Hinokitiol Protects Cardiomyocyte from Oxidative Damage by Inhibiting GSK3ß-Mediated Autophagy.

More and more attention has been paid to the use of traditional phytochemicals. Here, we first verified the therapeutic potential of a natural bioactive compound called Hinokitiol in myocardial ischemia reperfusion injury. Hinokitiol exerts cardioprotective effect through inhibition of GSK-3ß and subsequent elimination of excessive autophagy, tuning autophagic activity in moderate extent for remedial profit in acute myocardial infarction and myocardial ischemia reperfusion injury. Overall, our study establishes Hinokitiol as a novel available interventional treatment for myocardial ischemia reperfusion injury.

Mesenchymal stem cell-derived microvesicles alleviate pulmonary arterial hypertension by regulating renin-angiotensin system.

In recent years, microvesicles (MVs) derived from mesenchymal stem cells (MSCs) have been proved to be able to improve the outcome of pulmonary arterial hypertension (PAH) in many respects, but the underlying mechanisms of it still remain unclear. Because the renin-angiotensin system (RAS) has been found to be closely related to PAH, the present study was designed to investigate whether the effect of MSC-derived MVs on PAH was correlated with RAS. MVs were isolated and purified from bone marrow MSCs. PAH rat models were established by a single intraperitoneal injection of 1% monocrotaline (MCT, 50 mg/Kg). In vivo study, after 3 weeks of MCT exposure, Nor group and PAH group were injected with 0.5 mL saline every 2 days through tail vein, whereas MVs group was injected with 0.5 mL saline containing 30µg MVs and A-779 + MVs group injected with 0.5 mL saline containing 120µg A-779 and 30µg MVs until 5 weeks of MCT exposure. Whereafter all the groups were analyzed for hemodynamic evaluation, right ventricular hypertrophy index, pulmonary vessel wall thickness index and pulmonary vessel lumen area index, the inflammation score, the collagen fiber volume fraction, the levels of Ang-(1-7) and Ang-Ⅱin plasma and lung tissue, and the mRNA levels of ACE2 and ACE in the lung tissue. MVs derived from MSCs relieved the pulmonary artery pressure, right ventricular hypertrophy index, pulmonary vessel wall thickness index, pulmonary vessel lumen area index, the inflammation score, and the collagen fiber volume fraction. Moreover, in MVs group, ACE2 mRNA in the lung tissues and plasma levels of Ang-(1-7) were both upregulated compared with PAH group. On the contrary, ACE and Ang-II were decreased compared with PAH group. However, the enhanced protective effects observed in MVs group were diminished by the use of A-779, an inhibitor of Mas receptor in ACE2-Ang-(1-7)-Mas axis. MVs derived from bone marrow MSCs can exert beneficial effects against MCT-induced PAH in vivo, meanwhile shifting the balance from ACE-Ang-II-AT1R axis toward the ACE2-Ang-(1-7)-Mas axis, which might be one of the possible therapeutic mechanisms for MVs subcellular treatment.

Proangiogenic compositions of microvesicles derived from human umbilical cord mesenchymal stem cells.

INTRODUCTION & OBJECTIVE: Microvesicles (MVs) derived from mesenchymal stem cells (MSCs) have been shown to promote angiogenesis. This study was aimed to shed a light on the mechanisms by analyzing the angiogenesis-promoting compositions of MSC-MVs. Also we try to figure out the impact of hypoxia on angiogenesis. METHODS: MVs were isolated from the culture supernatants of MSCs under hypoxia/normoxia and serum-deprivation condition. The morphological features of MVs were revealed by an electron microscope and the origin of the MVs was identified by a bead-bound assay. An antibody array was used to analyze the expression of angiogenic cytokines from MVs and the parent MSCs as well. The major candidate factors were screened and the results were validated by immune blotting. RESULTS: MSC-MVs were around 80 nm in diameter. They expressed CD29, CD44, and CD73, but not CD31 and CD45. Antibody array showed that both MSCs and MVs expressed many angiogenesis-promoting biomolecules, including interleukin-6 (IL-6), basic fibroblast growth factors (bFGF), and recptor of urokinase-type plasminogen activator (UPAR). MSC-MVs contained angiogenin, vascular endothelial growth factor (VEGF), monocyte chemotactic protein-1 (MCP-1) and the receptor-2 for vascular endothelial growth factor at higher levels than the parent MSCs. Under hypoxic condition most cytokines were expressed in greater quantity than normoxic in MSCs while in MVs there was no significant difference between hypoxic and normoxic conditions except UPAR, Angiogenin, VEGF, IGF, Tie-2/TEK, and IL-6 which were higher in MVs under hypoxic conditions than those in normoxic condition. CONCLUSION: Upon serum-deprivation condition, MSCs could secrete MVs that contain a variety of factors contributing to their angiogenesis-promoting function. And among them, Angiogenin, VEGF, MCP-1, VEGF R2 might be of greater importance than the other cytokines. Also UPAR, Angiogenin, VEGF, IGF, Tie-2/TEK, IL-6 might be responsible for hypoxia-augmented proangiogenic effects of MVs.

Therapeutic effects of mesenchymal stem cell-derived microvesicles on pulmonary arterial hypertension in rats.

AIM: Microvesicles (MVs) are nanoscale membrane fragments released from virtually all cell types upon activation or apoptosis, and may contribute to the beneficial effects of stem cell therapy. In this study, we investigated the therapeutic effects of mesenchymal stem cell (MSC) derived MVs (MSC-MVs) on pulmonary artery hypertension (PAH) in rats. METHODS: MSC-MVs were isolated from rat bone marrow MSCs that were cultured in a serum-free conditioned medium. Transmission electron microscopy (TEM), flow cytometry and nanoparticle tracking analysis (NTA) were used to characterize the MVs. Adult SD rats were injected with monocrotaline (50 mg/kg, sc) to induce PAH. Three weeks later, the rats were intravenously injected with MSCs, MSC-MVs or saline for 2 weeks. At the end of treatments, the hemodynamic parameters and pathological right ventricular and pulmonary arterial remodeling were analyzed in each group. RESULTS: The MSC-MVs showed general morphologic characteristics of MVs and expressed annexin V and CD29 markers under TEM, and their size ranged from 40 to 300 nm. Intravenous injection of MSC-MVs or MSCs significantly ameliorated the mean pulmonary artery pressure (mPAP) and mean right ventricle pressure (mRVP) in PAH rats. Furthermore, intravenous injection of MSC-MVs or MSCs significantly decreased the right ventricle (RV) hypertrophy and pulmonary arteriole area index (AI) and thickness index (TI) in PAH rats. CONCLUSION: Intravenous injection of MSC-MVs or MSCs produces similar beneficial effects for treating PAH, and our results provide a basis for cell-free approach in stem cell therapy.

Transfer of human hepatocyte growth factor reduces inflammation and prevents pulmonary arterial remodeling in monocrotaline-induced.

Inflammation and endothelial dysfunction contribute to the pathogenesis and development of pulmonary arterial hypertension (PAH). This study was to investigate the therapeutic effect of human hepatocyte growth factor (HGF) gene transfer on monocrotaline (MCT) induced PAH rat models. PAH was induced by injecting MCT for 4 weeks. The rats were randomly assigned to phosphate buffered saline control group, MCT group, and HGF treatment group. After 2 weeks of induction, measures of mean pulmonary artery pressure (mPAP), weight ratio of the RV to the LV plus septum, percent wall thickness index (TI) and area index (AI) were significantly increased in MCT-group and HGF treatment-group compared with those in control group (P < 0.05). Those measurements in MCT-group were significantly higher than those in HGF treatment-group (P < 0.05). IL-6 significantly decreased in HGF treatment-group compared with MCT-group, but higher than that of control group (all P < 0.05). IL-10 in HGF treatment-group significantly increased compared with MCT-group, but lower than that of control group (all P < 0.05). Endothelial microparticles (EMP) started to decrease in the HGF treatment-group 3 days after treatment and was most significant after 1 and 2 weeks of treatment (all P < 0.05). Our results showed that transfer of human HGF may attenuate the inflammatory cell infiltrate, reduce the expression of inflammatory factors, and those effects are possibly due to the inhibition of EMP production which may decrease pulmonary vascular wall damage in PAH.

[The impact of HLA high resolution typing mismatching of donor-recipient pairs on outcome of unrelated donor hematopoietic stem cell transplantation].

OBJECTIVE: To study the impact of various human leukocyte antigen (HLA) high resolution typing mismatching of donor-recipient pairs on prognosis of unrelated donor hematopoietic stem cell transplantation. METHODS: 835 donor-recipient pairs of CMDP data from 2005 to 2010 were analyzed retrospectively. HLA-A, B, C, DRB1 and DQB1 typing were performed using SBT, SSOP and SSP methods. The diseases involved in acute myeloid leukemia (AML) (n = 288), acute lymphoid leukemia (ALL) (n = 227), chronic myeloid leukemia (CML) (n = 187), myelodysplastic syndrome (MDS) (n = 52), non-hodgkin's lymphoma(NHL) (n = 25), aplastic anemia(AA) (n = 42) and thalassemia (n = 14). Of 835 donor-recipient pairs, 362 were completely matched, 159 had a mismatch for a single allele, 125 had a mismatch for a single antigen, 95 had mismatched for both single allele and single antigen, 29 were mismatched at double allele, 20 at double antigen, 45 at multiple allele and antigen. The follow-up assessment was completed before March 2011. RESULTS: HLA-matched pairs had higher overall survival (OS) than HLA-mismatched pairs (79.83% vs 73.15%), but there was no statistically significant differences (P > 0.05). HLA mismatch for a single allele plus a single antigen was a significantly risk factor for OS, disease free survival (DFS) and transplant-related mortality (TRM). The OS from high to low in different diseases were thalassemia, AA, CML, MDS, AML, NHL, and ALL. OS of HLA locus mismatch were DRB1 (94.4%), DQB1 (83.3%), B (75%), A (74.4%) and C (71.4%), respectively. OS of single allele mismatch at HLA locus from high to low were DRB1, C, A, B and DQB1.HLA-A, B, C locus mismatch were statistically significantly associated with lower OS and grade II-IV acute GVHD compared with HLA-matched pairs (P < 0.05). The donor-recipient pairs with HLA-B*15:01/B*15:05, DRB1*12:01/DRB1*12:02, C*04:01/C*03:04, DQB1*03:02/DQB1*03:03 alleles mismatch were given priority. But the donor-recipient pairs with HLA-B*39:01/B*39:05, C*15:02/C*14:02, C*08:01/C*03:04, C*07:02/C*15:02 alleles mismatch were risk factors for influence of OS and aGVHD. CONCLUSION: The high resolution typing for HLA-A, B, C, DRB1, DQB1 can be identified nonpermissive mismatch, which is beneficial for the selection of a suitable donor improves survival on unrelated donor HSCT.

[Occupational exposure induced human transmissible highly pathogenic H5N1 avian influenza in one patient].

OBJECTIVE: To describe the clinical manifestations and lung imaging characteristics of the human transmissible highly pathogenic H5N1 avian influenza. METHODS: The clinical manifestations and lung imaging characteristics of human transmissible highly pathogenic H5N1 avian influenza in one patient were reviewed and analyzed. RESULTS: The patient had the clear history of occupational exposure. The fever and symptoms of influenza were prominent at onset and associated with the symptoms of the digestive tract. The laboratory findings comprised the significant decrease of the white blood cell count and the lymphocyte number and the impairment of the liver function and the myocardial enzymes. The disease progressed rapidly and multiple organs including lung, heart, liver and kidneys were involved. It was ineffective to administer anti-fungal, anti-virus and anti-inflammation medicines. It was in vain to use mechanical ventilation and pneumothorax intubation and closed drainage as well as the support therapy. In the X-ray film, the lesions progressed quickly and changed diversely with absorption and development at the same time. The nasal and throat swabs and the gargle specimen were detected with RT-PCR and real time PCR by Chinese Center for Disease Control and Prevention. The results showed that both the specific HA and NA genes of the avian influenza virus H5N1 subtype were positive and in the same time a strain of avian influenza virus A/jiangxi/1/2005H5N1) was separated and obtained from the nasal and throat swabs. The autopsy showed that diffuse injury of alveolus in lungs, DIC and multiple organ injury. CONCLUSION: The human transmissible highly pathogenic H5N1 avian influenza is a lethal disease. The disease progresses rapidly with the absorption and development at the same time in the lungs and unfortunately there are no effective therapeutic measures. The prevention of the contagious disease for the occupationally exposed population should be emphasized.