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BackgroundChronic coronary syndromes (CCS) is a common clinical condition that increases the risk of cardiovascular events at any time. Tongxinluo capsules (TXL) are widely used in China for treating CCS.ObjectivesTo systematically evaluate the therapeutic effects and safety of adding TXL to Western medical treatment (WM) for CCS.MethodsWe searched PubMed, Cochrane Library, CNKI, VIP, and Wanfang databases up to August 2024 for randomized controlled trials (RCTs) investigating the therapeutic effects and safety of combining TXL with WM compared to WM alone for CCS. Data analyses were conducted using RevMan 5.4 software.ResultsTwenty studies involving 2091 participants were identified. Evidence supports the use of TXL plus WM for reducing angina frequency [SMD −2.50, 95% CI (−3.53, −1.48)], improving seattle angina questionnaire scores (P

Objective: To investigate the effects of Tongxinluo (TXL) on thromboangiitis obliterans (TAO) and the underlying mechanisms. Methods: Ninety male C57/BL6J mice were randomly divided into 6 groups according to a random number table: the sham group, TAO model group, Compound Danshen Tablet (CDT) group, and the high-, medium-, and low-dose TXL groups. All mice except the sham group were injected with sodium laurate (0.1 mL, 5 mg/mL) in the femoral artery to establish TAO mouse model. After modeling, mice in the sham and TAO model groups were intragastrically administered 0.5% (w/v) sodium carboxymethylcellulose, mice in the CDT group were intragastrically administered 0.52 g/kg CDT, and mice in the TXL-H, TXL-M, and TXL-L groups were intragastrically administered 1.5, 0.75, and 0.38 g/kg TXL, respectively. After 4 weeks of gavage, the recovery of blood flow in the lower limbs of mice was detected by Laser Doppler Imaging. The pathological changes and thrombosis of the femoral artery were observed by morphological examination. The expressions of tumor necrosis factor α (TNF-α) and inducible nitric oxide synthase (iNOS) in the femoral artery wall were detected by HE staining. Levels of thromboxane B2 (TXB2), 6-keto-prostaglandin F1α (6-keto-PGF1α), endothelin-1 (ET-1), interleukin (IL)-1β and IL-6 were measured using enzyme-linked immunosorbent assay (ELISA). Levels of activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT) and fibrinogen (FIB) were detected by a fully automated biochemical analyzer. Results: TXL promoted the restoration of blood flow in the lower limbs, reduced the area of thrombosis in the femoral artery, and alleviated the pathological changes in the femoral artery wall. Moreover, the levels of TXB2, ET-1, IL-6, IL-1β, TNF-α and iNOS were significantly lower in the TXL groups compared with the model group (P<0.05 or P<0.01), while the level of 6-keto-PGF1α was significantly higher (P<0.01). In addition, APTT, PT, and TT were significantly prolonged in TXL groups compared with the model group (P<0.05 or P<0.01), and FIB levels were significantly decreased compared with the model group (P<0.01). Conclusions: TXL had a protective effect on TAO mice, and the mechanism may involve inhibition of thrombosis and inflammatory responses. TXL may be a potential drug for the treatment of TAO. [ABSTRACT FROM AUTHOR]

Abstract Background Bone marrow cells (BMCs), especially mesenchymal stem cells (MSCs), have shown attractive application prospects in acute myocardial infarction (AMI). However, the weak efficacy becomes their main limitation in clinical translation. Based on the anti-inflammation and anti-apoptosis effects of a Chinese medicine-Tongxinluo (TXL), we aimed to explore the effects of TXL-pretreated MSCs (MSCsTXL) in enhancing cardiac repair and further investigated the underlying mechanism. Methods MSCsTXL or MSCs and the derived exosomes (MSCsTXL-exo or MSCs-exo) were collected and injected into the infarct zone of rat hearts. In vivo, the anti-apoptotic and anti-inflammation effects, and cardiac functional and histological recovery were evaluated. In vitro, the apoptosis was evaluated by western blotting and flow cytometry. miRNA sequencing was utilized to identify the significant differentially expressed miRNAs between MSCsTXL-exo and MSCs-exo, and the miRNA mimics and inhibitors were applied to explore the specific mechanism. Results Compared to MSCs, MSCsTXL enhanced cardiac repair with reduced cardiomyocytes apoptosis and inflammation at the early stage of AMI and significantly improved left ventricular ejection fraction (LVEF) with reduced infarct size in an exosome-dependent way. Similarly, MSCsTXL-exo exerted superior therapeutic effects in anti-apoptosis and anti-inflammation, as well as improving LVEF and reducing infarct size compared to MSCs-exo. Further exosomal miRNA analysis demonstrated that miR-146a-5p was the candidate effector of the superior effects of MSCsTXL-exo. Besides, miR-146a-5p targeted and decreased IRAK1, which inhibited the nuclear translocation of NF-κB p65 thus protecting H9C2 cells from hypoxia injury. Conclusions This study suggested that MSCsTXL markedly facilitated cardiac repair via a new mechanism of the exosomal transfer of miR-146a-5p targeting IRAK1/NF-κB p65 pathway, which has great potential for clinical translation.

Atherosclerosis (AS) is a common comorbidity of chronic obstructive pulmonary disease (COPD), and systemic inflammation is an important mechanism of COPD with AS. Tongxinluo (TXL) improves the function of vascular endothelial cells. We aimed to prove that impairment of pulmonary microvascular barrier function is involved in COPD‐mediated aggravation of AS and investigate whether TXL enhances the effect of Ato (atorvastatin) on COPD with AS by protecting pulmonary microvascular endothelial barrier function. In vivo, a COPD with atherosclerotic apolipoprotein E knockout (AS ApoE−/−) mouse model was established by cigarette smoke combined with a high‐fat diet. The animals were administered TXL, Ato, and TXL + Ato once a day for 20 weeks. Lung function, lung microvascular permeability, lung inflammation, systemic inflammation, serum lipid levels, atheromatous plaque formation, and endothelial damage biomarkers were measured. In vitro, human pulmonary microvascular endothelial cells (HPMECs) were pretreated with TXL and incubated with cigarette smoke extract to establish the model. The permeability of the endothelial monolayer, inflammatory cytokines, endothelial damage biomarkers, and tight junction (Tj) proteins were determined. Cigarette smoking significantly exacerbated the high‐fat diet‐induced pulmonary function decline, pulmonary microvascular endothelial barrier dysfunction, inflammation, and atherosclerotic plaques. These changes were reversed by TXL–Ato; the combination was more effective than Ato alone. Furthermore, TXL protected the HPMEC barrier and inhibited inflammation in HPMECs. COPD aggravates AS, possibly through the destruction of pulmonary microvascular barrier function; thus, lung inflammation triggers systemic inflammation. In treating COPD with AS, TXL enhances the antiatherosclerotic effect of Ato, protecting the pulmonary microvascular barrier. [ABSTRACT FROM AUTHOR]

Objective: Bying comparing the correlation between three‐dimensional speckle tracking echocardiography (3D‐STE) and troponin I (cTn I), three‐dimensional left ventricular ejection fraction (3D‐LVEF), to explore the 3D‐STE to evaluate the left ventricle of patients with acute ST‐segment elevation myocardial infarction (AMI) after percutaneous coronary intervention (PCI) following routine treatment with Tongxinluo drugs. Methods: Altogether, 61 patients with AMI and 30 healthy adults were selected, and the patients were divided into the routine group and the Tongxinluo group. The serum creatine kinase isoenzyme (CK‐MB) and troponin I (cTn I) levels were detected in all patients after admission. All patients underwent PCI, and routine echocardiography and 3D‐STE assessments were performed for each group 72 h after PCI and 12 months after PCI to obtain the following left ventricular‐related functional parameters: left ventricular end‐diastolic diameter (LVEDD), end‐ventricular septal end‐diastolic thickness (IVSD), left ventricular posterior wall end‐diastolic thickness (LVPWD), left ventricular short axis shortening fraction (LVFS), Simpson's left ventricular ejection fraction (Simpson's LVEF), three‐dimensional left ventricular ejection fraction (3D‐LVEF), global longitudinal strain (GLS), global circumferential strain (GCS), left ventricular twist angle (LVtw), Torsion (Tor), peak strain dispersion (PSD), and myocardial comprehensive index (MCI). The same parameters were collected in the control group, the results were compared. The correlation analysis between 3D‐STE parameters and 3D‐LVE, cTn I was performed. A total of 10 individuals were selected for repeatability testing. Results: Compared with the control group, the LVFS, LVEF (Simpson), 3D‐LVEF, GLS, GCS, LVtw, Tor, and MCI significantly decreased in patients with STEMI after PCI, while the PSD significantly increased (p < 0.05). Compared with the values 72 h after PCI, the LVEDD, LVFS, LVEF (Simpson), 3D‐LVEF, GLS, GCS, LVtw, Tor, and MCI significantly increased at 12 m after PCI, while PSD significantly decreased (p < 0.05). No significant difference was observed between the two groups at 72 h after PCI (p > 0.05). At 12 months after PCI, the LVEF, GLS, GCS, LVtw, Tor, and MCI of the Tongxinluo group were higher than those of the routine group. The PSD was significantly lower in the Tongxinluo group (p < 0.05). MCI and 3D‐LVEF, cTn I have the strongest correlation and the highest consistency, which can best reflect the changes in the left ventricular function in patients with AMI after PCI. Conclusion: 3D‐STE can be used to evaluate the protective effect of Tongxinluo on the left ventricular function in patients with AMI after PCI. [ABSTRACT FROM AUTHOR]

Diabetic foot has become one of the leading causes of disability and death in diabetic patients. Restoring blood supply to the lower limbs, especially by increasing collateral vessels, is currently the most effective strategy. We report a 70-year-old female patient diagnosed with diabetic foot who was treated with integrated traditional Chinese and Western medicine. Western medicine treatment includes blood glucose control, lipid regulation, plaque stabilization, antiplatelet coagulation and anti-inflammation. Traditional Chinese medicine (TCM) treatment is based on the principles of promoting blood circulation and relieving pain, benefiting Qi and activating blood circulation, including oral Chinese medicine Tongxinluo and electro-acupuncture treatment. The vascular morphology of the patient's lower limbs and the levels of glucolipid metabolism were evaluated before and after treatment. The results showed that after treatment, the patient had increased blood flow in the lower limbs, reduced plaque in the femoral arteries, and improved levels of glucolipid metabolism.

Tongxinluo, a traditional Chinese medicine compound, has shown promise in improving outcomes for patients with ST-segment elevation myocardial infarction (STEMI). This randomized, double-blind, placebo-controlled trial investigated the efficacy of Tongxinluo in reducing major adverse cardiac and cerebrovascular events (MACCEs) in STEMI patients. The study enrolled 3777 patients from 124 hospitals in China, all of whom received standard STEMI treatments in addition to either Tongxinluo or placebo for 12 months. The primary endpoint was the occurrence of MACCEs at 30 days, with secondary endpoints including individual components of MACCEs, severe STEMI complications, major bleeding, and all-cause mortality at 1 yr. Results showed that Tongxinluo significantly reduced the 30-day MACCE rate compared to placebo (3.4 % vs 5.2 %), and this benefit persisted at 1 year (5.3 % vs 8.3 %). Cardiac death and myocardial reinfarction rates were also significantly lower in the Tongxinluo group. These findings underscore the importance of integrating traditional Chinese medicine with conventional Western medical treatments, providing significant evidence to support the development of evidence-based practices in traditional Chinese medicine. This study represents a pivotal advancement in the field of TCM, demonstrating its potential to contribute meaningfully to modern clinical practice and highlighting the necessity for further high-quality research in this area. [ABSTRACT FROM AUTHOR]

Background: Bone marrow cells (BMCs), especially mesenchymal stem cells (MSCs), have shown attractive application prospects in acute myocardial infarction (AMI). However, the weak efficacy becomes their main limitation in clinical translation. Based on the anti-inflammation and anti-apoptosis effects of a Chinese medicine-Tongxinluo (TXL), we aimed to explore the effects of TXL-pretreated MSCs (MSCsTXL) in enhancing cardiac repair and further investigated the underlying mechanism. Methods: MSCsTXL or MSCs and the derived exosomes (MSCsTXL-exo or MSCs-exo) were collected and injected into the infarct zone of rat hearts. In vivo, the anti-apoptotic and anti-inflammation effects, and cardiac functional and histological recovery were evaluated. In vitro, the apoptosis was evaluated by western blotting and flow cytometry. miRNA sequencing was utilized to identify the significant differentially expressed miRNAs between MSCsTXL-exo and MSCs-exo, and the miRNA mimics and inhibitors were applied to explore the specific mechanism. Results: Compared to MSCs, MSCsTXL enhanced cardiac repair with reduced cardiomyocytes apoptosis and inflammation at the early stage of AMI and significantly improved left ventricular ejection fraction (LVEF) with reduced infarct size in an exosome-dependent way. Similarly, MSCsTXL-exo exerted superior therapeutic effects in anti-apoptosis and anti-inflammation, as well as improving LVEF and reducing infarct size compared to MSCs-exo. Further exosomal miRNA analysis demonstrated that miR-146a-5p was the candidate effector of the superior effects of MSCsTXL-exo. Besides, miR-146a-5p targeted and decreased IRAK1, which inhibited the nuclear translocation of NF-κB p65 thus protecting H9C2 cells from hypoxia injury. Conclusions: This study suggested that MSCsTXL markedly facilitated cardiac repair via a new mechanism of the exosomal transfer of miR-146a-5p targeting IRAK1/NF-κB p65 pathway, which has great potential for clinical translation. [ABSTRACT FROM AUTHOR]

Intestinal flora plays an important role in atherosclerosis. Tongxinluo, as a multi-target Chinese medicine to improve atherosclerosis, whether it can improve atherosclerosis by affecting the intestinal flora is worth exploring. We established a vulnerable plaque model of atherosclerosis in New Zealand white rabbits by high cholesterol diet and balloon injury (HCB), and performed Tongxinluo intervention. We detected the level of inflammation by immunohistochemistry, Western Blot, and ELISA, analyzed plaque characteristics by calculating the vulnerability index, and analyzed the changes of gut microbiota and metabolites by 16S rRNA gene sequencing and untargeted metabolomic sequencing. The results showed that Tongxinluo intervention improved plaque stability, reduced inflammatory response, inhibited NLRP3 inflammatory pathway, increased the relative abundance of beneficial bacteria such as Alistipes which reduced by HCB, and increased the content of beneficial metabolites such as trans-ferulic acid in feces. Through correlation analysis, we found that some metabolites were significantly correlated with some bacteria and some inflammatory factors. In particular, the metabolite trans-ferulic acid was also significantly positively correlated with plaque stability. Our further studies showed that trans-ferulic acid could also inhibit the NLRP3 inflammatory pathway. In conclusion, Tongxinluo can improve plaque stability and reduce inflammation in atherosclerotic rabbits, which may be achieved by modulating intestinal flora and intestinal metabolism. Our study provides new views for the role of Tongxinluo in improving atherosclerotic vulnerable plaque, which has important clinical significance. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the neural plasticity in contralesional cortex and the effects of tongxinluo (TXL) in cerebral ischemic rats.

Intestinal flora plays an important role in atherosclerosis. Tongxinluo, as a multi-target Chinese medicine to improve atherosclerosis, whether it can improve atherosclerosis by affecting the intestinal flora is worth exploring. We established a vulnerable plaque model of atherosclerosis in New Zealand white rabbits by high cholesterol diet and balloon injury (HCB), and performed Tongxinluo intervention. We detected the level of inflammation by immunohistochemistry, Western Blot, and ELISA, analyzed plaque characteristics by calculating the vulnerability index, and analyzed the changes of gut microbiota and metabolites by 16S rRNA gene sequencing and untargeted metabolomic sequencing. The results showed that Tongxinluo intervention improved plaque stability, reduced inflammatory response, inhibited NLRP3 inflammatory pathway, increased the relative abundance of beneficial bacteria such as Alistipes which reduced by HCB, and increased the content of beneficial metabolites such as trans-ferulic acid in feces. Through correlation analysis, we found that some metabolites were significantly correlated with some bacteria and some inflammatory factors. In particular, the metabolite trans-ferulic acid was also significantly positively correlated with plaque stability. Our further studies showed that trans-ferulic acid could also inhibit the NLRP3 inflammatory pathway. In conclusion, Tongxinluo can improve plaque stability and reduce inflammation in atherosclerotic rabbits, which may be achieved by modulating intestinal flora and intestinal metabolism. Our study provides new views for the role of Tongxinluo in improving atherosclerotic vulnerable plaque, which has important clinical significance.

Tongxinluo (TXL), a traditional Chinese medication, plays a key role in the formation and progression of plaques in atherosclerosis. The formation of foam cells by macrophages accelerates the destabilisation of plaques. In previous research, we had found that TXL significantly inhibits ox-LDL-induced apoptosis in macrophages in vitro by improving the dissociation of the Beclin-1-Bcl-2 complex. Therefore, here, we explored the effect of TXL on lipid metabolism in macrophages and the mechanism involved. To evaluate the role of TXL in atherosclerotic plaques, we construct the atherosclerotic animal model with lentiviral injection and performed immunofluorescence staining analysis in vivo. Western blot, immunofluorescence staining and microscopy were performed to elucidate the mechanism underlying TXL-mediated regulation of autophagy in THP-1 macrophages in vitro. Immunofluorescence assay revealed that TXL treatment inhibited lipid deposition in advanced atherosclerotic plaques. In vitro TXL treatment inhibited lipid deposition in THP-1 macrophages by enhancing autophagy via Beclin-1. TXL reversed the high expression of class I histone deacetylases (HDACs) induced by ox-LDL (p < 0.05). Compared with the TXL + ox-LDL group, TXL failed to promote intracellular lipid droplet decomposition after the addition of the histone deacetylase agonist. We found that TXL attenuates the accumulation of lipids in macrophage by enhancing Beclin-1-induced autophagy, and additionally, it inhibits the inhibitory effect of class I HDAC on the expression of Beclin-1.

Tongxinluo (TXL), a traditional Chinese medication, plays a key role in the formation and progression of plaques in atherosclerosis. The formation of foam cells by macrophages accelerates the destabilisation of plaques. In previous research, we had found that TXL significantly inhibits ox-LDL-induced apoptosis in macrophages in vitro by improving the dissociation of the Beclin-1-Bcl-2 complex. Therefore, here, we explored the effect of TXL on lipid metabolism in macrophages and the mechanism involved. To evaluate the role of TXL in atherosclerotic plaques, we construct the atherosclerotic animal model with lentiviral injection and performed immunofluorescence staining analysis in vivo. Western blot, immunofluorescence staining and microscopy were performed to elucidate the mechanism underlying TXL-mediated regulation of autophagy in THP-1 macrophages in vitro. Immunofluorescence assay revealed that TXL treatment inhibited lipid deposition in advanced atherosclerotic plaques. In vitro TXL treatment inhibited lipid deposition in THP-1 macrophages by enhancing autophagy via Beclin-1. TXL reversed the high expression of class I histone deacetylases (HDACs) induced by ox-LDL (p < 0.05). Compared with the TXL + ox-LDL group, TXL failed to promote intracellular lipid droplet decomposition after the addition of the histone deacetylase agonist. We found that TXL attenuates the accumulation of lipids in macrophage by enhancing Beclin-1-induced autophagy, and additionally, it inhibits the inhibitory effect of class I HDAC on the expression of Beclin-1. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of early intervention of Tongxinluo (通心络, TXL) on right ventricular function (RVF) of rats with pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT). Methods: A total of 30 adult male Sprague-Dawley rats were assigned to 5 groups with complete random experiment design: Sham group (Sham), MCT group, TXL group, sildenafil (SIL) group and combination group (TXL+SIL), 6 rats in each group. Rats were injected with 50 mg/kg MCT solution for inducing PAH model except for those in the sham group. From the day of modeling, rats of TXL, SIL and TXL+SIL groups were given TXL (1.2 g/kg), SIL (10 mg/kg) and combination solution (TXL:1.2 g/kg, SIL: 10 mg/kg) respectively, and rats in Sham and MCT groups were given normal saline (5 mL/kg). The samples were collected and tested after 21 consecutive days of intragastric administration. Echocardiography was used to measure the related indices of RVF, including pulmonary arterial flow spectrum, pulmonary artery diameter (PAD), right ventricular wall thickness (RVWT), right ventricular diameter (RVD), tricuspidannular plane systolic excursion (TAPSE), right atrium transverse diameter (RAT), and inferior vena cava diameter (IVCD). Elastic Verhoeff-Van Gieson staining was adopted to measure the percentage of wall thickness (WT%) of pulmonary arteriols. Hematoxylin-eosin staining was used to measure the cross-sectional area (CSA) of right ventricular cardiomyocytes. Results: MCT-induced PAH rat model was successfully established. In MCT group the wall of pulmonary arterioles exhibited a prominent-increase thickness, PAD, RVWT, RVD, RAT, IVCD, WT%, right ventricular hypertrophy index (RVHI) as well as CSA of RV cardiomyocyte significantly increased (all P<0.01), and TAPSE markedly decreased (P<0.01). At the same time, TXL prominently improved all of the above indices (all P<0.01). In comparison with SIL, TXL significantly reduced RVD (P<0.05) and decreased CAS of RV cardiomyocytes (P<0.01), but TAPSE in SIL group was much larger than in TXL group (P<0.01). Moreover, TAPSE in TXL+SIL group was larger than that in TXL group (P<0.01), while the two groups performed equally well in terms of the other indices. Conclusion: Early intervention of TXL could inhibit pulmonary arterioles remodeling, and improve RVF by attenuating right ventricular hypertrophy, and TXL has a stronger effect on inhibiting right ventricular remodeling than SIL. [ABSTRACT FROM AUTHOR]

Objective To evaluate the sustained therapy of intragastric administration of Tongxinluo on microvascular endothelial barrier injury swine after the late-stage of acute myocardial infarction (AMI) -reperfusion. Methods: Forty swine were randomly divided into the sham operation group, control group, low-dose (0. l glkg), medium-dose (0. 2 glkg) and high-dose (0. 4 glkg) groups. The AMI and reperfusion model was established by 90 min occlusion of left anterior descending, followed by 120 min reperfusion. No coronary artery was blocked in the sham operation group. Tongxinluo was administrated with double routine dosage before coronary occlusion and with routine dosage from the next day till the seventh day, which was 0. 1, 0. 2, and 0. 4 glkg, respectively. The serum levels of endothelin-1 (ET-1) and von Willebrand Factor (vWF) were detected by ELISA. Patholo护c myocardial tissues were collected seven days after acute ischemia and reperfusion. The mRNA and protein expression levels of endothelial nitric oxide synthase (eNOS) and vascular endo-thelial cadherin ( VE-cadherin) were detected by in situ hybridization ( !SH) and Western blotting. Results: Compared with the sham operation group, the serum ET-1 and vWF increased significantly after coronary occlusion in the control group. On the 7th day of reperfusion, both ET-1 and vWF were restored, but vWF was still significantly higher than that in the sham operation group. Compared with the control group, the serum ET-1 of the high-dose group significantly decreased at 90 min of coronary occlusion, at 120 min, l and 3 days of reperfusion, while v WF decreased at all check points. Compared with the sham operation group, the pos山ve expression of eNOS and VE-cadherin mRNA of infarcted area significantly decreased in the other groups on the 7th day of reperfusion, as well as the eNOS, but VE-cadherin significantly decreased only in the control, low-dose and medium-dose groups. Compared with the control group, Tongxinluo increased both mRNA and protein expression of eNOS and VE-cadherin, which was more significantly effective in the infarcted area than the marginal and normal area with high dosage ( all P < 0. 05) . Conclusion: The intragastric administration of Tongxinluo can alleviate the injury of microvascular endothelial barrier on the 7th day after is chemic reperfusion, with a dose-dependent manner, and be more effective in the infarcted area. [ABSTRACT FROM AUTHOR]

Background: Our previous studies have shown that Tongxinluo (TXL), a compound Chinese medicine, can decrease myocardial ischemia-reperfusion injury, protect capillary endothelium function, and lessen cardiac ventricle reconstitution in animal models. The aim of this study was to illuminate whether TXL can improve hypercholesterolemia-impaired heart function by protecting artery endothelial function and increasing microvascular density (MVD) in heart. Furthermore, we will explore the underlying molecular mechanism of TXL cardiovascular protection. Methods: After intragastric administration of TXL (0.1 ml/10 g body weight) to C57BL/6J wild-type mice (n = 8) and ApoE-/- mice (n = 8), total cholesterol, high-density lipoprotein-cholesterol, very-low-density lipoprotein (VLDL)-cholesterol, triglyceride, and blood glucose levels in serum were measured. The parameters of heart rate (HR), left ventricular diastolic end diameter, and left ventricular systolic end diameter were harvested by ultrasonic cardiogram. The left ventricular ejection fraction, stroke volume, cardiac output, and left ventricular fractional shortening were calculated. Meanwhile, aorta peak systolic flow velocity (PSV), end diastolic flow velocity, and mean flow velocity (MFV) were measured. The pulsatility index (PI) and resistant index were calculated in order to evaluate the vascular elasticity and resistance. The endothelium-dependent vasodilatation was evaluated by relaxation of aortic rings in response to acetylcholine. Western blotting and real-time quantitative reverse transcription polymerase chain reaction were performed for protein and gene analyses of vascular endothelial growth factor (VEGF). Immunohistochemical detection was performed for myocardial CD34 expression. Data in this study were compared by one-way analysis of variance between groups. A value of P < 0.05 was considered statistically significant. Results: Although there was no significant decrease of cholesterol level (F = 2.300, P = 0.240), TXL inhibited the level of triglyceride and VLDL (F = 9.209, P = 0.024 and F = 9.786, P = 0.020, respectively) in ApoE-/- mice. TXL improved heart function of ApoE-/- mice owing to the elevations of LVEF, SV, CO, and LVFS (all P < 0.05). TXL enhanced aortic PSV and MFV (F = 10.774, P = 0.024 and F = 11.354, P = 0.020, respectively) and reduced PI of ApoE-/- mice (1.41 ± 0.17 vs. 1.60 ± 0.17; P = 0.037). After incubation with 10 μmol/L acetylcholine, the ApoE-/- mice treated with TXL aortic segment relaxed by 44% ± 3%, significantly higher than control group mice (F = 9.280, P = 0.040). TXL also restrain the angiogenesis of ApoE-/- mice aorta (F = 21.223, P = 0.010). Compared with C57BL/6J mice, the MVD was decreased in heart tissue of untreated ApoE-/- mice (54.0 ± 3.0/mm2 vs. 75.0 ± 2.0/mm2; F = 16.054, P = 0.010). However, TXL could significantly enhance MVD (65.0 ± 5.0/mm2 vs. 54.0 ± 3.0/mm2; F = 11.929, P = 0.020) in treated ApoE-/- mice. In addition, TXL obviously increased the expression of VEGF protein determined by Western blot (F = 20.247, P = 0.004). Conclusions: TXL obviously improves the ApoE-/- mouse heart function from different pathways, including reduces blood fat to lessen atherosclerosis; enhances aortic impulsivity, blood supply capacity, and vessel elasticity; improves endothelium-dependent vasodilatation; restraines angiogenesis of aorta-contained plaque; and enhances MVD of heart. The molecular mechanism of MVD enhancement maybe relate with increased VEGF expression.

Background: The protection of endothelial cells (ECs) against reperfusion injury has received little attention. In this study, we used Tandem Mass Tag (TMT) labeling proteomics to investigate the modulated proteins in an in vitro model of cardiac microvascular endothelial cells (CMECs) subjected to ischemia/reperfusion (I/R) injury and their alteration by traditional Chinese medicine Tongxinluo (TXL). Methods: Human CMECs were subjected to 2 h of hypoxia followed by 2 h of reoxygenation with different concentrations of TXL Protein expression profiles of CMECs were determined using tandem mass spectrometry. We evaluated several proteins with altered expression in I/R injury and summarized some reported proteins related to I/R injury. Results: TXL dose-dependently decreased CMEC apoptosis, and the optimal concentration was 800 µg/mL. I/R significantly altered proteins in CMECs, and 30 different proteins were detected between a normal group and a hypoxia and serum deprivation group. In I/R injury, TXL treatment up-regulated 6 types of proteins including acyl-coenzyme A synthetase ACSM2B mitochondrial (ACSM2B), cyclin-dependent kinase inhibitor 1B (CDKN1B), heme oxygenase 1 (HMOX1), transcription factor SOX-17 (SOX17), sequestosome-1 isoform 1 (SQSTM1), and TBC1 domain family member 10B (TBC1D10B). Also, TXL down-regulated 5 proteins including angiopoietin-2 isoform c precursor (ANGPT2), cytochrome c oxidase assembly factor 5 (COA5), connective tissue growth factor precursor (CTGF), cathepsin L1 isoform 2 (CTSL), and eukaryotic elongation factor 2 kinase (LOC101930123). These types of proteins mainly had vital functions, including cell proliferation, stress response, and regulation of metabolic process. Conclusions: The study presented differential proteins upon I/R injury through a proteomic analysis. TXL modulated the expression of proteins in CMECs and has a protective role in response to I/R.

Background: The aim of treatment of stable ischemic heart disease is not only to improve prognosis but also to decrease symptoms and increase the patient's quality of life. Pharmaceutical therapy remains the cornerstone of stable angina treatment, and Tongxinluo is a traditional oriental medicine used in the treatment of ischemic heart disease. Objective: To evaluate the effectiveness of Tongxinluo for improving angina symptoms and exertion ability in Vietnamese patients. Methods: This open-label clinical trial was conducted as one branch in 300 Vietnamese patients at Cho Ray Hospital. The diagnosis of stable angina followed the 2013 European Society of Cardiology Guidelines. The patients were supplemented with Tongxinluo at a dose of 6 tablets bid. Patients were reassessed for angina symptoms and any subclinical side effects of the drug at 2 weeks and 6 weeks after initiation of the drug treatment. Results: Exercise time on rolling mats, metabolic equivalents (METs), and other subclinical indices were decreased significantly after 6 weeks of Tongxinluo administration. Side effects of halitosis, a burning sensation, diarrhea, and headaches were mild and tolerable. Conclusion: Tongxinluo provides a significant reduction in the frequency, duration, and severity of angina. Tongxinluo was well tolerated by this Vietnamese study population. [ABSTRACT FROM AUTHOR]

Background ‒ The aim of this study was to investigate the neural plasticity in contralesional cortex and the effects of tongxinluo (TXL) in cerebral ischemic rats. Methodology ‒ We used stroke-prone renovascular hypertensive (RHRSP) cerebral ischemia rat models to study the effect of TXL and the underlying mechanisms. We performed foot-fault and beam-walking tests to evaluate the motor function of rats after cortical infarction. Biotinylated dextran amine (BDA) was used to track axonal sprouting and neural connections. Results ‒ TXL enhanced the recovery of motor function in cerebral infarction rats. TXL increased axonal sprouting in the peri-infarcted area but not in the corpus callosum, indicating in situ origination instead of crossing between cortical hemispheres through the corpus callosum. TXL promoted the sprouting of corticospinal axons into the denervated side of spinal gray matter. The synaptophysin (SYN)-positive intensity in the peri-infarcted area of TXL-treated group was greater than that in the vehicle group. We observed co-localization of SYN with BDA-positive fibers in the denervated spinal cord gray matter in the TXL group, suggesting that axonal remodeling and synaptic connections were promoted by TXL. Conclusion ‒ TXL may promote the recovery of neurological function by promoting the axonal remodeling and synapse formation of motor neuronal fibers after focal cortical infarction in hypertensive rats. [ABSTRACT FROM AUTHOR]

Background: Chinese patent medicine Tongxinluo capsule (TXL) is commonly used for cardio-cerebrovascular diseases. Previous research had demonstrated that TXL exhibited great clinical effects on the treatment of acute myocardial infarction (AMI), however there is a lack of systematic review. The purpose of this study was to evaluate the potential effectiveness and safety of TXL for secondary prevention in patients with AMI.Method: We searched 6 databases to identify relevant randomized controlled trials (RCTs) from inceptions to December 30, 2017. Two review authors independently assessed the methodological quality and analyzed data by the RevMan 5.3 software. The publication bias was assessed through funnel plot and Begg's test. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used for evaluating the quality of evidence.Results: We included 19 RCTs in this review and performed a meta-analysis based on 16 studies. There were statistical differences of TXL treatment group in reducing primary cardiovascular events (cardiac death [RR = 0.27, 95%CI: 0.08~0.95, I2 = 0%], recurrent myocardial reinfarction [RR = 0.38, 95%CI: 0.20~0.74, I2 = 0%], arrhythmia [RR = 0.44, 95%CI: 0.30~0.66, I2 = 0%], recurrent angina pectoris [RR = 0.34, 95%CI: 0.17~0.69, I2 = 0%]). TXL could improve cardiac function (LVEF [MD = 4.10, 95%CI: 3.95~4.25, I2 = 0%]), regulate blood lipid TC [MD = −0.66, 95%CI: −0.94 ~ −0.37, I2 = 74%], TG [MD = −0.38, 95%CI: −0.62 ~ −0.14, I2 = 70%], LDL-C[−0.40, 95%CI: −0.65 ~ −0.16, I2 = 88%), decrease the level of hs-CRP (4-week: MD = −0.78, 95%CI: −0.97 ~ −0.60, I2 = 20%; Over 4-week: MD = −1.36, 95%CI: −1.55 ~ −1.17, I2 = 20%). However, TXL has little effects on revascularization [RR = 0.45, 95%CI: 0.13~1.56, I2 = 0%], recurrent heart failure (RR = 0.83, 95%CI: 0.27~2.57, I2 = 0%), and HDL-C (MD = 0.14, 95%CI: 0.00 ~0.29, I2 = 73%). Furthermore, TXL treatment group was more prone to suffer gastrointestinal discomfort.Conclusion: Chinese patent medicine TXL seemed beneficial for secondary prevention after AMI. This potential benefit needs to be further assessed through more rigorous RCTs.Systematic review registration number in the PROSPERO register: CRD42017068417.

Background: Claudin-5, claudin-9, and claudin-11 are expressed in endothelial cells to constitute tight junctions, and their deficiency may lead to hyperpermeability, which is the initiating process and pathological basis of cardiovascular disease. Although tongxinluo (TXL) has satisfactory antianginal effects, whether and how it modulates claudin-5, claudin-9, and claudin-11 in hypoxia-stimulated human cardiac microvascular endothelial cells (HCMECs) have not been reported. Methods: In this study, HCMECs were stimulated with CoCl2to mimic hypoxia and treated with TXL. First, the messenger RNA (mRNA) expression of claudin-5, claudin-9, and claudin-11 was confirmed. Then, the protein content and distribution of claudin-9, as well as cell morphological changes were evaluated after TXL treatment. Furthermore, the distribution and content histone H3K9 acetylation (H3K9ac) in the claudin-9 gene promoter, which guarantees transcriptional activation, were examined to explore the underlying mechanism, by which TXL up-regulates claudin-9 in hypoxia-stimulated HCMECs. Results: We found that hypoxia-suppressed claudin-9 gene expression in HCMECs (F = 7.244; P = 0.011) and the hypoxia-suppressed claudin-9 could be reversed by TXL (F = 61.911; P = 0.000), which was verified by its protein content changes (F = 29.142; P = 0.000). Moreover, high-dose TXL promoted the cytomembrane localization of claudin-9 in hypoxia-stimulated HCMECs, with attenuation of cell injury. Furthermore, high-dose TXL elevated the hypoxia-inhibited H3K9ac in the claudin-9 gene promoter (F = 37.766; P = 0.000), activating claudin-9 transcription. Conclusions: The results manifested that TXL reversed the hypoxia-suppressed claudin-9 by elevating H3K9ac in its gene promoter, playing protective roles in HCMECs.

This study was design to investigate preventive function of Tongxinluo (TXL) capsule on micro vascular function and endothelial survival in rats model of intestine ischemia/reperfusion (I/R) injury. We randomly divided fifty male Sprague-Dawley rats into Sham group, I/R group, TXL0.4+I/R group, TXL0.8+I/R group, TXL1.6+I/R group (10 rats each). Rat intestine I/R injury was carried out using a model of acute superior mesenteric artery occlusion with 30 min ischemia followed by 60 min reperfusion. The distribution of endothelial apoptosis in intestine was determined by CD31+TUNEL immunofluorescent double staining analysis. VE-Cadherin, ANGPTL4, HMGB1 and NF-κB were determined by immunohistochemical analysis. I/R induced massively endothelial cell apoptosis, accompanied with reduced expression of adherens junction protein VE-Cadherin and up regulation of inflammatory mediator HMGB1 and NF-κB. TXL pretreatment groups (TXL0.4+I/R, TXL0.8+I/R and TXL1.6+I/R group) significantly attenuated endothelial cell apoptosis with a dose-dependent effect. TXL pretreatment could maintain the expression of VE-Cadherin and promote the expression of ANGPTL4 which help to maintain endothelial integrity. TXL pretreatment also exert great influence in inhibiting HMGB1 expression and NF-κB expression induced by I/R. It could be concluded from this study that micro vascular dysfunction and endothelial damage play a causal role in rat intestine I/R injury. TXL pretreatment could significantly prevent the I/R induced pathology of endothelial apoptosis, micro vascular integrity disruption and inflammatory reaction. [ABSTRACT FROM AUTHOR]

In advanced atherosclerosis, a large number of necrotic core increases plaque vulnerability, which leads to the occurrence of acute atherothrombotic cardiovascular events. Macrophage apoptosis plays an important role in secondary necrosis. The present study aimed to examine and describe the effect of the traditional Chinese medication Tongxinluo (TXL) on macrophage apoptosis in advanced atherosclerotic plaques and to explore its mechanism. By observing the effect of TXL on ox-LDL-stimulated macrophage apoptosis, it was shown that TXL significantly inhibited ox-LDL-induced apoptosis of macrophages by enhancing autophagy. Therapeutic mechanism of TXL included increasing the expression of Beclin-1 and improving the dissociation of Bcl-2-Beclin-1 Complex. Apolipoprotein E knockout (apoE−/−) mice with a high fat diet were divided into four groups: saline group (Saline gavage), low dose TXL group (0.38 g/kg/d, gavage), medium dose TXL group (0.75 g/kg/day, gavage), and high dose TXL group (1.5 g/kg/day, gavage). 4 weeks after carotid-artery surgery, lentiviral of Beclin-1 silencing was injected through the tail vein. TXL treatment significantly reduced macrophage apoptosis dose-dependently and the result was blocked by Beclin-1 silencing. In addition, the increased Lc3b dots by TXL almost localized to macrophages in advanced atherosclerotic plaque. Compared with the same dose of TXL shBeclin-1 group, plaque area and vulnerability index of TXL groups decreased. The anti-apoptosis effects of TXL on atherosclerosis was related to the improvement of autophagy via Beclin-1. [ABSTRACT FROM AUTHOR]

Ischemic stroke brings a huge family and social burden. Although the reperfusion of ischemic cerebral tissue is the most important way to rescue ischemic stroke, ischemia–reperfusion (I/R) injury further results in brain damage and even lead to death. Recent studies demonstrated that Tongxinluo (TXL) helps to protect the brain against focal cerebral I/R injury in rats by reducing neuronal apoptosis, and the MEK1/2/ERK1/2/90 ribosomal S6 kinase (p90RSK) pathway may be involved in this protective effect. Therefore, our present research was designed to identify the potential mechanisms involved. Adult male Sprague-Dawley rats (n = 108) were randomly divided into 4 groups: sham, cerebral ischemia and reperfusion (I/R), I/R plus TXL (TXL), and TXL plus U0126, a highly selective inhibitor of MEK 1 and MEK 2 (TXL + U0126). Brain edema was measured by T2-weighted magnetic resonance imaging (MRI). Pathological destruction of the blood brain barrier (BBB) ultrastructure was assessed by transmission electron microscopy, and proteins involved in the MEK1/2/ERK1/2/p90RSK pathway were detected by immunofluorescence and Western blotting. Our results indicated that TXL significantly improved neurological function, reduced brain edema, ameliorated the destruction of the BBB ultrastructure and markedly reduced neuronal injury. However, these benefits were diminished when the MEK1/2/ERK1/2/p90RSK pathway was inhibited by U0126. We also found that TXL upregulated the expression levels of p-MEK1/2, p-ERK1/2, p-p90RSK and p-bad, which were all significantly reversed by U0126. Collectively, our data demonstrate that TXL provides neuroprotection against cerebral I/R injury and neuronal injury, and that these effects are mediated, in part, by activation of the MEK1/2/ERK1/2/p90RSK pathway. [ABSTRACT FROM AUTHOR]

Abstract: Objective: The aim of this study was to examine the effect of TXL, a Chinese medicine prescription, on cerebral microcirculatory disturbances after pMCAO in mice using TPLSM and further explore the underlying mechanisms. Methods: Adlut male C57BL/6J mice were subjected to pMCAO and orally administered with TXL (3.0, 1.5 and 0.75 g/kg/d) at 1, 3, and 21 hours after pMCAO. The following parameters were examined at 6 and 24 hours after pMCAO: neurological deficits, infarct volume, BBB permeability, cerebral microvessel structure, brain microcirculation (TPLSM imaging), vasoactive factors, and adhesion molecules. Results: TXL improved neurological deficits, reduced infarct volume, attenuated BBB disruption, protected cerebral microvessel structure, increased cerebral capillary flow velocity and volume flux, and inhibited leukocyte–endothelial cell interactions at 6 or 24 hours after pMCAO. The therapeutic efficacy was exerted in a dose‐dependent manner. Further study revealed that TXL (high dose) regulated the expression of PGI2, TXA2, and ET‐1, and suppressed ICAM‐1 and P‐selectin. Conclusions: TXL alleviates cerebral microcirculatory disturbances against ischemic injury by modulating endothelial function and inhibiting leukocyte–endothelial cell interactions. These effects are associated with regulating the expression of PGI2, TXA2, and ET‐1, and suppressing ICAM‐1 and P‐selectin expression. [ABSTRACT FROM AUTHOR]

Background: Endothelial dysfunction is considered as the initiating process and pathological basis of cardiovascular disease. Cyclooxygenase-2 (COX-2) and prostacyclin synthase (PGIS), inducible nitric oxide synthase (iNOS) and endothelial NOS (eNOS) are key enzymes with opposing actions in inflammation and oxidative stress, which are believed to be the major driver of endothelial dysfunction. And in hypoxia (Hx), Hx-inducible factor (HIF)-1α and HIF-2α are predominantly induced to activate vascular endothelial growth factor (VEGF), resulting in abnormal proliferation. Whether and how Tongxinluo (TXL) modulates COX-2, PGIS, iNOS, eNOS, HIF-1α, HIF-2α, and VEGF in Hx-stimulated human cardiac microvascular endothelial cells (HCMECs) have not been clarified. Methods: HCMEC were treated with CoCl 2 to mimic Hx and the mRNA expressions of COX-2, PGIS, iNOS, eNOS, HIF-1α, HIF-2α, and VEGF were first confirmed, and then their mRNA expression and protein content as well as the cell pathological alterations were evaluated for TXL treatment with different concentrations. In addition, the effector molecular of inflammation prostaglandin E 2 (PGE 2 ) and the oxidative marker nitrotyrosine (NT) was adopted to reflect HCMEC injury. Results: Hx could induce time-dependent increase of COX-2, iNOS, HIF-2α, and VEGF in HCMEC. Based on the Hx-induced increase, TXL could mainly decrease COX-2, iNOS, HIF-2α, and VEGF in a concentration-dependent manner, with limited effect on the increase of PGIS and eNOS. Their protein contents verified the mRNA expression changes, which was consistent with the cell morphological alterations. Furthermore, high dose TXL could inhibit the Hx-induced increase of PGE 2 and NT contents, attenuating the inflammatory and oxidative injury. Conclusions: TXL could inhibit inflammation-related COX-2, oxidative stress-related iNOS, and HIF-2α/VEGF to antagonize Hx-induced HCMEC injury.

Background and Aims: Tongxinluo (TXL) is a multifunctional traditional Chinese medicine that has been widely used to treat cardiovascular and cerebrovascular diseases. However, no studies have explored whether TXL can protect human cardiomyocytes (HCMs) from ischemia/reperfusion (I/R) injury. Reperfusion Injury Salvage Kinase (RISK) pathway activation was previously demonstrated to protect the hearts against I/R injury and it is generally activated via Akt or (and) Erk 1/2, and their common downstream protein, ribosomal protein S6 kinase (p70s6k). In addition, prior studies proved that TXL treatment of cells promoted secretion of VEGF, which could be stimulated by the increased phosphorylation of one p70s6k subtype, p70s6k1. Consequently, we hypothesized TXL could protect HCMs from I/R injury by activating p70s6k1 and investigated the underlying mechanism.Methods and Results: HCMs were exposed to hypoxia (18 h) and reoxygenation (2 h) (H/R), with or without TXL pretreatment. H/R reduced mitochondrial membrane potential, increased bax/bcl-2 ratios and cytochrome C levels and induced HCM apoptosis. TXL preconditioning reversed these H/R-induced changes in a dose-dependent manner and was most effective at 400 μg/mL. The anti-apoptotic effect of TXL was abrogated by rapamycin, an inhibitor of p70s6k. However, inhibitors of Erk1/2 (U0126) or Akt (LY294002) failed to inhibit the protective effect of TXL. TXL increased p70s6k1 expression and, thus, enhanced its phosphorylation. Furthermore, transfection of cardiomyocytes with siRNA to p70s6k1 abolished the protective effects of TXL. Among the micro-RNAs (miR-145-5p, miR-128-3p and miR-497-5p) previously reported to target p70s6k1, TXL downregulated miR-128-3p in HCMs during H/R, but had no effects on miR-145-5p and miR-497-5p. An in vivo study confirmed the role of the p70s6k1 pathway in the infarct-sparing effect of TXL, demonstrating that TXL decreased miR-128-3p levels in the rat myocardium during I/R. Transfection of HCMs with a hsa-miR-128-3p mimic eliminated the protective effects of TXL.Conclusions: The miR-128-3p/p70s6k1 signaling pathway is involved in protection by TXL against HCM apoptosis during H/R. Overexpression of p70s6k1 is, therefore, a potential new strategy for alleviating myocardial reperfusion injury.

Glomerular mesangial cells (GMCs) activation is implicated in the pathogenesis of diabetic nephropathy (DN). Our previous study revealed that high glucose (HG)-treated glomerular endothelial cells (GECs) produce an increased number of TGF-ß1-containing exosomes to activate GMCs through the TGF-ß1/Smad3 signaling pathway. We also identified that Tongxinluo (TXL), a traditional Chinese medicine, has beneficial effects on the treatment of DN in DN patients and type 2 diabetic mice. However, it remained elusive whether TXL could ameliorate renal structure and function through suppression of intercellular transfer of TGF-ß1-containing exosomes from GECs to GMCs. In this study, we demonstrate that TXL can inhibit the secretion of TGF-ß1-containing exosomes from HGtreated GECs. Furthermore, exosomes produced by HG induced-GECs treated with TXL cannot trigger GMC activation, proliferation and extracellular matrix (ECM) overproduction both in vitro and in vivo. These results suggest that TXL can prevent the transfer of TGF-ß1 from GECs to GMCs via exosomes, which may be one of the mechanisms of TXL in the treatment of DN. [ABSTRACT FROM AUTHOR]

Background: The protection of endothelial cells (ECs) against reperfusion injury has received little attention. In this study, we used Tandem Mass Tag (TMT) labeling proteomics to investigate the modulated proteins in an in vitro model of cardiac microvascular endothelial cells (CMECs) subjected to ischemia/reperfusion (I/R) injury and their alteration by traditional Chinese medicine Tongxinluo (TXL). Methods: Human CMECs were subjected to 2 h of hypoxia followed by 2 h of reoxygenation with different concentrations of TXL. Protein expression profiles of CMECs were determined using tandem mass spectrometry. We evaluated several proteins with altered expression in I/R injury and summarized some reported proteins related to I/R injury. Results: TXL dose-dependently decreased CMEC apoptosis, and the optimal concentration was 800 μg/mL. I/R significantly altered proteins in CMECs, and 30 different proteins were detected between a normal group and a hypoxia and serum deprivation group. In I/R injury, TXL treatment up-regulated 6 types of proteins including acyl-coenzyme A synthetase ACSM2B mitochondrial (ACSM2B), cyclin-dependent kinase inhibitor 1B (CDKN1B), heme oxygenase 1 (HMOX1), transcription factor SOX-17 (SOX17), sequestosome-1 isoform 1 (SQSTM1), and TBC1 domain family member 10B (TBC1D10B). Also, TXL down-regulated 5 proteins including angiopoietin-2 isoform c precursor (ANGPT2), cytochrome c oxidase assembly factor 5 (COA5), connective tissue growth factor precursor (CTGF), cathepsin L1 isoform 2 (CTSL), and eukaryotic elongation factor 2 kinase (LOC101930123). These types of proteins mainly had vital functions, including cell proliferation, stress response, and regulation of metabolic process. Conclusions: The study presented differential proteins upon I/R injury through a proteomic analysis. TXL modulated the expression of proteins in CMECs and has a protective role in response to I/R. [ABSTRACT FROM AUTHOR]

β-Amyloid (Aβ) accumulation in the brain is the major pathophysiology of Alzheimer disease (AD). Hypertension is a risk factor for AD by promoting Aβ deposition. Traditional Chinese medicinal compound tongxinluo (TXL) can improve blood circulation and endothelium-dependent vasodilation. This study investigates the effects of TXL on cognition and Aβ using spontaneously hypertensive rats (SHRs). TXL was intragastrically administered to SHRs at low-dose, mid-dose and high-dose for 15, 30 or 60 days. Cognition was evaluated with a Morris Water Maze (MWM). Aβ in the brain was detected by western blot, ELISA and Thioflavin-S staining. Western blot and RT-PCR were employed to exam the expression of receptor for advanced glycation end products (RAGE), low-density lipoprotein receptor-related protein-1 (LRP-1) and amyloid precursor protein (APP). After TXL treatment for 60 days, compared with the vehicle, the number of crossed platform and the time spent in the target quadrant increased in parallel with the increasing length of treatment in MWM. Moreover, the Aβ in the hippocampus significantly decreased compared to the vehicle group, both in western blot and ELISA. Additionally, TXL reduced RAGE expression in a dose- and time-depended manner, but LRP-1 expression had no difference between TXL groups and vehicle groups. Furthermore, the β-secretase expression was significantly decreased compared to the vehicle group, but APP expression had no difference. In conclusion, TXL improved cognition and decreased Aβ in SHRs in a dose- and time-dependent manner, the underlying mechanism may involved in inhibiting RAGE and β-secretase expression. [ABSTRACT FROM AUTHOR]

New Findings What is the central question of this study? In a rat model of acute myocardial infarction (AMI), we investigated the effect of Tongxinluo (TXL) treatment. Does TXL activate autophagy and attenuate apoptosis of cardiomyocytes through the AMPK pathway to facilitate survival of cardiomyocytes and improve cardiac function?, What is the main finding and its importance? Major findings are as follows: (i) TXL treatment preserved cardiac function and reduced ventricular remodelling, infarct size and inflammation in rat hearts after AMI; (ii) TXL treatment dramatically increased autophagy and inhibited apoptosis in myocardium; and (iii) the AMPK signalling pathway played a crucial role in mediating the beneficial effects of TXL., Tongxinluo (TXL) has been demonstrated to have a protective role during ischaemia-reperfusion after acute myocardial infarction, but the long-term effects and underlying mechanisms are still unknown. The aim of this study was to investigate whether TXL could have an effect on apoptosis or autophagy of cardiomyocytes through the AMP-activated protein kinase (AMPK) pathway. Male Sprague-Dawley rats ( n = 75) were randomly divided to sham, control, TXL (4 mg kg−1 day−1 orally), compound C ( i.p. injection of 10 mg kg−1 day−1) and TXL + compound C groups. The extent of fibrosis, infarct size and angiogenesis were determined by pathological and histological studies. Four weeks after acute myocardial infarction, TXL treatment significantly increased ejection fraction, promoted angiogenesis in the peri-infarct region and substantially decreased fibrosis and the size of the infarcted area ( P < 0.05). Treatment with TXL also increased AMPK/mTOR phosphorylation, upregulated expression of the autophagic protein LC3 and downregulated expression of the apoptotic protein Bax in the infarcted myocardium ( P < 0.05). Addition of the AMPK inhibitor, compound C, counteracted these beneficial effects significantly ( P < 0.05). The cardioprotective benefits of TXL against myocardial infarction are related to the inhibition of apoptosis and promotion of autophagy in rat hearts after acute myocardial infarction. This effect may occur through the AMPK signalling pathway. [ABSTRACT FROM AUTHOR]

Purpose/aim of the study: Claudins-5, -9, and -11 are tight-junction proteins that are mainly expressed in endothelial cells. Their deficiency may lead to cell barrier dysfunction, which is considered as the initiating process and pathological basis of cardiovascular disease in diabetes. We investigated whether high glucose (HG) affects claudins-5, -9, and -11 in human cardiac microvascular endothelial cells (HCMECs), and examined the effects of the traditional Chinese medication tongxinluo (TXL) on these tight junction proteins.Materials and methods: HCMECs were exposed to HG with and without TXL treatment, and then mRNA and protein levels of claudins-5, -9, and -11 were examined. The distribution of claudins-5 and -11 was also investigated. Histone H3K9 acetylation (H3K9ac) inclaudin-5andclaudin-11gene promoters, which functions in transactivation, was measured.Results: We found that HG suppressed claudins-5 and -11 gene expression in HCMECs, and TXL reversed the HG-mediated inhibition of claudins-5 and -11 mRNA and protein expressions. Treatment with high-dose of TXL promoted cell membrane localization of claudins-5 and -11 in HG-stimulated HCMECs. Furthermore, high-dose of TXL blocked the inhibition of H3K9ac inclaudin-5andclaudin-11gene promoters caused by exposure to HG, thus activating gene transcription.Conclusions: Our results show that HG suppressed claudins-5 and -11 in HCMECs, and TXL could reverse the HG-induced suppression of claudins-5 and -11 by increasing H3K9ac in their respective gene promoters. [ABSTRACT FROM AUTHOR]

Tongxinluo (TXL) is one of the most common traditional Chinese medicines and plays a vital role in treating atherosclerosis (AS). Endothelial cell (EC) pyroptosis plays a crucial role in the development of AS. Previous research revealed the inhibitory function of TXL in EC apoptosis and autophagy. However, whether TXL can inhibit the pyroptosis of ECs has not been determined. To explore the influence of TXL on EC pyroptosis and determine its underlying mechanism of action in AS. The TXL components were determined by ultra-performance liquid chromatography coupled with a photodiode array detector. We used ApoE−/− mice to establish a disease model of AS. After treatment with TXL, we recorded pathological changes in the mice and performed immunofluorescence staining of mice aortas. We also measured protein and gene levels to explore the influence of TXL on pyroptosis in vivo. The model was established by stimulating mouse aortic endothelial cells (MAECs) with oxidized low-density lipoprotein (ox-LDL) and analyzing the effect of TXL on pyroptosis by Western blotting (WB), real-time PCR (RT-PCR), and flow cytometry (FCM). We also investigated the impact of TXL on reactive oxygen species (ROS) by FCM and WB. Ten major components of TXL were detected. The vivo results showed that TXL inhibited the development of AS and decreased EC pyroptosis, the activation of caspase-1, and the release of inflammatory cytokines. The vitro experiments showed that TXL significantly reduced the extent of injury to MAECs by oxidized LDL (ox-LDL). TXL reversed the high expression of gasdermin D and other proteins induced by ox-LDL and had a significant synergistic effect with the caspase-1 inhibitor VX-765. We also confirmed that TXL decreased the accumulation of ROS and the expression levels of its essential regulatory proteins Cox2 and iNOS. When ROS accumulation was reduced, EC pyroptotic damage was reduced accordingly. Our results indicated that TXL inhibited EC pyroptosis in AS. Reducing the accumulation of ROS may be the essential mechanism of AS inhibition by TXL. [Display omitted] • Tongxinluo (TXL) delayed the development of atherosclerosis (AS). • TXL inhibited endothelial cell pyroptosis during the development of AS. • TXL inhibited endothelial cell pyroptosis by reducing the accumulation of ROS. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Tongxinluo (TXL), which is a Chinese medicine rooted from traditional used herbs, has been used in clinic to treat cardiovascular and cerebrovascular diseases. However, it remains unknown whether TXL alleviates low pressure hypoxic pulmonary hypertension. Aim of the study Here, we aimed to observe the influence of TXL on pulmonary hypertension in a rat model that exposed to high altitude environment characterized by low pressure hypoxia. Materials and methods A total of 32 male Sprague-Dawley rats were divided into four groups: control group (normal pressure and normoxia), pulmonary hypertension group (PAH, the parameter is equal to that in altitude 5000 m), TXL group (rats living in environment equal to that at altitude of 5000 m received TXL treatment), vardenafil group (VDNF, rats living in environment equal to that altitude of 5000 m received vardenafil treatment). The high altitude environment was created in chamber by adjusting the inner pressure and oxygen content concomitantly. Before entering the chamber, the TXL group was given TXL (1.2 g kg −1 d −1 ) for 28 days, and the VDNF group was given VDNF (0.1 g kg −1 d −1 ) for 28 days. After 28 days, the mean pulmonary artery pressure (mPAP) and right ventricular pressure was measured using right heart catheterization. The weight of the right ventricle (RV), left ventricle (LV) and interventricular septum (IVS) was measured, and the right ventricular mass index was calculated. Lung tissue was subjected to hematoxylin and elastic fiber staining, and the medial wall thickness (MT), medial wall cross-sectional area (MA), MT%, and MA% were measured. Proliferative activity within the pulmonary arteries was quantified by Ki67staining. Results After 28 days, as compared with that in normal control group, animals living in the chamber (PAH group) showed a significant increase in mPAP( 47.5 mmHg versus 18 mmHg), RV/LV+IVS (0.45 versus 0.21) and MA% (78% versus 44%), respectively. Administration of TXL resulted in a significant decrease of 20 mmHg in mPAP, returning of RV/LV+IVS to 0.27, and a 40% reduction in MT% compared with that in PAH group. In the VDNF group, RV/LV+IVS and MT% was 0.268 and 38.77, significantly lower than that in PAH group. While, mPAP increased by 12.5 mmHg with treatment by VDNF. In contrast to the PAH group, alpha- Smooth Muscle Actin (α-SMA reduced by 19% in the TXL group (p=0.005) and 16% in the VDNF group (p=0.01). Ki67 expression in the VDNF group was significantly lower than the PAH group (P<0.01). Ki67 expression in the TXL group was significantly lower than the PAH group (P<0.01). Compared with the VDNF group, the indexes above reduced in the TXL group. Our results indicate that TXL significantly reduces pulmonary artery pressure, right ventricular hypertrophy, pulmonary small artery wall thickness, and luminal stenosis. In addition, smooth muscle proliferation markedly decreased and muscular artery decreased. However, TXL was unable to restore parameters to control levels. Conclusions The automatic-adjusted low pressure hypoxic chamber was capable of establishing a pulmonary hypertension rat model at an altitude of 5000 m. Compared with VDNF, TXL decreased mPAP and right ventricular hypertrophy index (RVHI) in the pulmonary hypertension rat model, and prevented vascular remodeling by reducing small pulmonary artery thickening, smooth muscle thickening and proliferation. Thus, TXL may be a potential treatment for pulmonary hypertension. [ABSTRACT FROM AUTHOR]

Atherosclerosis, as a common arterial disease with high morbidity rate, is reported to be closely associated with adventitia angiogenesis. The present study aimed to investigate the effect of tongxinluo (TXL) on angiogenesis in the carotid adventitia of hyperlipidemic rabbits and the underlying mechanism. A total of 90 experimental rabbits were randomly assigned into the following six groups (n=15 per group): Normal group, model group, low-dose TXL group, moderate-dose TXL group, high-dose TXL group and atorvastatin group. The normal group was fed with a standard diet. The model and treatment groups were on a high cholesterol diet for 4 weeks. The serum lipid level of the model group was significantly higher compared with the normal group. TXL serum lipid level compared with the model group. Hematoxylin and eosin, and CD31 staining demonstrated that TXL inhibited adventitia angiogenesis in a dose-dependent manner. The dihydroethidium probe and fluorescence in situ hybridization results indicated that TXL reduced O2 - level and positive signal of gp91phox and p22phox mRNA in adventitia. Reverse transcription-polymerase chain reaction and western blot analysis determined that TXL treatment significantly downregulated the expression levels of the gp91phox, p22phox genes and the vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor-2 (VEGFR-2) proteins compared with the model group. TXL exhibited a dose-dependent inhibitory effect on angiogenesis in the carotid adventitia of hyperlipidemic rabbits. This may be associated with the downregulation of reactive oxygen species generation in the adventitia and the suppression of VEGF/VEGFR-2 expression. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Tongxinluo (TXL), a widely used traditional Chinese medicine, has been proved multiple therapeutic effects in cerebral ischemic infraction. The purpose of this study was to investigate the protective effects of TXL on the brain edema and post-ischemic inflammatory response. Materials and Methods Middle cerebral artery occlusion in the rat was used as the ischemia model. Rats were treated with TXL. In the first stage, the best dosage was chosen based on functional assessment and infarct size. In the second stage, rats were randomly divided into 5 groups: sham control (sham), ischemia and reperfusion (IR) 24 h, TXL24h, I/R72h, TXL72h. TXL(1.6 g/kg/day) administration was pre-performed for 3 days in TXL groups, and was post-performed for 24 h (TXL24h group) or 72 h (TXL72h group). Brain edema was measured by water content, MRI and AQP4 expression. Iba1, HMGB1, TLR4, NF-κB expression were examined by immunofluorescence staining or Western blot. TNF-α was determined by enzyme-linked immunosorbent assay. Results High dose (1.6 g/kg/day) of TXL remarkably reduced neurological deficit scores and cerebral infarct area. Compared with those results of I/R24h group, pre-post treatment with TXL for 3 days decreased brain water content, down-regulated AQP4 expression, lowered relative signal intensity of T2WI, reduced lesion volume ratio, and inhibited the activation of microglia, HMGB1, TLR4, NF-κB and TNF-α. Conclusions These results indicated that the TXL pre-post treatment for 3 days could be an effective therapy for brain ischemia by inhibiting the development of brain edema and post-ischemic inflammation. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Tongxinluo (TXL), a compound prescription, is formulated according to the collateral disease doctrine of traditional Chinese medicine, and is widely used for the treatment of cardio-cerebrovascular diseases in China. Aim of the study We aimed to investigate the neuroprotective effect of TXL on focal cerebral ischemia and reperfusion injury in rats by attenuating its brain damage and neuronal apoptosis, and to assess the potential role of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway in this protection. Materials and methods Adult Male Sprague-Dawley rats ( n =120) were randomly divided into 5 groups: sham, cerebral ischemia and reperfusion (I/R), cerebral ischemia and reperfusion plus TXL (1.6 g/kg/day) (TXL1.6), TXL1.6 plus LY294002 and dimethyl sulfoxide (DMSO) (TXL1.6+LY294002), TXL1.6 plus DMSO (TXL1.6+vehicle). Prior to the grouping, TXL1.6 was selected to be the optimal dose of TXL by evaluating the neurological deficits score of five group rats (Sham, I/R, TXL0.4, TXL0.8 and TXL1.6, n =30) at 0, 1, 3, 5, and 7 days after reperfusion. Rats, being subjected to middle cerebral artery occlusion (MCAO) for 90 min followed by 24 h reperfusion, were the cerebral ischemia/reperfusion models. At 24 h after reperfusion, cerebral infarct area was measured via tetrazolium staining and neuronal damage was showed by Nissl staining. The double staining of Terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphosphate nick end labeling (TUNEL) staining and immunofluorescence labeling with NeuN, was performed to evaluate neuronal apoptosis. Proteins involved in PI3K/Akt pathway were detected by Western blot. Results The results showed that TXL markedly improved neurological function, reduced cerebral infarct area, decreased neuronal damage, and significantly attenuated neuronal apoptosis, while these effects were eliminated by inhibition of PI3K/Akt with LY294002. We also found that TXL up-regulated the expression levels of p-PDK1, p-Akt, p-c-Raf, p-BAD and down-regulated Cleaved caspase 3 expression notably, which were partially reversed by LY294002. Additionally, the increment of p-PTEN level on which LY294002 had little effect was also detected in response to TXL treatment. Conclusions These findings demonstrated that TXL provided neuroprotection against cerebral ischemia/reperfusion injury and neuronal apoptosis, and this effect was mediated partly by activation of the PI3K/Akt pathway. [ABSTRACT FROM AUTHOR]

Background The aim of this study was to explore the effect of Tongxinluo on myocardial fibrosis in diabetic rats and its possible mechanism of action. Methods Diabetic rat models were established and then divided into three groups: control, diabetes, and Tongxinluo groups. Heart function and myocardial interstitial collagen volume fraction were investigated, and the protein and mRNA expression levels of transforming growth factor beta 1 (TGF-β 1 ), Smad 3 , and Smad 7 were measured. Results Heart function was clearly abnormal in the diabetes group compared with that in the control group, and the collagen volume fraction and mRNA expression levels of TGF-β 1 and Smad 3 were higher. However, the protein and mRNA expression levels of Smad 7 were lower. In the Tongxinluo group, it was observed that these indicators were improved. Conclusion Tongxinluo was effective for the prevention and treatment of myocardial fibrosis in diabetic rats. It probably mediates the expressions of TGF-β 1 , Smad 3 , and Smad 7 in rat cardiomyocytes to reduce the occurrence of myocardial fibrosis in diabetic rats. [ABSTRACT FROM AUTHOR]

Tongxinluo (TXL) is a compound prescription formulated according to the meridian theory of traditional Chinese medicine. It may play an important role in cardiovascular protection by improving endothelial cell function. The aim of present study was to investigate whether endothelial protection with TXL is related to its regulation of tight junction protein expression. Human cardiac microvascular endothelial cells (HCMECs) were cultured and treated with 10-7 moll-1 angiotensin II (Ang II) and the different doses of TXL; the expression of tight junction proteins occludin, claudin, VE-cadherin and beta-catenin was determined by Western blotting and real-time PCR. Gain-of-function and loss-of-function of Krüppel-like factor 5 (KLF5) were carried out in HCMEC transfected with either KLF5 adenovirus pAd-KLF5 or siRNA specific for KLF5. Angiotensinogen transgenic mice were treated with TXL by oral administration of TXL of 0.75 g kg-1 day-1, and immunohistochemical staining was performed with antioccludin, anticlaudin, anti-VE-cadherin, antibeta-catenin and anti-KLF5 antibodies. Ang II treatment significantly reduced the expression of tight junction proteins occludin, claudin, VE-cadherin and beta-catenin in cultured HCMECs. TXL pretreatment could abrogate the down-regulation of these tight junction proteins induced by Ang II. Ang II treatment also decreased KLF5 expression at the mRNA and protein levels; TXL pretreatment markedly reversed the inhibitory effect of Ang II on KLF5 expression. Gain-of-function and loss-of-function of KLF5 showed that KLF5 mediated the expression of tight junction proteins in HCMECs. TXL-enhanced expression of the tight junction proteins was mediated by KLF5. In angiotensinogen transgenic mice, TXL also increased the tight junction protein levels by inducing KLF5 expression. Chinese medicine TXL increases tight junction protein levels by inducing KLF5 expression in microvascular endothelial cells. [ABSTRACT FROM AUTHOR]

Activated macrophages contribute to endothelial dysfunction; however, it is unclear how peroxynitrite contributes to macrophage-mediated human cardiac microvascular endothelial cell (HCMEC) injury in hypoxia. In macrophage-HCMEC co-cultures subjected to hypoxia, there was an increase in hypoxia-inducible factor (HIF)-1α, HIF-2α, inducible nitric oxide synthase (iNOS), endothelin-converting enzyme (ECE)-1 and cyclooxygenase-2 (COX-2), and concomitant decrease in prostacyclin synthase (PGIS). This was mimicked by a peroxynitrite donor and attenuated by its decomposition catalyst. Tongxinluo (TXL) could decrease HIF-2α, iNOS, ECE-1 and COX-2 and increase PGIS in a dose-dependent manner, with increase of vascular endothelial growth factor. The protein alterations verified the remarkably affected mRNAs, indicating that the effects of TXL were similar to but better than that of peroxynitrite decomposition catalyst. Furthermore, TXL inhibited macrophage-mediated nitrotyrosine accumulation and attenuated HCMEC injury. The results suggest that peroxynitrite contributes to macrophage-mediated HCMEC injury in hypoxia, and TXL attenuates HCMEC injury mainly by inhibiting peroxynitrite. [ABSTRACT FROM AUTHOR]

Objective: Tongxinluo (TXL) is a traditional Chinese medicine (TCM). It is used to treat coronary heart disease and atherosclerosis. We investigated the effects of TXL on the neointima formation and expression of inflammatory cytokines in rats after carotid artery balloon injury. Materials and Methods: Male Sprague-Dawley rats were randomly divided into four groups: sham operation group (Sham, n = 15), balloon injury group treated with vehicle (Control, n = 15), TXL low-dose group treated with TXL of 0.5 g/kg/d (TXL-L, n = 15), and TXL high-dose group treated with TXL of 1.0 g/kg/d (TXL-H, n = 15). TXL was given by gavage daily. 14 days after injury`, the levels of serum nitric oxide (NO), endothelin-1 (ET-1), monocyte chemoattractant protein-1 (MCP-1), and soluble intercellular adhesion molecule-1 (sICAM-1) were evaluated. The morphology of carotid artery tissue was observed with hematoxylin-eosin staining. Expressions of MCP-1 and ICAM-1 in the artery were detected by real-time polymerase chain reaction (RT-PCR) and western blotting. Results: 14 days after injury, a signifi cant increase in concentrations of serum ET-1, MCP-1, and sICAM-1 (P < 0.05), as well as a signifi cant decrease in NO serum level were observed in rats subjected to artery injury compared to the sham rats (P < 0.05). TXL significantly decreased ET-1, MCP-1 and sICAM-1 serum levels (P < 0.05), whereas significantly increased NO serum level compared with the control (P < 0.05). TXL significantly reduced the neointimal thickening at day 14 after injury (P < 0.05). In addition, TXL significantly reduced mRNA and protein expressions of ICAM-1 and MCP-1 in injured artery (P < 0.05). Conclusions: This study demonstrates that TXL is effective in improving endothelial function, attenuating neointimal formation of artery after balloon injury, and reducing expression of infl ammatory cytokine MCP-1 and ICAM-1. It may be a useful agent for protecting the artery against injury. [ABSTRACT FROM AUTHOR]

Tongxinluo (TXL), a traditional Chinese medicine, has multiple vasoprotective effects, including anti-inflammation. MicroRNA-155 (miR-155) is involved in vascular inflammation and atherosclerosis. However, a direct relationship between TXL and miR-155 in the development of vascular inflammation and remodeling had not yet been shown. The objective of the present study was to investigate whether TXL exerts an inhibitory effect on the vascular inflammatory response and neointimal hyperplasia by regulating miR-155 expression. Using the carotid artery ligation model in mice, we have shown that TXL dose dependently inhibited neointimal formation and reduced the vascular inflammatory response by inhibiting inflammatory cytokine production and macrophage infiltration. miR-155 was induced by carotid artery ligation, and neointimal hyperplasia was strongly reduced in miR-155-/- mice. In contrast, miR-155 overexpression partly reversed the inhibitory effect of TXL on neointimal hyperplasia. In bone marrow-derived macrophages, miR-155 and TNF-α formed a positive feedback loop to promote the inflammatory response, which could be blocked by TXL. Furthermore, TXL increased Akt1 protein expression and phosphorylation in TNF--stimulated marrow-derived macrophages, and knockdown of Akt1 abrogated the TXL-induced suppression of miR-155. In conclusion, TXL inhibits the vascular inflammatory response and neointimal hyperplasia induced by carotid artery ligation in mice. Suppression of miR-155 expression mediated by Akt1 and blockade of the feedback loop between miR-155 and TNF-α are important pathways whereby TXL exerts its vasoprotective effects. [ABSTRACT FROM AUTHOR]

Purpose: Tongxinluo, a well-known traditional Chinese medicine complex, has been widely used for the treatment of cerebrovascular diseases in China. The present study was to explore whether treatment with tongxinluo could improve neurological function and alleviate secondary damage in the ipsilateral thalamus after focal cortical infarction in hypertensive rats. Methods: Tongxinluo was given through oral gavage starting 24 h after distal middle cerebral artery occlusion (MCAO). Neurological function was assessed and then rats were sacrificed 7 and 14 days after MCAO. Brains were harvested for examining infarction volume, Nissl staining and immunofluorescence analysis. Results: Compared with vehicle treatment, tongxinluo remarkably improved neurological function without reducing infarction volume, attenuated neuronal loss and astrocyte activation in the ipsilateral thalamus 7 and 14 days after MCAO (all p < 0.05). Also, tongxinluo markedly increased the number of BrdU+/nestin+ and BrdU+/NeuN+ cells 14 days after MCAO. Moreover, vascular density, the number of BrdU+ vascular endothelial cells, and vascular perimeter in the ipsilateral thalamus were markedly increased in the tongxinluo group relative to that of the vehicle group (all p < 0.05). Conclusion: Administration of tongxinluo 24 h after cortical infarction may promote neurogenesis and angiogenesis in the ipsilateral thalamus and improves neurological function after cortical infarction in rats. [ABSTRACT FROM AUTHOR]