Lack of the inhibitory effect of intragastrically administered capsaicin on NNK-induced lung tumor formation in the A.J mouse.

Capsaicin is the principal component in Capsicum fruits consumed by humans worldwide as a food additive. The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is thought to be an important causative factor in human lung cancer. Dietary factors are reported to modify lung tumor formation in laboratory animals and in humans. In this study, NNK-induced lung tumor formation in female A/J mice given intragastric doses of capsaicin (5 mg/kg body wt) was compared to mice not receiving capsaicin. At the end of the 21 week study, mice treated with capsaicin had an average of 17.1 +/- 1.8 lung tumors/mouse while untreated mice had 19.6 +/- 2. There were 100% lung tumor bearers in each group. Capsaicin alone did not affect spontaneous formation of lung tumors. Our results do not support a possible chemoprotective effect of dietary capsaicin toward NNK-induced lung tumors in human smokers.     

Inhibitory effect of Perilla leaf extract and luteolin on mouse skin tumor promotion

In the present study, the effects of perilla leaf extract (PLE) and luteolin on 7,12-dimethylbenz[a]anthracene (DMBA)- and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin papillomas in mice were investigated. Topical application of PLE prior to TPA treatment in DMBA-initiated mouse skin resulted in a significant reduction in tumor incidence and multiplicity. An even more potent preventive effect was observed with topical application of luteolin, which we previously identified as an antiinflammatory constituent. PLE was dissolved in drinking water at a 0.05% dose and mice ingested it ad libitum; no significant difference was observed in tumor incidence or multiplicity but there was a significant reduction in tumor volume between the PLE-treated and untreated groups. These results suggest that PLE has potent antipromotion activity and ingesting it as a daily food may provide a beneficial chemopreventive effect.     

Inhibitory effect of capsaicin on cholinergic transmission in ovine airways: evidence for non-cholinergic contractions

Electrical stimulation of ovine trachealis smooth muscle and bronchial ring segments induced neurogenic and monophasic atropine-sensitive contractions. Pretreatment of the tissues with capsaicin (100 microM) significantly reduced these contractions indicating a possible contribution of a peptidergic neurotransmitter to the contractions. The effect of capsaicin on electrically induced contractions was significantly inhibited by capsazepin indicating an action on vanilloid receptors. In both preparations, electrically induced contractions were not modified by tachykinin NK(1)- and NK(2)-receptor antagonists singly and in combination. It was therefore concluded that a component of the atropine-sensitive electrically induced contractions of ovine airways smooth muscles involved the release of a peptide neurotransmitter which is probably not a tachykinin. However, an action of capsaicin on prejunctional vanilloid receptors located on cholinergic nerves cannot be ruled out.     

海参硫酸软骨素抑制小鼠黑色素瘤肺转移作用的研究

目的海参硫酸软骨素(sea cucumber chondroitin sul-fate,SC-CHS)由美国肉参中分离所得,研究其结构及对小鼠黑色素瘤B16-F10细胞实验性肺转移模型的抑制作用。方法采用MTT法检测了SC-CHS对B16-F10细胞生长的影响;细胞黏附实验研究了SC-CHS对B16-F10细胞黏附能力的影响;体内实验,预先腹腔给药5 d后,建立实验性肺转移模型,继续腹腔注射SC-CHS 20d后,检测小鼠肺转移灶形成,血清中唾液酸的含量、γ-谷氨酰转肽酶活力和肺组织中羟脯氨酸、氨基己糖、糖醛酸的含量。结果实验结果显示SC-CHS体外对B16-F10细胞的生长没有影响,但可以明显降低B16-F10细胞同基质和血管内皮细胞的黏附能力(P<0.05)。SC-CHS剂量组小鼠的肺转移灶数量明显减少(P<0.01),平均转移抑制率为62.66%,血清唾液酸含量和γ-谷氨酰转肽酶活力明显降低(P<0.01),肺组织中羟脯氨酸、氨基己糖、糖醛酸的含量明显下降(P<0.01)。结论 SC-CHS能抑制肿瘤细胞在小鼠体内的转移和生长,其机制可能与降低肿瘤细胞与基质的黏附能力和细胞的转移能力有关。     

Inhibitory effect of stevioside on tumor promotion by 12-O-tetradecanoylphorbol-13-acetate in two-stage carcinogenesis in mouse skin

Four steviol (ent-kaurene-type diterpenoid) glycosides, stevioside, rebaudiosides A and C, and dulcoside A, have been isolated from Stevia rebaudiana BERTONI. These compounds showed strong inhibitory activity against 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation in mice. The 50% inhibitory dose of these compounds for TPA-induced inflammation was 54.1-291.6 micro g/ear. Furthermore, at 1.0 and 0.1 mg/mouse of stevioside mixture, the mixture of these compounds markedly inhibited the promoting effect of TPA (1 micro g/mouse) on skin tumor formation initiated with 7,12-dimethylbenz[a]anthracene (50 micro g/mouse).     

蜂毒素对人胚肺成纤维细胞生长的抑制作用及其机制探讨

目的研究蜂毒素(melittin)对人胚肺成纤维细胞(MRC-5)生长的抑制作用及其机制。方法采用MTT法检测蜂毒素对MRC-5细胞的增殖抑制作用;流式细胞仪检测细胞周期;RT-PCR法检测细胞中Cyclin D1、CDK4及E2F-1mRNA的表达变化;Western blot法检测Cyclin D1、CDK4、p21及E2F-1蛋白表达。结果与对照组比较,蜂毒素处理组细胞增殖明显受到抑制,并呈剂量和时间依赖性(P<0.05);流式细胞仪检测结果发现,随着浓度的增大,G0/G1期细胞百分比逐渐上升,S期细胞百分比逐渐下降;同时Western blot结果提示蜂毒素(1,2,4 mg.L-1)可以明显降低Cyclin D1、CDK4及E2F-1表达,而上调p21表达。结论蜂毒素能抑制MRC-5细胞增殖,其机制可能与干扰该细胞G0/G1期相关基因的转录相关且抑制Cyclin D1/E2F信号转导。     

Ameliorating effect of capsaicin on alterations in lipid metabolism during mice lung carcinoma

Spices and vegetables possess antioxidant activity that can be applied for preservation of lipids and lower lipid peroxidation in biological systems. In the present study, we have investigated the effect of capsaicin on lipid metabolism during benzo(a)pyrene induced lung cancer in Swiss albino mice. Benzo(a)pyrene (50 mg/kg wt) induced lung cancer animals showed abnormal changes in the tissue and serum lipids, lipoproteins and lipid metabolizing enzymes. Treatment with capsaicin (10 mg/kg body wt) remarkably attenuated all the above alterations and restored normalcy. These findings reveal the chemomodulatory potential of capsaicin in attenuating the alterations in lipid metabolism during experimental lung carcinogenesis.     

Inhibitory effect of glycyrrhizin on lipopolysaccharide and d-galactosamine-induced mouse liver injury

The effects of glycyrrhizin isolated from licorice root were investigated on acute hepatitis induced by lipopolysaccharide (LPS) and d-galactosamine in mice. Serum alanine aminotransferase (ALT) activity was markedly increased 6 h to 8 h after administration of LPS/d-galactosamine. Levels in serum of cytokines such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-10 and IL-12 reached a maximum by 2 h, whereas levels of IL-18, as well as of ALT, were maximal at 8 h. Glycyrrhizin (ED(50): 14.3 mg/kg) inhibited the increase in ALT levels when it was given to mice at 30 min before administration of LPS/d-galactosamine. Inflammatory responses, including infiltration of neutrophils and macrophages in the liver injury, were modulated by glycyrrhizin. Increases in ALT levels were reduced by an administration of glycyrrhizin at 10 min and 60 min but not 3 h, even after LPS/d-galactosamine treatment. However, glycyrrhizin had no effect on the production of TNF-alpha, IL-6, IL-10 and IL-12, whereas it significantly inhibited IL-18 production. Exogenous IL-18 further increased the elevation in ALT levels in mice treated with LPS/d-galactosamine. Glycyrrhizin completely suppressed the effect of IL-18 of increasing ALT levels. IL-18 was detected by immunohistochemistry in inflammatory cells such neutrophils and macrophages in liver injury. Glycyrrhizin reduced the responsiveness of cells to IL-18 in the liver injury. These results suggest that glycyrrhizin inhibits the LPS/d-galactosamine-induced liver injury through preventing inflammatory responses and IL-18 production. Furthermore, it seems that glycyrrhizin prevents IL-18-mediated inflammation in liver injury.     

不同纯度的有机溶剂对2株肿瘤细胞的抑制作用

目的 给脂溶性的抗肿瘤药物筛选高溶解性、低细胞毒性的有机溶剂.方法 采用MTT法,按照不同纯度,对8种能溶于水的有机溶剂,测试其对黑色素瘤B16、人胃癌细胞SGC-7901两种细胞株的细胞毒性.结果 不同有机溶剂对不同细胞株的抑制皆不同,甲醇与丙酮对两种细胞株的毒性相对都较弱,纯度越高的有机溶剂对细胞毒害越小.结论 光谱纯的甲醇与丙酮是脂溶性抗肿瘤药物有效的有机溶剂.     

咯利普兰对脂多糖诱导的小鼠急性肺损伤的抑制作用

目的探讨磷酸二酯酶4(PDE4)抑制剂治疗急性肺损伤的作用机制。方法气道内滴入脂多糖3 mg.kg-1制备小鼠急性肺损伤模型,10 min后一次性ip不同剂量咯利普兰或地塞米松;同时设假手术和模型组。给药6 h后处死小鼠,观察肺湿重/干重比值和肺组织的病理改变;用细胞形态学方法计数支气管肺泡灌洗液(BALF)中白细胞和中性粒细胞;考马斯亮蓝法测定BALF总蛋白含量;髓过氧化物酶(MPO)活性测定试剂盒测定肺组织匀浆MPO活性;ELISA法测定肺组织匀浆肿瘤坏死因子α(TNF-α)含量;高效液相色谱法测定肺组织匀浆中cAMP-PDE和PDE4活性。结果小鼠气道内滴入脂多糖6 h后,与假手术组比较,模型组肺湿重/干重比值明显升高;肺组织病理观察可见肺血管和气道周围有大量中性粒细胞浸润;BALF中白细胞和中性粒细胞增多,蛋白含量增加;肺组织MPO活性、TNF-α水平、cAMP-PDE和PDE4活性升高。与模型组比较,咯利普兰(0.1,0.3及1.0 mg.kg-1)和地塞米松(0.5 mg.kg-1)可降低肺组织湿重/干重比值,降低BALF中白细胞总数、中性粒细胞数目和蛋白含量,改善肺组织病理变化,肺组织中MPO活性、TNF-α含量、cAMP-PDE和PDE4活性亦明显降低。结论咯利普兰治疗急性肺损伤的作用机制可能与抑制PDE4活性、抑制中性粒细胞黏附和趋化及降低TNF-α水平有关。     

Inhibitory effect of capsaicin on the ascending pathway of the guinea-pig ileum and antagonism of this effect by ruthenium red.

A segment of guinea-pig ileum, which was continuous with a strip of longitudinal muscle-myenteric plexus (LM-MP) at the anal end, was used to examine the effect of capsaicin on ascending excitatory pathways. Electrical field stimulation of the LM-MP caused an ascending contraction of the segment. After initially causing contraction capsaicin (3 microM) inhibited the ascending contraction. This inhibitory effect of capsaicin exhibited rapid desensitization and was abolished after extrinsic (mesenteric) denervation. Desensitization to calcitonin gene-related peptide (CGRP) prevented the capsaicin-induced inhibition without affecting the ascending contraction. Neither naloxone nor alpha- and beta-adrenoceptor antagonists affected the capsaicin-induced inhibition. CGRP (25 nM) also inhibited the ascending contraction, mimicking the inhibition induced by capsaicin. Ruthenium red (0.1-3 microM) antagonized the capsaicin-induced inhibition in a concentration-related manner, but did not affect the CGRP-induced inhibition. These findings suggest that the inhibitory effect of capsaicin on the ascending pathways might be mediated via the release of CGRP from extrinsic nerve terminals, and that the site of the antagonism of the action of capsaicin by ruthenium red is prejunctional.     

FTY720 and lung tumor development

FTY720 has been shown to prevent cancer development in experimental models but there is no report whether this beneficial effect is associated with the time point of the drug administration. Lung adenoma was induced in mice by urethane injection followed by different periods of FTY720 administration in order to evaluate lung tumor development. BALB/c mice received urethane intraperitoneally in two doses of 1.5 g/kg and were submitted to five daily doses of FTY720 (1 mg/kg/day) starting just after urethane injection (G2 n = 5), 4 weeks after urethane injection (G3 n = 10), 8 weeks after urethane injection (G4 n = 10) and no FTY720 administration (G1 n = 5). Twenty-four weeks after urethane administration mice were evaluated for the number of leukocyte in blood, lymphocytes in spleen, and lungs were evaluated for changes in histology, PCNA and VEGF expression. Lung nodules were present in higher numbers both in non treated (G1; 0.0–7.0) and FTY720 treated 8 weeks after urethane injection (G4; 0.0–6.0). G4 Group also presented the highest number of papillary nodules. G1 and G4 groups presented the lower number of splenocytes and neutrophils. In early time FTY720 treated mice (G2) we observed a slight decrease in PCNA staining and also the lower percentage of VEGF intense staining. Therefore, our data suggest that the benefits of FTY720 treatment are time-dependent and when administered in early periods after lung tumor induction this drug could impair cancer development.     

Antitumor effect of kigamicin D on mouse tumor models

Kigamicin D is a novel anticancer agent that was identified using a new screening strategy that targets the tolerance of cancer cells to nutrient starvation [1, 2]. Oral administration of kigamicin D was previously described to show a strong antitumor effect in human tumor xenograft models of pancreatic tumors [2]. In this paper we describe that kigamicin D shows the same selective cytotoxicity against normal human cells such as lung fibroblast and prostate stromal cells under nutrient starved condition as against cancer cells. Kigamicin D inhibited tumor cell-induced angiogenesis in a dorsal air sac assay. On the basis of these results we tested other human tumor xenograft models and transplantable syngeneic tumor models in order to determine the spectrum of activity of kigamicin D against various cancers. Kigamicin D showed a weak antitumor effect against LX-1 and DMS-273 lung cancers, but had no effect on DLD-1 colon cancers. When tested against syngeneic tumors, kigamicin D showed a weak antitumor effect against colon26, but showed augmentation of tumor growth on IMC carcinoma at a broad dosage level. Kigamicin D does not show good antitumor activity against human xenograft tumors except pancreatic tumors and murine syngeneic tumors. We found that kigamicin D has excellent antitumor effect specific to pancreatic cancers. Surprisingly, high dosage of kigamicin D increased tumor growth of IMC carcinoma by than 200%. The phenomenon suggests that kigamicin D may cause some immunological response to the tumor.     

Inhibitory effect of tributyltin on expression of steroidogenic enzymes in mouse testis

Tributyltin (TBT) is known to disrupt the development of reproductive organs, thereby reducing fertility. The aim of this study was to evaluate the acute toxicity of TBT on the testicular development and steroid hormone production. Immature (3-week-old) male mice were given a single administration of 25, 50, or 100 mg/kg of TBT by oral gavage. Lumen formation in seminiferous tubule was remarkably delayed, and the number of apoptotic germ cells found inside the tubules was increased in the TBT-exposed animals, whereas no apoptotic signal was observed in interstitial Leydig cells. Reduced serum testosterone concentration and down-regulated expressions of the mRNAs for cholesterol side-chain cleavage enzyme (P450scc), 17alpha -hydroxylase/C(17-20) lyase (P450(17alpha)), 3beta -hydroxysteroid-dehydrogenase (3beta -HSD), and 17beta -hydroxysteroid-dehydrogenase (17beta -HSD) were also observed after TBT exposure. Altogether, these findings demonstrate that exposure to TBT is associated with induced apoptosis of testicular germ cells and inhibition of steroidogenesis by reduction in the expression of steroidogenic enzymes in interstitial Leydig cells. These adverse effects of TBT would cause serious defects in testicular development and function.     

Inhibitory effect of olopatadine hydrochloride on the sneezing response induced by intranasal capsaicin challenge in guinea pigs.

To investigate the possible inhibitory effect of olopatadine hydrochloride (olopatadine), an antiallergic drug, on the tachykinin-mediated nasal responses, we examined the effect of olopatadine on the sneezing and the nasal rubbing responses induced by intranasal capsaicin challenge in guinea pigs. Olopatadine (10 mg/kg, p.o.) inhibited the sneezing response by 57% without affecting the nasal rubbing one. The antihistamines chlorpheniramine and clemastine did not affect the responses. Morphine caused the inhibition of both responses, which was antagonized by naloxone. These results suggest that olopatadine inhibits the sneezing response by the inhibition of the tachykinin release and not by its antihistaminic action.     

Inhibitory effect of glycyrrhetinic acid derivatives on arachidonic acid-induced mouse ear oedema

The inhibitory effects of glycyrrhetinic acid and its derivatives were examined on arachidonic acid (AA)-induced ear oedema in mice. Of the compounds, dihemiphthalate derivatives of 18 beta-olean-12-ene-3 beta, 30-diol (IId, IId'), 18 beta-olean-9(11)12-diene-3 beta, 30-diol (IIIa, IIIa') and olean-11, 13(18)-diene-3 beta, 30-diol (IVa, IVa') showed a strong inhibition of ear oedema on both tropical (ID50, 1.9, 2.8 and 1.7 mg/ear, respectively) and oral (ID50, 90, 130 and 88 mg kg-1, respectively) administration. Topical ID50 values were approximately the same potency as nordihydroguaiaretic acid (ID50, 2.1 mg/ear). Given topically these compounds were also capable of inhibiting PGE2 and LTC4 formation at an early stage of AA-induced ear oedema. However, glycyrrhetinic acid (Ia) and deoxoglycyrrhetol (IIa), the fundamental skeletons of the derivatives, showed no detectable inhibition of oedema at a dose of 1 mg/ear (topical) or 200 mg kg-1 (oral). The most effective time for the topical administration of the compound IId against ear oedema was 0-30 min before AA application; this is different from dexamethasone which requires a time lag for reaction. The results suggest that the inhibitory effect of the hemiphthalate compounds (IId, IId', IIIa, IIIa', IVa and IVa') is a direct action, and does not involve the anti-inflammatory action of steroids mediated by the secondary formation of a reactive protein.     

Inhibitory effect of antidepressants on B16F10 melanoma tumor growth

BackgroundAntidepressant drugs, like fluoxetine, a selective serotonin reuptake inhibitor, desipramine, a nonselective noradrenaline reuptake inhibitor, and mirtazapine, an antagonist of noradrenaline α₂ auto- and heteroreceptors, are widely used for the treatment of depressive symptoms in cancer patients. Since these antidepressants have different activities targeting the immune system, they might also modulate tumor growth in cancer patients.MethodsIn the present study, we investigated the effects of administration of antidepressant drugs: fluoxetine, desipramine and mirtazapine on B16F10 melanoma tumor growth. These drugs were administered intraperitoneally (ip) for 17 days after subcutaneous injection of B16F10 melanoma cells to male C57BL/6J mice.ResultsFluoxetine significantly inhibited melanoma solid tumor growth and desipramine tended to decrease this parameter whereas mirtazapine had no effect.ConclusionThe inhibitory effect of fluoxetine on melanoma growth was associated with an increased mitogen-induced T cell proliferation which may at least partly participate in the mechanism of the antitumor effect of this antidepressant. It appears that the inhibitory effect of fluoxetine on tumor growth is not related with changes in cytokine levels except for IL-10.