The role of Vav3 expression for inflammation and cell death during experimental myocardial infarction.

OBJECTIVES: Myocardial Infarction (MI) is the leading cause of chronic heart failure. Previous studies have suggested that Vav3, a receptor protein tyrosine kinase signal transducer, is associated with a variety of cellular signaling processes such as cell morphology regulation and cell transformation with oncogenic activity. However, the mechanism of Vav3-mediated MI development requires further investigation. METHOD: Here, The authors established an MI rat model by ligating the anterior descending branch of the left coronary artery, and an MI cell model by treating cardiomyocytes with H2O2. Microarray analysis was conducted to identify genes with differential expression in heart tissues relevant to MI occurrence and development. Vav3 was thus selected for further investigation. RESULTS: Vav3 downregulation was observed in MI heart tissue and H2O2-treated cardiomyocytes. Administration of Lentiviral Vav3 (LV-VAV3) in MI rats upregulated Vav3 expression in MI heart tissue. Restoration of Vav3 expression reduced infarct area and ameliorated cardiac function in MI rats. Cardiac inflammation, apoptosis, and upregulation of NFκB signal in heart tissue of MI animals were assessed using ELISA, TUNEL staining, real-time PCR, and WB. Vav3 overexpression reduced cardiac inflammation and apoptosis and inhibited NFκB expression and activation. Betulinic Acid (BA) was then used to re-activate NFκB in Vav3-overexpressed and H2O2-induced cardiomyocytes. The expression of P50 and P65, as well as nuclear P65, was significantly increased by BA exposure. CONCLUSIONS: Vav3 might serve as a target to reduce ischemia damage by suppressing the inflammation and apoptosis of cardiomyocytes.

The role of Vav3 expression for inflammation and cell death during experimental myocardial infarction

Abstract Objectives Myocardial Infarction (MI) is the leading cause of chronic heart failure. Previous studies have suggested that Vav3, a receptor protein tyrosine kinase signal transducer, is associated with a variety of cellular signaling processes such as cell morphology regulation and cell transformation with oncogenic activity. However, the mechanism of Vav3-mediated MI development requires further investigation. Method Here, The authors established an MI rat model by ligating the anterior descending branch of the left coronary artery, and an MI cell model by treating cardiomyocytes with H2O2. Microarray analysis was conducted to identify genes with differential expression in heart tissues relevant to MI occurrence and development. Vav3 was thus selected for further investigation. Results Vav3 downregulation was observed in MI heart tissue and H2O2-treated cardiomyocytes. Administration of Lentiviral Vav3 (LV-VAV3) in MI rats upregulated Vav3 expression in MI heart tissue. Restoration of Vav3 expression reduced infarct area and ameliorated cardiac function in MI rats. Cardiac inflammation, apoptosis, and upregulation of NFκB signal in heart tissue of MI animals were assessed using ELISA, TUNEL staining, real-time PCR, and WB. Vav3 overexpression reduced cardiac inflammation and apoptosis and inhibited NFκB expression and activation. Betulinic Acid (BA) was then used to re-activate NFκB in Vav3-overexpressed and H2O2-induced cardiomyocytes. The expression of P50 and P65, as well as nuclear P65, was significantly increased by BA exposure. Conclusions Vav3 might serve as a target to reduce ischemia damage by suppressing the inflammation and apoptosis of cardiomyocytes.

Efficacy Evaluation of High-Volume Hemofiltration in Patients with Severe Acute Respiratory Distress Syndrome.

Objective: To investigate the efficacy of high-volume hemofiltration (HVHF) in the treatment of severe acute respiratory distress syndrome (ARDS) caused by sepsis and its effect on serum levels of miR-126, miR-184, and MAP1-LC3. Methods: From July 1, 2015 to December 31, 2021, patients with severe ARDS caused by sepsis who were admitted to our hospital were retrospectively analyzed. Patients who received conventional treatment were summarized into the control group, and those who received HVHF were summarized into the study group. The treatment effects of the two groups were compared. Results: Ninety-five qualified patients were retrieved, with 42 patients in the control group and 53 patients in the study group. After treatment, the levels of IL-6, IL-10, TNF-α, miR-126, miR-184, and MAP1-LC3 were significantly lower in the study group (P < 0.05 for all), whereas PEF, FRC, TEF25%, heart rate, mean arterial pressure, and blood oxygen were significantly higher in the study group (P < 0.05 for all). Conclusion: HVHF has a good clinical effect on improving patients with severe ARDS caused by sepsis and can improve the pulmonary function of patients.

Expression of RhoA and COX-2 and their roles in the occurrence and progression of brain glioma.

This study was conducted to detect the expression of RhoA and COX-2 in the brain glioma and to discuss their roles in the occurrence and progression of brain glioma. Brain glioma tissues were collected from 22 cases with brain glioma by surgical resection (tumor group); normal brain tissues were collected from 15 cases with brain trauma by surgical resection (healthy group). Western Blot and immunohistochemistry were applied to detect the expression of RhoA and COX-2 in the tissues. The brain glioma cell lines with silenced RhoA expression or silenced COX-2 expression were used to analyze the roles of RhoA and COX-2 in the occurrence and progression of brain glioma through the cell proliferation and invasion/migration assays. The relative expression of RhoA and COX-2 in the brain glioma was 0.82±0.13 and 0.75±0.14, respectively, which was significantly higher than that in the normal brain tissues (0.12±0.08 and 0.043±0.14) (P<0.05). The percentage of RhoA-positive brain glioma cells and COX-2-positive cells was 75.32±15.02% and 82.39±17.82%, respectively; it was significantly higher than that of the normal brain tissues (17.03±7.72 and 5.83±4.01) (P<0.05). As compared with glioma cell line SHG-44, the relative proliferation rate of C8-D9 and E5-B9 was 20.72% and 25.45%, respectively; the relative invasion/migration rate was 20.91% and 20.97%, respectively. The G0/G1 phase decreased significantly (P<0.05) and significantly increased in stage S and G2/M (P<0.05). Both RhoA and COX-2 were upregulated in the brain glioma tissues; their over-expression contributed to the proliferation and invasion/migration of the brain glioma cells.

Neuroprotective effect of aspirin combined with ginkgolide injection on cerebral ischemic stroke rats and its effect on ERK12 signal pathway.

The main aim of this study was to evaluate the neuroprotective effect of aspirin combined with ginkgolide injection on cerebral ischemic stroke model rats and its effect on extracellular regulated protein kinase 1/2 (REK1/2) signaling pathway, and to clarify the possible mechanism of aspirin combined with ginkgolide injection on neuroprotective mechanism. Experimental rats were randomly divided into sham group, model group, aspirin group, ginkgolide group and combination group (aspirin + ginkgolide injection) (n = 20). The results revealed scores of neurological dysfunction and infarct volume in aspirin group, ginkgolide group and combination group rats were lower than those in model group (P < 0.05). Score of neurological dysfunction and the volume of cerebral infarction in combination group rats were lower than those in aspirin group and ginkgolide group (P < 0.05). Combination of aspirin and ginkgolide injection could better reduce brain water content, reduce apoptosis rate of cortical cells P < 0.05, reduce expression levels of caspase-3, Bax and p-REK1/2 proteins in ischemic brain tissue P < 0.05, and increase expression level of Bcl-2 protein than aspirin and ginkgolide injection alone P < 0.05). In conclusion, the synergistic neuroprotective effect of aspirin and ginkgolide injection on cerebral ischemic stroke rats is better than that of aspirin and ginkgolide injection alone. The mechanism of action may be that the two compounds can play a synergistic role and inhibit the activation of REK1/2 signaling pathway, thus inhibiting apoptosis of nerve cells and exerting neuroprotective effect.

Predictive value of serum CTRP9 and STIM1 for restenosis after cerebrovascular stent implantation and its relationship with vasoactive substances and inflammatory cytokines.

Predictive value of serum complement Clq tumor necrosis factor-related protein 9 (CTRP9) and serum stromal interaction molecule 1 (STIM1) was investigated for restenosis after cerebrovascular stent implantation, as well as its relationship with vasoactive substances and inflammatory cytokines. In this prospective study, 128 patients with cerebral infarction treated with cerebrovascular stent implantation in Yantaishan Hospital were recruited. A total of 66 cases with restenosis after cerebrovascular stent implantation were included in group A, and 62 cases without stenosis were included in group B. Serum CTRP9 and STIM1 levels were measured by enzyme-linked immunosorbent assay (ELISA). ROC curves of serum CTRP9 and STIM1 levels in patients with postoperative restenosis were drawn. The vasoactive substances nitric oxide (NO), tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) were analyzed by ELISA. The correlation of serum CTRP9, STIM1 levels and NO, TNF-α, IL-6 were analyzed by Pearson correlation coefficient. Serum CTRP9 and NO levels in group A were significantly lower than those in group B. The levels of serum STIM1, TNF-α and IL-6 in group A were significantly higher than those in group B (P<0.001). The sensitivity and specificity of serum CTRP9 level in the diagnosis of restenosis after cerebrovascular stent implantation were, respectively, 59.68 and 75.76%. Those of serum STIM1 were, respectively, 87.10 and 46.97% and those of the combination of serum CTRP9 and STIM1 were 90.32 and 48.48%. Serum CTRP9 level was positively correlated with NO, and negatively correlated with TNF-α and IL-6. STIM1 was positively correlated with TNF-α and IL-6, and negatively correlated with NO (P<0.001). Serum CTRP9 level was significantly decreased in patients with restenosis after cerebrovascular stent implantation, while STIM1 level was significantly up-regulated. Both were correlated with the change of NO, IL-6 and TNF-α levels, therefore they could be used as biological indicators for prediction of restenosis after cerebrovascular stent implantation.

Dexamethasone suppresses osteogenesis of osteoblast via the PI3K/Akt signaling pathway in vitro and in vivo.

The hypofunction of osteoblasts induced by glucocorticoids (GCs) has been identified as a major contributing factor for GC-induced osteoporosis (GIO). However, the biological mechanism underlying the effect of GC in osteoblasts are not fully elucidated. Recent studies implicated an important role of phosphoinositide 3-kinase (PI3K)/protein kinase B(Akt) signaling pathway in the regulation of bone growth. We propose that the PI3K/Akt signaling may be implicated in the process of GC-induced osteogenic inhibition in osteoblasts. In this study, primary osteoblasts were used in vitro and in rats in vivo to evaluate the biological significance of the PI3K/Akt pathway in GC-induced bone loss. In vivo, dexamethasone (Dex)-treated rats had low bone mineral density and decreased expression levels of alkaline phosphatase (ALP), osteocalcin (OCN), and phosphorylated Akt (p-Akt) in bone tissue. In vitro study shows that Dex over the dose of 10-8 M remarkably inhibited cellular osteogenesis, as represented by decreased cell viability, lessened ALP activity, and suppressed osteogenic protein expressions including ALP and OCN. Meanwhile, a dramatic downregulation in the PI3K/Akt pathway phosphorylation was also observed in Dex-treated osteoblasts. These changes were marked rescued by treatment with a PI3K agonist 740Y-P. Moreover, downregulation of ALP and OCN expressions by LY294002 can mimic the suppressive effects of Dex. These data together reveal that the suppressed PI3K/Akt pathway is involved in the regulatory action of Dex on osteogenesis.

Fatsioside A inhibits the growth of glioma cells via the induction of endoplasmic reticulum stress-mediated apoptosis.

Malignant gliomas are a common type of primary tumor of the central nervous system. In spite of current intensive therapy, the prognosis of patients with malignant glioma remains poor, hence the development of novel therapeutic modalities is necessary. Cell apoptosis is a frequent target in the development of anti­cancer drugs. Fatsioside A, a novel baccharane­type triterpenoid glycoside, is extracted from the fruits of Fatsia japonica. Previous studies have shown that Fatsioside A induces growth inhibition, cell cycle arrest and apoptosis in C6 rat glioma cells and U251 human glioma cells. However, to the best of our knowledge, no detailed studies have reported its effect on U87MG glioma cells and its exact mechanisms remain unknown. In the current study, the growth inhibitory effect of Fatsioside A on U87MG cells was evaluated and the underlying molecular mechanisms were explored. Through the use of flow cytometry and a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, it was determined that Fatsioside A markedly inhibits the growth of U87MG cells. Mechanistic studies demonstrated that Fatsioside A induces growth inhibition of U87MG cells via the induction of endoplasmic reticulum (ER) stress, which was supported by the upregulation of ER stress markers, including elevated levels of phosphorylation of PERK and eIF2α, the increased expression levels of CHOP and the accelerated cleavage of caspase­4. The downregulation of CHOP via CHOP­specific siRNA reduced the growth­inhibitive effect of Fatsioside A on U87MG cells, further confirming the role of the ER stress response in mediating Fatsioside A­induced growth inhibition. In conclusion, Fatsioside A inhibits glioma cell growth via the induction of ER stress­mediated apoptosis. This may provide a molecular basis for the development of Fatsioside A into a drug candidate for the treatment of malignant glioma.