The effect of tetrandrine (Tet) on the infarction area and volume of rat brain induced by middle cerebral artery occlusion (MCAO) was investigated. The treatment with Tet 7.5, 12.0 or 15.0 mg·kg 1 , or with...The effect of tetrandrine (Tet) on the infarction area and volume of rat brain induced by middle cerebral artery occlusion (MCAO) was investigated. The treatment with Tet 7.5, 12.0 or 15.0 mg·kg 1 , or with fructose 1,6 diphosphate (FDP) 200 and 350 mg·kg 1 ip immediately after MCAO, respectively, significantly reduced the infarction area and volume in a dose dependent manner. MK801 and FDP also displayed a protective effect on brain ischemia. A combination of Tet and FDP administered immediately after MCAO, produced a more potent protective effect than those treated with Tet or FDP alone. When Tet or FDP was administered 1 h and 2 h after MCAO, respectively, they could still significantly reduce the infarction area and volume of brain tissue. But, there was no significant protective effect when these two compounds were given 3 h after MCAO.展开更多
\ The effects of tetrandrine (Tet) on cytosolic free calcium ([Ca2+]i) in subcultured bovine aortic smooth muscle cells (SMC) were studied by Fura2 and ARCMMIC cation measurement system. Tet (1～100 μmol·L-1) ...\ The effects of tetrandrine (Tet) on cytosolic free calcium ([Ca2+]i) in subcultured bovine aortic smooth muscle cells (SMC) were studied by Fura2 and ARCMMIC cation measurement system. Tet (1～100 μmol·L-1) had no effect on the resting [Ca2+]i, but had inhibitory effects on [Ca2+]i elevation induced by high K+, 5HT, ATP, Ang II and NE in the presence of extracellular Ca2+. High concentration of Tet also inhibited Pheinduced [Ca2+]i elevation in absence of extracellular Ca2+. Tet (1～100 μmol·L-1) inhibited KCl (60 mmol·L-1) induced [Ca2+]i elevation in dosedependent manner, the IC50 value was 9.2 (95% confidence limits: 5.7～14.9) mmol·L-1. The results suggested that Tet had blocking effects on both VOC and ROC in bovine aortic SMC. It appears that the mechanisms of blocking effect of Tet on ROC might be primarily due to its Ca2+ entry blocking effects.展开更多
It has been reported that augmentative effect of tetrandrine on pentobarbital hypnosis in mice may be related to serotonergic system. The present study was undertaken to investigate the interaction of tetrandrine and ...It has been reported that augmentative effect of tetrandrine on pentobarbital hypnosis in mice may be related to serotonergic system. The present study was undertaken to investigate the interaction of tetrandrine and different 5-HT receptors on pentobarbital-induced sleep by using the loss-of-righting reflex method. The results showed that augmentative effect of tetrandrine on pentobarbital hypnosis in mice were potentiated by the p-MPPI （5-HT1A receptor antagonist） （1 mg/kg, i.p.） and ketanserin （5-HT2A/2C receptor antagonist） （1.5 mg/kg, i.p.）, respectively. Pretreatment with either 8-OH-DPAT （5-HT1A receptor agonist） （0.1 mg/kg, s.c.） or DOI （5-HT2A/2C receptor agonist） （0.2 mg/kg, i.p.） significantly decreased pentobarbital-induced sleep time, and tetrandrine （60 mg/kg, i.g.） significantly reversed this effect. These results suggest that both the 5-HTLA and 5-HT2A/2C subfamily may be involved in the potentiating mechanism of tetrandrine＇s effects on pantobarbital hypnosis.展开更多
The purpose of this work was to explore the feasibility of ethosomes for improving the anti-arthritic efficacy of topically administered tetrandrine, a bisbenzylisoquinoline alkaloid. Ethosomes were prepared by using ...The purpose of this work was to explore the feasibility of ethosomes for improving the anti-arthritic efficacy of topically administered tetrandrine, a bisbenzylisoquinoline alkaloid. Ethosomes were prepared by using the transmembrane pH-gradient loading method and characterized by mean diameter, morphology and entrapment efficiency. The prepared tetrandrine-loaded ethosomes exhibited spherical shape with about 78 nm of average diameter and entrapment efficiency of （52.87±3.81）%, whereas the liposomes had bigger size （99 nm） and higher entrapment efficiency （98.80±0.01）%. In addition, ethosomes exhibited favorable and enhanced penetration behavior as compared with liposomes. More importantly, tetrandrine-loaded ethosomes had a significantly better anti-adjuvant arthritis efficacy in rats compared to liposomes formulation, but no significant difference in the anti-arthritic efficacy between tetrandrine-loaded ethosomes and commercial dexamethasone ointment was observed. These results suggest that ethosomes would be a promising nanocarrier for topical delivery of tetrandrine across skin.展开更多
Tetrandrine （TET）, a traditional Chinese medicine, exerts remarkable anticancer activity on various cancer cells. However, little is known about the effect of TET on human prostate cancer cells, and the mechanism of...Tetrandrine （TET）, a traditional Chinese medicine, exerts remarkable anticancer activity on various cancer cells. However, little is known about the effect of TET on human prostate cancer cells, and the mechanism of function of TET on prostate cancer has not yet been elucidated. To investigate the effects of TET on the suppression of proliferation, induction of apoptosis, and inhibition of migration and invasion in human prostate cancer cell lines, DU145 and PC-3. Inhibition of growth was determined by 3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyltetrazolium bromide assay and clone formation assay, and flow cytometry analysis was performed to detect the induction of apoptosis. Activation of poly （ADP-ribose） polymerase, caspase-3, Akt, phospho-Akt, Bcl-2, and Bax was analyzed by Western blotting. Wound healing assay and transwell migration assay were used to evaluate the effect of TET on migration and invasion of cancer cells. TET inhibited the growth of DU145 and PC-3 cells in a dose- and time-dependent manner. Cell cloning was inhibited in the presence of TET in DU145 and PC-3 cells. TET suppressed the migration of DU145 and PC-3 cells. Transwell invasion assay showed that TET significantly weakened invasion capacity of DU 145 and PC-3 cells. TET exhibited strong inhibitory effect on proliferation, migration, and invasion of prostate cancer cells. In addition, TET induced apoptosis in a dose-dependent manner by activating the caspase cascade and inhibiting phosphoinositide 3-kinase-Akt signal pathway. The accumulating evidence suggests that TET could be a potential therapeutic candidate against prostate cancer in a clinical setting.展开更多
AIM： To investigate the therapeutic effect of tetrandrine on liver fibrosis induced by thioacetamide in rats in vivo and in vitro. METHODS： In vitro study： we investigated the effect of tetrandrine on the apoptosis...AIM： To investigate the therapeutic effect of tetrandrine on liver fibrosis induced by thioacetamide in rats in vivo and in vitro. METHODS： In vitro study： we investigated the effect of tetrandrine on the apoptosis of rat hepatic stellate cells transformed by simian virus 40 （T-HSC/CI-6）, which retains the features of activated cells. In vivo study： hepatic fibrosis was induced in rats by thioacetamide. Tetrandrine was given orally to rats at doses of 5, 10 or 20 mg/kg for 4 wk compared with intraperitoneal injection of interferon-r. RESULTS： In vitro study： 5, 10 or 25 μg/mL of tetrandrine-induced activation of caspase-3 in t-HSC/CI-6 cells occurred dose-dependently. In vivo study： tetrandrine treatment as well as interferon-r significantly ameliorated the development of fibrosis as determined by lowered serum levels of aspartate aminotransferase （AST）, alanine aminotransferase （ALT）, total bilirubin （T-Bil） and the levels of liver hydroxyproline （Hyp）, hyaluronic acid （HA）, laminin （LN） and also improved histological findings. The effects of tetrandrine at the concentration of 20 mg/kg were better than the other concentration groups. CONCLUSION： Tetrandrine promotes the apoptosis of activated HSCs in vitro. Tetrandrine administration can prevent liver fibrosis and liver damage induced by thioacetamide in rats in vivo, indicating that it might exert a direct effect on rat HSCs.展开更多
Tetrandrine （Tet）, the main active constituent of Stephania tetrandra root, has been demonstrated to alleviate adjuvant-induced arthritis in rats. The present study was designed to investigate the effects of Tet on ...Tetrandrine （Tet）, the main active constituent of Stephania tetrandra root, has been demonstrated to alleviate adjuvant-induced arthritis in rats. The present study was designed to investigate the effects of Tet on the migration and invasion of rheumatoid arthritis fibroblast-like synovioeytes （RA-FLS） and explore the underlying mechanisms. By using cultures of primary FLS isolated from synoviums of RA patients and cell line MH7A, Tet （0.3, 1 μmol L-1） was proven to significantly impede migration and invasion of RA-FLS, but not cell proliferation. Tet also greatly reduced the activation and expressions of matrix degrading enzymes MMP-2/9, the expression of F-actin and the activation of FAK, which controlled the morphologic changes in migration process of FLS. To identify the key signaling pathways by which Tet exerts anti-migration effect, the specific inhibitors of multiple signaling pathways LY294002, Triciribine, SP600125, U0126, SB203580, and PDTC （against PI3K, Akt, JNK, ERK, p38 MAPK and NF-kB-p65, respectively） were used. Among them, LY294002, Triciribine, and SP600125 were shown to obviously inhibit the migration of MH7A cells. Consistently, Tet was able to down-regulate the activation of Akt and JNK as demonstrated by Western blotting assay. Moreover, Tet could reduce the expressions of migration-related proteins Rho GTPases Rac 1, Cdc42, and RhoA in MH7A cells. In conclusion, Tet can impede the migration and invasion of RA-FLS, which provides a plausible explanation for its protective effect on RA. The underlying mechanisms involve the reduction of the expressions of Racl, Cdc42, and RhoA, inhibition of the activation of Akt and JNK, and subsequent down-regulation of activation and/or expressions of MMP-2/9, F-actin, and FAK.展开更多
Objective:To evaluate the effects of tetrandrine citrate, a novel tetrandrine salt with high water solubility, on the growth of imatinib (IM)-resistant chronic myeloid leukemia (CML) in vitro and in vivo, and reveal a...Objective:To evaluate the effects of tetrandrine citrate, a novel tetrandrine salt with high water solubility, on the growth of imatinib (IM)-resistant chronic myeloid leukemia (CML) in vitro and in vivo, and reveal action molecular mechanisms. Methods:Cell viability in vitro was measured using methyl thiazolyl tetrazolium (MTT) assay. CML cell growth in vivo was assessed using a xenograft model in nude mice. Bcr-Abl and β-catenin protein levels were determined using Western blotting. Bcr-Abl messenger RNA (mRNA) was measured by reverse transcription polymerase chain reaction (RT-PCR). Flow cytometry (FCM) was used to determine cell cycle status. Results:Tetrandrine citrate inhibited the growth of IM-resistant K562 cells, primary leukemia cells, and primitive CD34 + leukemia cells, and their inhibition concentration that inhibited 50% of target cells (IC 50 ) ranged from 1.20 to 2.97 μg/ml. In contrast, tetrandrine citrate did not affect normal blood cells under the same conditions, and IC 50 values were about 10.12-13.11 μg/ml. Oral administration of tetrandrine citrate caused complete regression of IM-resistant K562 xeno-grafts in nude mice without overt toxicity. Western blot results revealed that treatment of IM-resistant K562 cells with tetrandrine citrate resulted in a significant decrease of both p210 Bcr-Abl and β-catenin proteins, but IM did not affect the Bcr-Abl protein levels. Proteasome inhibitor, MG132, did not prevent tetrandrine-mediated decrease of the p210 Bcr-Abl protein. RT-PCR results showed that tetrandrine treatment caused a decrease of Bcr-Abl mRNA. FCM analysis indicated that tetrandrine induced gap 1 (G 1 ) arrest in CML cells. Conclusions:Tetrandrine citrate is a novel orally active tetrandrine salt with potent anti-tumor activity against IM-resistant K562 cells and CML cells. Tetrandrine citrate-induced growth inhibition of leukemia cells may be involved in the depletion of p210 Bcr-Abl mRNA and β-catenin protein.展开更多
AIM: To investigate the effect of various concentrations of tetrandrine on activation of quiescent rat hepatic stellate cells (HSCs) and transforming growth factor-β (TGF-β) signaling in vitro.METHODS: HSCs were iso...AIM: To investigate the effect of various concentrations of tetrandrine on activation of quiescent rat hepatic stellate cells (HSCs) and transforming growth factor-β (TGF-β) signaling in vitro.METHODS: HSCs were isolated from rats by in situperfusion of liver and 18% Nycodenz gradient centrifugation, and primarily cultured on uncoated plastic plates for 24 hwith DMEM containing 20% fetal bovine serum (FBS/DMEM) before the culture medium was substituted with 2% FBS/DMEM for another 24 h. Then, the HSCs were cultured in 2% FBS/DMEM with tetrandrine (0.25, 0.5, 1,2 mg/L, respectively). Cell morphological features were observed under an inverted microscope, smooth muscleα-actin (α-SMA) was detected by immunocytochemistry and image analysis system, laminin (LN) and type Ⅲprocollagen (PCⅢ) in supernatants were determined byradioimmunoassay. TGF-β1 mRNA, Smad 7 mRNA and Smad 7 protein were analyzed with RT-PCR and Western blotting, respectively.RESULTS: Tetrandrine at the concentrations of 0.25-2 mg/L prevented morphological transformation of HSC from the quiescent state to the activated one, while α-SMA, LN and PCⅢ expressions were inhibited. As estimated by gray values, the expression of α-SMA in tetrandrine groups (0.25, 0.5, 1, 2 mg/L) was reduced from 21.3% to 42.2%(control: 0.67, tetrandrine groups: 0.82, 0.85, 0.96, or 0.96, respectively, which were statistically different from the control, P＜0.01), and the difference was more significant in tetrandrine at 1 and 2 mg/L. The content of LN in supernatants was significantly decreased in tetrandrine groups to 58.5%, 69.1%, 65.8% or 60.0% that of the control respectively, and that of PCⅢ to 84.6%, 81.5%,75.7% or 80.7% respectively (P＜0.05 vs control), with no significant difference among tetrandrine groups. RTPCR showed that TGF-β1 mRNA expression was reduced by tetrandrine treatments from 56.56% to 87.90% in comparison with the control, while Smad 7 mRNA was increased 1.4-4.8 times. The TGF-β1 mRNA and Smad 7 mRNA expression was in a significant negative correlation (r= -0.755, P＜0.01), and both were significantly correlated with α-SMA protein expression (r = -0.938, P＜0.01;r = 0.938, P＜0.01, respectively). The up-regulation of Smad 7 protein by tetrandrine (1 mg/L)was confirmed by Western blotting as well.CONCLUSION: Tetrandrine has a direct inhibiting effect on the activation of rat HSCs in culture. It up-regulates the expression of Smad 7 which in turn blocks TGF-β1 expression and signaling.展开更多
[ABSTRACT] The aim of the study was to investigate the anti-proliferation and apoptosis-inducing effects of S1, a novel tetrandrine derivative, in human gastric cancer BGC-823 cells and explore the possible mechanism ...[ABSTRACT] The aim of the study was to investigate the anti-proliferation and apoptosis-inducing effects of S1, a novel tetrandrine derivative, in human gastric cancer BGC-823 cells and explore the possible mechanism of action. The anti-proliferative activity was determined by MTT assay; the induction of cell cycle arrest and apoptosis were detected by flow cytometry. Quantitative real time RT-PCR and Western blotting were used to evaluate the mRNA and protein expression levels in mitochondrial pathway. SI significantly reduced cell viability and induced a G2/M phase arrest and apoptosis in dose- and time-dependent manner. Further studies showed that S1 increased mRNA and protein expression of Bax and the Bax/Bcl-2 ratio. Moreover, S1 decreased the protein expression of procaspase-9 and procaspase-3, suggesting that the induction of apoptosis may be related to the alteration of the ratio of Bax/Bcl-2 and the activation of caspases. These findings suggested that S1 merits further investigation as a novel therapeutic agent for the treatment of human gastric cancer.展开更多
In the screening tests of drugs for silicosis in our laboratory, we found that TT, a type of alkaloid isolated from Stephania tetrandra, could inhibit the development of experimental silicosis of rats and the synthesi...In the screening tests of drugs for silicosis in our laboratory, we found that TT, a type of alkaloid isolated from Stephania tetrandra, could inhibit the development of experimental silicosis of rats and the synthesis of collagen in rat lung. Chest X-rays of silicotic patients treaied with TT for 1-3 years showed obvious changes. The silicotic nodules became smallel and shadows became clearer. PVNO was proved to have anti-silicotic effect on animal and clinically. This presentation reports the effect of them on collagen mRNA.Dot blot results showed that 1 (Ⅰ) and 1 (Ⅲ) mRNA levels increased significantly at 60 and 120 days after the rats were exposed to silica dust. The mRNA levels went down at 1 and 3 months after treated by TT and PVNO. In situ hybridization observation revealed that the silver grains of Type Ⅰand Type Ⅲ collagen were scattered within the fibroblasts in cellular nodules and in thickened interstitium of silicosis tissue. The amounts of mRNA silver grains decreased in the lung tissue treated by TT and PVNO. It was suggested that TT and PVNO may inhibil the gene expression of collagen during silicosis展开更多
Objective There is a lack of effective and long-term safe drugs for the treatment of osteoarthritis(OA).Tetrandrine(Tet)has been approved and used to treat rheumatoid arthritis for several decades,but its effect on OA...Objective There is a lack of effective and long-term safe drugs for the treatment of osteoarthritis(OA).Tetrandrine(Tet)has been approved and used to treat rheumatoid arthritis for several decades,but its effect on OA has not been investigated.Herein,we explored the effect of Tet on OA and its underlying mechanism.Methods OA was induced using destabilization of the medial meniscus(DMM)in C57BL/6J mice.The animals were randomly divided into sham,DMM,Tet,celecoxib(CXB),and indomethacin(INDO)groups.Each group was given solvent or corresponding drugs by gavage for 7 weeks after convalescence.Pathological staining,OARSI scores,micro-computed tomography and behavior tests were performed to evaluate the effects of Tet.Results Tet remarkably alleviated cartilage injury in the knee joint,limited bone remodeling in the subchondral bone,and delayed progression of OA.Tet also significantly relieved joint pain and maintained function.Further mechanistic studies revealed that Tet lowered inflammatory cytokine levels and selectively suppressed gene and protein expression of cyclooxygenase(COX)-2 but not COX-1(P<0.01).Tet also reduced the production of prostaglandin E2 without damaging the gastric mucosa.Conclusion We found that Tet could selectively inhibit COX-2 gene expression and decrease cytokine levels in mice,thus reducing inflammation and improving OA without obvious gastric adverse events.These results provide a scientific basis for the clinical application of Tet in the treatment of OA.展开更多
Tetrandrine(TET) and fangchinoline(FAN) are dominant bisbenzylisoquinoline(BBIQ) alkaloids from the roots of Stephania tetrandra of the family Menispermaceae. BBIQ alkaloids comprise two benzylisoquinoline units linke...Tetrandrine(TET) and fangchinoline(FAN) are dominant bisbenzylisoquinoline(BBIQ) alkaloids from the roots of Stephania tetrandra of the family Menispermaceae. BBIQ alkaloids comprise two benzylisoquinoline units linked by oxygen bridges. The molecular structures of TET and FAN are exactly the same, except that TET has a methoxy(-OCH3) group, while FAN has a hydroxyl(-OH) group at C7. In this overview,the current knowledge on the chemistry, pharmacology and anticancer properties of TET and FAN have been updated. The focus is on colon and breast cancer cells, because they are most susceptible to TET and FAN, respectively. Against colon cancer cells, TET inhibits cell proliferation and tumor growth by inducing apoptosis and G1 cell cycle arrest, and suppresses adhesion, migration and invasion of cells.Against breast cancer cells, FAN inhibits cell proliferation by inducing apoptosis, G1-phase cell cycle arrest and inhibits cell migration. The processes involve various molecular mechanisms and signaling pathways. Some insights on the ability of TET and FAN to reverse multi-drug resistance in cancer cells and suggestions for future research are provided.展开更多
As an important bis-benzylisoquinoline alkaloid isolated from the bulbous root ofStephania tetrandra S. Moore, tetrandrine （Tet） is widely used for the treatment of malignant tumor due to its properties of reversing...As an important bis-benzylisoquinoline alkaloid isolated from the bulbous root ofStephania tetrandra S. Moore, tetrandrine （Tet） is widely used for the treatment of malignant tumor due to its properties of reversing the multidrug resistance and apoptosis induction. In the present study, we aimed to evaluate the pharmacokinetics, tissue distribution and excretion of Tet in rats. Drug concentration in plasma and tissues was measured by high performance liquid chromatography （HPLC）, and the experimental data were analyzed using pharmacokinetic software DAS 2.0. The results showed that the plasma protein binding rate of Tet was 68.7%, indicating a higher protein binding drug. Tissue distribution was found in a descending order as follows： lung〉heart〉liver〉kidney〉spleen. Renal excretion was a major route of excretion, and the urine, bile and fecal excretion accounted for 25.73% of the administered dose. A UC0-∞ of Tet in the liver was 20 times greater than that in plasma, indicating that Tet had a higher affinity for the liver. Moreover, CL in the liver was the lowest among all tissues, indicating that Tet with slow elimination might result in the accumulation. Therefore, we need to adjust the dose for patients who have dysfunction in liver and kidney. In addition, therapeutic drug monitoring in long-term clinical treatment, if necessary, should be carried out.展开更多
AIM: To investigate the effect of Tetrandrine (Tet) on LPS-induced NF-κB activation and cell injury in pancreatic acinar cells and to explore the mechanism of Tetrandrine preventing LPS-induced acinar cell injury. ME...AIM: To investigate the effect of Tetrandrine (Tet) on LPS-induced NF-κB activation and cell injury in pancreatic acinar cells and to explore the mechanism of Tetrandrine preventing LPS-induced acinar cell injury. METHODS: Male rat pancreatic acinar cells were isolated by collagenase digestion, then exposed to LPS (10 mg/L), Tet (50μmol/L, 100μmol/L) or normal media. At different time point (30 min, 1 h, 4 h, 10 h) after treatment with the agents, cell viability was determined by MTT, the product and nuclear translocation of subunit p65 of NF-κB was visualized by immunofluorescence staining and nuclear protein was extracted to perform EMSA which was used to assay the NF-κB binding activity. RESULTS: LPS induced cell damage directly in a time dependent manner and Tet attenuated LPS-induced cell damage (50μmol/L, P < 0.05; 100μmol/L, P < 0.01). NF-κB p65 immunofluorescence staining in cytoplasm increased and began showing its nuclear translocation within 30 min and the peak was shown at 1 h of LPS 10 mg/L treatment. NF-κB DNA binding activity showed the same alteration pattern as p65 immunofluorescence staining. In Tet group, the immunofluorescence staining in cytoplasm and nuclear translocation of NF-κB were inhibited significantly. CONCLUSION: NF-κB activation is an important early event that may contribute to inflammatory responses and cell injury in pancreatic acinar cells. Tet possesses the protective effect on LPS-induced acinar cell injury by inhibiting NF-κB activation.展开更多
Objective To assess the ability of tetrandrine （Tet） to enhance the sensitivity to irradiation and its mechanism in cell lines of human breast cancer p53-mutant MCF-7/ADR, p53-wild-type MCF-7 and human colon carcino...Objective To assess the ability of tetrandrine （Tet） to enhance the sensitivity to irradiation and its mechanism in cell lines of human breast cancer p53-mutant MCF-7/ADR, p53-wild-type MCF-7 and human colon carcinoma p53-mutant HT-29 as well as in C26 colorectal carcinoma-bearing BALB/c mice. Methods MCF-7/ADR, HT-29 and MCF-7 cells were exposed to irradiation in the absence or presence of tetrandrine. The effect of Tet on the cytotoxicity of X-irradiation in these three cells was determined and the effect of tetrandrine on cell cycle arrest induced by irradiation in its absence or presence was studied by flow cytometry. Moreover, mitotic index measurement determined mitosis of cells to enter mitosis. Western blotting was employed to detect cyclin B1 and Cdc2 proteins in extracts from irradiated or non-irradiated cells of MCF-7/ADR, HT-29 and MCF-7 treated with tetrandrine at various concentrations. Tumor growth delay assay was conducted to determine the radio-sensitization of tetrandrine in vivo. Results Clonogenic assay showed that tetrandrine markedly enhanced the lethal effect of X-rays on p53-mutant MCF-7/ADR and HT-29 cells and the sensitization enhancement ratio （SER） of tetrandrine was 1.51 and 1.63, but its SER was only 1.1 in p53-wt MCF-7 cells. Irradiated p53-mutant MCF-7/ADR and HT-29 cells were only arrested in G2/M phase while MCF-7 cells were arrested in G1 and G2/M phases. Radiation-induced G2 phase arrests were abrogated by tetrandrine in a concentration-dependent manner in MCF-7/ADR and HT-29 cells, whereas redistribution within MCF-7 cell cycle changed slightly. The proportion of cells in M phase increased from 1.3% to 14.7% in MCF-7/ADR cells, and from 1.5% to 13.2% in HT-29 cells, but 2.4% to 7.1% in MCF-7 cells. Furthermore, the levels of cyclin B 1 and Cdc2 expression decreased after X-irradiation in MCF-7/ADR and HT-29 cells, and the mitotic index was also lower. Tet could reverse the decrease and induce the irradiated cells to enter mitosis （M phase）. Endosomatic experiment showed that tetrandrine caused tumor growth delay in irradiated mice. Conclusion Tetrandrine boosts the cell killing activity of irradiation both in vitro and in vivo. Tetrandrine is a potent abrogator for G2 checkpoint control and can sensitize the cells to radiation.展开更多
Tetrandrine is one of the major active ingredients in Menispermaceae Stephania tetrandra S.Moore,and has specific therapeutic effects in ischemic cerebrovascular disease.Its use in vascular dementia has not been studi...Tetrandrine is one of the major active ingredients in Menispermaceae Stephania tetrandra S.Moore,and has specific therapeutic effects in ischemic cerebrovascular disease.Its use in vascular dementia has not been studied fully.Here,we investigated whether tetrandrine would improve behavioral and cellular impairments in a two-vessel occlusion rat model of chronic vascular dementia.Eight weeks after model establishment,rats were injected intraperitoneally with 10 or 30 mg/kg tetrandrine every other day for 4 weeks.Behavioral assessment in the Morris water maze showed that model rats had longer escape latencies in training trials,and spent less time swimming in the target quadrant in probe trials,than sham-operated rats.However,rats that had received tetrandrine showed shorter escape latencies and longer target quadrant swimming time than untreated model rats.Hematoxylin-eosin and Nissl staining revealed less neuronal necrosis and pathological damage,and more living cells,in the hippocampus of rats treated with tetrandrine than in untreated model rats.Western blot assay showed that interleukin-1β expression,and phosphorylation of the N-methyl-D-aspartate 2B receptor at tyrosine 1472,were lower in model rats that received tetrandrine than in those that did not.The present findings suggest that tetrandrine may be neuroprotective in chronic vascular dementia by reducing interleukin-1β expression,N-methyl-D-aspartate receptor 2B phosphorylation at tyrosine 1472,and neuronal necrosis.展开更多
AIM To study the effects of tetrandrine on portal hypertensive gastric mucosal lesions. METHODS Portal hypertensive models were induced in Wistar rats by 60% CCl 4 3ml/kg body weight subcutaneous injection, once e...AIM To study the effects of tetrandrine on portal hypertensive gastric mucosal lesions. METHODS Portal hypertensive models were induced in Wistar rats by 60% CCl 4 3ml/kg body weight subcutaneous injection, once every 4 days for 56 days. The animals were randomly divided into portal hypertension, tetrandrine and propranolol groups and subsequently, treated by physiological saline, tetrandrine and propranolol respectively for 15 days. Some healthy rats were used as normal group. Portal venous pressure (PVP), gastric mucosal prostaglandin E 2 (PGE 2) content, gastric mucosal blood flow (GMBF), gastric adherent mucus (GAM), ALT, ALP and serum total bilirubin (STB), were measured and liver tissues were observed histologically. RESULTS In tetrandrine group and propranolol group, PVP was significantly lower (1 43±0 13, 1 45±0 12 vs 1 89±0 18kPa; P <0 01) and gastric mucosal PGE 2 content (138 59±12 68, 129 98±14 31 vs 104 65±12 97pg/mg; P <0 01), GMBF (11 80±3 47, 10 54±3 63 vs 6 61±2 82ml·h·kg; P <0 05) and GAM (3 01±0 15, 2 98±0 21 vs 2 24mg±0 26mg; P <0 01) was significantly higher than that in portal hypertension control group. In tetrandrine group intrahepatic proliferative fibrous tissues were reduced and serum ALT (47 67±25 90 vs 189 33±41 21 King U; P <0 01), ALP (0 22±0 04 vs 0 31±0 06μmol·s -1 /L; P <0 01) and STB (4 75±0 76 vs 11 12±2 93μmol/L; P <0 01) were lowered as compared with these in portal hypertension control group. ALT (209 34±36 91 vs 189 33±41 21 King U; P >0 05) and STB (11 63±3 01 vs 11 12±2 93μmol/L; P >0 05) in propranolol group were not different from that in portal hypertension controls group, but it showed more marked hepatocellular degeneration and necrosis and elevation of ALP (0 46±0 05 vs 0 31±0 06μmol·s -1 /L; P <0 01). CONCLUSION Tetrandrine can improve the functions of gastric mucosa and liver, and facilitate the absorption of intrahepatic proliferative fibrous tissues. Propranolol can aggravate hepatosis though it may improve portal hypertensive gastric mucosal lesions.展开更多
Tetrandrine(TET),a natural bisbenzyl isoquinoline alkaloid extracted from Stephania tetrandra S.Moore,has diverse pharmacological effects.However,its effects on melanoma remain unclear.Cellular prolif-eration assays,m...Tetrandrine(TET),a natural bisbenzyl isoquinoline alkaloid extracted from Stephania tetrandra S.Moore,has diverse pharmacological effects.However,its effects on melanoma remain unclear.Cellular prolif-eration assays,multi-omics analyses,and xenograft models were used to determine the effect of TET on melanoma.The direct target of TET was identified using biotin-TET pull-down liquid chromatograph-mass spectrometry(LC-MS),cellular thermal shift assays,and isothermal titration calorimetry(ITC)analysis.Our findings revealed that TET treatment induced robust cellular autophagy depending on activating transcription factor 6(ATF6)-mediated endoplasmic reticulum(ER)stress.Simultaneously,it hindered autophagic flux by inducing cytoskeletal protein depolymerization in melanoma cells.TET treatment resulted in excessive accumulation of reactive oxygen species(Ros)and simultaneously triggered mitophagy.Sirtuin 5(SIRT5)was ultimately found to be a direct target of TET.Mechanistically,TET led to the degradation of SIRT5 via the ubiquitin(Ub)-26S proteasome system.SIRT5 knockdown induced ROS accumulation,whereas SIRT5 overexpression attenuated the TET-induced ROS accumula-tion and autophagy.Importantly,TET exhibited anti-cancer effects in xenograft models depending on SIRT5 expression.This study highlights the potential of TET as an antimelanoma agent that targets SIRT5.These findings provide a promising avenue for the use of TET in melanoma treatment and underscore its potential as a therapeutic candidate.展开更多
文摘The effect of tetrandrine (Tet) on the infarction area and volume of rat brain induced by middle cerebral artery occlusion (MCAO) was investigated. The treatment with Tet 7.5, 12.0 or 15.0 mg·kg 1 , or with fructose 1,6 diphosphate (FDP) 200 and 350 mg·kg 1 ip immediately after MCAO, respectively, significantly reduced the infarction area and volume in a dose dependent manner. MK801 and FDP also displayed a protective effect on brain ischemia. A combination of Tet and FDP administered immediately after MCAO, produced a more potent protective effect than those treated with Tet or FDP alone. When Tet or FDP was administered 1 h and 2 h after MCAO, respectively, they could still significantly reduce the infarction area and volume of brain tissue. But, there was no significant protective effect when these two compounds were given 3 h after MCAO.
文摘\ The effects of tetrandrine (Tet) on cytosolic free calcium ([Ca2+]i) in subcultured bovine aortic smooth muscle cells (SMC) were studied by Fura2 and ARCMMIC cation measurement system. Tet (1～100 μmol·L-1) had no effect on the resting [Ca2+]i, but had inhibitory effects on [Ca2+]i elevation induced by high K+, 5HT, ATP, Ang II and NE in the presence of extracellular Ca2+. High concentration of Tet also inhibited Pheinduced [Ca2+]i elevation in absence of extracellular Ca2+. Tet (1～100 μmol·L-1) inhibited KCl (60 mmol·L-1) induced [Ca2+]i elevation in dosedependent manner, the IC50 value was 9.2 (95% confidence limits: 5.7～14.9) mmol·L-1. The results suggested that Tet had blocking effects on both VOC and ROC in bovine aortic SMC. It appears that the mechanisms of blocking effect of Tet on ROC might be primarily due to its Ca2+ entry blocking effects.
基金National Natural Science Foundation of China(Grant No.30772556 and 30640070)Research Fund of Janssen Research Council and the‘985'Project in Peking University.
文摘It has been reported that augmentative effect of tetrandrine on pentobarbital hypnosis in mice may be related to serotonergic system. The present study was undertaken to investigate the interaction of tetrandrine and different 5-HT receptors on pentobarbital-induced sleep by using the loss-of-righting reflex method. The results showed that augmentative effect of tetrandrine on pentobarbital hypnosis in mice were potentiated by the p-MPPI （5-HT1A receptor antagonist） （1 mg/kg, i.p.） and ketanserin （5-HT2A/2C receptor antagonist） （1.5 mg/kg, i.p.）, respectively. Pretreatment with either 8-OH-DPAT （5-HT1A receptor agonist） （0.1 mg/kg, s.c.） or DOI （5-HT2A/2C receptor agonist） （0.2 mg/kg, i.p.） significantly decreased pentobarbital-induced sleep time, and tetrandrine （60 mg/kg, i.g.） significantly reversed this effect. These results suggest that both the 5-HTLA and 5-HT2A/2C subfamily may be involved in the potentiating mechanism of tetrandrine＇s effects on pantobarbital hypnosis.
基金National Natural Science Foundation of China (Grant No. 81172990)National Development of Significant New Drugs of China (New Preparation and New Technology,Grant No. 2009zx09310-001)+1 种基金National Key Science Research Program of China (973 Program, Grant No. 2009CB930300)Innovation Team of Ministry of Education (Grant No. BMU20110263)
文摘The purpose of this work was to explore the feasibility of ethosomes for improving the anti-arthritic efficacy of topically administered tetrandrine, a bisbenzylisoquinoline alkaloid. Ethosomes were prepared by using the transmembrane pH-gradient loading method and characterized by mean diameter, morphology and entrapment efficiency. The prepared tetrandrine-loaded ethosomes exhibited spherical shape with about 78 nm of average diameter and entrapment efficiency of （52.87±3.81）%, whereas the liposomes had bigger size （99 nm） and higher entrapment efficiency （98.80±0.01）%. In addition, ethosomes exhibited favorable and enhanced penetration behavior as compared with liposomes. More importantly, tetrandrine-loaded ethosomes had a significantly better anti-adjuvant arthritis efficacy in rats compared to liposomes formulation, but no significant difference in the anti-arthritic efficacy between tetrandrine-loaded ethosomes and commercial dexamethasone ointment was observed. These results suggest that ethosomes would be a promising nanocarrier for topical delivery of tetrandrine across skin.
文摘Tetrandrine （TET）, a traditional Chinese medicine, exerts remarkable anticancer activity on various cancer cells. However, little is known about the effect of TET on human prostate cancer cells, and the mechanism of function of TET on prostate cancer has not yet been elucidated. To investigate the effects of TET on the suppression of proliferation, induction of apoptosis, and inhibition of migration and invasion in human prostate cancer cell lines, DU145 and PC-3. Inhibition of growth was determined by 3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyltetrazolium bromide assay and clone formation assay, and flow cytometry analysis was performed to detect the induction of apoptosis. Activation of poly （ADP-ribose） polymerase, caspase-3, Akt, phospho-Akt, Bcl-2, and Bax was analyzed by Western blotting. Wound healing assay and transwell migration assay were used to evaluate the effect of TET on migration and invasion of cancer cells. TET inhibited the growth of DU145 and PC-3 cells in a dose- and time-dependent manner. Cell cloning was inhibited in the presence of TET in DU145 and PC-3 cells. TET suppressed the migration of DU145 and PC-3 cells. Transwell invasion assay showed that TET significantly weakened invasion capacity of DU 145 and PC-3 cells. TET exhibited strong inhibitory effect on proliferation, migration, and invasion of prostate cancer cells. In addition, TET induced apoptosis in a dose-dependent manner by activating the caspase cascade and inhibiting phosphoinositide 3-kinase-Akt signal pathway. The accumulating evidence suggests that TET could be a potential therapeutic candidate against prostate cancer in a clinical setting.
基金the National Natural Science Foundation of China, No. 32060127 and No. 30660225
文摘AIM： To investigate the therapeutic effect of tetrandrine on liver fibrosis induced by thioacetamide in rats in vivo and in vitro. METHODS： In vitro study： we investigated the effect of tetrandrine on the apoptosis of rat hepatic stellate cells transformed by simian virus 40 （T-HSC/CI-6）, which retains the features of activated cells. In vivo study： hepatic fibrosis was induced in rats by thioacetamide. Tetrandrine was given orally to rats at doses of 5, 10 or 20 mg/kg for 4 wk compared with intraperitoneal injection of interferon-r. RESULTS： In vitro study： 5, 10 or 25 μg/mL of tetrandrine-induced activation of caspase-3 in t-HSC/CI-6 cells occurred dose-dependently. In vivo study： tetrandrine treatment as well as interferon-r significantly ameliorated the development of fibrosis as determined by lowered serum levels of aspartate aminotransferase （AST）, alanine aminotransferase （ALT）, total bilirubin （T-Bil） and the levels of liver hydroxyproline （Hyp）, hyaluronic acid （HA）, laminin （LN） and also improved histological findings. The effects of tetrandrine at the concentration of 20 mg/kg were better than the other concentration groups. CONCLUSION： Tetrandrine promotes the apoptosis of activated HSCs in vitro. Tetrandrine administration can prevent liver fibrosis and liver damage induced by thioacetamide in rats in vivo, indicating that it might exert a direct effect on rat HSCs.
基金supported by the National Natural Science Foundation of China(No.81373426)the Priority Academic Program Development of Jiangsu Higher Education Institutions
文摘Tetrandrine （Tet）, the main active constituent of Stephania tetrandra root, has been demonstrated to alleviate adjuvant-induced arthritis in rats. The present study was designed to investigate the effects of Tet on the migration and invasion of rheumatoid arthritis fibroblast-like synovioeytes （RA-FLS） and explore the underlying mechanisms. By using cultures of primary FLS isolated from synoviums of RA patients and cell line MH7A, Tet （0.3, 1 μmol L-1） was proven to significantly impede migration and invasion of RA-FLS, but not cell proliferation. Tet also greatly reduced the activation and expressions of matrix degrading enzymes MMP-2/9, the expression of F-actin and the activation of FAK, which controlled the morphologic changes in migration process of FLS. To identify the key signaling pathways by which Tet exerts anti-migration effect, the specific inhibitors of multiple signaling pathways LY294002, Triciribine, SP600125, U0126, SB203580, and PDTC （against PI3K, Akt, JNK, ERK, p38 MAPK and NF-kB-p65, respectively） were used. Among them, LY294002, Triciribine, and SP600125 were shown to obviously inhibit the migration of MH7A cells. Consistently, Tet was able to down-regulate the activation of Akt and JNK as demonstrated by Western blotting assay. Moreover, Tet could reduce the expressions of migration-related proteins Rho GTPases Rac 1, Cdc42, and RhoA in MH7A cells. In conclusion, Tet can impede the migration and invasion of RA-FLS, which provides a plausible explanation for its protective effect on RA. The underlying mechanisms involve the reduction of the expressions of Racl, Cdc42, and RhoA, inhibition of the activation of Akt and JNK, and subsequent down-regulation of activation and/or expressions of MMP-2/9, F-actin, and FAK.
基金supported by the National Natural Science Foundation of China (Nos. 30672381, 30873095, and 81070420)the Zhejiang Provincial Program for the Cultivation of High-Level Innovative Health Talentsthe Zhejiang Provincial Natural Science Foundation of China (Nos. Y206238, Y2080570, and Y2080210)
文摘Objective:To evaluate the effects of tetrandrine citrate, a novel tetrandrine salt with high water solubility, on the growth of imatinib (IM)-resistant chronic myeloid leukemia (CML) in vitro and in vivo, and reveal action molecular mechanisms. Methods:Cell viability in vitro was measured using methyl thiazolyl tetrazolium (MTT) assay. CML cell growth in vivo was assessed using a xenograft model in nude mice. Bcr-Abl and β-catenin protein levels were determined using Western blotting. Bcr-Abl messenger RNA (mRNA) was measured by reverse transcription polymerase chain reaction (RT-PCR). Flow cytometry (FCM) was used to determine cell cycle status. Results:Tetrandrine citrate inhibited the growth of IM-resistant K562 cells, primary leukemia cells, and primitive CD34 + leukemia cells, and their inhibition concentration that inhibited 50% of target cells (IC 50 ) ranged from 1.20 to 2.97 μg/ml. In contrast, tetrandrine citrate did not affect normal blood cells under the same conditions, and IC 50 values were about 10.12-13.11 μg/ml. Oral administration of tetrandrine citrate caused complete regression of IM-resistant K562 xeno-grafts in nude mice without overt toxicity. Western blot results revealed that treatment of IM-resistant K562 cells with tetrandrine citrate resulted in a significant decrease of both p210 Bcr-Abl and β-catenin proteins, but IM did not affect the Bcr-Abl protein levels. Proteasome inhibitor, MG132, did not prevent tetrandrine-mediated decrease of the p210 Bcr-Abl protein. RT-PCR results showed that tetrandrine treatment caused a decrease of Bcr-Abl mRNA. FCM analysis indicated that tetrandrine induced gap 1 (G 1 ) arrest in CML cells. Conclusions:Tetrandrine citrate is a novel orally active tetrandrine salt with potent anti-tumor activity against IM-resistant K562 cells and CML cells. Tetrandrine citrate-induced growth inhibition of leukemia cells may be involved in the depletion of p210 Bcr-Abl mRNA and β-catenin protein.
基金Supported by the College Science and Technology Developing Foundation of Shanghai, No. 02BK14
文摘AIM: To investigate the effect of various concentrations of tetrandrine on activation of quiescent rat hepatic stellate cells (HSCs) and transforming growth factor-β (TGF-β) signaling in vitro.METHODS: HSCs were isolated from rats by in situperfusion of liver and 18% Nycodenz gradient centrifugation, and primarily cultured on uncoated plastic plates for 24 hwith DMEM containing 20% fetal bovine serum (FBS/DMEM) before the culture medium was substituted with 2% FBS/DMEM for another 24 h. Then, the HSCs were cultured in 2% FBS/DMEM with tetrandrine (0.25, 0.5, 1,2 mg/L, respectively). Cell morphological features were observed under an inverted microscope, smooth muscleα-actin (α-SMA) was detected by immunocytochemistry and image analysis system, laminin (LN) and type Ⅲprocollagen (PCⅢ) in supernatants were determined byradioimmunoassay. TGF-β1 mRNA, Smad 7 mRNA and Smad 7 protein were analyzed with RT-PCR and Western blotting, respectively.RESULTS: Tetrandrine at the concentrations of 0.25-2 mg/L prevented morphological transformation of HSC from the quiescent state to the activated one, while α-SMA, LN and PCⅢ expressions were inhibited. As estimated by gray values, the expression of α-SMA in tetrandrine groups (0.25, 0.5, 1, 2 mg/L) was reduced from 21.3% to 42.2%(control: 0.67, tetrandrine groups: 0.82, 0.85, 0.96, or 0.96, respectively, which were statistically different from the control, P＜0.01), and the difference was more significant in tetrandrine at 1 and 2 mg/L. The content of LN in supernatants was significantly decreased in tetrandrine groups to 58.5%, 69.1%, 65.8% or 60.0% that of the control respectively, and that of PCⅢ to 84.6%, 81.5%,75.7% or 80.7% respectively (P＜0.05 vs control), with no significant difference among tetrandrine groups. RTPCR showed that TGF-β1 mRNA expression was reduced by tetrandrine treatments from 56.56% to 87.90% in comparison with the control, while Smad 7 mRNA was increased 1.4-4.8 times. The TGF-β1 mRNA and Smad 7 mRNA expression was in a significant negative correlation (r= -0.755, P＜0.01), and both were significantly correlated with α-SMA protein expression (r = -0.938, P＜0.01;r = 0.938, P＜0.01, respectively). The up-regulation of Smad 7 protein by tetrandrine (1 mg/L)was confirmed by Western blotting as well.CONCLUSION: Tetrandrine has a direct inhibiting effect on the activation of rat HSCs in culture. It up-regulates the expression of Smad 7 which in turn blocks TGF-β1 expression and signaling.
基金supported by the 11th Five Plan for Major Scientific and Technological Specialized Project for Significant Formulation of New Drugs(No.2009ZX09301-007)
文摘[ABSTRACT] The aim of the study was to investigate the anti-proliferation and apoptosis-inducing effects of S1, a novel tetrandrine derivative, in human gastric cancer BGC-823 cells and explore the possible mechanism of action. The anti-proliferative activity was determined by MTT assay; the induction of cell cycle arrest and apoptosis were detected by flow cytometry. Quantitative real time RT-PCR and Western blotting were used to evaluate the mRNA and protein expression levels in mitochondrial pathway. SI significantly reduced cell viability and induced a G2/M phase arrest and apoptosis in dose- and time-dependent manner. Further studies showed that S1 increased mRNA and protein expression of Bax and the Bax/Bcl-2 ratio. Moreover, S1 decreased the protein expression of procaspase-9 and procaspase-3, suggesting that the induction of apoptosis may be related to the alteration of the ratio of Bax/Bcl-2 and the activation of caspases. These findings suggested that S1 merits further investigation as a novel therapeutic agent for the treatment of human gastric cancer.
文摘In the screening tests of drugs for silicosis in our laboratory, we found that TT, a type of alkaloid isolated from Stephania tetrandra, could inhibit the development of experimental silicosis of rats and the synthesis of collagen in rat lung. Chest X-rays of silicotic patients treaied with TT for 1-3 years showed obvious changes. The silicotic nodules became smallel and shadows became clearer. PVNO was proved to have anti-silicotic effect on animal and clinically. This presentation reports the effect of them on collagen mRNA.Dot blot results showed that 1 (Ⅰ) and 1 (Ⅲ) mRNA levels increased significantly at 60 and 120 days after the rats were exposed to silica dust. The mRNA levels went down at 1 and 3 months after treated by TT and PVNO. In situ hybridization observation revealed that the silver grains of Type Ⅰand Type Ⅲ collagen were scattered within the fibroblasts in cellular nodules and in thickened interstitium of silicosis tissue. The amounts of mRNA silver grains decreased in the lung tissue treated by TT and PVNO. It was suggested that TT and PVNO may inhibil the gene expression of collagen during silicosis
基金This study was supported by the Natural Science Foundation of Hubei Province(No.2020CFB868).
文摘Objective There is a lack of effective and long-term safe drugs for the treatment of osteoarthritis(OA).Tetrandrine(Tet)has been approved and used to treat rheumatoid arthritis for several decades,but its effect on OA has not been investigated.Herein,we explored the effect of Tet on OA and its underlying mechanism.Methods OA was induced using destabilization of the medial meniscus(DMM)in C57BL/6J mice.The animals were randomly divided into sham,DMM,Tet,celecoxib(CXB),and indomethacin(INDO)groups.Each group was given solvent or corresponding drugs by gavage for 7 weeks after convalescence.Pathological staining,OARSI scores,micro-computed tomography and behavior tests were performed to evaluate the effects of Tet.Results Tet remarkably alleviated cartilage injury in the knee joint,limited bone remodeling in the subchondral bone,and delayed progression of OA.Tet also significantly relieved joint pain and maintained function.Further mechanistic studies revealed that Tet lowered inflammatory cytokine levels and selectively suppressed gene and protein expression of cyclooxygenase(COX)-2 but not COX-1(P<0.01).Tet also reduced the production of prostaglandin E2 without damaging the gastric mucosa.Conclusion We found that Tet could selectively inhibit COX-2 gene expression and decrease cytokine levels in mice,thus reducing inflammation and improving OA without obvious gastric adverse events.These results provide a scientific basis for the clinical application of Tet in the treatment of OA.
文摘Tetrandrine(TET) and fangchinoline(FAN) are dominant bisbenzylisoquinoline(BBIQ) alkaloids from the roots of Stephania tetrandra of the family Menispermaceae. BBIQ alkaloids comprise two benzylisoquinoline units linked by oxygen bridges. The molecular structures of TET and FAN are exactly the same, except that TET has a methoxy(-OCH3) group, while FAN has a hydroxyl(-OH) group at C7. In this overview,the current knowledge on the chemistry, pharmacology and anticancer properties of TET and FAN have been updated. The focus is on colon and breast cancer cells, because they are most susceptible to TET and FAN, respectively. Against colon cancer cells, TET inhibits cell proliferation and tumor growth by inducing apoptosis and G1 cell cycle arrest, and suppresses adhesion, migration and invasion of cells.Against breast cancer cells, FAN inhibits cell proliferation by inducing apoptosis, G1-phase cell cycle arrest and inhibits cell migration. The processes involve various molecular mechanisms and signaling pathways. Some insights on the ability of TET and FAN to reverse multi-drug resistance in cancer cells and suggestions for future research are provided.
基金The Scientific Research Fund Project of Heilongjiang University of Chinese Medicine(Grant No.201408)
文摘As an important bis-benzylisoquinoline alkaloid isolated from the bulbous root ofStephania tetrandra S. Moore, tetrandrine （Tet） is widely used for the treatment of malignant tumor due to its properties of reversing the multidrug resistance and apoptosis induction. In the present study, we aimed to evaluate the pharmacokinetics, tissue distribution and excretion of Tet in rats. Drug concentration in plasma and tissues was measured by high performance liquid chromatography （HPLC）, and the experimental data were analyzed using pharmacokinetic software DAS 2.0. The results showed that the plasma protein binding rate of Tet was 68.7%, indicating a higher protein binding drug. Tissue distribution was found in a descending order as follows： lung〉heart〉liver〉kidney〉spleen. Renal excretion was a major route of excretion, and the urine, bile and fecal excretion accounted for 25.73% of the administered dose. A UC0-∞ of Tet in the liver was 20 times greater than that in plasma, indicating that Tet had a higher affinity for the liver. Moreover, CL in the liver was the lowest among all tissues, indicating that Tet with slow elimination might result in the accumulation. Therefore, we need to adjust the dose for patients who have dysfunction in liver and kidney. In addition, therapeutic drug monitoring in long-term clinical treatment, if necessary, should be carried out.
基金Supported by the National Natural Science Foundation of China, No. 30370643
文摘AIM: To investigate the effect of Tetrandrine (Tet) on LPS-induced NF-κB activation and cell injury in pancreatic acinar cells and to explore the mechanism of Tetrandrine preventing LPS-induced acinar cell injury. METHODS: Male rat pancreatic acinar cells were isolated by collagenase digestion, then exposed to LPS (10 mg/L), Tet (50μmol/L, 100μmol/L) or normal media. At different time point (30 min, 1 h, 4 h, 10 h) after treatment with the agents, cell viability was determined by MTT, the product and nuclear translocation of subunit p65 of NF-κB was visualized by immunofluorescence staining and nuclear protein was extracted to perform EMSA which was used to assay the NF-κB binding activity. RESULTS: LPS induced cell damage directly in a time dependent manner and Tet attenuated LPS-induced cell damage (50μmol/L, P < 0.05; 100μmol/L, P < 0.01). NF-κB p65 immunofluorescence staining in cytoplasm increased and began showing its nuclear translocation within 30 min and the peak was shown at 1 h of LPS 10 mg/L treatment. NF-κB DNA binding activity showed the same alteration pattern as p65 immunofluorescence staining. In Tet group, the immunofluorescence staining in cytoplasm and nuclear translocation of NF-κB were inhibited significantly. CONCLUSION: NF-κB activation is an important early event that may contribute to inflammatory responses and cell injury in pancreatic acinar cells. Tet possesses the protective effect on LPS-induced acinar cell injury by inhibiting NF-κB activation.
基金supported by a grant from the Jiangsu Natural Science Foundation (No. BK2005203).
文摘Objective To assess the ability of tetrandrine （Tet） to enhance the sensitivity to irradiation and its mechanism in cell lines of human breast cancer p53-mutant MCF-7/ADR, p53-wild-type MCF-7 and human colon carcinoma p53-mutant HT-29 as well as in C26 colorectal carcinoma-bearing BALB/c mice. Methods MCF-7/ADR, HT-29 and MCF-7 cells were exposed to irradiation in the absence or presence of tetrandrine. The effect of Tet on the cytotoxicity of X-irradiation in these three cells was determined and the effect of tetrandrine on cell cycle arrest induced by irradiation in its absence or presence was studied by flow cytometry. Moreover, mitotic index measurement determined mitosis of cells to enter mitosis. Western blotting was employed to detect cyclin B1 and Cdc2 proteins in extracts from irradiated or non-irradiated cells of MCF-7/ADR, HT-29 and MCF-7 treated with tetrandrine at various concentrations. Tumor growth delay assay was conducted to determine the radio-sensitization of tetrandrine in vivo. Results Clonogenic assay showed that tetrandrine markedly enhanced the lethal effect of X-rays on p53-mutant MCF-7/ADR and HT-29 cells and the sensitization enhancement ratio （SER） of tetrandrine was 1.51 and 1.63, but its SER was only 1.1 in p53-wt MCF-7 cells. Irradiated p53-mutant MCF-7/ADR and HT-29 cells were only arrested in G2/M phase while MCF-7 cells were arrested in G1 and G2/M phases. Radiation-induced G2 phase arrests were abrogated by tetrandrine in a concentration-dependent manner in MCF-7/ADR and HT-29 cells, whereas redistribution within MCF-7 cell cycle changed slightly. The proportion of cells in M phase increased from 1.3% to 14.7% in MCF-7/ADR cells, and from 1.5% to 13.2% in HT-29 cells, but 2.4% to 7.1% in MCF-7 cells. Furthermore, the levels of cyclin B 1 and Cdc2 expression decreased after X-irradiation in MCF-7/ADR and HT-29 cells, and the mitotic index was also lower. Tet could reverse the decrease and induce the irradiated cells to enter mitosis （M phase）. Endosomatic experiment showed that tetrandrine caused tumor growth delay in irradiated mice. Conclusion Tetrandrine boosts the cell killing activity of irradiation both in vitro and in vivo. Tetrandrine is a potent abrogator for G2 checkpoint control and can sensitize the cells to radiation.
基金supported by the National Natural Science Foundation of China,No.81070886
文摘Tetrandrine is one of the major active ingredients in Menispermaceae Stephania tetrandra S.Moore,and has specific therapeutic effects in ischemic cerebrovascular disease.Its use in vascular dementia has not been studied fully.Here,we investigated whether tetrandrine would improve behavioral and cellular impairments in a two-vessel occlusion rat model of chronic vascular dementia.Eight weeks after model establishment,rats were injected intraperitoneally with 10 or 30 mg/kg tetrandrine every other day for 4 weeks.Behavioral assessment in the Morris water maze showed that model rats had longer escape latencies in training trials,and spent less time swimming in the target quadrant in probe trials,than sham-operated rats.However,rats that had received tetrandrine showed shorter escape latencies and longer target quadrant swimming time than untreated model rats.Hematoxylin-eosin and Nissl staining revealed less neuronal necrosis and pathological damage,and more living cells,in the hippocampus of rats treated with tetrandrine than in untreated model rats.Western blot assay showed that interleukin-1β expression,and phosphorylation of the N-methyl-D-aspartate 2B receptor at tyrosine 1472,were lower in model rats that received tetrandrine than in those that did not.The present findings suggest that tetrandrine may be neuroprotective in chronic vascular dementia by reducing interleukin-1β expression,N-methyl-D-aspartate receptor 2B phosphorylation at tyrosine 1472,and neuronal necrosis.
文摘AIM To study the effects of tetrandrine on portal hypertensive gastric mucosal lesions. METHODS Portal hypertensive models were induced in Wistar rats by 60% CCl 4 3ml/kg body weight subcutaneous injection, once every 4 days for 56 days. The animals were randomly divided into portal hypertension, tetrandrine and propranolol groups and subsequently, treated by physiological saline, tetrandrine and propranolol respectively for 15 days. Some healthy rats were used as normal group. Portal venous pressure (PVP), gastric mucosal prostaglandin E 2 (PGE 2) content, gastric mucosal blood flow (GMBF), gastric adherent mucus (GAM), ALT, ALP and serum total bilirubin (STB), were measured and liver tissues were observed histologically. RESULTS In tetrandrine group and propranolol group, PVP was significantly lower (1 43±0 13, 1 45±0 12 vs 1 89±0 18kPa; P <0 01) and gastric mucosal PGE 2 content (138 59±12 68, 129 98±14 31 vs 104 65±12 97pg/mg; P <0 01), GMBF (11 80±3 47, 10 54±3 63 vs 6 61±2 82ml·h·kg; P <0 05) and GAM (3 01±0 15, 2 98±0 21 vs 2 24mg±0 26mg; P <0 01) was significantly higher than that in portal hypertension control group. In tetrandrine group intrahepatic proliferative fibrous tissues were reduced and serum ALT (47 67±25 90 vs 189 33±41 21 King U; P <0 01), ALP (0 22±0 04 vs 0 31±0 06μmol·s -1 /L; P <0 01) and STB (4 75±0 76 vs 11 12±2 93μmol/L; P <0 01) were lowered as compared with these in portal hypertension control group. ALT (209 34±36 91 vs 189 33±41 21 King U; P >0 05) and STB (11 63±3 01 vs 11 12±2 93μmol/L; P >0 05) in propranolol group were not different from that in portal hypertension controls group, but it showed more marked hepatocellular degeneration and necrosis and elevation of ALP (0 46±0 05 vs 0 31±0 06μmol·s -1 /L; P <0 01). CONCLUSION Tetrandrine can improve the functions of gastric mucosa and liver, and facilitate the absorption of intrahepatic proliferative fibrous tissues. Propranolol can aggravate hepatosis though it may improve portal hypertensive gastric mucosal lesions.
基金This work was supported by funding from Natural Science Foundation of China(Grant Nos.:82372519 and 81902664)the PostdoctoralFellowshipProgramof CPSF(GrantNo.:GZB20240544)+3 种基金the China Postdoctoral Science Foundation(Grant No.:2024M752432)the Natural Science Foundation of Hebei Province(Grant Nos.:H2022206368 and H2022206446)Medical Science Research Program of the Hebei Provincial Health Commission(Grant No.:20241603)Pilot Program of Southwest University(Program No.:SWU-XDZD22006)。
文摘Tetrandrine(TET),a natural bisbenzyl isoquinoline alkaloid extracted from Stephania tetrandra S.Moore,has diverse pharmacological effects.However,its effects on melanoma remain unclear.Cellular prolif-eration assays,multi-omics analyses,and xenograft models were used to determine the effect of TET on melanoma.The direct target of TET was identified using biotin-TET pull-down liquid chromatograph-mass spectrometry(LC-MS),cellular thermal shift assays,and isothermal titration calorimetry(ITC)analysis.Our findings revealed that TET treatment induced robust cellular autophagy depending on activating transcription factor 6(ATF6)-mediated endoplasmic reticulum(ER)stress.Simultaneously,it hindered autophagic flux by inducing cytoskeletal protein depolymerization in melanoma cells.TET treatment resulted in excessive accumulation of reactive oxygen species(Ros)and simultaneously triggered mitophagy.Sirtuin 5(SIRT5)was ultimately found to be a direct target of TET.Mechanistically,TET led to the degradation of SIRT5 via the ubiquitin(Ub)-26S proteasome system.SIRT5 knockdown induced ROS accumulation,whereas SIRT5 overexpression attenuated the TET-induced ROS accumula-tion and autophagy.Importantly,TET exhibited anti-cancer effects in xenograft models depending on SIRT5 expression.This study highlights the potential of TET as an antimelanoma agent that targets SIRT5.These findings provide a promising avenue for the use of TET in melanoma treatment and underscore its potential as a therapeutic candidate.
