€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****ARTHRITIS AND RHEUMATISM***** Tao X Davis LS Lipsky PE Effect of an extract of the Chinese herbal remedy Tripterygium wilfordii Hook F on human immune responsiveness. In: Arthritis Rheum (1991 Oct) 34(10):1274-81 ISSN: 0004-3591 Tripterygium wilfordii Hook F (TWH) is a vine-like plant that grows in a wide area of south China. An alcohol extract of this plant known as T2 has been suggested to be effective in the treatment of rheumatoid arthritis (RA). To examine the mechanism by which this herbal remedy might be effective in RA, the capacity of T2 to alter human immune responsiveness in vitro was investigated. Human peripheral blood mononuclear cells were obtained from normal adults and separated into purified populations of monocytes, T cells, and B cells. T2 at 0.1-1 micrograms/ml inhibited antigen- and mitogen- stimulated proliferation of T cells and B cells, interleukin-2 (IL-2) production by T cells, and immunoglobulin production by B cells. T2 did not affect IL-2 receptor expression by T cells, IL-1 production by monocytes, or the capacity of monocytes to present antigen. Inhibition could not be accounted for by nonspecific toxicity. These results support the conclusion that T2 exerts a powerful suppressive effect on human immune responses. This action might account for its therapeutic effectiveness in RA. €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ Gu WZ Banerjee S Rauch J Brandwein SR Suppression of renal disease and arthritis, and prolongation of survival in MRL-lpr mice treated with an extract of Tripterygium wilfordii Hook f. In: Arthritis Rheum (1992 Nov) 35(11):1381-6 ISSN: 0004-3591 OBJECTIVE. Treatment of MRL-lpr/lpr mice with Tripterygium wilfordii Hook f (TWHf) to evaluate its effects on mortality, renal disease, and arthritis. METHODS. Mice were fed water (group A, control), TWHf (group B), or first water and then TWHf (group C) from age 7 weeks until age 21 weeks. RESULTS. Arthritis and glomerulonephritis were decreased in groups B and C mice, and survival was increased in group B mice. CONCLUSION. TWHf decreases the mortality rate, and severity of glomerulonephritis and arthritis in MRL-lpr/lpr mice. €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS***** Tao X Cai JJ Lipsky PE The identity of immunosuppressive components of the ethyl acetate extract and chloroform methanol extract (T2) of Tripterygium wilfordii Hook. F. In: J Pharmacol Exp Ther (1995 Mar) 272(3):1305-12 ISSN: 0022-3565 A variety of preparations of Tripterygium wilfordii Hook.F (TWHF) have been reported to be effective in the treatment of autoimmune diseases, including a chloroform methanol extract termed T2 and an ethyl acetate (EA) extract. The immunosuppressive activity of the EA extract was analyzed and the components accounting for this effect determined and compared to those of T2. More than 0.25 microgram/ml of the EA extract inhibited antigen- and mitogen-stimulated human T cell proliferation. The inhibitory effect of the EA extract on T cell proliferation resulted largely from suppression of interleukin-2 production. At concentrations that inhibited T cell function, the EA extract also profoundly suppressed [3H]-thymidine incorporation by mitogen-stimulated B cells, but it did not inhibit antigen presentation by monocytes and only modestly affected interleukin-6 production by lipopolysaccharide-stimulated monocytes. The profile of inhibition was comparable to that previously reported for the chloroform-methanol extract of Tripterygium wilfordii Hook.F, T2. To delineate the components of these extracts that might account for their immunosuppressive effect, we analyzed the composition of diterpenoid compounds. Both extracts contained triptolide and tripdiolide as the major immunosuppressive diterpenoids, but at different concentrations. Comparison of the composition of these extracts and the inhibitory capacity of the purified components indicated that the triptolide concentration of the EA extract can account for its immunosuppressive activity, although the combination of both triptolide and tripdiolide or other unknown components may be necessary to explain the inhibitory effects of T2. Registry Numbers: 141-78-6 (ethyl acetate) 38748-32-2 (triptolide) 67-56-1 (Alcohol, Methyl) 67-66-3 (Chloroform) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ Tao X Davis LS Hashimoto K Lipsky PE The Chinese herbal remedy, T2, inhibits mitogen-induced cytokine gene transcription by T cells, but not initial signal transduction. In: J Pharmacol Exp Ther (1996 Jan) 276(1):316-25 ISSN: 0022-3565 T2, an extract of Tripterygium wilfordii Hook F, has been reported to be effective in the treatment of a variety of autoimmune diseases, including rheumatoid arthritis. Previous studies have shown that T2 inhibited mitogen- or antigen-induced proliferation of human peripheral blood T cells and B cells, IL-2 production by T cells and Ig production by B cells. In contrast, T2 did not affect monocyte functions, such as IL-1 production and antigen presentation. The current studies sought to localize the immunosuppressive action of T2 more precisely. Results show that T2 prevented [3H]-uridine uptake by mitogen-stimulated T cells and arrested them in the early GI phase of the cell cycle. The inhibitory effects of T2 could be partially overcome by costimulating PHA activated T cells with PMA and completely nullified by costimulation with PMA plus a monoclonal antibody to CD28. Moreover, T2 had no effect on expression of IL-2R or the transferrin receptor (CD71), but inhibited production of a number of cytokines, including IL-2 and IFN-gamma by activated T cells. T2 suppressed IL-2 mRNA levels, but not IL-2R mRNA levels, in activated T cells. T2-mediated inhibition reflected suppression of IL- 2 gene transcription as indicated by suppression of the expression of a reporter gene driven by the IL-2 promoter. T2 had little inhibitory effect on either IL-2 gene expression or cell cycle progression when added after initial mitogenic stimulation, indicating that an early step in the cascade of activation events was inhibited. However, initial activation events including protein tyrosine phosphorylation, the generation of diacylglycerol, IP3, and the translocation of protein kinase C were not inhibited by T2. Moreover, T2 did not inhibit the phosphatase activity of calcineurin. These results have localized the effect of T2 to a step in the T cell activation cascade after initial second messenger generation, tyrosine phosphorylation and protein kinase activation, but before IL-2 gene transcription. Registry Numbers: EC 2.7.1.- (Protein Kinase C) EC 3.1.3.- (calcineurin) EC 3.1.3.16 (Phosphoprotein Phosphatase) 10028-17-8 (Tritium) 16561-29-8 (Tetradecanoylphorbol Acetate) 55520-40-6 (Tyrosine) 58-96-8 (Uridine) 82115-62-6 (Interferon Type II) 85166-31-0 (Inositol 1,4,5-Trisphosphate) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****BIOORGANIC AND MEDICINAL CHEMISTRY***** Chen K Shi Q Fujioka T Nakano T Hu CQ Jin JQ Kilkuskie RE Lee KH Anti-AIDS agents--XIX. Neotripterifordin, a novel anti-HIV principle from Tripterygium wilfordii: isolation and structural elucidation. In: Bioorg Med Chem (1995 Oct) 3(10):1345-8 ISSN: 0968-0896 A new kaurane type diterpene lactone, neotripterifordin (1), has been isolated from the roots of Tripterygium wilfordii. The structure of 1 was elucidated by spectroscopic methods, which included the concerted application of a number of 2-D NMR techniques including 1H-1H COSY, phase-sensitive NOESY, HETCOR, and long-range HETCOR. Compound 1 showed potent anti-HIV replication activity in H9 lymphocyte cells with an EC50 of 25 nM and TI of 125. €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****CANCER LETTERS***** Takaishi Y Ujita K Tokuda H Nishino H Iwashima A Fujita T Inhibitory effects of dihydroagarofuran sesquiterpenes on Epstein- Barr virus activation [published erratum appears in Cancer Lett 1992 Dec 24;67(2-3):215] In: Cancer Lett (1992 Jul 31) 65(1):19-26 ISSN: 0304-3835 To search for possible antitumor promoters, we carried out a primary screening of thirty-seven dihydroagarofuran sesquiterpenes from Tripterygium wilfordii Hook fil. var. regelii Makino and Euonymus sieboldianus Blume, using their possible inhibitory effects on the Epstein-Barr virus early antigen (EBV-EA) activation which is induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells. Some of these sesquiterpenes, triptofordin F-2 (Takaishi et al., 1988), 1,2,6,8,15-pentaacetoxy-9-benzoyloxy-4-hydroxy-beta-dihydroagarofuran and triptogelin A-1 (Takaishi et al., 1990) were observed to significantly inhibit the EBV-EA activation at low doses. Based on the results, the structural requirements for the activity of these compounds were discussed [corrected]. €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ Shamon LA Pezzuto JM Graves JM Mehta RR Wangcharoentrakul S Sangsuwan R Chaichana S Tuchinda P Cleason P Reutrakul V Evaluation of the mutagenic, cytotoxic, and antitumor potential of triptolide, a highly oxygenated diterpene isolated from Tripterygium wilfordii. In: Cancer Lett (1997 Jan 15) 112(1):113-7 ISSN: 0304-3835 Triptolide, a highly oxygenated diterpene isolated from Tripterygium wilfordii Hook f. (Celastraceae), has been shown to demonstrate potent antileukemic activity in rodent models at remarkably low treatment doses. A variety of other physiological responses are known to be mediated by this compound, including immunosuppressive and antifertility effects. We currently report that triptolide was not mutagenic toward Salmonella typhimurium strain TM677, either in the presence or absence of a metabolic activating system. Relatively potent but non-specific cytotoxicity was observed with a panel of cultured mammalian cell lines, and modest antitumor activity was observed when an i.p. dose of 25 microg was administered three times weekly to athymic mice carrying human breast tumors. Treatment regimens involving higher doses of triptolide (e.g. 50 microg/mouse three times weekly) were lethal. Registry Numbers: 38748-32-2 (triptolide) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****CHINESE MEDICAL JOURNAL***** Jia TH Sun HC Wang XX Xiu HM Ding WD Hao XD Wu L Wang GX Lei JZ Ultrastructural observation on macrophage-lymphocyte interactions in semen from Tripterygium wilfordii Hook.f. takers. In: Chin Med J (Engl) (1994 Dec) 107(12):892-6 ISSN: 0366-6999 Sixty-nine specimens from Tripterygium Wilfordii Hook.f. (TWH) users were investigated by electron microscopy. No macrophages were demonstrated in the 21 specimens collected prior to the administration of TWH. However, it was found in 23 out of the 48 semen specimens obtained following the TWH administration. The macrophages were functionally active as shown by the presence of a large number of cytoplasmic processes and pseudopodia on the surface, and primary and secondary lysosomes in the cytoplasm. The macrophages phagocytized sperm debris and degenerated or dead spermatids with formation of specific phagosomes. Around those macrophages, lymphocytes were commonly noted. The cytoplasmic processes of the two cell types could come into contact or even fuse with each other, leading to tight junction-like structure; in some of the contacts, the plasma membranes were found dissolved so as to form direct cytoplasmic linkage. €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ Liao CX Li JS Low-dose cyclosporin A and Tripterygium wilfordii inhibited porcine intestinal allograft rejection. In: Chin Med J (Engl) (1994 Sep) 107(9):669-72 ISSN: 0366-6999 The aim of this study was to evaluate whether Tripterygium wilfordii (TW) could be used as an immunosuppressant, and whether antirejection therapy with low-dose cyclosporin A (CsA) and TW was better than the treatment with large-dose CsA alone in intestinal transplantation in pigs. 100 cm intestines were transplanted by using two-step models. Four pigs which received large-dose CsA for 100 days and then were given TW survived 251.5 +/- 181.5 days; 2 of these died of pneumonia 92 and 97 days after the operations respectively. Five pigs which received low-dose CsA and TW for 100 days, then TW was the only drug used in the survival animals, survived 243.2 +/- 90.9 days; none of these succumbed to infection. All the grafts in those which were administered with low-dose CsA were destroyed by acute rejection at 12.4 +/- 2.6 days. These results indicated that TW had some immunosuppressive effects, and antirejection treatment with low-dose CsA and TW could be considered as an acceptable therapy in small bowel transplantation. Registry Numbers: 59865-13-3 (Cyclosporine) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****CHINESE MEDICAL SCIENCES JOURNAL***** Ye W Den Y Huang Y Xue S Antispermatogenic effect of Tripterygium wilfordii and tripchlorolide (T4) on rat gametogenesis and spermatozoa. In: Chin Med Sci J (1994 Jun) 9(2):110-3 ISSN: 1001-9294 The multiglycosides of Tripterygium wilfordii (TII), a ready-made Chinese herbal medicine used for the treatment of rheumatoid arthritis, have been shown to cause oligospermia in patients. In the present study, the antifertility effects of TII and tripchlorolide (T4, isolated from TII) were observed in male rats. In rats fed with TII at a dose of 10 mg.kg.d for 7 weeks, the seminiferous tubules were essentially not influenced. However, most of the sperm heads along the surface of the tubular lumen were transformed from the normal sickle-shaped to round shaped, suggesting a possible mutagenic action. There was minimal testicular change but prominent epididymal spermatozoa damage in all rats treated with T4 (0.05 mg.kg.d) for 7 weeks. The epididymal spermatozoa showed various structural abnormalities, including disrupted connecting pieces and cracked midpieces, and more than 80% of the spermatozoa were decapitated. No significant changes were seen in the main visceral organs. The data suggest that T4 may have good prospects as a male contraceptive. Registry Numbers: 132368-08-2 (tripchlorolide) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ Yang X Xu L Ren H Li Z Sun C Zhang Z The effect of multi-glycosides of Tripterygium wilfordii Hook f. (GTW) on the survival time of cardiac allografts in rats. In: Chin Med Sci J (1992 Dec) 7(4):232-4 ISSN: 1001-9294 Heterotopic heart transplantation was carried out in rats and the influence of multi-glycosides of Tripterygium wilfordii Hook f. (GTW) and a subtherapeutic dose of cyclosporine A (CsA) on the mean survival time (MST) of the cardiac allografts was investigated. The results showed that the MSTs of cardiac allografts in both the GTW and CsA-treated groups were significantly prolonged (P < 0.01 vs control). The rate of allograft rejection in the drug-treated groups was much lower than that in the control group. Registry Numbers: 59865-13-3 (Cyclosporine) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****CHUNG-HUA I HSUEH TSA CHIH [CHINESE MEDICAL JOURNAL]***** Zhou ZS [Rejection and tripterygium wilfordii treated small bowel allografts in pigs: pathological studies] In: Chung Hua I Hsueh Tsa Chih (1993 Sep) 73(9):541-3, 575 ISSN: 0376-2491 (Published in Chinese) Segmental small bowel allografts in pigs were examined histologically to elucidate the rejection process. The specimens were obtained by biopsy at regular intervals after transplantation. Early characteristics of acute rejection were marked by infiltration of mononuclear cells in the lamina propria. Moderate rejection showed increased infiltrated mononuclear cells and mucosal lesions. Mucosal necrosis occurred in the acute phase of rejection. Rejection was seen in the animals that received only low-dose cyclosporin A but not in those treated with tripterygium wilfordii (TW) and low-dose cyclosporin A. These results suggest that mucosal biopsy as a way of monitoring rejection can show sequential pattern of changes. Normal morphological appearance of TW-treated allografts confirmed that TW is an effective immunosuppressant. €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****CHUNG-HUA WAI KO TSA CHIH [CHINESE JOURNAL OF SURGERY]***** Li N Li J Li Y [Experimental and clinical studies of small bowel allotransplantation] In: Chung Hua Wai Ko Tsa Chih (1995 Jan) 33(1):11-4 ISSN: 0529-5815 (Published in Chinese) The pigs with allograft were divided into 5 groups according to the different immunosuppressive regimens. Acute rejection of allograft occurred in animals not treated with immunosuppressive agents or treated with low dose of cyclosporine (CsA). There was no rejection developed in the pigs treated with high dose CsA or low dose CsA and tripterygium wilfordii (TW). No evidence of chronic rejection was detected in animals with continued administration of TW after living longer than 100 days when the immunosuppressive treatment was discontinued. A woman with enterocolitis, ileus and short-gut syndrome received a complete cadaveric small bowel transplantation in march 12, 1994. The graft had 6 minutes for warm ischemia and 9 hours and 45 minutes for cold ischemia. The immunosuppressive therapy consisted of CsA, TW and methylprednisolone. The patient is alive and the function of graft is normal. Registry Numbers: 59865-13-3 (Cyclosporine) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ Ao JH Li YT Xiao XR [Clinical study on the use of multiglycosides of Tripterygium wilfordii after cadaveric kidney transplantation] In: Chung Hua Wai Ko Tsa Chih (1994 Mar) 32(3):175-7 ISSN: 0529-5815 (Published in Chinese) Based on the animal experiments, we first used the multiglycosides of Tripterygium wilfordii (GTW) as a main immunosuppressive agent to treat the patients with cadaveric kidney transplantation instead of Azathioprine (Aza) from 1990. By clinical observation and 3-year follow-up, the result showed the GTW having a satisfactory immunosuppressive effect. In this study, there were 85 cases in control group (Aza+CSA+Pred) and 87 cases in therapeutic group (GTW+CSA+Pred). The normalizing times of graft function after transplantation taked 18.17 +/- 1.61 days in control group and 10.9 +/- 0.18 days in therapeutic group respectively. The 1-, and 2-year graft survival rates were 89.3 +/- 0.3% and 87.0 +/- 0.3% in control group, 96.1 +/- 0.2% and 90.4 +/- 0.6% in therapeutic group respectively. The difference of the normalization times of graft function and graft survival rates between the two groups had statistically significant (P < 0.01). The incidence of complication such as infection, liver function damaging, etc, in therapeutic group was lower than in control group. €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****CHUNG-KUO CHUNG HSI I CHIEH HO TSA CHIH***** Xu JY Yang J Li LZ [Antitumor effect of Tripterygium wilfordii] In: Chung Kuo Chung Hsi I Chieh Ho Tsa Chih (1992 Mar) 12(3):161-4, 134 ISSN: 1003-5370 (Published in Chinese) A new component of antitumor action TG has been isolated from the ethyl acetate extract of Tripterygium wilfordii (besides Triptolide, Tripdiolide and Triptonide). TG was shown in this study to have obvious antitumor effects. The average life span of H22, S180, EAC and breast carcinoma-bearing mice treated with TG ip x 2 days were 100% more than those of the control mice (P less than 0.01) TG was able to inhibit tumor growth of S37-bearing mice at the dose of 150 mg/kg per day, ig x 3, its inhibitory rate was 42% (P less than 0.01). TG could also inhibit squamous epithelial lung carcinoma induced by 3-methylcholanthrene. The inhibitory rate was 65.13% (P less than 0.05). TG had remarkable killing effect on human HL60 and Daudi cells and two direction effects on function M phi of mouse abdominal cavity in vitro. €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ Xu DS Shen ZY Lu W [Clinical and experimental study of RA mixture in treatment of rheumatoid arthritis] In: Chung Kuo Chung Hsi I Chieh Ho Tsa Chih (1996 Jan) 16(1):14-7, 23 ISSN: 1003-5370 (Published in Chinese) The RA mixture is composed of Tripterygium Wilfordii (TW) and other Chinese medicinal herbs with effect of expelling Wind, activiting blood circulation, invigorating the Kidney and Qi. The authors treated rheumatoid arthritis (RA) patients with RA mixture and compared it with D-penicillamine as control. The two group's therapeutical effect is similar (P > 0.05), but the side effect occuring ratio in treatment group was obviously lower than that of control group (P < 0.01). After treatment with RA mixture, the patient's human lymphocytic antigen-degenerative reaction (HLA-DR+) cell, CD4/CD8 ratio reduced and auto-mixed lymphocytic reaction (AMLR) level enhanced (P < 0.05). The results of animal experiment showed that swelling of RA model mouse's joint could be reduced by both RA mixture and TW. Comparing with TW, RA mixture had stronger effect in controlling the inflammation of synovial cell and fibroid degeneration of fibrocytes. At the same time, RA mixture had stronger effect in protecting the immune organ from atrophy and protecting functions of cellular immunity. All above suggest that RA mixture reduce the syndroms of RA by improving distribution of T lymphocyte subsets and the functions of cellular immunity. The other Chinese medicinal herbs in the RA mixture could enhance TW's therapeutical effect and reduce it's side effect. €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ Li RL Liu PL Wu XC [Clinical and experimental study on sustained release tablet of Tripterygium wilfordii in treating rheumatoid arthritis] In: Chung Kuo Chung Hsi I Chieh Ho Tsa Chih (1996 Jan) 16(1):10-3 ISSN: 1003-5370 (Published in Chinese) Adopt to the prospective, multi-center, random, single-blind, equal rank-control methods, 226 patients of rheumatoid arthritis diagnosed according to the ARA criteria, were divided into 2 groups. One hundred and fourteen patients of test group were treated with sustained release tablets of Tripterygium wilfordii (TW-SR) orally, 2 tablets, twice a day for 4 weeks, 112 patients of control group received tablets of Tripterygium wilfordii (TW) orally, 2 tablets 3 times per day for 4 weeks. Results showed that the total effective rate of the two groups were 92.11% and 90.65%, respectively (P > 0.05). The adverse reaction rate of TW-SR group was 20.18%, which was lowered than that of TW group (70.54%, P < 0.01). Results of pre- clinical pharmacologic experimental study showed that the TW-SR has obvious anti-inflammatory, analgesia and immunosuppress'ive action as the TW has, while its toxicity was less than the latter significantly. €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ **CHUNG-KUO CHUNG YAO TSA CHIH CHINA JOURNAL OF CHINESE MATERIA MEDICA* Guo XH Yang MX [Studies on culturing seeds of Tripterygium hypoglaucum (Level.) Hutch. in vitro] In: Chung Kuo Chung Yao Tsa Chih (1994 Jan) 19(1):16-20, 61 ISSN: 1001-5302 (Published in Chinese) This paper for the first time reports the embryo culturing in vitro of Tripterygium hypoglaucum. Tests were conducted of every condition for the normal germination and growth of the excised embryo. The result shows that the germination ratio reaches the highest on the white basic medium when the intensity of light is 400Lx, sucrose concentration is 3% and whole nitrogen content is 230 mg/L. Intact plantlets are obtained from the aseptic shoots. A method using aseptic shoots to accelerate the propagation of plantlets is found primarily. €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ ***CHUNG-KUO I HSUEH KO HSUEH YUAN HSUEH PAO ACTA ACADEMIAE MEDICINAE** Zhang C Yan Z Chen Y Zhang Y Lu X [Studies on triterpenoids of total glucosides of tripterygium wilfordii] In: Chung Kuo I Hsueh Ko Hsueh Yuan Hsueh Pao (1994 Dec) 16(6):466-8 ISSN: 1000-503X (Published in Chinese) Three more triterpenoids were isolated from total glucosides of tripterygium wilfordii (T1). T16 and T17 were identified as salaspermic acid and as wilforlide B. T18 was a new compound. The structure of T18 was determined, as 3-oxo-22 alpha-hydroxy-delta 12- oleanen-29-oic acid by detail spectroscopic and chemical analysis, and named triptotriterpenonic acid A. Registry Numbers: 144629-85-6 (triptotriterpenonic acid A) 508-02-1 (Oleanolic Acid) 71247-78-4 (salaspermic acid) 84104-70-1 (wilforlide B) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ Yao Q Zhang N [Effects of tripchlorolide (T4) of Tripterygium wilfordii Hook on the proliferation of peripheral blood mononuclear cells of rheumatoid arthritis patients] In: Chung Kuo I Hsueh Ko Hsueh Yuan Hsueh Pao (1994 Oct) 16(5):352-5 ISSN: 1000-503X (Published in Chinese) Tripchlorolide (T4) is a single active ingredient recently isolated from Tripterygium wilfordii Hook. The effects of T4 on the proliferation of peripheral blood mononuclear cells (PBMC) of rheumatoid arthritis (RA) patients and normal subjects were studied, RA patients and sex- and age-matched normal subjects (each 8 cases) were selected. PBMC were incubated with T4 of various doses (10, 20, 30 and 40 ng/ml) in the presence or absence of PHA for 72 hours. The results were as follows: T4 remarkably inhibited the proliferation of both PHA-stimulated and unstimulated PBMC of normal subjects and PHA- stimulated PBMC of RA patients as measured by MTT colormetric method. However, T4 showed a biphasic reaction in unstimulated PBMC of 3 RA patients. These results indicates that T4 would be useful in the therapy of RA. The significance of biphasic reaction occurring in RA patients needs to be further investigated. Registry Numbers: 132368-08-2 (tripchlorolide) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ Zhang L Bi Z Li X [Inhibitory effects of monomer T4 from Tripterygium wilfordii hook on cultured mesangial cells proliferation and IL-1 production] In: Chung Kuo I Hsueh Ko Hsueh Yuan Hsueh Pao (1994 Aug) 16(4):270-4 ISSN: 1000-503X (Published in Chinese) The cultured mesangial cells (MSc) went through three serial passages before being using. Quantitation of MSc growth rate was obtained by measuring the ratio of 3H-TdR uptake in a medium containing various concentrations of T4. IL-1 activity was tested by 3H-TdR incorporation in C57BL/c mice thymocytes. The results show that T4 inhibited MSc proliferation and IL-1 production. Registry Numbers: 132368-08-2 (tripchlorolide) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ Zheng J Feng K Gu K [Screening of anti-inflammatory, immunosuppressive and antifertility components of Tripterygium wilfordii V. Effects of 7 diterpene lactone epoxide compounds on the proliferation of T and B lymphocytes in vitro] In: Chung Kuo I Hsueh Ko Hsueh Yuan Hsueh Pao (1994 Feb) 16(1):24-8 ISSN: 1000-503X (Published in Chinese) The inhibitory effects and their IC50 values of Tripterygium wilfordii (TW) on T and B lymphocytes were assayed using mice splenocytes induced to proliferate by mitogens ConA and LPS in vitro. The results indicated that 6 compounds (T4,T7,T8,T9,T10,L2) and component T1 had significant inhibitory effects on the proliferation of lymphocytes in response to ConA and LPS. The inhibitory potencies of these compounds were in the range of 10(-5)-10(-9) micrograms/ml for both T and B cells, while those of T1 were 3.5 and 4.2 micrograms/ml, respectively. The IC50 values, from low to high, were in the following order: T10,T4,T8,L2,T7,T9 and T1, The dose-effect curves for LPS were to the right of ConA curves, though both were nearly parallel. The relative order of the IC50 values determined from ConA and LPS curves were also coincident. Another compound, T11, showed no suppressive effect on the proliferation of T and B lymphocytes induced by either mitogen, even when its concentration reached 50 micrograms/ml. The results suggest that the suppressive effects of the componends on the proliferation of T and B lymphocytes in vitro were direct and non-selective. €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ Dai W Liu P Han Y [The effect of Tripterygium wilfordii monomers T4,T7,T15 and Triptolide on rat nuclear protein] In: Chung Kuo I Hsueh Ko Hsueh Yuan Hsueh Pao (1994 Feb) 16(1):20-3 ISSN: 1000-503X (Published in Chinese) Rat epididymal sperms were collected after 7 weeks of treatment with Tripterygium wilfordii monomers T4,T7,T15 and triptolide. Total nuclear basic protein (TNBP) were extracted from sperm nuclei isolated by sonication. The relative proportions of histones and protamine were determined by scanning microdensitometry following electrophoresis of TNBP in polyacrylamide gels. It was found that the content of TNBP was reduced while the total histone/protamine ratios were increased following treatment, indicating a marked decrease of protamine levels as compared with the control group. These results suggest that the interruption of nuclear protein transition of spermatids induced by T4,T7,T15 and triptolide might lead to infertility. Registry Numbers: 38748-32-2 (triptolide) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ Liu Y Wang W Zhu G Chen J Xu C [The role of substance P in immunosuppression induced by Tripterygium wilfordii] In: Chung Kuo I Hsueh Ko Hsueh Yuan Hsueh Pao (1995 Aug) 17(4):269-73 ISSN: 1000-503X (Published in Chinese) The effects of T II (extracted from Tripterygium wilfordii) and substance P (SP) on imunoregulation were investigated. It has been shown that Tripterygium wilfordii is an immunosuppresive. In order to assess the immunosuppression elicited by T II was mediated by SP in spinal dorsal horn, Wistar rats were injected intrathecally with capsaicin (CAP) to deplete SP in spinal dorsal horn prior to T II given orally. The level of interleukin 2 (IL-2) produced by splenic lymphocytes of rats and the contents of SP in some brain areas and spinal cord in mice were assayed after T II treatment. Our findings were as follows: 1. The level of IL-2 was decreased significantly after T II treatment only. However the level of IL-2 was increased markedly after CAP was given intrathecally. Moreover, CAP administration also enhanced the level of IL-2 even in immunosuppression group induced by T II treatment. 2. SP contents in spinal cord, hypothalamus and brain stem of mice were increased dramatically during immunosuppression produced by T II. The results suggested that SP in spinal dorsal horn was involved in regulation of cellular immunity, the suppressive effect of T II on cellular immunity might be mediated by SP in spinal dorsal horn. Registry Numbers: 33507-63-0 (Substance P) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ Dong Y [The suppressive effect of Tripterygium wilfordii hook F on the IL-2 autocrine loop of human T cells] In: Chung Kuo I Hsueh Ko Hsueh Yuan Hsueh Pao (1993 Jun) 15(3):193-6 ISSN: 1000-503X (Published in Chinese) We studied the effect of Tripterygium wilfordii Hook F on the IL-2 autocrine loop of human T cells in vitro. The results revealed that GTW significantly inhibited the activation of T cells production of IL-2, expression of IL-2R and proliferation response of activated T cells exogenous IL-2. €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****CHUNG-KUO YAO LI HSUEH PAO [ACTA PHARMACOLOGICA SINICA]***** Wei YS Adachi I Inhibitory effect of triptolide on colony formation of breast and stomach cancer cell lines. In: Chung Kuo Yao Li Hsueh Pao (1991 Sep) 12(5):406-10 ISSN: 0253-9756 Triptolide (Tri) is a diterpenoid triepoxide isolated from Tripterygium wilfordii Hook F. The effects of Tri on the colony formation of breast cancer cell lines MCF-7 and BT-20, stomach cancer cell lines MKN-45, MKN-7, and KATO-III, and promyelocytic leukemia cell line HL-60 were reported. Using Hamburger-Salmon's double layer agar technique with certain modifications, cancer cells were cultured in 0.3% agar in a highly humidified atmosphere of 5% CO2 at 37 degrees C for 14-21 d. Colonies were counted on d 14 (occasionally d 21) with the colony analyzer system CA-7A. Of the 5 solid tumor cell lines tested, 4 showed diminished colony formation in soft agar by greater than 70% of control value in Tri 10(-8) mol.L-1 (continuous exposure). The magnitudes of the inhibitory effect of Tri on most breast and stomach cancer cell lines were similar to that on the leukemia cell line HL-60. IC50 were 0.504-1.22 micrograms.L-1. The clinically achievable peak plasma concentration (PPC) of Tri was estimated as 0.15 mg.L-1, being 72-126 times higher than the IC70 of the cancer cell lines except KATO-III. The results suggest that Tri might have a potential therapeutic effect on some types of solid tumors, e.g., breast and stomach cancers. Registry Numbers: 38748-32-2 (triptolide) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ Zheng YL Lin JF Lin CC Xu Y [Anti-inflammatory effect of triptolide] In: Chung Kuo Yao Li Hsueh Pao (1994 Nov) 15(6):540-3 ISSN: 0253-9756 (Published in Chinese) Triptolide (Tri) was isolated from Tripterygium wilfordii Hook f. Tri 0.1-0.2 mg.kg-1 sc or 0.15-0.3 mg.kg-1 ig inhibited markedly the increased vascular permeability induced by ip 0.7% HAc in mice. Tri 0.05-0.1 mg.kg-1 ip or 0.15-0.3 mg.kg-1 ig inhibited hind paws swelling induced by sc 0.15 ml carrageenan and also inhibited the same swelling induced by sc 2.5% formaldehyde 0.1 ml in rats. Tri 0.05-0.1 mg.kg-1 ip inhibited markedly proliferation of granuloma induced by sc implantation of cotton-pellets in rats, but 0.2 mg.kg-1 ip can not inhibit the same swelling induced by sc 0.15 ml carrageenan in adrenalectomized rats. Tri 0.2 mg.kg-1 ip decreased markedly weight of thymus. Tri 0.2 mg.kg-1 ip, but 0.1 mg.kg-1 ip did not reduced the content of ascorbic acid of adrenal gland in rats. Tri 0.2 mg.kg-1 ip did not decrease the pro-staglandin E content in inflammatory tissues. These results indicate that high dose of Tri can stimulate the pituitary-adrenal axis. Registry Numbers: 38748-32-2 (triptolide) 50-81-7 (Ascorbic Acid) 9000-07-1 (Carrageenan) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ Pei RJ Qi LH Liu XJ Effects of triptonide on mouse immune functions. In: Chung Kuo Yao Li Hsueh Pao (1993 May) 14(3):238-42 ISSN: 0253-9756 Triptonide (Tri) extracted from Tripterygium wilfordii Hook inhibited the proliferation of mouse splenocytes induced by suboptimal concentration of concanavalin A or lipopolysaccharide at concentrations of 0.02, 0.1, and 0.5 microgram.ml-1. It showed a suppressive effect on one way mixed lymphocyte culture (MLC) at 0.1- 0.4 microgram.ml-1. The lymphocytes harvested from the first Tri (0.4 microgram.ml-1)-containing MLC inhibited the second MLC after being washed and irradiated with 60Co source (30 Gy). Serum anti-sheep red blood cell antibody (hemolysin) formation and clearance of charcoal particles were also suppressed by Tri in vivo. Although delayed hypersensitivity (DH) reaction to dinitrofluorobenzene (DNFB) was inhibited by Tri 1.2, 2.5, and 5.0 mg.kg-1 (ip, qd x 5 d), the spleen cell interleukin-2 secretion activities of these mice were not suppressed. Graft vs host reaction (GVHR) was not inhibited by Tri 2.5 and 5.0 mg.kg-1 (ig, qd x 5 d). Helper T cells (Th)/suppressor T cells (Ts) ratio was reduced at 2.5 mg.kg-1. The effects of Tri on mouse thymus and spleen weight were related to the age. Tri (1.2, 2.5, 5.0 mg.kg-1) had no effect on thymus and spleen weights in 8-wk- old mice. However, it increased the thymus and spleen weights in 12- wk-old mice at doses of 1.2 and 2.5 mg.kg-1. The data indicated that Tri had extensive suppressive effects on mouse immune function and its mechanism may be related to the reduction of Th/Ts ratio and the induction of Ts cells. Registry Numbers: 38647-11-9 (triptonide) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****CONTRACEPTION***** Lan ZJ Gu ZP Lu RF Zhuang LZ Effects of multiglycosides of Tripterygium wilfordii (GTW) on rat fertility and Leydig and Sertoli cells. In: Contraception (1992 Mar) 45(3):249-61 ISSN: 0010-7824 Primary cultures of rat Leydig and Sertoli cells were used to evaluate the direct effects of GTW on testicular cells and to compare these to the effects of gossypol acetate. Both GTW and gossypol acetate can affect the survival of Leydig and Sertoli cells. But Sertoli cells are much more sensitive than Leydig cells, either to gossypol acetate or GTW. Leydig and Sertoli cells all died when they were exposed to gossypol acetate or GTW at a dose of 3.0 micrograms/ml or 30 micrograms/ml, respectively, for 24 hours. The cell survival-time course demonstrated that the cell numbers were decreased after 2 hours, and especially so after 8 hours. No significant changes were observed in testosterone production in Leydig cells after 24 hours of exposure to 1.0-20 micrograms/ml GTW. The forward motility of epididymal spermatozoa was completely lost and fertility of rat was significantly inhibited after the treatment of GTW in vivo. It is concluded that GTW does affect the fertility of rat and viability of cultured rat Leydig and Sertoli cells. Registry Numbers: 303-45-7 (Gossypol) 57-85-2 (Testosterone) 9002-68-0 (FSH) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ Zhen QS Ye X Wei ZJ Recent progress in research on Tripterygium: a male antifertility plant. In: Contraception (1995 Feb) 51(2):121-9 ISSN: 0010-7824 The discovery of the reversible antifertility action of an extract from Tripterygium wilfordii both in male rats and in men in 1986 stimulated worldwide interest. International and national collaborations aimed at the bioassay-directed sub-fractionation of materials extracted from the plant was then organized and to date, a series of six male antifertility diterpene epoxides have been isolated. Their chemical structures have been identified and found to be triptolide, tripdiolide, triptolidenol, tripchlorolide, 16- hydroxytriptolide and T7/19 (structure not yet published). At the ED95 dosage levels, they act mainly on metamorphosing spermatids and testicular and epdidymal spermatozoa with exfoliation and inhibition of basic nuclear protein turnover of late spermatids, delayed spermiation and sperm head-tail separation and microtubule, microfilament and membrane damages. A preliminary toxic evaluation indicated that these compounds were immunosuppressive at dose levels 5-12 times their antifertility doses. Immuno-suppression is an important weakness for an antifertility agent, but if the immuno- suppressive dose of a drug is much higher than its antifertility dose, it could yet be regarded as a safe contraceptive. Therefore, in the safety evaluation of compounds isolated from Tripterygium wilfordii, it warrants our attention to probe deeply into their precise dose/immuno-effect relationship. €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ Chan WY Ng TB Adverse effect of Tripterygium wilfordii extract on mouse embryonic development. In: Contraception (1995 Jan) 51(1):65-71 ISSN: 0010-7824 Tripterygium wilfordii Hook f. is a medicinal plant which possesses anti-fertility activity in males and has been used in China for the treatment of rheumatoid arthritis, chronic nephritis and other pulmonary diseases for years. The effect of Tripterygium wilfordii extract on in vitro development in day 9 and day 10 mouse embryos was examined. The embryotoxicity of T. wilfordii extract was obvious on day 9 and day 10 embryos at doses of 50 and 100 micrograms/ml, respectively. The embryonic abnormalities produced included abnormal branchial apparatus, open cranial neural tube and absence of forelimb bud in day 9 embryos. In day 10 embryos, the abnormality appeared first in the branchial apparatus. At higher doses, additional abnormalities appeared: abnormal optic and otic vesicles and twisted body axis in day 9 embryos; microcephaly, hematoma in cranial region and absence of hindlimb buds in day 10 embryos. There were reductions in final somite number, yolk sac surface area and axial length. Dead cells were present all over the embryo. The blood circulation of the visceral yolk sac of the abnormal embryos became defective. Ultrastructural analysis of the visceral yolk sac revealed abnormalities including decrease in the amount of microvilli, reduction in the number of storage vesicles, appearance of large vacant vacuoles and decrease in the number of pinocytotic invaginations on the apical surface of the yolk sac epithelium. The embryotoxic effect of T. wilfordii extract was, however, destroyed by heat treatment of the extract at 80 degrees C for 6 hours. €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ Matlin SA Belenguer A Stacey VE Qian SZ Xu Y Zhang JW Sanders JK Amor SR Pearce CM Male antifertility compounds from Tripterygium wilfordii Hook f. In: Contraception (1993 Apr) 47(4):387-400 ISSN: 0010-7824 Extracts of the Chinese medicinal plant, Tripterygium wilfordii, cause reversible infertility in male animals. Sub-fractionation studies have now revealed that the plant extracts contain a number of compounds which are potent antifertility agents in male mammals, including the diterpenes triptolide and tripdiolide and an isomer of the latter. A triptolide, 12,13-chlorohydrin, which is a transformation product formed reversibly by interaction of triptolide with HCl, was also found to be active. Registry Numbers: 132368-08-2 (tripchlorolide) 38647-10-8 (tripdiolide) 38748-32-2 (triptolide) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****FUKUOKA IGAKU ZASSHI. FUKUOKA ACTA MEDICA***** Ren L Yasuda M Nonaka S Shiokawa S Wada T Nobunaga M The effects of Tripterygium wilfordii extract on adjuvant arthritis in rats. In: Fukuoka Igaku Zasshi (1995 Jan) 86(1):6-11 ISSN: 0016-254X The effects of the extract of Tripterygium wilfordii. (TWE) on experimental adjuvant arthritis (AA) in the rat was studied. Lewis rats induced with AA were administered with TWE at 50 mg/kg/day for 10 weeks. The paw volume, its ratio to the body weight (paw ratio) and the radiologic changes in the feet of the rats with AA taking TWE were compared with those in the rats taking indomethacin (0.5 mg/kg/day) and no additional drugs. The rats taking TWE showed a smaller paw volume, a lower paw ratio and milder radiologic changes than the rats taking no drugs, however, the beneficial effects were weaker than those of indomethacin. We concluded that the beneficial effects of TWE on rats with AA was suggested. However, these results still need to be further confirmed by additional experiments. €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****GENERAL PHARMACOLOGY***** Yu KT Nuss G Boyce R Jariwala N Owens G Pennetti A Chan W Zhang DC Chang MN Zilberstein A Inhibition of IL-1 release from human monocytes and suppression of streptococcal cell wall and adjuvant-induced arthritis in rats by an extract of Tripterygium wilfordii Hook. In: Gen Pharmacol (1994 Oct) 25(6):1115-22 ISSN: 0306-3623 1. It was investigated whether an extract of Tripterygium wilfordii Hook f (TW) inhibits IL-1 production by monocytes and suppresses the development of IL-1-dependent arthritis induced in rats with streptococcal cell wall and adjuvant. 2. TW preferentially inhibited IL-1 alpha and IL-1 beta production by bacterial lipopolysaccharide (LPS)-stimulated human monocytes with IC50 of approximately 1 microgram/ml. 3. Oral administration of TW dose-dependently suppressed joint swelling and structural damage in streptococcal cell wall-induced arthritis (ED50 = 20 mg/kg/day) and in adjuvant-induced arthritis (ED50 = 46 mg/kg/day for developing and 8 mg/kg/day for established arthritis). €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****HUMAN AND EXPERIMENTAL TOXICOLOGY***** Chan WY Ng TB Lu JL Cao YX Wang MZ Liu WK Effects of decoctions prepared from Aconitum carmichaeli, Aconitum kusnezoffii and Tripterygium wilfordii on serum lactate dehydrogenase activity and histology of liver, kidney, heart and gonad in mice. In: Hum Exp Toxicol (1995 Jun) 14(6):489-93 ISSN: 0960-3271 Mature ICR mice were randomly divided into groups and treated with various doses (1 mg, 5 mg or 10 mg herb/25 g body weight) of a decoction of one of three following Chinese medicinal herbs: Aconitum carmichaeli, Aconitum kusnezoffi and Tripterygium wilfordii, once daily for 4 days. Twenty four hours after the last injection the animals were bled and the blood samples were stored at -20 degrees C until assay for liver lactate dehydrogenase (LDH) isozyme activity. The livers, kidneys, hearts and gonads were dissected out, immediately fixed in Bouin's fluid, and subsequently processed for histological examination. It was found that the gonads and hearts of the drug-treated mice were histologically similar to those of control animals. After treatment with the lowest dose of the herbs i.e. 1 mg/25 body weight, the liver and kidney did not undergo observable changes. However, the herbs at the doses of 5 mg and 10 mg/25 g body weight produced damaging effects on the liver and kidney, the effects produced by the higher dose being more dramatic. The tissue damage was accompanied by elevations of liver LDH isozyme activity in the serum. Registry Numbers: EC 1.1.1.27 (Lactate Dehydrogenase) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****INTERNATIONAL JOURNAL OF CARDIOLOGY***** Chou WC Wu CC Yang PC Lee YT Hypovolemic shock and mortality after ingestion of Tripterygium wilfordii hook F.: a case report. In: Int J Cardiol (1995 Apr) 49(2):173-7 ISSN: 0167-5273 Tripterygium wilfordii Hook F (TWHF) is a kind of Chinese herbal medicine used for 2000 years. It was applied externally for treatment of arthritis and inflammatory tissue swelling in early years. Recently, this drug has been found to have immunosuppressive effects which could successfully induce remission of some autoimmune disorders without obvious adverse effects. Although there are side effects of gastrointestinal upset, infertility and suppression of lymphocyte proliferation, little information about lethal toxicities has been reported. A case is presented here of a previously healthy young man who developed profuse vomiting and diarrhea, leukopenia, renal failure, profound hypotension and shock after ingestion of an extract of TWHF. In addition to his hypovolemic shock, serial electrocardiograms (ECG), cardiac enzyme studies, and echocardiography also showed some evidence of coexisting cardiac damage. He died of intractable shock 3 days after the abuse of TWHF. Further studies of the pathogenesis of peripheral collapse and possible cardiac toxicity, and determination of the therapeutic range of this drug are necessary before it is used extensively. Registry Numbers: EC 2.7.3.- (Creatine Kinase Isoenzymes) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****INTERNATIONAL JOURNAL OF IMMUNOPHARMACOLOGY***** Gu WZ Chen R Brandwein S McAlpine J Burres N Isolation, purification, and characterization of immunosuppressive compounds from tripterygium: triptolide and tripdiolide. In: Int J Immunopharmacol (1995 May) 17(5):351-6 ISSN: 0192-0561 Crude extracts derived from the root of Tripterygium wilfordii Hook f (TWHf) have previously been demonstrated to have immunosuppressive properties and have been used as anti-rheumatic therapy in Chinese traditional medicine. Although these extracts contain a large number of chemical components, the precise nature of the compound(s) responsible for this therapeutic effect has not been established with certainty. An aqueous extract of TWHf was resolved into chemical components by medium-pressure and high-performance liquid chromatography. Immunosuppressive fractions were identified with a mixed lymphocyte reaction (MLR) and chemically characterized by nuclear magnetic resonance spectroscopy and mass spectrometry. Two major peaks of immunosuppressive activity were identified. These were the closely related diterpenoid triepoxides, triptolide and tripdiolide. No other immunosuppressive compounds were identified using MLR as the biologic screening assay. Triptolide and tripdiolide may be responsible for the anti-rheumatic properties of crude aqueous extracts of TWHf and represent a novel class of immunosuppressive drugs with potential clinical utility. Registry Numbers: 38647-10-8 (tripdiolide) 38748-32-2 (triptolide) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY***** Hayashi K Hayashi T Ujita K Takaishi Y Characterization of antiviral activity of a sesquiterpene, triptofordin C-2. In: J Antimicrob Chemother (1996 Apr) 37(4):759-68 ISSN: 0305-7453 The activities of 13 sesquiterpenes isolated from Tripterygium wilfordii Hook fil. var. regelii Makino were studied against herpes simplex virus type 1 (HSV-1) in vitro. Among these compounds, only triptofordin C-2 showed a selectivity index of more than 10. The compound, which could also inhibit the replication of human cytomegalovirus (HCMV), did not affect either adsorption or penetration of HSV-1 to host cells, but showed moderate virucidal activity against several enveloped viruses including HSV-1, HCMV, measles virus and influenza A virus. Triptofordin C-2 suppressed viral protein synthesis of infected cells when added at early steps of HSV-1 replication and exerted inhibition of translation of the transcripts of the immediate early genes. When acyclovir and triptofordin C-2 were evaluated in combination for antiviral activity against HSV-1 replication, additive antiviral effects were observed for this virus. Registry Numbers: 111514-63-7 (triptofordin C 2) 59277-89-3 (Acyclovir) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****JOURNAL OF DERMATOLOGY***** Weng MW Qiu BS Kang KF An analysis of 24 patients with IgA deposition at the BMZ. In: J Dermatol (1993 May) 20(5):276-8 ISSN: 0385-2407 A study of 24 patients with IgA deposition at the BMZ of the skin showed that five conditions could be recognized: 1) linear IgA bullous dermatosis in adults (LAD, 7 cases); 2) linear IgA and IgG bullous dermatosis in adults (LAGD, 10 cases); 3) chronic bullous disease of childhood (CBDC, 3 cases); 4) dermatitis herpetiformis (DH, 1 case), and 5) systemic lupus erythematosus (SLE, 3 cases). Histopathologically, 5 of 7 patients with LAD were similar to the DH group, but 7 of 10 patients with LAGD were similar to the BP group. Half the patients with LAD and LAGD had oral lesions, and most of them had excellent responses to dapsone and Tripterygium Wilfordii, but the patients with CBDC did not respond to these treatments. In the patients with LAD and LAGD, the positivity rates of IgA anti-BMZ antibodies examined by indirect immunofluorescence (IIF) on intact skin and NaCl split skin were 41% and 64%, respectively. The heterogeneity of the histopathologic pictures of LAD and LAGD, the incidence of DH, and the value of using NaCl split skin for IIF are discussed. Registry Numbers: 80-08-0 (Dapsone) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****JOURNAL OF TONGJI MEDICAL UNIVERSITY***** Zheng JF Chen SY Observations on therapeutic effects of huangdan decoction and Tripterygium Wilfordii compound tablet on membranous glomerulonephritis in rats. In: J Tongji Med Univ (1995) 15(1):31-4 ISSN: 0257-716X The model of membranous glomerulonephritis (MGN) in rats was successfully established using self-made cationic bovine serum albumin (C-BSA) and treated with Huangdan Decoction (HDD) and Tripterygium Wilfordii Co. tablet (TW). Results indicated that the levels of urinary protein, blood urea nitrogen (BUN) and serum creatinine (Scr) in treated groups (groups A, B and C) were significantly decreased as compared with the control group (group D) (P < 0.01). By light and electron microscope and immunofluorescent technique, the damage to kidney in groups A, B and C was found much milder than that in group D with lesion in group A being slightest. These findings suggest that HDD and TW may alleviate the pathological lesions of MGN, prevent or retard its progression, and have remarkable therapeutic effects on MGN. €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ Zhang MM Liu PL Ye WY Effect of Tripterygium Wilfordii on adrenal cortex in rat with adjuvant arthritis. In: J Tongji Med Univ (1994) 14(3):158-61 ISSN: 0257-716X This paper reports the effects of Tripterygium Wilfordii (TW) on adrenal cortex in rats with adjuvant arthritis. Forty rats were divided into 5 groups. Adjuvant arthritis (AA) models were made with complete freund's adjuvant (CFA) in groups I-IV. Each of which was treated with sodium carboxyl methyl cellulose, TW, prednisone and cyclophosphamide respectively. The untreated rats allocated to group V served as normal controls. The swelling of AA markedly subsided in group II, III and IV as compared with group I (P < 0.01), whereas no significant differences were noted among groups II, III and IV (P > 0.05). The obviously increased plasma corticosterone levels and decreased adrenal ascorbic acid levels were observed in group II, whereas decreased plasma corticosterone levels and increased adrenal ascorbic acid levels were noted in group III. There was a striking contrast between groups II and III. The morphological changes of adrenal glands under light microscope revealed hypertrophic adrenal cortices in group II, and atrophic adrenal cortices in group III. The above findings suggest that the effect of promoting production of corticosteroids may be one of the mechanism by which TW can effectively treating autoimmune diseases. Registry Numbers: 50-22-6 (Corticosterone) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****MUTAGENESIS***** Wang X Zhuo R He Z Aneuploidy induction by water extract from Tripterygium hypoglaucum (Level) Hutch in mouse bone marrow cells. In: Mutagenesis (1993 Sep) 8(5):395-8 ISSN: 0267-8357 The aneuploidy-inducing activity of a Chinese medicinal herb, Tripterygium hypoglaucum (level) Hutch (THH), was investigated by means of three cytogenetic end-points, i.e. C-mitotic (CM) effects, micronuclei (MN) and parallel chromosome structural aberration (CA) analyses in vivo. The CA analysis was expected to reflect the origins of MN induced by clastogens or aneugens. The experiments were performed on mouse bone marrow cells. The animals were treated with the crude water extracts of THH (single i.p. injection) in the dose range 120-686 mg/kg. Colchicine (COL) was taken as a positive control for its known aneuploidy-inducing effects. THH showed similar genotoxic effects to COL in CM, MN and CA analyses: positive CM effects were observed accompanied with increases of mitotic index and frequencies of CM cells as well as decreased frequencies of anaphase in all of the THH-treated groups. The compound showed a positive MN response in bone marrow polychromatic erythrocytes but was negative in CA analyses. No sex differences were found in any treated group. The preliminary results suggested that THH is an aneuploidy inducer in mouse bone marrow cells under the present experimental conditions. Registry Numbers: 64-86-8 (Colchicine) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****PEDIATRIC NEPHROLOGY***** Jiang X Clinical observations on the use of the Chinese herb Tripterygium wilfordii Hook for the treatment of nephrotic syndrome. In: Pediatr Nephrol (1994 Jun) 8(3):343-4 ISSN: 0931-041X A preparation of extracts from the root of the Chinese medicinal herb Tripterygium wilfordii Hook was administered orally at a dose of 1 mg/kg body weight per day to 13 children with idiopathic nephrotic syndrome. Eight children, including 4 who were steroid resistant, went into remission which was maintained in 4 for up to 3 years after withdrawal of treatment. In 3 children the proteinuria lessened with the return of plasma protein concentration to normal, and in 1 child this improvement was maintained for 4 years after treatment ceased. No serious side-effects were noted, but a temporary anti-fertility activity has been noted in other studies of both men and women. €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****PLANTA MEDICA***** Lee GI Ha JY Min KR Nakagawa H Tsurufuji S Chang IM Kim Y Inhibitory effects of Oriental herbal medicines on IL-8 induction in lipopolysaccharide-activated rat macrophages. In: Planta Med (1995 Feb) 61(1):26-30 ISSN: 0032-0943 Cytokine-induced neutrophil chemoattractant (CINC), a rat interleukin- 8 (IL-8), was quantitated by using a sensitive ELISA. The CINC was induced up to 20 ng/ml from basal 1-2 ng/ml in lipopolysaccharide (LPS)-activated peritoneal macrophages. This CINC induction was significantly inhibited by steroidal anti-inflammatory drugs including dexamethasone, but not by non-steroidal drugs including indomethacin at all. Nine out of 59 herbal medicines which are frequently used in Korean traditional prescriptions for inflammatory diseases exhibited more than 50% of inhibition on the CINC induction by their total methanol extracts with 0.1 mg/ml as a final concentration. The active 9 total extracts were prepared from radix of Aralia continentalis, rhizoma of Cnidium officinale, rhizoma of Coptis chinensis, tuber of Fritillaria verticillata, radix of Saussurea lappa, tuber of Sparganium stoloniferum, flower of Syzygium aromaticum, semen of Trichosanthes kirilowii, and herba of Tripterygium regelii. These total extracts were sequentially fractionated with dichloromethane, ethyl acetate, butanol, and water. Among the solvent-fractionated extracts with 0.05 mg/ml as a final concentration, more than 50% of inhibition on the CINC induction was exhibited by the dichloromethane fraction of Aralia continentalis; the water fraction of Fritillaria verticillata; the dichloromethane fraction of Saussurea lappa; the dichloromethane, ethyl acetate, and butanol fractions of Syzygium aromaticum; the dichloromethane, ethyl acetate, and water fractions of Trichosanthes kirilowii; and the dichloromethane and ethyl acetate fractions of Tripterygium regelii. €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****PROCEEDINGS / ANNUAL MEETING OF THE AMERICAN ASSOCIATION FOR***** King IC Chu M Ramos R Nunez I Robertson N Chen P Li Z Liu M Patel M Catino JJ Antitumor effect of celastrol, an inhibitor of tyrosine kinases and type I topoisomerase (Meeting abstract). In: Proc Annu Meet Am Assoc Cancer Res (1995) 36:A2319 ISSN: 0197-016X Celastrol (Sch 9964), a triterpenoid isolated from the root of a Chinese medicinal herb Tripterygium regeli, exhibited potent antitumor effect in vivo. Celastrol, given 3 times a wk at doses ranging from 1.5 to 7.5 mg/kg, inhibited the growth of subcutaneously implanted M27 lung epidermoid carcinoma by 25 to 75%. Similar antitumor activity was obtained when the drug was given to animals bearing human colon adenocarcinoma cells SW620. Using human melanoma LOX cells implanted into SCID mice as a model, we found celastrol at 3.0 mg/kg with a 3x/wk schedule inhibited tumor growth completely. The drug was equally active when it was given orally or intraperitoneally. Celastrol inhibited EGF-receptor associated tyrosine kinase with an IC50 value of 5 uM. It also inhibited human type I topoisomerase in a cell-free system using a supercoiled DNA as the substrate; its activity was comparable to camptothecin. The in vivo antitumor activity of celastrol may be due to its inhibitory activity against topoisomerase, or tyrosine kinase, or both. Similar to other topoisomerase I inhibitors, celastrol may possess a broad spectrum of antitumor activity. Registry Numbers: 34157-83-0 (tripterine) EC 5.99.1.2 (DNA Topoisomerase) EC 2.7.1.112 (Protein-Tyrosine Kinase) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ Ushiro S Kawahara N Komatsu Y Kohno K Ono M Kuwano M Anti-angiogenesis and anti-tumor effects of nortriterpenoid (Tz-93) (Meeting abstract). In: Proc Annu Meet Am Assoc Cancer Res (1996) 37:A382 ISSN: 0197-016X Angiogenesis is involved in various 'angiogenesis diseases' such as tumor growth, diabetic retinopathy and rheumatoid arthritis. Anti- angiogenesis agents have been recently developed to treat the above diseases by targeting angiogenesis. In China, the preparations of Tripterygium wilfordii Hook F. (Thunder God Vine) have been clinically used for the treatment of the patients with rheumatoid arthritis and effective for more than 90% of patients. We examined whether one component, nortriterpenoid (Tz-93), which was extracted from this preparations had anti-angiogenesis activity in vitro and in vivo. Tz-93 showed a preferential inhibition on vascular endothelial cells and also inhibited the migration as well as tube formation by endothelial cells. Tz-93 also inhibited the development of the new vessels on chick chorioallantoic membrane and in the mouse dorsal subcutaneous tissue where the diffusion chamber filled with a human cancer cell was implanted. Oral administration of Tz-93 at 3-30 mg/kg/day induced dramatic decrease in tumor growth as well as vasculatures of various implanted tumor types, but no loss of body weight appeared. This novel anti-angiogenesis and anti-tumor effect of Tz-93 is discussed in relation to the mechanism of the inhibition of angiogenesis. €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****YAO HSUEH HSUEH PAO [ACTA PHARMACEUTICA SINICA]***** Xu WM Zhang LX Cheng ZH Cai WZ Miao HH Pan DJ [Inhibitory effect of tripterine on activities of IL-1, IL-2 and release of PGE2] In: Yao Hsueh Hsueh Pao (1991) 26(9):641-5 ISSN: 0513-4870 (Published in Chinese) Tripterine is one of the components isolated from Tripterygium wilfordii Hook. Previous studies demonstrated that tripterine inhibited not only humoral and cellular immune responses but also some inflammatory responses. The present investigation attempted to observe effect of the drug on productions of IL-1 from macrophages, IL-2 from splenocytes and PGE2 from synovial cells. The results showed that tripterine (0.1-1.0 microgram/ml) significantly inhibited IL-1 activity of murine peritoneal macrophages induced by LPS. Because both intracellular and extracellular IL-1 activities were decreased, so tripterine might be able to reduce the production and release of IL-1. Besides, inhibition of IL-1 production was observed when macrophages were pretreated with the drug for 8 h and 16 h. A good relationship was found between the effect and concentration of tripterine which inhibited IL-2 production from ConA-activated murine splenocytes. Kinetic study indicated that IL-2 production was decreased when splenocytes were pretreated with the drug for 3 h, 6 h and 12 h. Synovial cells obtained from rabbit knee joint were cultured successfully. A23187 was found to augment PGE2 synthesis modestly. Tripterine significantly reduced PGE2 release from synovial cells in a concentration dependent manner. Registry Numbers: 34157-83-0 (tripterine) 363-24-6 (Dinoprostone) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ Yuan YY Gu ZP Shi QX Qin GW Xu RS Cao L [In vitro inhibition of celastrol on spermatozoa fertilization ability of guinea pig] In: Yao Hsueh Hsueh Pao (1995) 30(5):331-5 ISSN: 0513-4870 (Published in Chinese) The effects of celastrol (Cel), isolated from Tripterygium wilfordii, on guinea pig sperm forward motility (FM), capacitation (Cap), the acrosome reaction (AR) and sperm penetration assay (SPA) were assessed in vitro. Cel (5 micrograms.ml-1) was found to inhibit these spermatozoal functions, and the inhibitions were proportional to the concentrations of Cel used. The potency of inhibition of Cel on the fertilizing ability in guinea pig spermatozoa in vitro seems to follow the order: Cap > FM > SPA > AR. The inhibitory effect appeared to be reversible after washing away Cel if the duration of exposure of spermatozoa to Cel was shorter than 3 h. In a comparative study, the inhibitory effects of Cel on guinea pig sperm FM and AR were significantly stronger than those of gossypol acetic acid. Registry Numbers: 34157-83-0 (tripterine) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ Yao QP Zhang NZ [Effects of tripchlorolide (T4) of Tripterygium wilfordii hook on the production of prostaglandin E2 by synovial cells of rheumatoid arthritis] In: Yao Hsueh Hsueh Pao (1994) 29(10):790-2 ISSN: 0513-4870 (Published in Chinese) The effects of tripchlorolide, an active ingredient (T4) of Tripterygium wilfordii Hook on the production of prostaglandin E2(PGE2) by synovial cells of rheumatoid arthritis (RA) patients were investigated. Six cases of definite RA (female 5, male 1, mean age 45 with an average course of disease of 9 years) were selected. Surgically obtained synovium specimen were dissociated into digested synovial single cells (DSSC). The cells were incubated with various concentrations of T4 for 48 hours. Using radioimmunoassay T4 was found to significantly inhibit the production of PGE2 (control 6.10 +/- 2.30 vs T4 treated 0.58 +/- 0.47 x 10(-5) mol.L-1) by short-term cultured DSSC of RA patients. The results of this study suggests that T4 may be useful in the forthcoming treatment of RA due to its inhibition of production of PGE2 by synovial cells. Registry Numbers: 132368-08-2 (tripchlorolide) 363-24-6 (Dinoprostone) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ Zhang CP Lu XY Ma PC Chen Y Zhang YG Yan Z Chen GF Zheng QT He CH Yu DQ [Studies on diterpenoids from leaves of Tripterygium wilfordii] In: Yao Hsueh Hsueh Pao (1993) 28(2):110-5 ISSN: 0513-4870 (Published in Chinese) Tripterygium wilfordii Hook f. has been used as a medicinal herb in traditional Chinese medicine and as an insecticide by the Chinese for hundreds of years. Recently, this plant has been used to treat cancer, rheumatic arthritis and various skin diseases in some Chinese clinics. It is of interest to note that Tripterygium also showed significant antifertility activities. The active principles of the anti-inflammatory, immunosuppressive and antifertile actions in Tripterygium are diterpenoid containing triepoxides, but information on its chemistry is limited to the woody part of the root and the root bark. Recently, we have studies the leaves of Tripterygium (collected at Zhejiang province, China), and isolated two novel diterpenoids by chromatography named tripdioltonide (8) and 13,14- epoxide 9,11,12-trihydroxytriptolide (9), besides triptonide (1), triptolide (2), tripdiolide (3), triptolidenol (4), 16-hydroxyl- triptolide (5), tripchlorolide (6) and triptriolide (7). Their structures were established by chemical reactions, TLC, UV, MS, IR, 1H-1H COSY, 1H-13C COSY, DEPT spectrometric investigation. The structure of tripdioltonide was further confirmed by X-ray analysis. Registry Numbers: 147809-20-9 (13,14-epoxide-9,11,12-trihydroxytriptolide) 149183-67-5 (tripdioltonide) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ Zhang L Zhang ZX Sheng LS An DK Lu Y Zheng QT Wang SC [Study on the chemical constituents of Tripterygium hypoglaucum (Levl.) Hutch] In: Yao Hsueh Hsueh Pao (1993) 28(1):32-4 ISSN: 0513-4870 (Published in Chinese) Two new diterpenes, named triptoditerpenic acid B(2) and hypodiolide A(3), respectively, were isolated from Tripterygium hypoglaucum (Levl.) Hutch. Their structures were elucidated on the basis of spectra and X-ray analysis. Registry Numbers: 139122-81-9 (tripterifordin) 147362-43-4 (triptoditerpenic acid B) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****YEN KO HSUEH PAO [EYE SCIENCE]***** Li Z Li C Effect of the multiglycoside of Tripterygium Wilfordii Hook f. (Tii) on cornea allograft rejection model in rabbit. In: Yen Ko Hsueh Pao (1995 Sep) 11(3):168-72 ISSN: 1000-4432 PURPOSE: To examine the effect of Tii treatment of cornea graft survival in a rabbit model. METHODS: Tii was administered orally after eccentrical corneal transplantation. Survival times were determined by biomicroscopy. Cytotoxic T lymphocytes (CTL) and delayed-type hypersensitivity (DTH) responses to donor alloantigens were assessed at day 16 after heterotopic corneal grafts. RESULTS: Administration of Tii reduced the incidence and prolonged the graft survival time. Both CTL and DTH responses to donor alloantigens were severely depressed in hosts treated with Tii. However, combination of Tii and cyclosporine further enhanced the immunosuppressive effects described above. CONCLUSIONS: Tii is a potent immunosuppressant with the ability to prolong allograft survival in the rabbit penetrating keratoplasty model and may have coordinative effects with CsA through different mechanisms. Further studies are necessary to define any potentially coordinative role in the prevention of allograft rejection in human keratoplasty. Registry Numbers: 59865-13-3 (Cyclosporine) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€