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PubMed1998

Effect of luteinizing hormone (LH), PGE2, 8-EPI-PGE1, 8-EPI-PGE2, trichosanthin, and pregnancy specific protein B (PSPB) on secretion of progesterone in vitro by corpora lutea (CL) from nonpregnant and pregnant cows.

Secretion of progesterone by Day 14 bovine corpora lutea (CL) of the estrous cycle and Day 200 CL of pregnancy was evaluated in vitro to determine what regulates secretion of progesterone by CL of pregnancy. Weights of Day 200 CL of pregnancy (4356 +/- 223 g) were heavier when compared to Day 14 CL of the estrous cycle of Brahman cows (3643 +/- 128 g; p < or = 0.05); however, both Day 14 and Day 200 minced CL slices secreted similar basal amounts of progesterone per unit mass (p > or = 0.05). Secretion of progesterone in vitro by Day 14 CL of the estrous cycle was increased at 4 and 8 h (p < or = 0.05) by 10 or 100 ng/mL luteinizing hormone (LH) and did not differ between doses (p > or = 0.05). Progesterone secretion in vitro by Day 200 CL of pregnancy was not increased (p > or = 0.05) by LH at 4 or 8 h. However, progesterone secretion in vitro by Day 14 CL of the estrous cycle or Day 200 CL of pregnancy was increased (p < or = 0.05) at 4 h by 10 or 100 ng/mL PGE2, which did not differ by dose or reproductive status (p > or = 0.05). At 8 h, Day 14 CL of the estrous cycle secretion of progesterone in vitro was increased (p < or = 0.05) by both doses of PGE2 but only at 8 h by 100 ng/mL from Day 200 CL of pregnancy (p < or = 0.05). Secretion of progesterone in vitro was not affected (p > or = 0.05) by 10 or 100 ng/mL 8-Epi-PGE1 or 8-Epi-PGE2 at 4 or 8 h from Day 14 CL of the estrous cycle or Day 200 of pregnancy. Trichosanthin increased (p < or = 0.05) secretion of progesterone in vitro by 10 ng/mL at 4 h and at 8 h by Day 14 CL of the estrous cycle or at 8 h by Day 200 CL of pregnancy but trichosanthin at 100 ng/mL did not affect (p > or = 0.05) secretion of progesterone in vitro by Day 14 CL of the estrous cycle or Day 200 CL of pregnancy at 4 or 8 h. Pregnancy specific protein B (PSPB) increased (p < or = 0.05) secretion of progesterone in vitro at 4 and 8 h by Day 14 CL of the estrous cycle and did not differ between incubation times (p > or = 0.05). PSPB increased secretion of progesterone at 4 h but not at 8 h (p > or = 0.05) by Day 200 CL of pregnancy. These data suggest that PGE2 or PSPB but not LH, 8-Epi-PGE1 or 8-Epi-PGE2 regulates luteal secretion of progesterone by bovine CL at mid-pregnancy. In addition, it is suggested that weights of bovine CL of pregnancy increase to compensate for a lack of placental secretion of progesterone.

Animals↗
PubMed1997

Structural analysis and molecular modeling of two anti-trichosanthin IgE clones from phage antibody library.

Recently we constructed a murine IgE phage surface display library and screened out two IgE (Fab) clones with specific binding activity to Trichosanthin (TCS). In this work, the V epsilon and V kappa genes of the two clones were sequenced and their putative germline gene usages were studied. On the basis of the known 3D structure of Trichosanthin and antibody, molecular modeling was carried out to study the antigen-antibody interaction. The possible antigenic determinant sites on the surface of TCS recognized by both the clones were analyzed, and the reaction forces between TCS and two Fab fragments were also analyzed respectively.

Animals↗
PubMed1998

Trichosanthin inhibits T cell activation by interfering with the recruitment of ZAP-70 to CD3 zeta chain.

Plant protein Trichosanthin (Tk) has been shown in our previous experiments to suppress antigenic response of T cells. Here we explored its inhibitory mechanisms on the proliferation of human Jurkat leukemia T cell triggered by anti-CD3 McAb. By examination of tyrosine phosphorylation of cell lysate, we were able to show that Tk could interfere with the PTK-related activity in the TCR/CD3-initiated signal transduction in addition to blocking the phosphorylation of PKC. As shown in our experiment, the expression intensity of ZAP-70, a kind of protein tyrosine kinase, was not changed but its phosphorylation could be inhibited. When physical link between CD3 zeta chain and ZAP-70 was further examined by using coimmunoprecipitation after pluse-treatment of the cell line with Tk, the anti-CD3 McAb-induced recruitment of ZAP-70 to CD3 zeta chain was observed to be blocked in some extent. This may account for, at least in part, how Trichosanthin was able to inhibit the TCR-triggered T cell proliferation.

Antibodies, Monoclonal↗
PubMed2001

Trichosanthin interacts with acidic ribosomal proteins P0 and P1 and mitotic checkpoint protein MAD2B.

Trichosanthin is a ribosome-inactivating protein with multiple pharmacological properties. By a yeast two-hybrid system, ribosomal phosphoproteins P0 and P1 and a putative mitotic checkpoint protein, MAD2B, were found to interact with an active-site mutated trichosanthin (TCS). The interactions were verified by an in vitro binding assay of recombinant wild-type TCS and target proteins. The interaction domain of P0 was mapped to amino acids 220-273, which had been previously reported to be involved in the interaction with P1 and P2 in yeast. Consistent with our previous finding that the last seven residues of TCS are not essential for an active conformation, the same deletion did not affect the interaction with P0. Our present study suggests that TCS may disrupt the binding of elongation factors to the P-complex, in addition to the well-known N-glycosidase activity for ribosome inactivation.

Binding Sites↗
PubMed2003

Trichosanthin induces leakage and membrane fusion of liposome.

Trichosanthin (TCS) is a ribosome inactivating protein with multiple pharmacological properties. Here the interaction between TCS and a phospholipid bilayer is investigated to provide evidence for membrane translocation mechanism of TCS. The results show that TCS can destabilize liposomes made by phospholipids with negatively charged head group. The destabilization effect is pH-dependent and happens only under acidic conditions. Membrane fusion is also seen to accompany the destabilizing process. The interaction between a phospholipid bilayer and C7, a mutant of TCS with 7 residues at its C-terminus deleted, has been investigated. Deleting the C-terminus almost completely abolishes the destabilizing effect of TCS on the phospholipid bilayer, which implicates the C-terminus in the interaction between trichosanthin and the membrane.

Amino Acid Sequence↗
PubMed1996

Intravenous injections of the ribosome inactivating protein trichosanthin did not affect methionine enkephalin and beta-endorphin levels in the mouse brain and pituitary.

The effect of trichosanthin on levels of the neuropeptides beta-endorphin (beta-EP) and methionine enkephalin (met-EK) in the mouse brain and pituitary was investigated. Mature male ICR mice were divided into two groups. One group received intravenous injections of physiological saline and served as the control. Another group received daily intravenous injections of trichosanthin (0.2 mg/25g/injection) for three consecutive days. The animals were sacrificed four hours after the last injection. Their brains were dissected into three regions: A (thalamus and hypothalamus), B (cerebral cortex) and C (cerebellum and brainstem) and their pituitaries were collected. The samples were then extracted and assayed for beta-EP and met-EK by specific radioimmunoassays. It was found that there were no statistically significant changes in the levels of the two neuropeptides in the pituitary and the brain regions except for the level of beta-EP in brain region A.

Animals↗
PubMed1994

Renal reabsorption of trichosanthin and the effect on GFR.

Trichosanthin (TCS) is a ribosome-inactivating protein that has a wide range of biological and pharmacological activities. Due to its small molecular size, TCS is filtered by the glomerulus and can be recovered from urine. A previous experiment showed that the kidney is an important organ for its elimination. However, urine TCS recovery was unexpectedly small, suggesting renal reabsorption of this compound. To substantiate renal TCS reabsorption, different doses of TCS were injected intravenously into rats. Increasing the dose from 0.375 mg/kg to 12 mg/kg enhanced the percentage urine recovery from less than 0.29 +/- 0.06% to 39.07 +/- 2.46%. This demonstrated that TCS is reabsorbed by a saturable mechanism. Reabsorption of most small molecular weight filterable proteins shares a common endocytotic process. It is very likely that TCS utilizes the same process for reabsorption. When a filterable protein such as hemoglobin was infused with TCS, it competed with TCS for reabsorption and therefore increased the percentage urine TCS recovery to 35 +/- 2%. Infusion of another filterable protein, lysozyme, increased recovery to 3.2 +/- 0.8%. This supports the proposal that renal TCS uptake utilizes the common endocytotic mechanism. It was also found in this study that injection of TCS depressed the glomerular filtration rate (GFR), implying renal toxicity. This effect can be attributed to ribosome inactivation which takes place inside the cells. Should reabsorption of TCS be reduced, renal toxicity will disappear. For this purpose, dextran-trichosanthin (DXTCS) conjugate was synthesized to increase its effective molecular size.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Modulation of trichosanthin antigenicity by coupling to dextran.

Trichosanthin (TCS) is a plant-derived type I ribosome-inactivating protein with a wide spectrum of biological and pharmacological activities. Recently, it was covalently coupled to dextran in order to prolong its half-life in plasma. The major biological activities were generally retained but at lower potency. The immunogenicity of the dextran-trichosanthin (DX-TCS) was compared to that of TCS itself in this study. The results showed that mice immunized with TCS produced 8 times as much TCS-reactive IgE than those immunized with DX-TCS. However, both TCS and DX-TCS immunization produced similar titers of TCS-reactive IgG. A trace of dextran-reactive IgG was detected in mice immunized with DX-TCS. Thus, coupling of TCS to dextran reduced its antigenicity but slightly enhanced that of dextran, and the conjugate elicited less IgE than TCS.

Adjuvants, Immunologic↗
PubMed1992

Crystallographic refinement of trichosanthin at 2.6A resolution.

The molecule model of trichosanthin has been rebuilt by using the electron density map improved by the solvent flatten and in accordance with the primary structure put forward by Collins. The crystallographic refinement of two trichosanthin molecules (3828 nonhydrogen atoms) in an asymmetric unit has been carried out by means of the restrain least-square procedure and diffraction data to a resolution of 2.6 A. The results are: an R factor 0.223 and the r.m.s. deviation of the bond length = 0.023 A. The new molecular model is in good agreement with the electron density map calculated with the coefficient 2Fo-Fc.

Crystallography↗
PubMed2000

[Study on thermal unfolding process of trichosanthin by FTIR spectroscopy].

Fourier-transform infared spectroscopy, combined with resolution-enhancement techniques including second-derivative spectroscopy, Fourier self-deconvolution and curvefitting technique, was used to investigate the thermally induced unfolding process of anti-HIV-I toxin protein trichosanthin. During heating from 25 degrees C to 85 degrees C, the peak of Amide I shifted to 1618 cm-1 while the secondary structural contents change with the temperature. Upon cooling the protein from 85 degrees C to 25 degrees C, the contour of the Amide I do not change. All these show that the thermal unfolding of trichosanthin is an irreversible intermolecular aggregation process between 25 degrees C and 85 degrees C. The changes of secondary structures with temperature suggest the presence of folding intermediates.

Hot Temperature↗
PubMed2000

[Study on unfolding process of neo-trichosanthin in the presence of GdnHCl].

Fluorescence spectroscopy and circular dichroism are effective instruments to determine the chemical unfolding process of protein solution. In this paper, both of them were selected to investigate the unfolding processes of neo-trichosanthin in the presence of GdnHCl. One GdnHCl is added, both spectra of fluorescence and circular dichroism changed remarkedly. The denaturation curve of CD ellipticity meets that of fluorescence intensive excitation at 295 nm very well. The result shows that, in the presence of GdnHCl, the unfolding of neo-trichosantin matches the two-state process well. The model is different from the model of trichosanthin that others reported previously. The mechanism will be further probed later.

Circular Dichroism↗
PubMedDate not supplied

Trichosanthin as an abortifacient for terminating early pregnancy in mice.

OBJECTIVE: To test trichosanthin--a basic protein from Trichosanthes kirilowii--as abortifacient, and effect on subsequent pregnancy. METHODS: Female mice, on day 1, 2, or 3 of pregnancy, given 0.10, 0.15, 0.20, or 0.25 mg/25 g body wt., intraperitoneally. Animals killed on day 11 for assessment of abortion, or day 4 for examination of embryos. Subsequent pregnancy was tested after 20 days in mice that had aborted completely. RESULTS: With 0.20-0.25 mg/25 g, 64-80% aborted. At day 4, pre-implantation development was disturbed, many still being morulae (in the oviduct). Subsequent pregnancies and offspring were entirely normal. CONCLUSIONS: Trichosanthin, long used to effect abortion in humans in China, has congruent effects on ICR laboratory mice.

Abortion, Therapeutic↗
PubMed1985

[Intra-amniotic injection of crystal trichosanthin for induction of labour in second trimester pregnancy].

Labor was induced in a group of 200 women in 2nd trimester of pregnancy by crystal trichosanthia injected into the amniotic cavity. It was effective and the success rate was 99.5%. The average abortion inducing interval was 4.69 days porm 1.15 days. Blood loss was scanty during labor in 90.5% cases, being less than 100 ml. There was only 1 case suffering laceration of cervix. The side effects of crystal trichosanthin were dramatically reduced with the simultaneous use of betamethason intramuscularly for 3 successive days. Side effects were reduced because the drug was concentrated in the cavity and only a little was present in the blood stream and, what's more, the anti-allergic action of betamethason was effective. Trichosanthin is a kind of plant protein so it will possibly cause allergic reaction, which can induce the production of antibodies that will influence the effect of its reinjection.

Abortifacient Agents↗
PubMed1993

Developmental toxicity and teratogenicity of trichosanthin, a ribosome-inactivating protein, in mice.

The embryotoxic and teratogenic effects of trichosanthin (TCS), a protein isolated from tubers of Trichosanthes kirilowii (family Cucurbitaceae), were studied both in vivo and in vitro. The protein was administered i.p. to ICR mice on day 8.0 of pregnancy, and the animals were sacrificed 1 day before parturition. The fetuses were fixed and subsequently sectioned. At the highest TCS dose employed (7.5 mg/kg body weight), the viability of fetuses declined to 70.2%, compared with 96.5% in the saline-treated control group. The number of resorbed fetuses increased, and the crown-rump length of the surviving fetuses was reduced. At the doses of 5.0 and 7.5 mg TCS/kg body weight, 2.3% and 9.0%, respectively, of the surviving fetuses were found to be abnormal. The abnormalities observed included exencephaly, micromelia, and short tail. When mouse embryos at the early organogenesis stage were cultured with TCS at a dose of 200 micrograms/ml or above, a significantly larger number of embryos were found to be abnormal as compared with the controls. The abnormalities were observed in the head, trunk, and limb regions. Hence, TCS produced adverse effects on prenatal development both in vivo and in vitro.

Abnormalities, Drug-Induced↗
PubMed1993

Tb(III) and Eu(III) as fluorescent probes to investigate the metal-binding sites of trichosanthin.

Tb(III) and Eu(III) ions were used as fluorescent probes in the study of the trichosanthin (TCS). The fluorescence of Tb(III) was increased considerably when bound to TCS to replace the Ca(II) ions. The nonradiative energy transfer from fluorescent tryptophan (Trp) residues to the bound Tb(III) or Eu(III) took place. From a Foster d-d nonradiative energy transfer mechanism, it was obtained that the average distance between the bound Tb(III) and the Trp residue is 1.27nm. The results indicate that the major groups in TCS bound to Ca(II) ions should be the carboxylic side groups of the glutamic acid and/or aspartic acid. The fluorescent quenching of Ca(II)-free TCS by adding Tb(III) or Eu(III) into TCS from which the Ca(II) ions had been removed was discussed as well.

Binding Sites↗
PubMed1998

Refolding of denatured trichosanthin in the presence of GroEL.

The stability of trichosanthin (TCS), a 27-kDa ribosome-inactivating protein, was investigated in the presence of guanidinium chloride (GdnHCl). The process of unfolding was monitored by CD and fluorescence spectroscopy. Both methods show the presence of partially folded intermediates. Unfolding of TCS is attained in 6M GdnHCl, but the inactive species recover a good deal of its DNase activity upon dilution with buffer containing GroEL and ATP. The mechanism of recognition of unfolded TCS by GroEL was studied by fluorescence spectroscopy.

Adenosine Triphosphate↗
PubMed2001

Inhibition of Th1- and enhancement of Th2-initiating cytokines and chemokines in trichosanthin- treated macrophages.

Trichosanthin (TCS), the major effective component from Chinese herb Trichosanthes Kirilowii Maxim, is also a potent allergen. Our previous work has shown that TCS can upregulate interleukin-4 (IL-4) and interleukin-13 (IL-13) while inhibit interferon-gamma (IFN-gamma) in mesenteric lymph node cells after TCS immunization. Thus, TCS can arouse a T helper 2 (Th2) response in the draining lymph node. However, little is known about the early effects of TCS on antigen-presenting cells, the initiator of T cell response. In the current study, the effects of TCS on macrophage cytokines and chemokine expression were investigated. Peritoneal macrophages were treated with or without TCS in the presence of lipopolysaccharide (LPS). We found that TCS increased macrophage interleukin-10 (IL-10) and monocyte chemoattractant protein-1 (MCP-1) expression, whereas it decreased interleukin-12 (IL-12) and tumor necrosis factor-alpha (TNF-alpha) expression. Our study clearly demonstrated that TCS, as an allergen, has differential effects on macrophage Th1/Th2 initiative factors, effects that are likely to facilitate its inducing of Th2 and immunoglobulin E (IgE) response.

Allergens↗