Effects of anti-rheumatic herbal medicines on cellular adhesion molecules.
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OBJECTIVE: To test the hypothesis whether herbal medicines ameliorate inflammatory diseases via the modulation of cellular adhesion molecules (CAMs). METHODS: Human neutrophils, synovial fibroblasts, and endothelial cells were incubated with different concentrations of Tripterygium Wilfordii Hook-f (TWH-f) or Tetrandrine in the presence or absence of interleukin 1 (IL1). The amount of soluble E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cellular adhesion molecule-1 (VCAM-1) secreted by cells were determined by ELISA. The cell surface expression of these three CAMs was detected by flow cytometry. RESULTS: TWH-f at high concentration (50 ng/ml) has a significant (p<0.05) inhibitory effect on both the secretion and the expression of the cellular adhesion molecules. However, Tetrandrine did not demonstrate the same effects. CONCLUSIONS: The cellular adhesion molecules of the endothelium and leucocytes may constitute excellent targets for the development of new anti-inflammation medicines. These results indicate that TWH could be a potential therapeutic agent in the treatment of inflammatory diseases. (+info)
Effects of immunosuppressants on platelet-derived growth factor-A chain mRNA expression and coronary arteriosclerosis in rat cardiac allografts.
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Graft coronary arteriosclerosis (GCA) that results in proliferative and obstructive lesions limits the long-term success of cardiac transplantation. Despite extensive study, the pathogenic mechanisms underlying GCA are still unclear and therapeutic strategies for this condition have been inadequate. In this study, we compared the therapeutic effectiveness of cyclosporine A (CsA), 15-deoxyspergualin (DSG), and Multiglycosidorum tripterygii (MT) on GCA. In addition, we studied the correlation between the extent of GCA and the degree of platelet-derived growth facter (PDGF)-A chain mRNA expression in cardiac grafts. Lewis rats receiving heterotropic heart transplants from Wistar King donors were treated with 10 mg kg(-1) day(-1) of CsA (n=7), 5 mg kg(-1) day(-1) of DSG (n=7) or 30 mg kg(-1) day(-1) of MT (n=7) respectively. Histological evaluation of coronary arteriosclerosis and Northern blot analysis of cardiac allograft PDGF-A chain mRNA expression were conducted on day 60 after transplantation. Varying levels of GCA were observed in the 21 transplanted hearts. Significant differences in both the degree of PDGF-A mRNA expression and the extent of GCA were found among the 3 groups. GCA was significantly reduced in allografts treated with MT or DSG in comparison with the level seen in CsA-treated grafts. A significant correlation was found between PDGF-A chain mRNA expression and the grade of arterial intimal thickening (r=0.76, p<0.05) as well as with the incidence of diseased vessels (r=0.82, p<0.01). Our results indicate that both MT and DSG are more effective in the treatment of GCA than CsA. In our cardiac allografts, the degree of PDGF-A chain mRNA expression correlated well with the extent of GCA, suggesting that PDGF-A may play an important role in the development of transplant-related GCA. (+info)
Hematotoxicity of the chinese herbal medicine Tripterygium wilfordii hook f in CD34-positive human bone marrow cells.
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T2, a chloroform/methanol extract of the herb Tripterygium wilfordii Hook f, has been used in China for the treatment of autoimmune and inflammatory diseases for many years. Recent experimental evidence has confirmed that T2 has potent anti-inflammatory and immunosuppressive activity, and a United States Food and Drug Administration-approved clinical trial is currently exploring the efficacy of T2 in the treatment of rheumatoid arthritis. Despite the potential therapeutic benefits of T2, there is ample documentation that T2 is toxic, targeting, among other things, the hematopoietic system, and its use has resulted in cases of leukopenia, thrombocytopenia, and aplastic anemia. This investigation was undertaken to characterize the in vitro effects of T2 on primary human CD34-positive (CD34+) bone marrow cells. Our results demonstrate that T2 has a potent inhibitory effect on the clonogenic response of human bone marrow cells to exogenously added hematopoietic growth factors. The inhibition of colony formation by T2 is not the result of direct cytotoxicity or increased apoptosis and indicates a functional suppression of hematopoiesis. Additional experiments demonstrate that T2 also alters transcriptional regulation in bone marrow cells by inhibiting nuclear factor-kappaB. This transcription factor is found in CD34+ bone marrow cells and has been recently shown to be a requirement for colony formation. These results demonstrate that therapeutic concentrations of T2 exert a significant hematotoxic effect by inhibiting growth factor response in CD34+ bone marrow cells and suggest that inhibition of nuclear factor-kappaB may play a role in the blood dyscrasias encountered with the use of this drug. (+info)
The contribution of Asian scientists to global research in andrology.
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AIM: To present a personal account of the involvement of the World Health Organization (WHO) in the collaborative development in Asia of those areas of andrology concerned with male contraception and reproductive health. METHODS: The andrology training through workshops and institution support undertaken by the WHO Human Reproduction Programme (HRP) and how they contributed to the strengthening of andrology research in Asia are summarised. RESULTS: The author' s experience and the Asian scientific contributions to the global research in the following areas are reviewed: the safety of vasectomy and the development of new methods of vas occlusion; gossypol and its failure to become a safe, reversible male antifertility drug; Tripterygium and whether its pure extracts will pass through the appropriate toxicology and phased clinical studies to become acceptable contraceptive drugs; hormonal methods of contraception for men. CONCLUSION: The WHO policy of research capacity building through training and institution strengthening, together with the collaboration of Asian andrologists, has created strong National institutions now able to direct their own programmes of research in clinical and scientific andrology. (+info)
Chromosomal composition of micronuclei in mouse NIH 3T3 cells treated with acrylamide, extract of Tripterygium hypoglaucum (level) hutch, mitomycin C and colchicine, detected by multicolor FISH with centromeric and telomeric DNA probes.
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The chromosomal composition of micronuclei (MN) induced by the model mutagens mitomycin (MMC) and colchicine (COL) as well as by acrylamide (AA) and the traditional Chinese medicine Tripterygium hypoglaucum (level) hutch (THH) in NIH 3T3 cells was analyzed by multicolor fluorescence in situ hybridization (FISH) using DNA probes for the centromere repeated minor satellite DNA and the telomeric hexamer repeat (TTAGGG). The majority of MN (78.6%) from treatment with MMC (0.1 microg/ml) did not show centromeric signals, reflecting the clastogenic action of MMC. Following treatment with COL (0.1 microg/ml), 74.5% of the MN showed centromeric signals and several telomeric signals, indicating that MN induced by this well-known aneugen were mainly composed of whole chromosomes. After treatment with AA (100, 200 and 400 microg/ml) both MN containing whole chromosomes and MN containing acentric fragments were found to increase in a dose-dependent manner, demonstrating that AA is not only a clastogen but also an aneugen. THH induced a high frequency of MN harboring whole chromosomes at all concentrations tested (5, 10 and 20 microl/ml) and produced a dose-dependent increase in fragment-containing MN, indicating that THH has both aneugenic and clastogenic potential. (+info)
Tripterygium wilfordii Hook F extract suppresses proinflammatory cytokine-induced expression of matrix metalloproteinase genes in articular chondrocytes by inhibiting activating protein-1 and nuclear factor-kappaB activities.
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The major pathologic manifestations of rheumatoid arthritis (RA) and osteoarthritis (OA) are joint inflammation and articular cartilage resorption by proinflammatory cytokine-stimulated matrix metalloproteinases (MMPs) and aggrecanases. The Chinese herbal remedy Tripterygium wilfordii Hook F (TWHF) is effective for treatment of various types of arthritis. However, mechanisms and targets of its actions are poorly understood. Anti-inflammatory activities of the extracts of this plant were previously attributed to inhibition of cyclooxygenase-2 mRNA and prostaglandin E(2) synthesis. Here, we show that in primary human femoral head osteoarthritic and normal bovine chondrocytes, TWHF partially or completely inhibited mRNA and protein expression of tumor necrosis factor-alpha, interleukin (IL)-1, and IL-17-inducible MMP-3 and MMP-13. This agent also inhibited cytokine-stimulated MMP-3 protein expression in human synovial fibroblasts. A dose range of 2.5 to 10 ng/ml of TWHF was effectively inhibitory for IL-1. Pretreatment for 30 min or 1 h (but not 2-10 h) after IL-1 treatment with TWHF inhibited MMP-3 RNA induction. The inhibitory doses had no adverse effect on the viability of chondrocytes. Mechanistic studies revealed no impact on the activation of extracellular signal-regulated kinase, p38, and c-Jun N-terminal kinase mitogen-activated protein kinases. Instead, TWHF partially inhibited DNA binding capacity of cytokine-stimulated activating protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB) transcription factors. Therefore, besides its anti-inflammatory activity, this agent may also be effective in blocking cartilage matrix resorption by MMPs by impairing AP-1 and NF-kappaB binding activities. Thus, TWHF extract contains novel inhibitors of MMP expression that may be of therapeutic potential in arthritis and other conditions associated with increased MMPs. (+info)
Western and Chinese antirheumatic drug-induced T cell apoptotic DNA damage uses different caspase cascades and is independent of Fas/Fas ligand interaction.
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Spontaneous or therapeutic induction of T cell apoptosis plays a critical role in establishing transplantation tolerance and maintaining remission of autoimmune diseases. We investigated the mechanisms of apoptosis induced by Chinese and Western antirheumatic drugs (ARDs) in human T cells. We found that hydroxychloroquine, Tripterygium wilfordii hook F, and tetrandrine (Tet), but not methotrexate, at therapeutic concentrations can cause T cell death. In addition, Tet selectively killed T cells, especially activated T cells. Although ARD-induced cytotoxicity was mediated through apoptotic mechanisms, Fas/Fas ligand interaction was not required. We further demonstrated that the processes of phosphatidylserine externalization and DNA damage along the ARD-induced T cell apoptotic pathway could operate independently, and that selective inhibition of DNA damage by caspase inhibitors did not prevent T cells from undergoing cell death. Moreover, we found that Tet- and Tripterygium wilfordii hook F-induced T cell DNA damage required caspase-3 activity, and hydroxychloroquine-induced T cell DNA damage was mediated through a caspase-3- and caspase-8-independent, but Z-Asp-Glu-Val-Asp-fluomethyl ketone-sensitive, signaling pathway. Finally, the observation that ARD-induced activation of caspase-3 in both Fas-sensitive and Fas-resistant Jurkat T cells indicates that Fas/Fas ligand interaction plays no role in ARD-induced T cell apoptosis. Our observations provide new information about the complex apoptotic mechanisms of ARDs, and have implications for combining Western and Chinese ARDs that have different immunomodulatory mechanisms in the therapy of autoimmune diseases and transplantation rejection. (+info)
Tripterygium wilfordii saponins and interleukin-10 prevent induction of experimental autoimmune thyroiditis by dendritic cells.
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AIM: To study the roles of Tripterygium wilfordii saponins (TII) and interleukin-10 (IL-10) on dendritic cells (DC)-induced experimental autoimmune thyroiditis (EAT). METHODS: We used mice as autoimmune thyroiditis model animals and divided them into 4 groups, namely DC group, TII group, IL-10 group, and control group. The level of thyroglobulin (Tg) antibody was assayed by ELISA. TNF beta production in the cultured supernatants and nitric oxide (NO) in the serum were measured by biological activation assay and Griess reaction, respectively. Tg-stimulated proliferation of lymphocytes was detected with MTT incorporation assay. The histopathological analysis of thyroid was carried out. RESULTS: Tg-pulsed DC were able to induce EAT with increase in the concentration of TgAb in serum and lymphocytes infiltration in thyroid. After treatment with TII or IL-10, DC could not induce EAT with lower levels of TgAb and no lymphocyte infiltration. The concentration of NO in serum, TNF beta activation, and the proliferation of lymphocytes in response to thyroglobulin in TII or IL-10 group were lower than those in DC group. CONCLUSION: TII and IL-10 are able to strongly inhibit the ability of DC to induce experimental autoimmune thyroiditis. (+info)