Dissertation > Medicine, health > Pharmacy > Pharmacology

1. The Pharmacodynamics Study of the Anti-HIV Effect of Salvia Miltiorrhiza, and the Immune-modulating Evaluation of Traditional Chinese Medicine-WWLQ Suspension 2. Cell Growth Inhibitor p53 and p73 Differ in Their Ability to Inhibit Glucocorticoid Recept

Author ZhangLiLi
Tutor JiangJianDong;ChenHongShan;Carl G. Maki
School Peking Union Medical College , China
Course Microbial and Biochemical Pharmacy
Keywords Effective parts Growth inhibitory factor Transcriptional activity Pharmacodynamic study Doctoral Dissertation Murine leukemia virus Chinese herbal formula Salvia Mixture Immunology
Type PhD thesis
Year 2007
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This thesis includes two separate parts:(1) the pharmacodynamics evaluation of theanti-HIV effect of Salvia miltiorrhiza, and the anti-virus and immune-modulating evaluationof traditional Chinese medicine compound-WWLQ suspension (2) cell growth inhibitor p53and p73 differ in their ability to inhibit glucocorticoid receptor (GR) transcriptional activity;.The first part is about the study of anti-HIV drugs in traditional Chinese medicines.In this part we studied the anti-HIV effects of Salvia miltiorrhiza in vivo and vitro, aswell as the immune-modulating effect of WWLQ suspension. The results are as following.The active part A and Oligosaccharide components could inhibit both HIV-1 IN, RT invitro, and HIV-1 P24 antigen in cultured cells. 30 or 1 hr later, through administration orallyor intraperitioneal injection of active part A and Oligosaccharide components, the mouseserum could inhibit HIV in cultured cells. They could also increase the numbers of CD4~+,CD8~+ and NK cells and maintain the function of B cells in mouse after intraperitonealinjection. In addition, these two components could increase the numbers of lymphocytes,monocytes and granulocytes significantly. These results suggest that the active part A andOligosaccharide components have both the anti-HIV and immune-modulation effects.In cyclosporine A induced- mouse immune-suppressed model, WWLQ suspension couldincrease the percentage of CD3~+, CD4~+ cells and the ratio of CD4~+/CD8~+ cells. It could alsoenhance the immunologic functions partially in the murine leukemia virus infected mice,whereas it could not prevent the mice from infection. Moreover, it could promote thephagocytic function of mouse macrophage.The immune-modulation effects of anti-HIV agents could be detected in both murineleukemia virus infected mouse model and cyclosporine A or cyclophosphamide induced-mouse immune-suppressed model. The choice for using either model is according to thespecificity of drugs. Finally, we concluded that active part A, Oligosaccharide componentsand WWLQ suspension have both anti-HIV and immune-modulation effects, and they couldbe used as adjuvant in the treatment of AIDS.In the second part we did some p53 relative works. The study of p53 is very hot in the cell biology. It is reported that p53 was involved in the apoptosis pathway of HIV infectedcells. Therefore, it is possible for p53 to become a new target of AIDS therapy. However, themechamism of HIV induced apoptosis in immune cells and the anti-apoptosis effect of Salviamiltiorrhiza are still unclear. For this reason, p53 relative work will be helpful to make clearof the mechanism of the anti-HIV, anti-tumor and immunomodulator effects of Chinesetraditional drugs.p53 is a tumor suppressor and potent inhibitor of cell growth. P73 is highly similar top53 at both the amino acid sequence and structural levels. Given their similarities, it isimportant to determine whether p53 and p73 function in similar or distinct pathways. Thereis abundant evidence for negative cross-talk between glucocorticoid receptor (GR) and p53.Neither physical nor functional interactions between GR and p73 have been reported. Inthis study, we examined the ability of p53 and p73 to interact with and inhibit GRtranscriptional activity. The results show that both p53 and p73 can bind GR, and that p53and p73-mediated transcriptional activity is inhibited by GR co-expression. Wild-type p53efficiently inhibited GR transcriptional activity in cells expressing both proteins.Surprisingly, however, p73 was either unable to efficiently inhibit GR, or increased GRactivity slightly. To examine the basis for this difference, a series of p53:p73 chimericproteins were generated in which corresponding regions of either protein have been swapped.Replacing N- and C-terminal sequences in p53 with the corresponding sequences from p73prevented it from inhibiting GR. In contrast, replacing p73 N- and C-terminal sequenceswith the corresponding sequences from p53 allowed it to efficiently inhibit GR. Differencesin GR inhibition were not related to differences in transcriptional activity of the p53:p73chimeras or their ability to bind GR. Our results indicate that both N- and C-terminalregions of p53 contribute to its inhibition of GR. The differential ability of p53 and p73 toinhibit GR is due, in part, to differences in their N-terminal and C-terminal sequences.

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