Targeting delivery of miR-146a via IMTP modified milk exosomes exerted cardioprotective effects by inhibiting NF-κB signaling pathway after myocardial ischemia-reperfusion injury.

Reperfusion therapy is critical for saving heart muscle after myocardial infarction, but the process of restoring blood flow can itself exacerbate injury to the myocardium. This phenomenon is known as myocardial ischemia-reperfusion injury (MIRI), which includes oxidative stress, inflammation, and further cell death. microRNA-146a (miR-146a) is known to play a significant role in regulating the immune response and inflammation, and has been studied for its potential impact on the improvement of heart function after myocardial injury. However, the delivery of miR-146a to the heart in a specific and efficient manner remains a challenge as extracellular RNAs are unstable and rapidly degraded. Milk exosomes (MEs) have been proposed as ideal delivery platform for miRNA-based therapy as they can protect miRNAs from RNase degradation. In this study, the effects of miR-146a containing MEs (MEs-miR-146a) on improvement of cardiac function were examined in a rat model of MIRI. To enhance the targeting delivery of MEs-miR-146a to the site of myocardial injury, the ischemic myocardium-targeted peptide IMTP was modified onto the surfaces, and whether the modified MEs-miR-146a could exert a better therapeutic role was examined by echocardiography, myocardial injury indicators and the levels of inflammatory factors. Furthermore, the expressions of miR-146a mediated NF-κB signaling pathway-related proteins were detected by western blotting and qRT-PCR to further elucidate its mechanisms. MiR-146 mimics were successfully loaded into the MEs by electroporation at a square wave 1000 V voltage and 0.1 ms pulse duration. MEs-miR-146a can be up-taken by cardiomyocytes and protected the cells from oxygen glucose deprivation/reperfusion induced damage in vitro. Oral administration of MEs-miR-146a decreased myocardial tissue apoptosis and the expression of inflammatory factors and improved cardiac function after MIRI. The miR-146a level in myocardium tissues was significantly increased after the administration IMTP modified MEs-miR-146a, which was higher than that of the MEs-miR-146a group. In addition, intravenous injection of IMTP modified MEs-miR-146a enhanced the targeting to heart, improved cardiac function, reduced myocardial tissue apoptosis and suppressed inflammation after MIRI, which was more effective than the MEs-miR-146a treatment. Moreover, IMTP modified MEs-miR-146a reduced the protein levels of IRAK1, TRAF6 and p-p65. Therefore, IMTP modified MEs-miR-146a exerted their anti-inflammatory effect by inhibiting the IRAK1/TRAF6/NF-κB signaling pathway. Taken together, our findings suggested miR-146a containing MEs may be a promising strategy for the treatment of MIRI with better outcome after modification with ischemic myocardium-targeted peptide, which was expected to be applied in clinical practice in future.

Dihydrotanshinone I reduces H9c2 cell damage by regulating AKT and MAPK signaling pathways.

Cardiovascular disease is the deadliest disease in the world. Previous studies have shown that Dihydrotanshinone I (DHT) can improve cardiac function after myocardial injury. This study aimed to observe the protective effect and mechanism of DHT on H9c2 cells by establishing an oxygen-glucose deprivation/reoxygenation (OGD/R) injury model. By constructing OGD/R injury simulation of H9c2 cells in a myocardial injury model, the proliferation of H9c2 cells treated with DHT concentrations of 0.1 µmol/L were not affected at 24, 48, and 72 h. DHT can significantly reduce the apoptosis of H9c2 cells caused by OGD/R. Compared with the OGD/R group, DHT treatment significantly reduced the level of MDA and increased the level of SOD in cells. DHT treatment of cells can significantly reduce the levels of ROS and Superoxide in mitochondria in H9c2 cells caused by OGD/R and H2O2. DHT significantly reduced the phosphorylation levels of P38MAPK and ERK in H9c2 cells induced by OGD/R, and significantly increased the phosphorylation levels of AKT in H9c2 cells. DHT can significantly reduce the oxidative stress damage of H9c2 cells caused by H2O2 and OGD/R, thereby reducing the apoptosis of H9c2 cells. And this may be related to regulating the phosphorylation levels of AKT, ERK, and P38MAPK.

Screening and identification of effective components from modified Taohong Siwu decoction for protecting H9c2 cells from damage.

We found that modified Taohong Siwu decoction (MTHSWD) had cardioprotective effects after myocardial ischemia-reperfusion injury. This study was to screen the effective components of MTHSWD that have protective effects on H9c2 cell injury through H2O2 injury model. Fifty-three active components were screened by CCK8 assay to detect cell viability. The anti-oxidative stress ability was evaluated by detecting the levels of total superoxide dismutase (SOD) and malondialdehyde (MDA) in cells. The anti-apoptotic effect was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling (TUNEL). Finally, the phosphorylation levels of ERK, AKT, and P38MAPK were detected by WB (Western blot) to study the protective mechanism of effective monomers against H9c2 cell injury. Among the 53 active ingredients of MTHSWD, ginsenoside Rb3, levistilide A, ursolic acid, tanshinone I, danshensu, dihydrotanshinone I, and astragaloside I could significantly increase the viability of H9c2 cells. The results of SOD and MDA showed that ginsenoside Rb3, tanshinone I, danshensu, dihydrotanshinone I, and tanshinone IIA could significantly reduce the content of lipid peroxide in cells. TUNEL results showed that ginsenoside Rb3, tanshinone I, danshensu, dihydrotanshinone I, and tanshinone IIA reduced apoptosis to varying degrees. The tanshinone IIA, ginsenoside Rb3, dihydrotanshinone I, and tanshinone I reduced the phosphorylation levels of P38MAPK and ERK in H9c2 cells induced by H2O2, and the phosphorylation level of ERK was also significantly reduced by danshensu. At the same time, tanshinone IIA, ginsenoside Rb3, dihydrotanshinone I, tanshinone I, and danshensu significantly increased AKT phosphorylation level in H9c2 cells. In conclusion, the effective ingredients in MTHSWD provide basic basis and experimental reference for the prevention and treatment of cardiovascular diseases.

Effects and Mechanisms of Taohong Siwu Decoction on the Prevention and Treatment of Myocardial Injury.

Taohong Siwu decoction (THSWD) is one of the classic prescriptions for promoting blood circulation and removing blood stasis. With the continuous in-depth excavation in basic and clinical research, it has been found that THSWD has made greater progress in the prevention and treatment of cardiovascular diseases. Mechanisms of the current studies have shown that it could prevent and treat the myocardial injury by inhibiting inflammatory reaction, antioxidant stress, inhibiting platelet aggregation, prolonging clotting time, anti-fibrosis, reducing blood lipids, anti-atherosclerosis, improving hemorheology and vascular pathological changes, regulating related signal pathways and other mechanisms to prevent and treat the myocardial injury, so as to protect cardiomyocytes and improve cardiac function. Many clinical studies have shown that THSWD is effective in the prevention and treatment of cardiovascular diseases related to myocardial injuries, such as coronary heart disease angina pectoris (CHD-AP), and myocardial infarction. In clinical practice, it is often used by adding and subtracting prescriptions, the combination of compound prescriptions and combinations of chemicals and so on. However, there are some limitations and uncertainties in both basic and clinical research of prescriptions. According to the current research, although the molecular biological mechanism of various active ingredients needs to be further clarified, and the composition and dose of the drug have not been standardized and quantified, this study still has exploration for scientific research and clinical practice. Therefore, this review mainly discusses the basic mechanisms and clinical applications of THSWD in the prevention and treatment of the myocardial injury caused by CHD-AP and myocardial infarction. The authors hope to provide valuable ideas and references for researchers and clinicians.

Traditional Chinese Medicine Intervenes Ventricular Remodeling Following Acute Myocardial Infarction: Evidence From 40 Random Controlled Trials With 3,659 Subjects.

Objectives: We intend to conduct a meta-analysis on the systematic evaluation of traditional Chinese medicine (TCM) in the treatment of ventricular remodeling following acute myocardial infarction (AMI). Our findings may provide certain references for the clinical treatment of ventricular remodeling. Methods: A systematic literature search was conducted in PubMed, Web of Science, Cochrane Library, Embase, CNKI, Wanfang Data, CQVIP, and CBM before 20 July 2020. Data were analyzed using a random/fixed-effect model. Primary outcomes included the effectiveness and TCM syndrome score (TCMSS). Secondary outcomes included 1) echocardiography data, including the left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), left ventricular end-diastolic volume index (LVEDVi), left ventricular end-systolic volume index (LVESVi), left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), interventricular septum thickness (IVST), left ventricular posterior wall thickness (LVPWT), left ventricular ejection fraction (LVEF), E/A, stroke volume (SV), and wall motion score (WMS); 2) serum indicators, including the B-type natriuretic peptide (BNP) or N-terminal pro-B-type natriuretic peptide (NT-proBNP), and C-reactive protein (CRP) or high sensitivity CRP (hs-CRP); (3) major adverse cardiovascular events (MACE) and other adverse events Results: Forty RCTs involving 3,659 subjects were recruited. Our findings proved that a combination of TCM or TCM preparations with conventional Western medicine for preventing and reversing ventricular remodeling at post-AMI could remarkably enhance the total effectiveness and reduced TCMSS. Moreover, myocardial functions (LVEF, E/A, and SV), ventricular remodeling (LVEDVi, LVESVi, LVEDV, LVESV, LVEDD, LVESD, LVPWT, and WMS), serum levels of BNP and CRP, and MACE were significantly improved by the combination of TCM or TCM preparations with conventional Western medicine. Nevertheless, IVST and the incidence of other adverse events were comparable between control and experimental groups Conclusion: The combination of TCM or TCM preparations and conventional Western medicine can alleviate the process of ventricular remodeling, enhance cardiac function, and reduce the incidence of MACE in AMI patients.

Effect of Guanxin V in animal model of acute myocardial infarction.

BACKGROUND: Acute myocardial infarction (AMI) is the most serious and lethal manifestation of coronary heart disease worldwide, presenting extremely high disability and mortality. Our previous studies have shown that Guanxin V (GXV) could significantly improve the cardiac function and the blood flow dynamics, and reduce serum levels of inflammatory factors in AMI rats, thus triggering ventricular remodeling (VR) at post-AMI. METHODS: An in vivo AMI model was established in Syrian hamsters by performing the ligation of the left anterior descending coronary artery. Syrian hamsters were randomly divided into four groups, namely Sham operation group (n = 12), AMI group (n = 12), GXV group (GXV 6 g/Kg/d, n = 12), and Tranilast group (Tra 105 mg/Kg/d, n = 12). Drug intervention was conducted for consecutive 8 weeks. Relative biological indicators were measured in the 4th and 8th week, respectively. RESULTS: Cardiac functions were improved, and the infarcted size and heart weight index were limited in Syrian hamsters of GXV and Tra groups compared with those in AMI group. Furthermore, GXV was able to decrease the number of mast cells and chymase level in Syrian hamsters with AMI. Administration of GXV remarkably inactivated the renin-angiotension-aldosterone system, and alleviated myocardial fibrosis and cardiomyocyte apoptosis, thus slowing down VR at post-AMI. CONCLUSION: GXV slows down the process of VR at post-AMI by reducing chymase level and mast cells number, as well as inactivating the reninangiotension-aldosterone system..

Costunolide induces mitochondria-mediated apoptosis in human gastric adenocarcinoma BGC-823 cells.

BACKGROUND: Costunolide, a sesquiterpene lactone extracted from Radix Aucklandiae, has the activity against multiple cancers. However, the effect of costunolide on gastric cancer (GC) have remained to be ambiguous. In this study, we investigated the underlying mechanisms of apoptosis induced by costunolide in human gastric adenocarcinoma BGC-823 cells in vitro and in vivo. METHODS: The viability of BGC-823 cells was detected by MTT assay. The apoptosis and mitochondrial membrane potential (ΔΨm) of BGC-823 cells induced by costunolide were analyzed by flow cytometry. The inhibiton of costunolide on human gastric adenocarcinoma was estimated in xenografts in nude mice. Apoptosis related proteins and genes were detected by Western blot and Q-PCR. RESULTS: Costunolide inhibited the viability of BGC-823 cells in a time and concentration dependent manner. Costunolide induced the apoptosis and lowered the ΔΨm of BGC-823 cells significantly. Costunolide increased the expression of Bax, cleaved caspase 9, cleaved caspase 7, cleaved caspase 3 and cleaved poly ADP ribose polymerase (PARP) proteins and decreased the expression of Bcl-2, pro-caspase 9, pro-caspase 7, pro-caspase 3 and PARP proteins. Costunolide upregulated the expression of puma, Bak1 and Bax mRNA and downregulated the expression of Bcl-2 mRNA. In addition, we demonstrated that costunolide inhibited the growth and induced apoptosis of BGC-823 cells xenografted in athymic nude mice. Costunolide increased the expression of cleaved caspase 9, cleaved caspase 3 and Bax proteins and decreased the expression of Bcl-2 protein in xenografted tumor. Costunolide upregulated the expression of puma and Bax mRNA and decreased the expression of Bcl-2 mRNA in xenografted tumor. CONCLUSIONS: Collectively, our results suggested that costunolide induced mitochondria-mediated apoptosis in human gastric adenocarcinoma BGC-823 cells and could be the candidate drug against GC in clinical practice.

Intermolecular momentum transfer in poly(perfluorosulfonic acid) membrane hydrated by aqueous solution of methanol: A molecular dynamics simulation study.

Intermolecular momentum transfer in methanol-water mixture solvated poly(perfluoro-sulfonic acid) membrane is studied in terms of center of mass velocity cross-correlation functions between molecular mass centers in their first coordination shells based on molecular dynamics simulations. Moreover, the center of mass velocity cross-correlation functions are also decomposed into longitudinal and transversal contributions. The fastest momentum transfer is observed between hydronium cation and water molecule due to the strong hydrogen bond interaction. The center of mass velocity cross-correlation functions reach peak value in about 36 fs, corresponding to a single collision with a neighboring molecule. For the momentum transfer between the water molecule and methanol molecule, the peaking time is 70 fs or about twice of that between hydronium cation and water molecule. Oscillation of the center of mass velocity cross-correlation functions between hydronium cation and water molecule is also observed due to the cage effect in their equilibrium positions.

Evaluation of electroosmotic drag coefficient of water in hydrated sodium perfluorosulfonate electrolyte polymer.

The electroosmotic drag coefficient of water molecules in hydrated sodium perfluorosulfonate electrolyte polymer is evaluated on the basis of the velocity distribution functions of the sodium cations and water molecules with an electric field applied using molecular dynamics simulations. The simulation results indicate that both velocity distribution functions of water molecules and of sodium cations agree well with the classic Maxwellian velocity distribution functions when there is no electric field applied. If an electric field is applied, the distribution functions of velocity component in directions perpendicular to the applied electric field still agree with the Maxwellian velocity distribution functions but with different temperature parameters. In the direction of the applied electric field, the electric drag causes the velocity distribution function to deviate from the Maxwellian velocity distribution function; however, to obey the peak shifted Maxwellian distribution function. The peak shifting velocities coincide with the average transport velocities induced by the electric field, and could be applied to the evaluation of the electroosmotic drag coefficient of water. By evaluation of the transport velocities of water molecules in the first coordination shells of sodium cations, sulfonate anion groups, and in the bulk, it is clearly shown that the water molecules in the first coordination shell of sodium cations are the major contribution to the electroosmotic drag and momentum transfer from water molecules within the first coordination shell to the other water molecules also contributes to the electroosmotic drag.