Shu-Meng Cheng

Carvedilol, a new antioxidative β-blocker, blocks in vitro human peripheral blood T cell activation by downregulating NF-κB activity

Objective: The activation of T lymphocytes contributes to the inflammatory process of atherosclerosis. Here we examined the effects of carvedilol, a new β-blocker containing an antioxidative property, on the activation of T cells. Methods: Human peripheral blood T cells were negatively selected from whole blood. Cytokines were measured by ELISA. The NF-κB and related protein activity was determined by electrophoretic mobility shift assays, Western blotting, kinase assays and transfection assays. Results: Carvedilol was nontoxic at concentrations ≦10 μM, however, higher dosages (≥20 μM) induced T cell apoptosis. We demonstrated that carvedilol inhibited cytokine production from various stimuli-activated T cells. Carvedilol also suppressed the expression of T cell activation markers, including CD25, CD69 and CD71. Molecular investigation indicated that carvedilol specifically downregulated NF-κB but not activator protein 1 DNA-binding activity in activated T cells. The inhibitory effect was likely due to its antioxidative property. Meanwhile, carvedilol prevented stimuli-induced IκBα degradation. Such an effect was mediated through the inhibition of IκBα kinase activity. The inhibitory specificity on NF-κB by carvedilol was also demonstrated in transfection assays. Conclusions: Our results demonstrated a novel therapeutic mechanism of carvedilol in atherosclerosis, namely the inhibition of T cell activation via downregulating NF-κB activity.

Down-regulation of c-jun N-terminal kinase-activator protein-1 signaling pathway by Ginkgo biloba extract in human peripheral blood T cells.

The activation of T lymphocytes contributes to inflammatory process of cardiovascular and cerebrovascular diseases. We investigated the effects of the extract of Ginkgo biloba (EGb), an ancient plant preserving antioxidant property, on phorbol 12-myristate 13-acetate+ionomycin or anti-CD3+anti-CD28 monoclonal antibodies-activated T cells. Human peripheral blood T cells were negatively selected from whole blood. Cytokines were measured by ELISA, cell surface markers by flow cytometry and the activities of transcription factors and kinases were determined by electrophoresis mobility shift assays, kinase assays and transfection assays. We showed that EGb inhibited several cytokines, including tumor necrosis factor-alpha, interleukin (IL)-2, IL-4 and interferon-gamma production from activated T cells. Electrophoresis mobility shift assay analysis indicated that EGb down-regulated activator protein-1 (AP-1) but not nuclear factor kappa B DNA-binding activity. In addition, EGb inhibited c-jun N-terminal kinase but not extracellular signal regulated protein kinase activity. The inhibitory specificity on AP-1 by EGb was also demonstrated in transfection assays. The inhibition of AP-1 signaling pathway in T cells by EGb provides a support for its efficacy in cardiovascular and cerebrovascular diseases and raises a therapeutic potential for this drug in activated T cell-mediated pathologies.

Irbesartan inhibits human T-lymphocyte activation through downregulation of activator protein-1

Irbesartan is a promising antihypertensive drug with beneficial effects on atherosclerotic processes. In the progression of atherosclerosis, human T‐lymphocytes play an important role, but it is not yet known how irbesartan modulates human T‐lymphocytes activation. To gain insight into the mechanisms by which irbesartan acts, we investigated its effects on human T‐lymphocytes. Primary human T‐lymphocytes were isolated from whole blood. Cytokines were determined by ELISA. Activator protein‐1 (AP‐1) and related protein activities were determined by electrophoretic mobility shift assays, kinase assays, Western blotting and transfection assays. Irbesartan inhibited the production of both tumor necrosis factor‐alpha and interferon‐gamma by activated T‐cells, especially at therapeutic concentrations. Further investigation at the molecular level indicated that the inhibition of activated human T‐lymphocytes specifically correlated with the downregulation of AP‐1 DNA‐binding activity. In the Jurkat T‐cell line, irbesartan also inhibited AP‐1 transcriptional activity. Finally, we revealed that irbesartan is unique in its ability to inhibit the activation of both c‐Jun NH2‐terminal protein kinase and p38 MAPK. Our studies show that irbesartan may modulate inflammation‐based atherosclerotic diseases through a cell‐mediated mechanism involving suppression of human T‐lymphocytes activation via downregulation of AP‐1 activity.

Carvedilol differentially regulates cytokine production from activated human peripheral blood mononuclear cells

Chronic inflammation is one of the important mechanisms involved in atherosclerosis formation. The activated monocytes and their secreted cytokines contribute significantly to this inflammatory process. Here we examined the effects of carvedilol, a recently introduced cardio-protective alpha-1- and beta-receptor blocker, on cytokine production from various stimuli-activated human immune effector cells. By ELISA analysis, we showed that carvedilol inhibited interferon-gamma (IFN-γ), but enhanced interleukin (IL)-12 production in phytohemagglutinin (PHA)- and concanavalin A (ConA)-stimulated human peripheral blood mononuclear cells (PBMCs). The production of tumor necrosis factor-alpha (TNF-α) was marginally affected. When purified monocytes were examined, we observed the consistent up-regulation of IL-12 production while both IL-10 and TNF-α were unaffected or marginally down-regulated, respectively, by carvedilol. In agreement with the observation in monocytes, the production of IL-12 from activated macrophages was also up-regulated by carvedilol. We concluded that carvedilol might mediate its therapeutic effects through differentially regulating cytokine production from activated mononuclear cells, including at least monocytes and macrophages.

Stenting for coronary intervention-related dissection of the left main coronary artery with extension to the aortic root: a case report.

Retrograde aortocoronary dissection is a rare but devastating complication of coronary angioplasty. It occurs most frequently in the right coronary artery, rarely in the left. This is a case report of an aortic dissection complicated by coronary angioplasty of the left circumflex artery. Stenting of the left main coronary artery successfully sealed the entry point of dissection.

Carvedilol Modulates In‐Vitro Granulocyte‐Macrophage Colony‐Stimulating Factor‐Induced Interleukin‐10 Production in U937 Cells and Human Monocytes

Both granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) and interleukin‐10 (IL‐10) are important mediators regulating inflammatory responses. Inflammatory processes have an important role in atherogenesis. In this paper, the effects of carvedilol on GM‐CSF‐induced IL‐10 production were examined on human monocytic cell line, U937, and purified human monocytes. First, we showed that one‐time carvedilol pretreatment at concentrations 0.3–10 μM dose‐dependently inhibited GM‐CSF‐induced IL‐10 production in U937 cells. In addition, we found carvedilol to be non‐cytotoxic at concentrations equal to or less than 10 μM. However, at concentrations higher than 10 μM, carvedilol induced programmed cell death in U937 cells. The inhibition of GM‐CSF‐induced IL‐10 production by carvedilol was also observed at the expression of mRNA. Furthermore, the inhibition of IL‐10 production was demonstrated in GM‐CSF‐activated purified human peripheral blood monocytes. Finally, long‐term carvedilol pretreatment of U937 cells up to 2 months at concentrations of 1.0 μM mildly enhanced the IL‐10 production. Our observations that carvedilol modulated GM‐CSF‐induced IL‐10 production may have some implication in understanding the broad‐spectrum effects of carvedilol in regulating inflammatory reactions.

ECG Changes with Elevated Troponin I in a Patient with Tension Pneumothorax

An 86-year-old man presented with sudden onset of dyspnea during hospitalization. Initial electrocardiography (ECG) showed poor R-wave progression of precordial leads with elevation of troponin I. Tension pneumothorax was subsequently diagnosed and the ECG returned to normal after resolution of clinical compromise.

Torsade de pointes indicates early neurologic damage in acute ischemic stroke.

Torsade de pointes (TdP) is a life-threatening polymorphic ventricular tachycardia that is related to QT prolongation. Although QT prolongation is commonly seen in acute stroke, TdP is rare. We report the case of a 78-year-old woman with ischemic stroke who presented with TdP as the initial manifestation of early neurologic deterioration. We hypothesized that an increase in intracranial pressure may result in neurohormonal activation, QT prolongation, and then myocardial damage, leading to TdP. We highlight that new onset of TdP in a patient with stroke may reflect neurologic deterioration, requiring further evaluation and specific intervention.