Hainan Piao

Effects of bone marrow derived mesenchymal stem cells transplantation in acutely infarcting myocardium

Cellular cardiomyoplasty (CCM) is considered to be a novel therapeutic approach for post‐myocardial infarction (MI) heart failure. In this study, the functional effects of cultured mesenchymal stem cells (MSCs) transplantation and the associated histopathologic changes were evaluated in a rat model of MI.

Local delivery of green tea catechins inhibits neointimal formation in the rat carotid artery injury model

It has been shown that green tea catechins (GTC) suppress proliferation of vascular smooth muscle cells (VSMCs) and that epigallocatechin-3-gallate (EGCG), which is a major constituent of GTC, selectively inhibits the platelet-derived growth factor-BB (PDGF-BB)-induced intracellular signaling transduction pathway. Vascular smooth muscle cell proliferation is one of major mechanisms of restenosis following percutaneous coronary intervention. This study tested whether GTC can inhibit VSMC proliferation and prevent neointimal formation in a rat carotid artery injury model. Vascular smooth muscle cell proliferation inhibition was analyzed with [3H]thymidine incorporation. Green tea catechins were applied to the endothelium-denuded carotid arteries of rats for 20 min. Angiography and morphometric analysis was performed after 2 weeks. Green tea catechins decreased [3H]thymidine incorporation stimulated with PDGF-BB dose dependently. In the absence of PDGF-BB, the decrement of [3H]thymidine incorporation was evident above a concentration of 10 µg/ml of GTC. Carotid arteriographic evaluation showed that the minimum luminal diameter in the GTC-treated group (n = 12) was 5.9 ± 1.6 arbitrary units (a.u.) and was significantly larger than in the control group (4.3 ± 1.4 a.u., n = 10) (P < 0.05). The GTC-treated group also showed a significant reduction in neointimal formation compared with the control group (0.29 ± 0.11 vs 0.42 ± 0.10 mm2, P < 0.05). To identify the active ingredients, we performed a similar experiment using EGCG. The effects of EGCG were similar to those of GTC. Green tea catechins effectively inhibited VSMC proliferation. Neointimal formation was prevented in the rat carotid artery injury model by local delivery of GTC. As EGCG showed similar effects, it may be one of the major constituents of GTC having these effects.

Effects of the calcineurin dependent signaling pathway inhibition by cyclosporin A on early and late cardiac remodeling following myocardial infarction.

The calcineurin‐mediated signaling pathway has been implicated as one of the crucial pathways in cardiac hypertrophy. However, the role of calcineurin pathway on cardiac remodeling after myocardial infarction (MI) has not been well defined.

Herpes simplex virus thymidine kinase and granulocyte macrophage colony-stimulating factor combination gene therapy in a murine CT26 cell colon cancer model.

We evaluated the antitumor effects of combination gene therapy on CT26 mouse colon cancer cells, using the genes for herpes simplex virus thymidine kinase gene HSV-TK combined with granulocyte macrophage colony-stimulating factor (GM-CSF) compared with HSV-TK alone. Cells, unmodified or retrovirally transduced with HSV-TK or GM-CSF, were inoculated subcutaneously into syngeneic BALB/c mice in various combinations. HSV-TK and GM-CSF were also delivered using different routes (in separate cells vs doubly transfected single cells). Both HSV-TK (with i.p. ganciclovir — GCV — treatment) and GM-CSF genes had independent antitumor effects, and given together they caused significant reduction in tumor volumes compared with the HSV-TK gene alone (P<0.001). Following GCV treatment, however, the treated/control ratios for tumor volumes were not different between tumors containing either HSV-TK alone or both genes (0.27 vs 0.25, respectively). Thus, the presence of GM-CSF did not increase the bystander effect of HSV-TK. Tumors receiving genes transferred in separate cells tended to be more consistently suppressed after GCV treatment than when both genes were transferred in the same cells, although this was not statistically significant. Thus, combination GM-CSF and HSV-TK gene therapy produced greater therapeutic efficacy than HSV-TK alone, but the bystander effect was not enhanced by GM-CSF.

Dilated cardiomyopathy and cardiac arrhythmias in the transgenic mice overexpressing mouse cardiac junctate-1

(ACh) or adenosme (Ado) Drugs used: Selective IKs blocker chromanole 2938 (Cm); IKr blocker sotalol (Sot), dofetilide @of), lbutilide (Ibu), and RP58866 (F(P). Data are expressed as mean values *standard deviation. Results: ACh induced IK(ACh) density was 94il2 pAipF. IK(ACh) was almost com- pletely desensitlsed in the presence of 50 pM Ter. Ibu, or Dof. IC50 of IK(ACh) inhlbition by the three drugs was 4.8, 2.8, and 0.9pM (Ter, Ibu, Dof respectively; n=9). Ado induced and receptor independent GTP-g-S induced IK(ACh) was sensitive to Ter, Ibu, and Dof as well. Drug potency was not affected by the way of current activation (Ado, ACh, GTP- g-S; (n=7)). Sot is known to be a weak inhibitor of IKr. Inhibition of IK(ACh) by Sot was much less potent (IC50=35SvM; n=lZ) than inhibition by the high affinity IKr-blocker Ter. Ibu, and Dof. Sup&u&on of the cells with the IKs-blocker Cro showed no desensitisatlon of IK(ACh) (highest concentration used was 100pM). Applied via the patch pipette (4Omin) none of the class Ill drugs were effective. Conclusions: In contrast to the selective IKs blocker Cm the IKr blocker Sot, Dof, and Ibu induced a concentration dependent inhibition of IK(ACh). The weak IKr blocker Sot showed the highest IC50 value indicating inhibItIon of IK(ACh) and IKr but not IKs to be of slm!lar mechanism. Experiments with GTP-g-S and intracellular drug application suggest a direct channel blockade by the compounds. Additive desensitisation of muscarinic potassium current would be of clinical relevance especially in vagal induced AF. The pre- sented data could be the basis for a more specific antiarrhythmic therapy of vagal induced AF paralleled by a reduction of proarryhthmic side effect at the ventricular level.