Risk stratification system and visualized dynamic nomogram constructed for predicting diagnosis and prognosis in rare male breast cancer patients with bone metastases.

Background: Bone metastases (BM) from malignant tumors could disrupt the balance between osteoclasts and osteoblasts and affect bone homeostasis. Malignant breast cancer (BC) is rare in male patients, and co-occurrence of BM is even rarer. Given its low incidence, there is limited research evaluating risk and prognosis. Despite the widespread application of nomograms to predict uncommon malignancies, no studies have constructed predictive models focusing on the diagnosis and prognosis of male breast cancer with bone metastases (MBCBM). Methods: This study selected all male breast cancer patients (MBC) between 2010 and 2019 in the Surveillance, Epidemiology, and End Results (SEER) database. We used simple and multivariate Logistic regression analyses to identify independent risk factors for BM in MBC patients. Then simple and multivariate Cox regression analyses were employed to determine the independent prognostic factors for overall survival (OS) and cancer-specific survival (CSS) in MBCBM patients. We established and validated three new nomograms based on these independent factors. Result: A total of 4187 MBC patients were included, with 191 (4.56%) having bone metastases at the time of diagnosis. The independent risk factors of BM in MBC patients included age, tumor size, marital status, T stage, and N stage. In MBCBM patients, independent prognostic factors for OS and CSS were both age, T stage, ER status, PR status, and surgery. The concordance index (C-index), the area under the curve (AUC) of the receiver operating characteristic curve (ROC), the calibration curve, and the decision curve analysis (DCA) confirmed that these three nomograms could accurately predict the diagnosis and prognosis of MBCBM patients with excellent discrimination and clinical utility superior to the TNM staging system. We then established two prognostic-based risk stratification systems and three visualized dynamic nomograms that could be applied in clinical practice. Conclusion: In conclusion, this study aimed to establish and validate an accurate novel nomogram to objectively predict the diagnosis and prognosis of MBCBM patients. On this basis, prognostic-based risk stratification systems and visualized dynamic nomograms were constructed to facilitate doctors and patients to quantify individual BM risk probability and survival probability to assist in personalized risk assessment and clinical decision-making.

Risk stratification system and web-based nomogram constructed for predicting the overall survival of primary osteosarcoma patients after surgical resection.

Background: Previous prediction models of osteosarcoma have not focused on survival in patients undergoing surgery, nor have they distinguished and compared prognostic differences among amputation, radical and local resection. This study aimed to establish and validate the first reliable prognostic nomogram to accurately predict overall survival (OS) after surgical resection in patients with osteosarcoma. On this basis, we constructed a risk stratification system and a web-based nomogram. Methods: We enrolled all patients with primary osteosarcoma who underwent surgery between 2004 and 2015 in the Surveillance, Epidemiology, and End Results (SEER) database. In patients with primary osteosarcoma after surgical resection, univariate and multivariate cox proportional hazards regression analyses were utilized to identify independent prognostic factors and construct a novel nomogram for the 1-, 3-, and 5-year OS. Then the nomogram's predictive performance and clinical utility were evaluated by the concordance index (C-index), receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). Result: This study recruited 1,396 patients in all, with 837 serving as the training set (60%) and 559 as the validation set (40%). After COX regression analysis, we identified seven independent prognostic factors to develop the nomogram, including age, primary site, histological type, disease stage, AJCC stage, tumor size, and surgical method. The C-index indicated that this nomogram is considerably more accurate than the AJCC stage in predicting OS [Training set (HR: 0.741, 95% CI: 0.726-0.755) vs. (HR: 0.632, 95% CI: 0.619-0.645); Validation set (HR: 0.735, 95% CI: 0.718-0.753) vs. (HR: 0.635, 95% CI: 0.619-0.652)]. Moreover, the area under ROC curves, the calibration curves, and DCA demonstrated that this nomogram was significantly superior to the AJCC stage, with better predictive performance and more net clinical benefits. Conclusion: This study highlighted that radical surgery was the first choice for patients with primary osteosarcoma since it provided the best survival prognosis. We have established and validated a novel nomogram that could objectively predict the overall survival of patients with primary osteosarcoma after surgical resection. Furthermore, a risk stratification system and a web-based nomogram could be applied in clinical practice to assist in therapeutic decision-making.

Geniposide downregulates the VEGF/SphK1/S1P pathway and alleviates angiogenesis in rheumatoid arthritis in vivo and in vitro.

The VEGF/SphK1/S1P pathway is closely related to angiogenesis in rheumatoid arthritis (RA), but the precise underlying mechanisms are unclear at present. Here, we explored the involvement of the VEGF/SphK1/S1P cascade in RA models and determined the effects of GE intervention. Our results showed abnormal expression of proteins related to this pathway in RA synovial tissue. Treatment with GE effectively regulated the signal axis, inhibited angiogenesis, and alleviated RA symptoms. In vitro, TNF-ɑ enhanced the VEGF/SphK1/S1P pathway in a co-culture model of fibroblast-like synoviocytes (FLS) and vascular endothelial cells (VEC). GE induced downregulation of VEGF in FLS, restored the dynamic balance of pro-/antiangiogenic factors, and suppressed SphK1/S1P signaling in VEC, resulting in lower proliferation activity, migration ability, tube formation ability, and S1P secretion ability of VEC cells. Additionally, SphK1-specific small interfering RNA (siRNA) blocked the VEGF/SphK1/S1P cascade, which can effectively alleviate the stimulatory effect of FLS on VEC and further enhanced the therapeutic effect of GE. Taken together, our results demonstrate that GE suppresses the VEGF/SphK1/S1P pathway and alleviates the stimulation of VEC by FLS, thereby preventing angiogenesis and promoting therapeutic effects against RA.

Anti-Inflammatory Effect of Geniposide on Regulating the Functions of Rheumatoid Arthritis Synovial Fibroblasts via Inhibiting Sphingosine-1-Phosphate Receptors1/3 Coupling Gαi/Gαs Conversion.

The activated Gα protein subunit (Gαs) and the inhibitory Gα protein subunit (Gαi) are involved in the signal transduction of G protein coupled receptors (GPCRs). Moreover, the conversion of Gαi/Gαs can couple with sphingosine-1-phosphate receptors (S1PRs) and have a critical role in rheumatoid arthritis (RA). Through binding to S1PRs, sphingosine-1-phosphate (S1P) leads to activation of the pro-inflammatory signaling in rheumatoid arthritis synovial fibroblasts (RASFs). Geniposide (GE) can alleviate RASFs dysfunctions to against RA. However, its underlying mechanism of action in RA has not been elucidated so far. This study aimed to investigate whether GE could regulate the biological functions of MH7A cells by inhibiting S1PR1/3 coupling Gαi/Gαs conversion. We use RASFs cell line, namely MH7A cells, which were obtained from the patient with RA and considered to be the main effector cells in RA. The cells were stimulated with S1P (5 µmol/L) and then were treated with or without different inhibitors: Gαi inhibitor pertussis toxin (0.1 µg/mL), S1PR1/3 inhibitor VPC 23019 (5 µmol/L), Gαs activator cholera toxin (1 µg/mL) and GE (25, 50, and 100 µmol/L) for 24 h. The results showed that GE may inhibit the abnormal proliferation, migration and invasion by inhibiting the S1P-S1PR1/3 signaling pathway and activating Gαs or inhibiting Gαi protein in MH7A cells. Additionally, GE could inhibit the release of inflammatory factors and suppress the expression of cAMP, which is the key factor of the conversion of Gαi and Gαs. GE could also restore the dynamic balance of Gαi and Gαs by suppressing S1PR1/3 and inhibiting Gαi/Gαs conversion, in a manner, we demonstrated that GE inhibited the activation of Gα downstream ERK protein as well. Taken together, our results indicated that down-regulation of S1PR1/3-Gαi/Gαs conversion may play a critical role in the effects of GE on RA and GE could be an effective therapeutic agent for RA.

Application of a classroom-based positive psychology education course for Chinese medical students to increase their psychological well-being: a pilot study.

BACKGROUND: Anxiety and depression have been increasing among Chinese medical students. The psychological well-being of Chinese medical students has become a critical focus of attention for the medical education community. Increasing evidence shows that positive psychology interventions can be effective in the enhancement of psychological well-being, and may help to prevent depressive symptoms in university students. In the present study, we aimed to explore the potential effect of positive psychology education on improving the mental health of Chinese medical students. METHODS: An 8-week classroom-based positive psychology intervention workshop, which was established as an elective course embedded in the regular school curriculum, was conducted at the School of Medicine, South China University of Technology (SCUT), China. Undergraduate medical students of the institute in year-2 or year-3 of academic study participated in this training course voluntarily. The participants' self-reported data on the hope scale, life satisfaction scale, subjective happiness scale, and depression and anxiety scale were collected and analyzed at pre-course (n = 61) and post-course (n = 49) times. The investigation was also validated with an independent cohort of students who enrolled in the course in the year following the preliminary study. RESULTS: The analyses showed that the psychological well-being of the participants were improved after the intervention. Their mean scores on the hope scale, life satisfaction scale and subjective happiness scale were significantly improved (P < 0.05), while their symptom levels of depression and anxiety were significantly reduced (P < 0.01). A similar trend was observed in the validation cohort. CONCLUSIONS: These preliminary findings suggest that positive psychology education holds promise for improving psychological well-being among Chinese medical students. Further investigations with larger and well-controlled sample cohorts may yield more convincing and reliable results.

Acute stroke patients' knowledge of stroke at discharge in China: a cross-sectional study.

OBJECTIVES: A good mastery of stroke-related knowledge can be of great benefit in developing healthy behaviours. This study surveyed the knowledge about stroke and influencing factors among patients with acute ischaemic stroke (AIS) at discharge in a Chinese province. METHODS: A cross-section study was conducted from November 1, 2014 to January 31, 2015. A total of 1531 AIS patients in Hubei Province completed a questionnaire at discharge. Multivariate linear regression was used to identify the influencing factors of their knowledge of stroke. RESULTS: About 31.2% of the respondents did not know that stroke is caused by blockage or rupture of cerebral blood vessels and 20.3% did not realise they need immediate medical attention after onset. Approximately 50% did not know that sudden blurred vision, dizziness, headache and unconsciousness are the warning signs of stroke. Over 40% were not aware of the risk factors of the condition, such as hypertension, hyperlipidaemia, diabetes mellitus, smoking and obesity. Over 20% had no idea that they need long-term medication and strict control of blood pressure, blood lipids and blood sugar. Their knowledge levels were correlated with regions of residence (P < 0.0001), socioeconomic status (P < 0.05), physical condition (P < 0.01), previous stroke (P < 0.0001) and family members and friends having had a stroke (P < 0.01). CONCLUSIONS: Most AIS patients in Hubei Province, China, had little knowledge of stroke at discharge. Further efforts should be devoted to strengthening the in-hospital education of stroke patients, especially those with a low income and those from rural areas.

Chinese neurologists' perspective on intravenous thrombolysis for acute ischemic stroke.

Objectives: This study examined the neurologists' perspective toward intravenous thrombolysis for the treatment of acute ischemic stroke and the influencing factors in a Chinese Province. Methods: A cross-sectional study was conducted from 1 October 2014 to 31 January 2015. A total of 719 neurologists from 66 hospitals in Hubei Province were included. A questionnaire was designed, and multivariable logistic regression models were used to identify the factors associated with the neurologists' perspective toward intravenous thrombolysis. Results: Among the responding neurologists, 67.3% reported using intravenous thrombolysis and 32.9% believed the treatment was unsafe. Approximately 51.4% reported deficits in their knowledge of intravenous thrombolysis and 45.8% felt unconfident about their ability to employ the treatment. The majority (90.1%) supported hospitals in performing intravenous thrombolysis for eligible patients. Their safety concern was associated with hospital grade (odds ratio[OR] = 2.3; 95% confidence interval [CI], 1.4-3.7) and previous experiences with thrombolysis (OR = 3.1; 95% CI, 2.1-4.6). Their confidence was associated with their educational background (OR = 2.5; 95% CI, 1.3-4.5), knowledge mastery (OR = 10.4; 95% CI, 6.6-16.3), and previous experiences with thrombolysis (OR = 3.3; 95% CI, 2.1-5.3). Their attitudes were associated with gender (OR = 0.6; 95% CI, 0.3-1.0) and previous experiences with thrombolysis (OR = 4.9; 95% CI, 2.5-9.4). Conclusions: Most neurologists in Hubei Province, China, identified with intravenous thrombolysis for the treatment of acute ischemic stroke. However, they were weak in knowledge and lack confidence. Therefore, training, especially practical training, is needed to promote the use of thrombolysis in the region.

MicroRNA-130a regulates cerebral ischemia-induced blood-brain barrier permeability by targeting Homeobox A5.

Blood-brain barrier (BBB) disruption plays a critical role in brain injury induced by cerebral ischemia, and preserving BBB integrity during ischemia could alleviate cerebral injury. We examined the role of miR-130a in ischemic BBB disruption by using models of rat middle cerebral artery occlusion and cell oxygen-glucose deprivation. We found that ischemia significantly increased microRNA-130a (miR-130a) level and that miR-130a was predominantly from brain microvascular endothelial cells. Antagomir-130a, an antagonist of miR-130a, could attenuate brain edema, lower BBB permeability, reduce infarct volume, and improve neurologic function. MiR-130a overexpression induced by miR-130a mimic increased monolayer permeability, and intercellular inhibition of miR-130a by a miR-130a inhibitor suppressed oxygen-glucose deprivation-induced increase in monolayer permeability. Moreover, dual luciferase reporter system showed that Homeobox A5 was the direct target of miR-130a. MiR-130a, by inhibiting Homeobox A5 expression, could down-regulate occludin, thereby increasing BBB permeability. Our results suggested that miR-130a might be implicated in ischemia-induced BBB dysfunction and serve as a target for the treatment of ischemic stroke.-Wang, Y., Wang, M.-D., Xia, Y.-P., Gao, Y., Zhu, Y.-Y., Chen, S.-C., Mao, L., He, Q.-W., Yue, Z.-Y., Hu, B. MicroRNA-130a regulates cerebral ischemia-induced blood-brain barrier permeability by targeting Homeobox A5.

Gastrointestinal stability of dihydromyricetin, myricetin, and myricitrin: an in vitro investigation.

The gastrointestinal (GI) stability of three flavonoids, dihydromyricetin (DMY), myricetin (MYR), and myricitrin (MYT), was examined in simulated physiological fluids. Several factors that may influence the degradation rate of theses flavonoids were evaluated, including pH and the presence of pepsin and pancreatin enzymes. We found that GI stability followed the order of MYT > DMY > MYR. These flavonoids were stable in simulated gastric fluids and buffer solutions (pH 1.2), but encountered a pseudo-first-order kinetic degradation in simulated intestinal fluids and buffer solutions (pH 6.8). We conclude that it is the pH, rather than the presence of pepsin or pancreatin, which most strongly influences the stability of these three flavonoids. Further study of the stability of the compounds using a pH range (1.0-8.0) indicated potential instability in the duodenum, small intestine, and colon. Therefore, we conclude that the low bioavailability of these flavonoids may be due to their poor stability in the GI tract.

P2Y12 Promotes Migration of Vascular Smooth Muscle Cells Through Cofilin Dephosphorylation During Atherogenesis.

OBJECTIVE: P2Y12 is a well-recognized receptor expressed on platelets and the target of thienopyridine-type antiplatelet drugs. However, recent evidence suggests that P2Y12 expressed in vessel wall plays a role in atherogenesis, but the mechanisms remain elusive. In this study, we examined the molecular mechanisms of how vessel wall P2Y12 mediates vascular smooth muscle cells (VSMCs) migration and promotes the progression of atherosclerosis. APPROACH AND RESULTS: Using a high-fat diet-fed apolipoprotein E-deficient mice model, we found that the expression of P2Y12 in VSMCs increased in a time-dependent manner and had a linear relationship with the plaque area. Moreover, administration of P2Y12 receptor antagonist for 12 weeks caused significant reduction in atheroma and decreased the abundance of VSMCs in plaque. In cultured VSMCs, we found that activation of P2Y12 receptor inhibited cAMP/protein kinase A signaling pathway, which induced cofilin dephosphorylation and filamentous actin disassembly, thereby enhancing VSMCs motility and migration. In addition, the number of P2Y12-positive VSMCs was decreased in the carotid artery plaque from patients receiving clopidogrel. CONCLUSIONS: Vessel wall P2Y12 receptor, which promotes VSMCs migration through cofilin dephosphorylation, plays a critical role in the development of atherosclerotic lesion and may be used as a therapeutic target for atherosclerosis.

MiR-181b Antagonizes Atherosclerotic Plaque Vulnerability Through Modulating Macrophage Polarization by Directly Targeting Notch1.

Atherosclerotic plaque vulnerability is the major cause for acute stroke and could be regulated by macrophage polarization. MicroRNA-181b (miR-181b) was involved in macrophage differential. Here, we explore whether miR-181b could regulate atherosclerotic plaque vulnerability by modulating macrophage polarization and the underline mechanisms. In acute stroke patients with atherosclerotic plaque, we found that the serum level of miR-181b was decreased. Eight-week apolipoprotein E knockout (ApoE-/-) mice were randomly divided into three groups (N = 10): mice fed with normal saline (Ctrl), mice fed with high-fat diet, and tail vein injection with miRNA agomir negative control (AG-NC)/miR-181b agomir (181b-AG, a synthetic miR-181b agonist). We found that the serum level of miR-181b in AG-NC group was lower than that in Ctrl group. Moreover, 181b-AG could upregulate miR-181b expression, reduce artery burden and attenuate atherosclerotic plaque vulnerability by modulating macrophage polarization. In RAW264.7 cells treated with oxidized low-density lipoprotein (ox-LDL), we found miR-181b could reverse the function of ox-LDL on M1/M2 markers at both mRNA and protein levels. Furthermore, by employing luciferase reporter assay, we found that Notch1 was a direct target of miR-181b and could be regulated by miR-181b in vivo and in vitro. Finally, inhibition of Notch1 could abolish the function of downregulating miR-181b on increasing M2 phenotype macrophages. Our study demonstrates that administration of miR-181b could reduce atherosclerotic plaque vulnerability partially through modulating macrophage phenotype by directly targeting Notch1.

High Serum MiR-130a Levels Are Associated with Severe Perihematomal Edema and Predict Adverse Outcome in Acute ICH.

The development and/or progression of perihematomal edema (PHE) in patients with acute spontaneous intracerebral hemorrhage (ICH) vary substantially with different individuals. Although hematoma volume is a useful indicator for predicting PHE, its predictive power was not good at the early stage of ICH. Better predictors are urgently needed. In this study, we found that miR-130a was elevated in the serum of ICH patients and was an independent indicator positively associated with PHE volume within the first 3 days after onset. The R (2) was further evaluated when it is used in combination with hematoma mass. Serum miR-130a levels were associated with clinical outcome (National Institute of Health Stroke Scale (NIHSS) scores at day 14 and modified Rankin Scale (mRS) scores at day 90) only in patients with deep hematoma. Moreover, miR-130a was significantly increased in rat serum and perihematomal tissues and was in line with the change in brain edema. MiR-130a inhibitors reduced brain edema, blood-brain barrier (BBB) permeability, and increased neurological deficit scores, and miR-130a mimics increased monolayer permeability. Thrombin-stimulated brain microvascular endothelial cells (BMECs) were a main source of miR-130a under ICH. In the experimental model, the elevated miR-130a level was accompanied by the decreased caveolin-1 and increased matrix metalloproleinase (MMP)-2/9. Meanwhile, caveolin-1 (cav-1) was reduced by miR-130a mimics, accompanied by an increase in MMP-2/9 expression. The upregulated MMP-2/9 was then downregulated by cavtratin, a cav-1 scaffolding domain peptide. This regulation mechanism was authenticated in a thrombin-induced cellular ICH model. Our results suggest that serum miR-130a may serve as a useful early biomarker for monitoring post-ICH PHE and predicting prognosis and may be helpful in the decision-making of individualized therapy.

[Analysis and exploration on adverse reactions of four kinds of andrographolide injections].

Concerned literature on four kinds of andrographolide injections in recent 15 years were searched in CNKI, Wanfang and VIP databases. The adverse drug reaction(ADR) cases of Chuanhuning, Yanhuning, Xiyanping and Lianbizhi injections were classified and analyzed statistically, including a total of 194 articles and 3 479 cases. The ADR clinical characteristics and occurrence regularity of these four andrographolide injections were analyzed and compared from the gender, age, primary disease, emergence time of ADR, clinical manifestation, allergy history, dosage, prognosis and combined medication of the patients. It is useful to provide valuable references for rational use of these andrographolide injections in clinical practice.

CYP2C19 polymorphism and clinical outcomes among patients of different races treated with clopidogrel: A systematic review and meta-analysis.

Several studies have investigated the association between CYP2C19 polymorphism and clinical outcomes of patients treated with clopidogrel, but few have noticed the difference in association between Westerners and Asians. We searched MEDLINE, EMBASE and Cochrane Library database and conducted a systematic review and meta-analysis. Thirty-six studies involving 44 655 patients with coronary artery disease (CAD) treated with clopidogrel were included, of which more than 68% had undergone percutaneous coronary intervention (PCI). The primary outcome of our interest was the recurrence of major adverse cardiovascular events (MACE) in those CAD patients. Firstly, we found that the distribution of reduced-function CYP2C19 allele varied between Westerners and Asians. Among Asians, 1 and 2 reduced-function CYP2C19 mutant allele carriers accounted for 42.5% and 10%, respectively. While among Westerners, 1 and 2 reduced-function CYP2C19 mutant allele carriers accounted for 25.5% and 2.4%, respectively. Secondly, the impact of CYP2C19 polymorphism on clinical outcomes of patients treated with clopidogrel varied with races. Among Asians, only 2 reduced-function CYP2C19 mutant allele carriers had the reduced effect of clopidogrel. And the reduced effect was significant only after the 30th day of treatment. While among Westerners, both 1 and 2 reduced-function CYP2C19 allele carriers had the reduced effect, and it mainly occurred within the first 30 days. Thirdly, the safety of clopidogrel was almost the same among races. Reduced-function allele non-carriers had higher risk for total bleeding but did not have higher risk for major bleeding. It is suggested that CYP2C19 polymorphism affects the efficacy of clopidogrel differently among Westerners and Asians.

Endogenous endothelial progenitor cells participate in neovascularization via CXCR4/SDF-1 axis and improve outcome after stroke.

AIM: To study whether endogenous endothelial progenitor cells (EPCs) are involved in neovascularization after stroke. MATERIALS AND METHODS: Animal stroke models were established by subjecting male SD rats to permanent middle cerebral artery occlusion (pMCAO). Vessels in ischemic boundary zone (IBZ) were stained with antibody against laminin at 1 to 21 days after pMCAO. EPCs and newly formed vessels were identified by staining with special markers. After inhibiting recruitment of EPCs with AMD3100, a CXCR4 antagonist, endogenous EPCs, capillary density, cerebral blood flow (CBF) in IBZ, and neurobehavioral functions were assessed by staining, FITC-dextran, laser-Doppler perfusion monitor, and neurologic severity score. RESULTS: After pMCAO, vessels were found in IBZ at day 3, reaching a peak at day 14. The change in number of laminin-positive cells showed a similar pattern with that of vessels. Apart from few endothelial cells, most of laminin-positive cells were endogenous EPCs. After treatment with AMD3100, the number of endogenous EPCs, capillary density, and CBF in IBZ were significantly reduced, and neurobehavioral functions were worse as compared with the normal saline group. CONCLUSIONS: Our findings suggested that endogenous EPCs participated in the neovascularization via CXCR4/SDF-1 axis after pMCAO and mobilizing endogenous EPCs could be a treatment alternative for stroke.

Passive movement improves the learning and memory function of rats with cerebral infarction by inhibiting neuron cell apoptosis.

Passive movement has been found to improve evidently ischemic stroke patients' impaired capacity of learning and memory, but the optimal time window of initiating the therapy and the underlying mechanism are not fully understood. In this study, the effect of passive movement at different time windows on learning and memory of rats with cerebral infarction was detected. The results showed that the expression of caspase-3 and escape latency in the passive movement group were all considerably lower than those in the model group (P < 0.05), while the expression of Bcl-2 mRNA was significantly higher than those in the model group (P < 0.05). Moreover, we found that there were most significant changes of escape latency and expressions of Bcl-2 mRNA and caspase-3 when the therapy started at 24 h after focal cerebral infarction. These results suggest that passive movement is able to contribute to the recovery of learning and memory of rats with cerebral infarction, which is partially mediated by inhibiting neuron cell apoptosis, and the optimal therapeutic time is at 24 h after cerebral infarction.

Recombinant human sonic hedgehog protein regulates the expression of ZO-1 and occludin by activating angiopoietin-1 in stroke damage.

This study examines the regulating effect of Sonic Hedgehog (Shh) on the permeability of the blood-brain barrier (BBB) in cerebral ischemia. By employing permanent middle cerebral artery occlusion (pMCAO) model, we find that Shh significantly decreases brain edema and preserves BBB permeability. Moreover, Shh increases zonula occludens-1 (ZO-1), occludin and angiopiotetin-1 (Ang-1) expression in the ischemic penumbra. Blockage of Shh with cyclopamine abolishes the effects of Shh on brain edema, BBB permeability and ZO-1, occludin, Ang-1 expression. Primary brain microvessel endothelial cells (BMECs) and astrocytes were pre-treated with Shh, cyclopamine, Ang-1-neutralizing antibody, and subjected to oxygen-glucose deprivation (OGD). Results show that the Ang-1 protein level in the culture medium of Shh-treated astrocytes is significantly higher. Shh also increased ZO-1, occludin and Ang-1 expression in BMECs, while cyclopamine and Ang-1-neutralizing antibody inhibited the effects of Shh on the ZO-1 and occludin expression, respectively. This study suggests that, under ischemic insults, Shh triggers Ang-1 production predominantly in astrocytes, and the secreted Ang-1 acts on BMECs, thereby upregulating ZO-1 and occludin to repair the tight junction and ameliorate the brain edema and BBB leakage.