Salvianolic Acid B Improves Postresuscitation Myocardial and Cerebral Outcomes in a Murine Model of Cardiac Arrest: Involvement of Nrf2 Signaling Pathway.

Survival and outcome of cardiac arrest (CA) are dismal despite improvements in cardiopulmonary resuscitation (CPR). Salvianolic acid B (Sal B), extracted from Salvia miltiorrhiza, has been investigated for its cardioprotective properties in cardiac remodeling and ischemic heart disease, but less is known about its role in CA. The aim of this study was to learn whether Sal B improves cardiac and neurologic outcomes after CA/CPR in mice. Female C57BL/6 mice were subjected to eight minutes of CA induced by an intravenous injection of potassium chloride (KCl), followed by CPR. After 30 seconds of CPR, mice were blindly randomized to receive either Sal B (20 mg/kg) or vehicle (normal saline) intravenously. Hemodynamic variables and indices of left ventricular function were determined before CA and within three hours after CPR, the early postresuscitation period. Sal B administration resulted in a remarkable decrease in the time required for the return of spontaneous circulation (ROSC) in animals that successfully resuscitated compared to the vehicle-treated mice. Myocardial performance, including cardiac output and left ventricular systolic (dp/dtmax) and diastolic (dp/dtmin) function, was clearly ameliorated within three hours of ROSC in the Sal B-treated mice. Moreover, Sal B inhibited CA/CPR-induced cardiomyocyte apoptosis and preserved mitochondrial morphology and function. Mechanistically, Sal B dramatically promoted Nrf2 nuclear translocation through the downregulation of Keap1, which resulted in the expression of antioxidant enzymes, including HO-1 and NQO1, thereby counteracted the oxidative damage in response to CA/CPR. The aforementioned antiapoptotic and antioxidant effects of Sal B were impaired in the setting of gene silencing of Nrf2 with siRNA in vitro model. These improvements were associated with better neurological function and increased survival rate (75% vs. 40%, p < 0.05) up to 72 hours postresuscitation. Our findings suggest that the administration of Sal B improved cardiac function and neurological outcomes in a murine model of CA via activating the Nrf2 antioxidant signaling pathway, which may represent a novel therapeutic strategy for the treatment of CA.

Application of Feedback System Control Optimization Technique in Combined Use of Dual Antiplatelet Therapy and Herbal Medicines.

Aim: Combined use of herbal medicines in patients underwent dual antiplatelet therapy (DAPT) might cause bleeding or thrombosis because herbal medicines with anti-platelet activities may exhibit interactions with DAPT. In this study, we tried to use a feedback system control (FSC) optimization technique to optimize dose strategy and clarify possible interactions in combined use of DAPT and herbal medicines. Methods: Herbal medicines with reported anti-platelet activities were selected by searching related references in Pubmed. Experimental anti-platelet activities of representative compounds originated from these herbal medicines were investigated using in vitro assay, namely ADP-induced aggregation of rat platelet-rich-plasma. FSC scheme hybridized artificial intelligence calculation and bench experiments to iteratively optimize 4-drug combination and 2-drug combination from these drug candidates. Results: Totally 68 herbal medicines were reported to have anti-platelet activities. In the present study, 7 representative compounds from these herbal medicines were selected to study combinatorial drug optimization together with DAPT, i.e., aspirin and ticagrelor. FSC technique first down-selected 9 drug candidates to the most significant 5 drugs. Then, FSC further secured 4 drugs in the optimal combination, including aspirin, ticagrelor, ferulic acid from DangGui, and forskolin from MaoHouQiaoRuiHua. Finally, FSC quantitatively estimated the possible interactions between aspirin:ticagrelor, aspirin:ferulic acid, ticagrelor:forskolin, and ferulic acid:forskolin. The estimation was further verified by experimentally determined Combination Index (CI) values. Conclusion: Results of the present study suggested that FSC optimization technique could be used in optimization of anti-platelet drug combinations and might be helpful in designing personal anti-platelet therapy strategy. Furthermore, FSC analysis could also identify interactions between different drugs which might provide useful information for research of signal cascades in platelet.

Xuezhikang, an extract from red yeast rice, attenuates vulnerable plaque progression by suppressing endoplasmic reticulum stress-mediated apoptosis and inflammation.

Xuezhikang (XZK), an extract of red yeast rice, is a traditional Chinese medicine widely used for the treatment of cardiovascular diseases in China and other countries. However, whether XZK treatment can improve atherosclerotic plaque stability is not fully understood. Based on our previously developed mouse model of spontaneous vulnerable plaque formation and rupture in carotid arteries in ApoE-/- mice. We showed that low-dose (600 mg/kg/d) XZK improved plaque stability without decreasing plaque area, whereas high-dose (1200 mg/kg/d) XZK dramatically inhibited vulnerable plaque progression accompanied by decreased plaque area. Mechanistically, XZK significantly suppressed lesional endoplasmic reticulum (ER) stress in mouse carotid arteries. In vitro, XZK inhibited 7-KC-induced activation of ER stress in RAW264.7 macrophages, as assessed by the reduced levels of p-PERK, p-IRE1α, p-eIF2α, c-ATF6, s-XBP1, and CHOP. Compared to controls, the XZK-treated group displayed dramatically decreased apoptotic cell numbers (shown by decreased TUNEL- and cleaved caspase3-positive cells), lower necrotic core area and ratio, and reduced expression of NF-κB target gene. In RAW264.7 cells, XZK inhibited 7-KC-induced upregulation of apoptosis, protein expression of apoptotic markers (cleaved caspase-3 and cleaved PARP), and NF-κB activation (shown by target gene transcription and IκBα reduction). Collectively, our results suggest that XZK effectively suppresses vulnerable plaque progression and rupture by mitigating macrophage ER stress and consequently inhibiting apoptosis and the NF-κB pro-inflammatory pathway, thereby providing an alternative therapeutic strategy for stabilizing atherosclerotic plaques.

Electrophysiological features and catheter ablation of symptomatic frequent premature atrial contractions.

AIMS: Frequent premature atrial contractions (PACs) are associated with increased risk of atrial fibrillation (AF), stroke, and death. This study aimed to explore the electrophysiological features of PACs with and without inducing AF and to evaluate the effectiveness of catheter ablation for PACs. METHODS AND RESULTS: Thirty-five consecutive patients with symptomatic, frequent, and drug-refractory PACs in the absence of AF (group A) and 35 patients with PACs-induced AF (group B) were enrolled. Coupling intervals (CoIs) of PACs were compared. Premature atrial contractions were mapped by the point-by-point and/or circular mapping technique. Focal ablation or pulmonary vein/superior vena cava isolation was applied as appropriate. A total of 35 ectopic foci were identified in group A. The majority of them were at pulmonary vein (PV) (n = 7), crista terminalis (n = 6), and para-Hisian area (n = 6). In group B, ectopic foci were in left-sided PVs in 21 patients, in right-sided PVs in 13 patients, and in SVC in 1 patient. There was significant difference in CoIs of PACs triggering AF and those from PVs and non-PV areas but without causing AF (362.8 ± 23.0 ms vs. 470.6 ± 60.1 ms vs. 515.6 ± 77.2 ms, P< 0.001). Premature atrial contractions were abolished in 32 of 35 patients from group A and in all patients from group B. At the end of follow-up, 29 patients in group A and 28 patients in group B were free of recurrence (off antiarrhythmic drugs) after the initial ablation (P =0.97). CONCLUSIONS: Frequent PACs in the absence of AF were characterized as having their predilection sites and longer CoIs than those inducing AF. Catheter ablation was effective to eliminate symptomatic, frequent, and drug-refractory PACs.

Xuezhikang ameliorates contrast media-induced nephropathy in rats via suppression of oxidative stress, inflammatory responses and apoptosis.

BACKGROUND: The aim of this study was to assess the preventive effect of xuezhikang (XZK) to replace atorvastatin on the contrast media-induced acute kidney injury (CI-AKI). METHODS: The male Sprague-Dawley rats were divided into five groups: group 1 (sham), injected with normal saline; group 2 (XZK), treated with XZK; group 3 contrast media (CM), injected with CM; group 4 (CM + ATO), injected with CM + pretreatment with atorvastatin; group 5 (CM + XZK), injected with CM + pretreatment with XZK. Twenty-four hours after injection with normal saline or CM, the blood sample and the kidneys were collected for the measurement of biochemical parameters, oxidative stress markers, nitric oxide production, inflammatory parameters, as well as renal histopathology and apoptosis detection. RESULTS: Our results indicated that XZK restored the renal function by reducing serum blood urea nitrogen (BUN) and serum creatinine (Scr), depressing renal malondialdehyde (MDA), increasing renal NO production, decreasing TNF-ɑ and IL-6 expression, attenuating renal pathological changes and inhibiting the apoptosis of renal tubular cells. CONCLUSION: XZK's therapeutic effect is similar, or even better than atorvastatin at the same effectual dose in some parts.

YiXin-Shu, a ShengMai-San-based traditional Chinese medicine formula, attenuates myocardial ischemia/reperfusion injury by suppressing mitochondrial mediated apoptosis and upregulating liver-X-receptor α.

Positive evidence from clinical trials has fueled growing acceptance of traditional Chinese medicine (TCM) for the treatment of cardiac diseases; however, little is known about the underlying mechanisms. Here, we investigated the nature and underlying mechanisms of the effects of YiXin-Shu (YXS), an antioxidant-enriched TCM formula, on myocardial ischemia/reperfusion (MI/R) injury. YXS pretreatment significantly reduced infarct size and improved viable myocardium metabolism and cardiac function in hypercholesterolemic mice. Mechanistically, YXS attenuated myocardial apoptosis by inhibiting the mitochondrial mediated apoptosis pathway (as reflected by inhibition of mitochondrial swelling, cytochrome c release and caspase-9 activity, and normalization of Bcl-2 and Bax levels) without altering the death receptor and endoplasmic reticulum-stress death pathways. Moreover, YXS reduced oxidative/nitrative stress (as reflected by decreased superoxide and nitrotyrosine content and normalized pro- and anti-oxidant enzyme levels). Interestingly, YXS upregulated endogenous nuclear receptors including LXRα, PPARα, PPARß and ERα, and in-vivo knockdown of cardiac-specific LXRα significantly blunted the cardio-protective effects of YXS. Collectively, these data show that YXS is effective in mitigating MI/R injury by suppressing mitochondrial mediated apoptosis and oxidative stress and by upregulating LXRα, thereby providing a rationale for future clinical trials and clinical applications.

Cost-effectiveness of different strategies for stroke prevention in patients with atrial fibrillation in a health resource-limited setting.

PURPOSE: To compare the lifetime cost and effectiveness of five alternative chronic atrial fibrillation (AF) management strategies: rivaroxaban, warfarin, aspirin plus clopidogrel, aspirin and no prevention. METHODS: An individual-level state-transition model was developed to track the lifetime disease course associated with AF. The clinical and utility data were derived from published studies. The cost data were estimated based on local charges and current Chinese practices. Sensitivity analyses were used to explore the impact of uncertainty on the results. RESULTS: For base-case patients with a CHADS2 score of 3, the cost per additional quality-adjusted life-years (QALYs) gained for rivaroxaban compared with no prevention, aspirin, aspirin plus clopidogrel and warfarin was $116,884, $153,944, $155,979 and $216,273, respectively. CHADS2 score had a substantial impact on the model outcomes for different prevention strategies. The time distribution of warfarin international normalised ratio (INR), stroke and intracranial haemorrhage (ICH) risks, cost of rivaroxaban and utility of warfarin therapy had substantial impacts on the results. Based on a willingness-to-pay threshold of $16,350/QALY, no prevention strategy was the preferred therapy for a patient with a low risk for stroke and a high risk for ICH; aspirin was preferred for patients with a moderate risk for stroke and ICH; and warfarin was preferred for patients with a high risk for stroke and a low risk of ICH. CONCLUSION: In the context of limited health resources, rivaroxaban is unlikely to be cost-effective, although it provided more health benefits comparing with other strategies. Additionally, warfarin with good INR control might be more suitable for AF patients in developing regions.

Extraction, chemical analysis of Angelica sinensis polysaccharides and antioxidant activity of the polysaccharides in ischemia-reperfusion rats.

Angelica sinensis polysaccharides were analyzed using high performance liquid chromatography (HPLC) and Fourier Transform Infrared (FT-IR). The major sugar of the polysaccharide was saccharose (18.55%); and the sugar constituted about 83% of the monomer content. Glucose and fructose were found as minor components of the polysaccharides. The FT-IR spectra of A. sinensis polysaccharides are used for determination of their structural features. The FT-IR spectrum of A. sinensis polysaccharides showed bands at 1641 cm(-1), 1415 cm(-1), 1050 cm(-1) and 926 cm(-1) characteristic for the carboxylic group. Absorptions at 2920-2930 cm(-1) are attributed to asymmetrical stretching vibration of CH(2)-group. Medium stretch observed in the range 1650-1400 cm(-1) is assigned to C-C stretching of polysaccharides. Cardioprotective effects of A. sinensis polysaccharides were evaluated by using myocardial ischemia/reperfusion (IR) rats. A. sinensis polysaccharides treatment significantly reduced myocardial infarction size, enhanced CT-1 and antioxidant enzymes activity, downregulated caspase-12 mRNA expression in rats. The study strongly suggests the cardioprotective activity of A. sinensis polysaccharides in limiting ischemia-reperfusion induced myocardial injury.