Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0037116 (silicosis)
 1,822 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tetrandrine is a bisbenzylisoquinoline alkaloid which has been shown to exhibit antifibrotic activity against silicosis. Tetrandrine is characterized by its strong binding to alveolar macrophages and inhibition of particle-induced respiratory burst activity in these phagocytes. In contrast, tubocurine and tubocurarine are structurally similar to tetrandrine but exhibit little effect on fibrosis or activation of alveolar macrophages. The objective of the present study was to test the effect of tetrandrine on macrophage production of monokines in response to occupational dusts, and to determine tetrandrine's effect on monokine-medicated cell growth using a mouse thymocyte proliferation assay and lipopolysaccharide (LPS) as a positive control. Stimulation of alveolar macrophages by respirable silica dust resulted in a release of monokines which caused a fourfold increase in thymocyte proliferation. Coal dust, on the other hand, had no effect on macrophage production of this cytokine. Tetrandrine was found to exhibit a dose-dependent inhibition of monokine release from both silica and LPS-stimulated alveolar macrophages. In experiments where thymocytes were directly treated with tetrandrine, a dose-dependent inhibition of thymocyte proliferation was noted with both interleukin-1-(IL-1) specific and nonspecific mitogenic (concanavalin A) actions. In contrast to the inhibitory potency of tetrandrine, tubocurarine was found to have no effect on either the production of monokines by LPS-stimulated alveolar macrophages or IL-1-mediated thymocyte proliferation. These results provide a correlation between the antifibrotic effect of tetrandrine and inhibition of macrophage activation.
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PMID:Inhibitory action of tetrandrine on macrophage production of interleukin-1 (IL-1)-like activity and thymocyte proliferation. 139 14

Tetrandrine is an alkaloid obtained from the root of a medicinal herb which is employed in China as a treatment for silicosis. One proposed mechanism for the development of silica-induced fibrosis is lung damage resulting from particle-induced inflammation and secretion of reactive compounds from alveolar phagocytes. Therefore, the objective of the present study was to determine if tetrandrine exhibited the ability to inhibit respiratory burst activity of pulmonary phagocytes. The data indicate that although tetrandrine is not cytotoxic to phagocytic cells, it is a potent inhibitor in vitro of zymosan-stimulated oxygen consumption, superoxide anion release, and hydrogen peroxide secretion by alveolar macrophages. Tetrandrine is also effective in vivo in preventing activation of alveolar macrophages after inhalation or intratracheal instillation of silica. Tetrandrine also inhibits stimulant-induced chemiluminescence by polymorphonuclear leukocytes. Since tetrandrine does not alter stimulant-induced depolarization of phagocytic cells, its inhibitory action is not via interference with receptor-ligand binding but rather must occur elsewhere in the stimulus-secretion coupling scheme.
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PMID:Inhibition of stimulant-induced activation of phagocytic cells with tetrandrine. 165 39

A group of bisbenzylisoquinoline alkaloids has been shown to exhibit various degrees of effectiveness in preventing silica-induced fibrosis in animal models. The objective of the present study was to characterize the binding of several of these alkaloids to phosphatidylcholine vesicles and rat alveolar macrophages using fluorometric and equilibrium dialysis methods, respectively. The lipid binding affinity of these alkaloids was found to depend upon several structural factors including hydrophobic substitutions, chiral configurations, and double oxygen bridge-restricted confirmation of the benzylisoquinoline moieties. Tetrandrine, which is a highly effective agent in preventing fibrosis, showed strong binding to both lipid vesicles and alveolar macrophages. In contrast, certain analogues of tetrandrine such as curine and tubocurine, which have little or no effect on silicosis, exhibited only weak binding to lipid vesicles and almost no binding to cells. The moderate binding affinity of fangchinoline to vesicles and cells corresponded to a moderate effectiveness of the compound as an antifibrogenic agent. Methoxyadiantifoline, an alkaloid of unknown antifibrogenic potential, also exhibited high binding affinities for lipid and cells. In conclusion, the results of these studies indicate that alveolar macrophages exhibit large binding capacities for certain members of this class of bisbenzylisoquinoline alkaloids. A positive correlation was observed between binding affinity to alveolar macrophages and the reported antifibrotic potency of these compounds. These data also suggest that the ability of these drugs to interact with alveolar macrophages may be a key step in inhibition of the progression of silica-induced pulmonary disease.
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PMID:Binding of bisbenzylisoquinoline alkaloids to phosphatidylcholine vesicles and alveolar macrophages: relationship between binding affinity and antifibrogenic potential of these drugs. 166 32

Tetrandrine has been used for the treatment of silicosis in China. The potential genotoxic and carcinogenic hazards of this drug were studied using the Salmonella/histidine reversion assay and the SOS/Umu test. The results show that tetrandrine was weakly mutagenic to Salmonella typhimurium TA98 with metabolic activation and did not induce SOS response. However, tetrandrine increased the mutagenic activity of benzo[alpha]pyrene, trinitrofluorenone (TNF), 2-aminoanthracene (2AA), diesel emission particles, airborne particles, and cigarette smoke condensate by more than 100%; the activity of aflatoxin B1 and fried beef was increased by over 75%. It also increased the 2AA and TNF-induced SOS response by more than 300%. These results indicated that tetrandrine was a weak promutagen inducing frameshift mutations and was a potent genotoxic enhancer. The mechanism for the genotoxic enhancement is not known. However, the fact that the increase in mutagenicity was noted only in TA98 and not in TA1538 suggested that the enhancement of genotoxicity by tetrandrine may result from an increase in error-prone DNA repair.
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PMID:Genotoxicity and genotoxic enhancing effect of tetrandrine in Salmonella typhimurium. 264 34

The genotoxicity of tetrandrine, a drug potentially useful for the treatment of silicosis, was studied using the micronucleus and the sister-chromatid exchange (SCE) assay systems. Cultured Chinese hamster lung (V79) cells were used for the in vitro micronucleus and sister-chromatid exchange studies. Mouse bone marrow was used for the in vivo micronucleus assay and mouse spleen cells for the in vivo/in vitro sister-chromatid exchange analysis. The results show that SCE levels in V79 and in spleen cells were significantly elevated by treatment with tetrandrine at doses above 0.08 mg/ml and 100 mg/kg bw, respectively. Increased tetradrine-induced SCE in vitro was metabolic activation dependent. Tetrandrine failed to induce micronuclei at any of the doses tested. A decrease of replicative index with an increase in the concentration of tetrandrine was found both in vitro and in vivo. These results indicate that tetrandrine is a weak indirect-acting genotoxicant.
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PMID:Effect of tetrandrine on micronucleus formation and sister-chromatid exchange in both in vitro and in vivo assays. 277 Jul 74

Tetrandrine is an extract of the creeper Stephania tetrandra used in traditional Chinese medicine for the treatment of rheumatic diseases. It has recently been shown to retard and even reverse the lesions of silicosis in humans and rats. Data presented in this report indicate that tetrandrine has potent immunosuppressive properties. Mitogen-induced lymphoproliferative responses were markedly reduced even when tetrandrine was added after the initiation of cultures. In vitro antibody synthesis by B cells was also suppressed by tetrandrine, as was the natural killer cell-mediated lysis of K562 cells. It does not interfere with receptor-ligand binding, but does affect the inositol triphosphate second messenger system. These effects of tetrandrine were observed at nontoxic concentrations as shown by lymphocyte viability studies. These results indicate that tetrandrine possesses potent immunosuppressive properties, and may warrant further study in animal models of chronic inflammatory conditions, autoimmune diseases and transplant rejection.
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PMID:In vitro immunosuppressive properties of the plant alkaloid tetrandrine. 283 46

Tetrandrine is a plant alkaloid useful in the treatment of silicosis. Its mode of action is unknown, but results of the present study show dose-dependent inhibition of human neutrophil and monocyte adherence at concentrations (0.1-10 micrograms/ml) easily achieved in plasma during drug therapy. Monocytes were shown to be more sensitive to tetrandrine than neutrophils. Dye-exclusion experiments indicate that tetrandrine is non-toxic to these cells at 10 micrograms/ml concentrations. Suppression of adherence was reversible by washing, suggesting that the drug does not bind tightly to membrane components. Enhancement of adherence by the tumour promoter, phorbol myristate acetate, was abolished by tetrandrine. The uptake of deoxyglucose by neutrophils and monocytes was suppressed by tetrandrine. These results indicate that tetrandrine may act by interfering with the recruitment of these cells into silicotic lesions.
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PMID:Inhibitory effects of tetrandrine on human neutrophil and monocyte adherence. 375 46

Tetrandrine is a benzylisoquinoline alkaloid that has been used in China as an antifibrotic drug to treat the lesions of silicosis. Its mechanism in the treatment of silicosis is unclear. Electron spin resonance (ESR) spin trapping was employed to investigate the antioxidant properties of tetrandrine. The spin trap used was 5,5-dimethyl-1-pyrroline N-oxide (DMPO). Tetrandine efficiently reacted with hydroxyl (.OH) radicals with a reaction rate of approximately 1.4 x 10(10) M-1 s-1. The .OH radicals were generated by the Fenton reaction [Fe(II) + H2O2) as well as by reaction of chromium(V) with H2O2. Similar results were obtained using .OH radicals generated by reaction of freshly fractured quartz particles with aqueous medium. Tetrandrine also scavenged superoxide (O2-) radicals produced from xanthine/xanthine oxidase. The effect of tetrandrine on lipid peroxidation induced by freshly fractured quartz particles was evaluated using linoleic acid as a model lipid. The results showed that tetrandrine caused a significant inhibition on freshly fractured quartz-induced lipid peroxidation.
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PMID:Antioxidant activity of tetrandrine and its inhibition of quartz-induced lipid peroxidation. 756 20

Exposure to crystalline silica can result in damage to the lung parenchyma and scarring that can lead to fibrosis. Pulmonary damage may be the direct consequence of toxic interaction between quartz particles and cell membranes, or it may be due to silica-induced production of oxidant species by pulmonary phagocytes, that in turn overwhelms pulmonary antioxidant systems and causes lung injury. Data indicate that grinding or fracturing quartz particles breaks Si-O bonds and generates .Si and Si-O. radicals on the surface of the cleavage planes. Upon contact with water, these silica-based radicals can generate hydroxyl radicals (.OH). These surface radicals decay as fractured silica dust is aged. Freshly fractured quartz is significantly more potent than aged silica in directly causing lipid peroxidation, membrane damage, and cell death. Furthermore, freshly ground silica is a more potent stimulant of alveolar macrophages than aged silica. This silica-induced activation results in the production of superoxide (O2-), hydrogen peroxide (H2O2), nitric oxide (NO.), and other oxidant species that can damage lung cells. Tetrandrine, an herbal medicine that exhibits antifibrotic activity in rat models of silicosis, effectively blocks the ability of quartz to stimulate oxidant release from pulmonary phagocytes.
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PMID:Generation of oxygen radicals and mechanisms of injury prevention. 770 9

Tetrandrine, an herbal drug, has been employed in China to treat pulmonary fibrosis. To date, the mechanisms governing the antifibrotic action of tetrandrine are unknown. The present study employs a fibroblast mitogenic assay to determine whether tetrandrine directly inhibits the ability of fibroblasts to respond to stimulation by growth factors. The data indicate that tetrandrine blocks proliferation and the incorporation of tritiated thymidine into DNA by fibroblasts stimulated with human serum, PDGF plus plasma, FGF plus plasma, or TNF plus plasma. Since tetrandrine inhibits the response to a variety of growth factors, its action does not appear to involve the blockade of a specific stimulatory receptor. Tetrandrine is effective in inhibiting thymidine incorporation when added up to 6 hr after stimulation of quiescent cells, suggesting either that tetrandrine does not block the attainment of competence by fibroblasts or that its activity is not limited to blocking the attainment of competence by these cells. Growth factor-induced mitogenesis is also inhibited by nitrendipine, a calcium channel blocker, and by cytochalasin B, a microfilament blocker. However, tetrandrine treatment of fibroblasts neither results in the changes of morphology seen with cytochalasin B nor is limited to the early events of stimulus-response coupling. Therefore, the mechanism of action for tetrandrine is not identical to that for either cytochalasin B or nitrendipine. In summary, these results suggest that the antifibrotic action of tetrandrine may be mediated in part by direct inhibition of fibroblast proliferation normally associated with the development and progression of silicosis.
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PMID:Inhibition of proliferative activity of pulmonary fibroblasts by tetrandrine. 810 60


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