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The aim of the study was to develop a model of coronary microembolization (CME) in rats at a lower cost. We developed a novel rat model without thoracotomy and ventilation under the guidance of echocardiography. Rats were sacrificed at 3 h, 24 h and 1 month postoperatively in both the Echo-CME and Open-chest CME groups for the comparison of the modeling accuracy, mortality, cardiopulmonary circulation, pleural adhesion and ventilation-induced lung injury (VILI). Results showed that the coronary microthrombus formed at 3 h and reached its peak at 24 h postoperatively, which included platelet aggregation and fibrin web. The Echo-group increases success rates, decreased mortality, postoperative complications including pleural adhesion, cardiopulmonary dysfunction and VILI postoperatively than the Open-chest group at 1month postoperatively. The ejection fraction of the CME group decreased to 50% and obvious cardiac fibrosis formed at 3 months postoperatively. Our unique surgical method provided a platform to study molecular mechanisms and potential new pathways for CME treatment.

Background: The coronary microvascular dysfunction has attracted more and more attention in recent years, but there is still a lack of effective treatment. Shexiang Baoxin Pill is one of the commonly used drugs for the treatment of coronary artery disease in China. More recently, some studies found that it has the effect of improving coronary microvascular function.Objective: To evaluate the effects of Shexiang Baoxin Pill for coronary microvascular function.Methods: Databases including MEDLINE, Web of Science, CNKI, Wanfang, The Cochrane Library, EMbase, VIP and CBM were searched from inception to June 2021 to screen out relevant clinical studies. The 2019 version 2 of the Cochrane risk of bias tool (RoB2) were used to assess the methodological quality of the included studies. RevMan 5.3 software was used for meta-analysis.Results: Eleven studies meeting the criteria were included, with a total of 1,075 patients. The results of meta-analysis showed that compared with conventional treatment alone, combination of Shexiang Baoxin Pill and conventional treatment can further increase the coronary flow reserve (CFR) [mean difference (MD) = 0.43, 95%CI (0.28, 0.58), p < 0.000 01], decrease the index of microvascular resistance (IMR) [MD = −4.23, 95%CI (−5.49, −2.97), p < 0.000 01], increase serum nitric oxide (NO) [MD = 11.96, 95%CI (2.74, 21.18), p = 0.001] and decrease serum hypersensitive C-reactive protein (hs-CRP) [MD = −2.49, 95%CI (−3.08, −1.90), p < 0.000 01], but did not increase the time of duration on the exercise testing (TET) [MD = 3.64, 95%CI (−1.17, 8.45), p = 0.14]. In terms of safety, a total of 10 patients developed adverse reactions in the intervention group and 17 patients developed adverse reactions in the control group.Conclusion: Current evidence suggests that Shexiang Baoxin Pill may be effective in the improvement of coronary microvascular function when used in combination with conventional treatment. However, due to the low quality of the included studies, lack of placebo control and high heterogeneity among different studies, we should take a cautious attitude towards this conclusion. Moreover, the safety of Shexiang Baoxin Pill remains uncertain, more high-quality clinical studies are needed to verify the efficacy and safety of this drug in the future.Systematic Review Registration: [website], identifier [registration number: CRD42021265113].

Ferroptosis is a form of cell death induced by excess iron and accumulation of reactive oxygen species in cells. Recently, ferroptosis has been reported to be associated with cancer and ischemia/reperfusion (I/R) injury in multiple organs. However, the regulatory effects and underlying mechanisms of myocardial I/R injury are not well-understood. The role of miR-135b-3p as an oncogene that accelerates tumor development has been confirmed; however, its role in myocardial I/R is not fully understood. In this study, we established an in vivo myocardial I/R rat model and an in vitro hypoxia/reoxygenation (H/R)-induced H9C2 cardiomyocyte injury model and observed that ferroptosis occurred in tissues and cells during I/R myocardial injury. We used database analysis to find miR-135b-3p and validated its inhibitory effect on the ferroptosis-related gene glutathione peroxidase 4 (Gpx4), using a luciferase reporter assay. Furthermore, miR-135b-3p was found to promote the myocardial I/R injury by downregulating GPX4 expression. The results of this study elucidate a novel function of miR-135b-3p in exacerbating cardiomyocyte ferroptosis, providing a new therapeutic target for improving I/R injury.

Background: The number of heart failure with preserved ejection fraction (HFpEF) patients is increasing year by year, yet all western medicines currently used for heart failure have been shown to be ineffective for HFpEF. Qishen Yiqi Dripping Pill is one of the commonly drugs for the treatment of heart failure in China. In recent years, some clinical studies found that it has curative effect on HFpEF.Objective: To evaluate the efficacy and safety of Qishen Yiqi Dripping Pill in treatment of HFpEF.Methods: Databases including CNKI, Wanfang, VIP, CBM, PubMed, Web of Science, The Cochrane Library and EMbase were searched from their inception to May 2020 to screen relevant randomized controlled trials. The “risk of bias” evaluation tool in the Cochrane Handbook was used to evaluate the quality of the included studies. RevMan 5.3 software was used for meta-analysis.Results: Eight studies meeting the criteria were included, with a total of 895 patients. The results of meta-analysis showed that compared with western medicine alone, combination of western medicine and Qishen Yiqi Dripping Pill can further increase the quotient of early diastolic mitral inflow velocity and late diastolic mitral inflow velocity (E/A) in patients with HFpEF [mean difference (MD) = 0.20, 95% CI (0.14, 0.26), p < 0.000 01], decrease the quotient of early diastolic mitral inflow velocity and mitral annular tissue velocity (E/e′) [MD = −2.50, 95% CI (−3.18, −1.82), p < 0.000 01], decrease brain natriuretic peptide (BNP) [MD = −151.83, 95% CI (−245.78, −57.89), p = 0.002], increase cardiac function improvement rate [relative risk (RR) = 1.30, 95% CI (1.11, 1.52), p = 0.001], and increase six-minutes walking distance (6-MWD) [MD = 64.75, 95% CI (22.65, 106.85), p = 0.003]. Four studies reported the occurrence of adverse reactions, among which three studies reported no adverse reactions and one study reported three patients with mild adverse reactions in the intervention group.Conclusion: Current evidence suggests that Qishen Yiqi Dripping Pill may be effective in the treatment of HFpEF. However, due to the low quality of the included studies, lack of placebo control, large heterogeneity among different studies, and great possibility of publication bias, the results of our review should be evaluated with more prudence, more high-quality clinical studies are needed to verify the conclusion in the future. In addition, the safety of Qishen Yiqi Dripping Pill remains uncertain, further assessment is required in the future.

Background The inflammatory state of diabetes promotes high platelet response and endothelial adhesion, which are the main risk factors for cardiovascular events. Tetramethylpyrazine (TMP) is an amide alkaloid isolated from the traditional Chinese medicine Rhizoma Ligustici Chuanxiong, which has been widely used in the clinical treatment of ischemic cardiovascular disease. Purpose This study aimed to investigate whether TMP could alleviate diabetes-induced high platelet response and endothelial adhesion and the underlying mechanisms. Methods Type 2 diabetes mellitus (T2DM) rat model was established by high-fat feeding combined with low dose of streptozotocin. Rats in the TMP treatment group were administered with TMP (100 or 200 mg/kg) for 21 days. Cultured human umbilical vein endothelial cells (HUVECs) were stimulated with glucose (5.5 mM) to induce endothelial activation. The NOD-like receptor protein 3 (NLRP3) over- and low-expressing cell models were established via transfection of NLRP3 lentivirus plasmid into HUVECs. INF39 (25 mg/kg), a chemical inhibitor of NLRP3 inflammasome, was used to explore the role of NLRP3 in T2DM associated high platelet response and endothelial adhesion. Results TMP effectively improved the prothrombotic phenotypes and inhibited the expression of vascular inflammatory factors and adhesion molecules in T2DM rats. TMP inhibited NLRP3 inflammasome and reduced the adhesion of HUVECs to platelets and monocytes in vitro. Over-expression of NLRP3 blocked the effect of TMP on HUVECs activation and adhesion, while TMP had no effect on NLRP3 low-expressing HUVECs. The NLRP3 inhibitor INF39 produced similar effects of TMP on diabetes-induced high platelet response, endothelial adhesion and vascular inflammation. Conclusion TMP ameliorates diabetes-induced high platelet response and endothelial adhesion via inhibiting NLRP3 inflammasome activation in T2DM rats, which provide a new basis for the clinical prevention and treatment of diabetes-associated cardiovascular events.

Chongli Xu,1,2 Caihong Liang,2 Weixin Sun,3 Jiandong Chen,3 Xiaohu Chen3 1Nanjing University of Chinese Medicine, Nanjing 210029, People’s Republic of China; 2Jiangnin Hospital of Nanjing, Nanjing 211100, People’s Republic of China; 3Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, People’s Republic of China Background: Glycyrrhizic acid (GA), a bioactive triterpenoid saponin isolated from the roots of licorice plants (Glycyrrhiza glabra), has been shown to exert a variety of pharmacological activities and is considered to have potential therapeutic applications. The purpose of the present study was to investigate the cardioprotective effect of GA on myocardial ischemia (MI) injury rats induced by isoproterenol (ISO), and explore the potential mechanisms underlying these effects. Materials and methods: The rats were randomized into five groups: control, ISO, ISO+diltiazem (10 mg/kg), ISO+GA (10 mg/kg), and ISO+GA (20 mg/kg). Electrocardiogram and histopathological examination were performed. Markers of cardiac marker enzymes (creatine kinase-MB, lactate dehydrogenase), oxidative stress (superoxide dismutase, malondialdehyde [MDA]), and inflammation (TNF-α, IL-1β, and IL-6) were also measured in each group. Proteins involved in NF-κB and Nrf-2/HO-1 pathway were detected by Western blot. Results: GA decreased the ST elevation induced by MI, decreased serum levels of creatine kinase, lactate dehydrogenase, malondialdehyde, IL-6, IL-1β, and TNF-α, and increased serum superoxide dismutase and malondialdehyde activities. Furthermore, GA increased the protein levels of Nrf-2 and HO-1 and downregulated the phosphorylation of IκB, and NF-κB p65 in ISO-induced MI. Conclusion: These observations indicated that GA has cardioprotective effects against MI, and these effects might be related to the activation of Nrf-2/HO-1 and inhibition of NF-κB signaling pathway in the myocardium. Keywords: glycyrrhizic acid, myocardial ischemia, Nrf-2/HO-1, oxidative stress, inflammation

Aims and methods Acute myocardial infarction (AMI) is a common cardiovascular disease with high mortality. Astragaloside IV (AS-IV) was reported to have cardioprotective effect after AMI. We hypothesize that the cardioprotective role of AS-IV is exerted by enhancing angiogenesis via regulating PTEN/PI3K/Akt signaling pathway. To valid our hypothesis, AMI rats and human umbilical vein endothelial cells (HUVECs) were employed in our study. Key findings After treatment, cardiac function, survival rate, infarct size, pathological changes and fibrosis, cell apoptosis, ultrastructural changes, angiogenesis and expression of PTEN/PI3K/Akt signaling pathway were evaluated, respectively. In vitro study we detected proliferation, tube formation and signaling pathway activation of HUVECs treated with AS-IV, lentivirus overexpressed PTEN was employed to elucidate the potential mechanism. The results indicated that AS-IV administration significantly improved cardiac function and survival rate, limited infarct size, ameliorated pathological changes and fibrosis deposition, inhibited apoptosis, relieved ultrastructure injury and enhanced angiogenesis, PTEN/PI3K/Akt signaling pathway was activated simultaneously compared to the model group. In vitro study suggested that AS-IV treatment promoted cell proliferation and tube formation, and induced PTEN/PI3K/Akt signaling pathway activation. Importantly, overexpression of PTEN by lentivirus abolished AS-IV-induced angiogenesis. Significance Our study indicated that AS-IV could promote angiogenesis and cardioprotection after myocardial infarction. The mechanisms involve activation of PTEN/PI3K/Akt signaling pathway.

High on-aspirin platelet reactivity (HAPR) has been associated with compromised aspirin efficacy in patients with diabetes suffering from acute cardiovascular events, but the key mechanisms remain elusive. The objective of this study was to uncover the potential link between pathogenic accumulation of salicylic acid (SA), the major metabolite of aspirin, and HAPR in diabetic state. Aspirin failed to inhibit platelet CD62P expression and thromboxane (TX) B2/6-keto-prostaglandin（PG）F1α ratio in a type 2 diabetes mellitus (T2DM) mice model, particularly in the female, which were unanimously accompanied by significantly higher plasma SA concentrations. Pre-administration with SA increased both platelet CD62P expression and TXB2/6-keto-PGF1α ratio in female T2DM mice, while pretreatment with NaHCO3 caused the opposite effect. On the in vitro human umbilical vein endothelial cells (HUVECs)-platelet interaction assay, SA suppressed inflammation-induced cyclooxygenase-2 upregulation on HUVECs and attenuated their inhibitory effect on platelet aggregation in a dose-dependent manner. The prolonged retention of SA in diabetes may be partially explained by the downregulation of various SA efflux transporters in the kidney and the decreased urine pH. Importantly, in female aspirin non-responsive patients, the trough plasma concentration of SA are markedly increased with T2DM treated with long-term aspirin, and TXB2/6-keto-PGF1α ratio and uric acid level in plasma are positively correlated with SA concentration. Our findings support that the accumulation of SA represents an important factor in causing HAPR in diabetes, and that targeting impaired SA excretion may become a novel intervention strategy to diabetes-associated HAPR.

Migraine is a primary headache disorder characterized by recurrent attacks of throbbing pain associated with neurological, gastrointestinal and autonomic symptoms. Previous studies have detected structural deficits and functional impairments in migraine patients. However, researchers have failed to investigate the functional connectivity alterations of regions with structural deficits during the resting state. Twenty-one migraine patients without aura and 21 age-and gender-matched healthy controls participated in our study. Voxel-based morphometric (VBM) analysis and functional connectivity were employed to investigate the abnormal structural and resting-state properties, respectively, in migraine patients without aura. Relative to healthy comparison subjects, migraine patients showed significantly decreased gray matter volume in five brain regions: the left medial prefrontal cortex (MPFC), dorsal anterior cingulate cortex (dACC), right occipital lobe, cerebellum and brainstem. The gray matter volume of the dACC was correlated with the duration of disease in migraine patients, and thus we chose this region as the seeding area for resting-state analysis. We found that migraine patients showed increased functional connectivity between several regions and the left dACC, i.e. the bilateral middle temporal lobe, orbitofrontal cortex (OFC) and left dorsolateral prefrontal cortex (DLPFC). Furthermore, the functional connectivity between the dACC and two regions (i.e. DLPFC and OFC) was correlated with the duration of disease in migraine patients. We suggest that frequent nociceptive input has modified the structural and functional patterns of the frontal cortex, and these changes may explain the functional impairments in migraine patients. Copyright (C) 2012 John Wiley & Sons, Ltd.

Photoplethysmography (PPG) is an optical method for detecting blood volume changes in tissue. Respiratory-induced intensity, frequency and amplitude variations are contained in the PPG signal; thus, an understanding of the relationships between all of these variations and respiration is essential to advancing respiration monitoring based on PPG. This study investigated correlations between respiratory-induced variations extracted from PPG and simultaneous respiratory signals. PPG signals were recorded from 28 healthy subjects under eight different conditions. Six respiratory-induced variations, i.e. the period of the systole, diastole and pulse, the amplitude of the systole and diastole, and the intensity variation, were determined from the PPG signal. The results indicate that, compared with the period of the pulse, the period of the systole and diastole correlates weakly with respiration; the amplitude of the diastole has a stronger correlation with respiration than the amplitude of the systole. For men, when the respiratory rate is less than 10 breaths min(-1), the period of the pulse has the strongest correlation with respiration, whereas up to or above 15 breaths min(-1), the intensity variation becomes strongest in the sitting posture, while the amplitude of the diastole is strongest in the supine posture. For women, compared with the other variations, the period of the pulse has nearly the strongest correlation with respiration, independent of respiratory rate or posture.