably affect the values of LDL-C and triglycerides in both adult and pediatric populations. Furthermore, ALA has shown protective effects against hypertension, contributing to balancing blood pressure through customary diet. According to the 2009 EFSA statement, dietary ALA may contribute to reducing the risk of CVDs, thanks to anti-hypertensive, anti-atherosclerotic and cardioprotective effects.

Gram-Scale Total Synthesis of TAB with Cardioprotective Activity and the Structure-Activity Relationship of Its Analogs.

Traditional Chinese medicine has been proven to be of great significance in cardioprotective effects. Clinopodium chinense (Lamiaceae) has unique advantages in the treatment and prevention of cardiovascular diseases. Tournefolic acid B (TAB) was proven to be a potent component against myocardial ischemia reperfusion injury (MIRI) from Clinopodium chinense (Lamiaceae). This article will attempt to establish a gram-scale synthesis method of TAB and discuss the structure-activity relationship of its analogs. The total synthesis of TAB was completed in 10 steps with an overall yield of 13%. In addition, analogs were synthesized, and their cardioprotective activity was evaluated on the hypoxia/reoxygenation of H9c2 cells. Amidation of the acid position is helpful to the activity, while methylation of phenolic hydroxyl groups greatly decreased the cardioprotective activity. The easily prepared azxepin analogs also showed cardioprotective activity. Most of the clogP values calculated by Molinspiration ranged from 2.5 to 5, which is in accordance with Lipinski's rule of 5. These findings represent a novel kind of cardioprotective agent that is worthy of further study.

Stimulation of adenosine A1 receptor prevents oxidative injury in H9c2 cardiomyoblasts: Role of Gßγ-mediated Akt and ERK1/2 signaling.

Oxidative stress causes cellular injury and damage in the heart primarily through apoptosis resulting in cardiac abnormalities such as heart failure and cardiomyopathy. During oxidative stress, stimulation of adenosine receptor (AR) has been shown to protect against oxidative damage due to their cytoprotective properties. However, the subtype specificity and signal transductions of adenosine A1 receptor (A1R) on cardiac protection during oxidative stress have remained elusive. In this study, we found that stimulation of A1Rs with N6-cyclopentyladenosine (CPA), a specific A1R agonist, attenuated the H2O2-induced intracellular and mitochondrial reactive oxygen species (ROS) production and apoptosis. In addition, A1R stimulation upregulated the synthesis of antioxidant enzymes (catalase and GPx-1), antiapoptotic proteins (Bcl-2 and Bcl-xL), and mitochondria-related markers (UCP2 and UCP3). Blockades of Gßγ subunit of heterotrimeric Gαi protein antagonized A1R-mediated antioxidant and antiapoptotic effects, confirming the potential role of Gßγ subunit-mediated A1R signaling. Additionally, cardioprotective effects of CPA mediated through PI3K/Akt- and ERK1/2-dependent signaling pathways. Thus, we propose that A1R represents a promising therapeutic target for prevention of oxidative injury in the heart.

Impact of sodium-glucose co-transporter inhibitors on cardiac autonomic function and mortality: no time to die.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to improve cardiovascular outcomes not only in patients with diabetes but also in those with heart failure, irrespective of diabetic status. However, the mechanisms underlying the cardioprotective effects of these newer anti-diabetic drugs remain to be fully elucidated. One exciting avenue that has been recently explored in both preclinical and clinical studies is the modulation of the cardiovascular autonomic nervous system. A reduction in sympathetic nervous system activity by SGLT2 inhibitors may potentially translate into a reduction in arrhythmic risk and sudden arrhythmic death, which may explain, at least partly, the cardioprotection shown in the cardiovascular outcome trials with different SGLT2 inhibitors. Although some of the data from the preclinical and clinical studies are promising, overall the findings can be contradictory. This highlights the need for more studies to address gaps in our knowledge of these novel drugs. The present review offers an in depth overview of the existing literature regarding the role of SGLT2 inhibitors in modulating cardiovascular autonomic function as one of the possible pathways of their cardioprotective effects.

Evaluating the cardioprotective effect of metformin on myocardial ischemia-reperfusion injury using dynamic 18F-FDG micro-PET/CT imaging.

BACKGROUND: The molecular mechanisms of protective effect of metformin (Met) on ischemic myocardium have not been fully understood. This study aims to evaluate the cardioprotective effect of metformin on myocardial ischemia-reperfusion injury (MIRI) in rat models at different time points using dynamic 18F-FDG micro-PET/CT imaging. METHODS: The I/R injury model in SD rats was established by ligation of left anterior descending coronary artery near the pulmonary arch root for 30 min. SD rats (n = 12) were randomly divided into 2 groups: Control group (n = 6) without any intervention and Met group (n = 6) with oral administration of metformin (50 mg/kg) twice a day. Gated 18F-FDG (40Mbq) micro-PET/CT imaging was performed for 10 min at different time points (day 1st, day 7th, day 14th and day 30th after operation). Volumes of interest were drawn to identify different myocardium regions (ischemia center, peri-ischemia area and remote area). Standardized uptake values (SUVs) (SUVmean and SUVmax) were analyzed to evaluate the FDG uptake activity, and then the center/remote ratio was calculated. In addition, the left ventricular (LV) end-diastolic volume (EDV), end-systolic volume (ESV) and LV ejection fraction (LVEF) were obtained. On the 30th day, all rats were scarified and myocardial ischemia was analyzed by HE staining and confirmed by pathology. RESULTS: In the Control group, the center/remote ratio showed no obvious change trend at each time point after reperfusion, while the LV EDV increased gradually over time, and they were significantly negatively correlated (r = - 0.507, p < 0.05). In the Met group, the center/remote ratio gradually increased with time, there was no significant correlation between center/remote ratio and LV EDV (r = - 0.078, p > 0.05). On the 30th day, the center/remote ratio of the Met group was significantly higher than that of the Control group (0.81 ± 0.06 vs. 0.65 ± 0.09, p < 0.05), while LV EDV in Met group was significantly lower than in Control group (358.21 ± 22.62 vs. 457.53 ± 29.91, p < 0.05). There was no significant difference of LVEF between Met group and Control group at different time points after reperfusion (p < 0.05). HE staining showed that the myocardial infarction and fibrosis in ischemic center area of the Control group was more serious than that of the Met group. CONCLUSIONS: Met could attenuate the severity of MIRI, delay and prevent the progress of LV remodeling. The cardioprotective progress could be dynamically assessed by 18F-FDG micro-PET/CT imaging.

Gi-protein-coupled ß 1-adrenergic receptor: re-understanding the selectivity of ß 1-adrenergic receptor to G protein.

ß 1-adrenergic receptor (ß 1-AR), a member in the family of G-protein-coupled receptors, is a transmembrane receptor of great significance in the heart. Physiologically, catecholamines activate ß 1-AR to initiate a positive chronotropic, inotropic, and dromotropic change. It is believed that ß 1-AR couples to Gs protein and transmits the signal through second messenger cAMP. However, increasing research shows that ß 1-AR can also bind with Gi protein in addition to Gs. When ß 1-AR-Gi is biasedly activated, cardioprotective effects are introduced by the activated cGMP-protein kinase G (PKG) pathway and the transactivation of epidermal growth factor receptor (EGFR) pathway. The discovery of ß 1-AR-Gi signaling makes us reconsider the selectivity of G protein with regard to ß 1-AR, which also provides new ideas for the treatment of heart diseases. This review summarizes the discovery of ß 1-AR-Gi pathway, including the evidence that supports ß 1-AR's capability to couple Gi, details of the transduction process and functions of the ß 1-AR-Gi signaling pathway.

Eremophilane and Cadinene Sesquiterpenes from Syringa oblata and Their Protective Effects against Hypoxia-Induced Injury on H9c2 Cells.

Seven sesquiterpenes including four eremophilanes (1-4) and three cadinenes (5-7), were isolated from the heartwood of Syringa oblata Lindl. Among them, three new eremophilane-type sesquiterpenes were identified and named oblatanoids A-C (1-3), respectively. Their structures were established by extensive analyses of spectroscopic methods, and their absolute configurations were determined by electronic circular dichroism (ECD) calculations. All these new compounds were evaluated for protective effects against hypoxia-induced injury on H9c2 cells, and 1-3 exhibited significantly protective activities toward H9c2 cells in vitro.

Guanxin V attenuates myocardial ischaemia reperfusion injury through regulating iron homeostasis.

CONTEXT: Guanxin V (GX), a traditional Chinese medicine formula, is safe and effective in the treatment of coronary artery disease. However, its protective effect on myocardial ischaemia reperfusion injury (MIRI) is unclear. OBJECTIVE: To investigate the cardioprotective effect of GX on MIRI and explore the potential mechanism. MATERIALS AND METHODS: Sprague-Dawley male rats were divided into Sham, MIRI and MIRI + GX groups. GX (6 g/kg) was administered to rats via intragastric administration for seven days before ischaemia reperfusion (IR) surgery. The infarct size, histopathology, serum enzyme activities, ultrastructure of the cardiac mitochondria were assessed. H9c2 cells were pre-treated with GX (0.5 mg/mL), and then exposed to hypoxia/reoxygenation (HR). The cell viability and LDH levels were measured. Network pharmacology was conducted to predict the potential mechanism. The related targets of GX were predicted using the TCMSP database, DrugBank database, etc. Finally, pharmacological experiments were used to validate the predicted results. RESULTS: In vivo, GX significantly reduced the myocardial infarct size from 56.33% to 17.18%, decreased the levels of AST (239.32 vs. 369.18 U/L), CK-MB (1324.61 vs. 2066.47 U/L) and LDH (1245.26 vs. 1969.62 U/L), and reduced mitochondrial damage. In vitro, GX significantly increased H9c2 cell viability (IC50 = 3.913 mg/mL) and inhibited the release of LDH (207.35 vs. 314.33). In addition, GX could maintain iron homeostasis and reduce oxidative stress level by regulating iron metabolism-associated proteins. CONCLUSIONS: GX can attenuate MIRI via regulating iron homeostasis, indicating that GX may act as a potential candidate for the treatment of MIRI.

The Elabela-APJ axis: a promising therapeutic target for heart failure.

Heart failure (HF) is a growing epidemic with high morbidity and mortality at an international scale. The apelin-APJ receptor pathway has been implicated in HF, making it a promising therapeutic target. APJ has been shown to be activated by a novel endogenous peptide ligand known as Elabela (ELA, also called Toddler or Apela), with a critical role in cardiac development and function. Activation of the ELA-APJ receptor axis exerts a wide range of physiological effects, including depressor response, positive inotropic action, diuresis, anti-inflammatory, anti-fibrotic, and anti-remodeling, leading to its cardiovascular protection. The ELA-APJ axis is essential for diverse biological processes and has been shown to regulate fluid homeostasis, myocardial contractility, vasodilation, angiogenesis, cellular differentiation, apoptosis, oxidative stress, cardiorenal fibrosis, and dysfunction. The beneficial effects of the ELA-APJ receptor system are well-established by treating hypertension, myocardial infarction, and HF. Additionally, administration of ELA protects human embryonic stem cells against apoptosis and stress-induced cell death and promotes survival and self-renewal in an APJ-independent manner (X receptor) via the phosphatidylinositol 3-kinase/Akt pathway, which may provide a new therapeutic approach for HF. Thus, targeting the ELA-APJ axis has emerged as a pre-warning biomarker and a novel therapeutic approach against progression of HF. An increased understanding of cardiovascular actions of ELA will help to develop effective interventions. This article gives an overview of the characteristics of the ELA-apelin-APJ axis and summarizes the current knowledge on its cardioprotective roles, potential mechanisms, and prospective application for acute and chronic HF.

Structurally diverse alkaloids from Buxus sempervirens with cardioprotective activity.

Extensive phytochemical study of the methanol extract of twigs and leaves of Buxus sempervirens resulted in the identification of 17 Buxus alkaloids, including 12 new ones, namely buxusemines A-L (1-12). Their structures were delineated by detailed analysis of the HRESIMS and NMR data, as well as quantum chemical NMR calculations. Buxusemine A (1) represents the second Buxus alkaloid with a unique spiro[4.6]undecatriene moiety, buxusemines B-C (2-3) are a rarely occurring class of Buxus alkaloids featured with an additional five-membered ring through the ether or lactone linkage between C-10 and C-23, and buxusemines D-F (4-6) are another rare type of Buxus alkaloids with an epoxy motif. In the assessment of their bioactivities, buxusemine F (6) and buxanoldine (17) displayed more potent protective effects than the positive control cyclovirobuxinum D in the doxorubicin-induced cardiac injury model.

[Heart failure protection by SGLT2 inhibitors in patients with type 2 diabetes mellitus: evidence and possible mechanisms : A systematic review]. / Herzinsuffizienzprotektion bei Patienten mit Diabetes mellitus Typ 2 durch SGLT2-Inhibitoren ­ Evidenzlage und mögliche Mechanismen : Systematische Übersicht.

BACKGROUND: Renal sodium-glucose cotransporter­2 (SGLT2) inhibitors seem to have a cardioprotective effect beyond the antidiabetic effect. The underlying mechanisms are unclear. METHODS: Selective search in PubMed with a focus on heart failure endpoints and possible mechanisms of action. RESULTS: During treatment with three of the substances analyzed, there were fewer hospitalizations for heart failure compared with placebo; however, the numbers needed to treat within the primary analyses were relatively high (72-117). We found that loss of weight and lowering of blood pressure were more pronounced during treatment with verum than with placebo and an association of the preventive effect with more severely impaired renal function. CONCLUSION: The SGLT2 inhibitors show a moderate heart failure protective effect in diabetic patients. It is likely that a nephroprotective effect with modulation of the cardiorenal interaction is an important part of the mechanism of action but this must be substantiated in further investigations.

Cardioprotective effect of isorhamnetin against myocardial ischemia reperfusion (I/R) injury in isolated rat heart through attenuation of apoptosis.

In this study, we investigated the effects of isorhamnetin on myocardial ischaemia reperfusion (I/R) injury in Langendorff-perfused rat hearts. Isorhamnetin treatment (5, 10 and 20 µg/mL) significantly alleviated cardiac morphological injury, reduced myocardial infarct size, decreased the levels of marker enzymes (LDH and CK) and improved the haemodynamic parameters, reflected by the elevated levels of the left ventricular developed pressure (LVDP), coronary flow (CF) and the maximum up/down velocity of left ventricular pressure (+dp/dtmax ). Moreover, isorhamnetin reperfusion inhibited apoptosis of cardiomyocytes in the rats subjected to cardiac I/R in a dose-dependent manner concomitant with decreased protein expression of Bax and cleaved-caspase-3, as well as increased protein expression of Bcl-2. In addition, I/R-induced oxidative stress was manifestly mitigated by isorhamnetin treatment, as showed by the decreased malondialdehyde (MDA) level and increased antioxidant enzymes activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px). These results indicated that isorhamnetin exerts a protective effect against I/R-induced myocardial injury through the attenuation of apoptosis and oxidative stress.

Exploring the protective effects of schizandrol A in acute myocardial ischemia mice by comprehensive metabolomics profiling integrated with molecular mechanism studies.

Schizandrol A (SA) is an bioactive component isolated from the Schisandra chinensis (Turcz.) Baill., which has been used as a remedy to prevent oxidative injury. However, whether the cardioprotective effect of SA is associated with regulating endogenous metabolites remains unclear, thus we performed comprehensive metabolomics profiling in acute myocardial ischemia (AMI) mice following SA treatment. AMI was induced in ICR mice by coronary artery ligation, then SA (6 mg·kg-1·d-1, ip) was administered. SA treatment significantly decreased the infarct size, preserved the cardiac function, and improved the biochemical indicators and cardiac pathological alterations. Moreover, SA (10, 100 M) significantly decreased the apoptotic index in OGD-treated H8c2 cardiomycytes in vitro. By using HPLC-Q-TOF/MS, we conducted metabonomics analysis to screen the significantly changed endogenous metabolites and construct the network in both serum and urine. The results revealed that SA regulated the pathways of glycine, serine and threonine metabolism, lysine biosynthesis, pyrimidine metabolism, arginine and proline metabolism, cysteine and methionine metabolism, valine, leucine and isoleucine biosynthesis under the pathological conditions of AMI. Furthermore, we selected the regulatory enzymes related to heart disease, including ecto-5'-nucleotidase (NT5E), guanidinoacetate N-methyltransferase (GAMT), platelet-derived endothelial cell growth factor (PD-ECGF) and methionine synthase (MTR), for validation. In addition, SA was found to facilitate PI3K/Akt activation and inhibit the expression of NOX2 in AMI mice and OGD-treated H9c2 cells. In conclusion, we have elucidated SA-regulated endogenous metabolic pathways and constructed a regulatory metabolic network map. Furthermore, we have validated the new potential therapeutic targets and underlying molecular mechanisms of SA against AMI, which might provide a reference for its future application in cardiovascular diseases.

Stimulus-Responsive Anti-Oxidizing Drug Crystals and their Ecological Implication.

Various antioxidants are being used to neutralize the harmful effects of reactive oxygen species (ROS) overproduced in diseased tissues and contaminated environments. Polymer-directed crystallization of antioxidants has attracted attention as a way to control drug efficacy through molecular dissolution. However, most recrystallized antioxidants undertake continuous dissolution independent of the ROS level, thus causing side-effects. This study demonstrates a unique method to assemble antioxidant crystals that modulate their dissolution rate in response to the ROS level. We hypothesized that antioxidants recrystallized using a ROS-labile polymer would be triggered to dissolve when the ROS level increases. We examined this hypothesis by using catechin as a model antioxidant. Catechin was recrystallized using polyethylenimine cross-linked with ROS-labile diselanediylbis-(ethane-2,1-diyl)-diacrylate. Catechin crystallized with the ROS-labile polymer displays accelerated dissolution proportional to the H2 O2 concentration. The ROS-responsive catechin crystals protect vascular cells from oxidative insults by activating intracellular glutathione peroxidase expression and, in turn, inhibiting an increase in the intracellular oxidative stress. In addition, ROS-responsive catechin crystals alleviate changes in the heart rate of Daphnia magna in oxidative media. We propose that the results of this study would be broadly useful for improving the therapeutic efficacy of a broad array of drug compounds.

Protective effect of ghrelin against tilmicosin-induced left ventricular dysfunction in rats.

This study was conducted to investigate the possible protective effects of ghrelin against tilmicosin-induced acute ventricular dysfunction in rats. Forty adult male Sprague Dawley rats were randomly divided into 4 equal groups: control, ghrelin, tilmicosin, and ghrelin + tilmicosin. The left ventricular structural and functional parameters together with cardiac biomarker levels were evaluated. The results showed that tilmicosin treatment alone significantly decreased the left ventricular fractional shortening, left ventricular ejection fraction, left ventricular stroke volume, and cardiac output when compared with control group. In addition, tilmicosin led to a significant increase in left ventricular internal dimension in systole and left ventricular fractional end-systolic volume. At the same time, serum lactate dehydrogenase, creatine kinase, and creatine kinase-myocardial B fraction levels were significantly increased in tilmicosin-treated group when compared with control group. However, ghrelin pretreatment significantly prevented the left ventricular internal dimension in systole, left ventricular fractional end-systolic volume, left ventricular stroke volume, left ventricular ejection fraction, left ventricular fractional shortening, and cardiac output changes caused by tilmicosin. Moreover, ghrelin pretreatment could reduce significantly serum lactate dehydrogenase, creatine kinase, and creatine kinase-myocardial B fraction levels. These data indicated that ghrelin treatment may provide a protective effect against tilmicosin-induced left ventricular systolic dysfunction.