Zerumbone,Sesquiterpene Photochemical from Ginger,Inhibits Angiogenesis

Here, we investigated the role of zerumbone, a natural cyclic sesquiterpene of Zingiber zerumbet Smith, on angiogenesis using human umbilical vein endothelial cells (HUVECs). Zerumbone inhibited HUVECs proliferation, migration and tubule formation, as well as angiogenic activity by rat aorta explants. In particular, zerumbone inhibited phosphorylation of vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1, which are key regulators of endothelial cell function and angiogenesis. In vivo matrigel plug assay in mice demonstrated significant decrease in vascularization and hemoglobin content in the plugs from zerumbone-treated mice, compared with control mice. Overall, these results suggest that zerumbone inhibits various attributes of angiogenesis, which might contribute to its reported antitumor effects.     

不同剂量花姜酮对大鼠重症急性胰腺炎的影响

目的:探讨花姜酮( Zerumbone)静脉给药对大鼠重症急性胰腺炎(SAP)的治疗作用。方法:雄性Wistar大鼠50只,随机分为5组:假手术组(SO组)、SAP模型组(SAP组)、5mg/kg花姜酮预处理组(5mg/kg花姜酮组)、10mg/kg花姜酮预处理组(10mg/kg花姜酮组)、20 mg/kg花姜酮预处理组(20mg/kg花姜酮组)。胆胰管逆行注射5%牛磺胆酸钠制备SAP模型。SO组、SAP组造模前30 min股静脉注射10%二甲基亚砜(DMSO)(2ml/kg),余三组注射等量10%DMSO溶解的等体积、不同浓度花姜酮。术后12h心脏取血检测各组血清淀粉酶(AMY),谷氨酸氨基转移酶(ALT),血肌酐(Cr)浓度变化,并观察胰腺组织病理学改变。结果:与SAP组比较,5 mg/kg花姜酮组AMY和胰腺病理评分没有改变,ALT和Cr有改善(P0.05);10mg/kg花姜酮组上述指标较SAP组显著降低(P0.05);20mg/kg花姜酮组AMY、Cr和胰腺组织病理学评分较SAP组显著降低(P0.05),但ALT与SAP组比较差异无统计学意义(P0.05)。结论:花姜酮治疗大鼠SAP,以10 mg/kg静脉注射比较安全、有效。     

Antiulcer principle from Zingiber montanum

Ethnopharmacological relevance

Rhizome of Zingiber montanum has been extensively used as a folk medicine to ameliorate peptic ulcer at northern part of Bangladesh.

Aim of the study

To identify the antiulcer principle of the MeOH extract of the rhizome of Zingiber montanum by an ex vivo bioassay guided chromatographic separation and purification, and structure elucidation of the purified compound by spectroscopic methods.

Materials and methods

Dried powder of Zingiber montanum rhizomes was extracted with MeOH. The antiulcer activity of the crude extract and its chromatographic fractions were evaluated by the inhibition of 1 N HCl induced gastric lesions in Swiss albino mice. The pure compound was purified from the active fraction by crystallization with hexanes. Structure of the pure compound was elucidated by spectroscopic methods. The antiulcer activity of the pure compound was evaluated by the inhibition of 1 N HCl, 95% ethanol and indomethacin induced gastric lesions in mice.

Results

The MeOH extract of Zingiber montanum showed 61.97% and 83.10% inhibition of the 1 N HCl induced gastric lesions at doses of 200 mg/kg and 400 mg/kg, respectively, in mice. Chromatographic separation on silica gel of the extract was yielded seven fractions and the fraction 2 was found to have most potent antiulcer activity in mice. This fraction showed 77.46% inhibition of the 1 N HCl induced gastric lesions at a dose of 40 mg/kg in mice. Crystallization of the fraction yielded 1 (zerumbone, 180 mg). It showed statistically 45.77% and 92.25% inhibition of 1 N HCl induced gastric lesions in mice at doses of 20 mg/kg and 40 mg/kg, respectively. It also showed 29.07% and 45.35% inhibition of 95% ethanol induced gastric mucosal damage, and 64.76% and 72.38% inhibition of indomethacin induced gastric lesions in mice at doses of 20 mg/kg and 40 mg/kg, respectively.

Conclusion

Zerumbone (1) showed potent cytoprotective effect against necrotizing agent (HCl) and non-steroidal anti-inflammatory drug (indomethacin) induced gastric ulceration. It also exhibited moderate cytoprotective effect against noxious agent (EtOH) induced gastric lesions. It can be considered as a promising new antiulcer natural drug lead.     

花姜酮对人肝癌SMMC-7721细胞侵袭及CXCR4表达的影响

目的研究花姜酮对人肝癌SMMC-7721细胞生长侵袭能力的影响及对CXCR4 mRNA和蛋白表达的影响,探讨花姜酮抗肝癌侵袭可能的作用机制。方法分别应用花姜酮10μmol/L、20μmol/L处理人肝癌细胞,采用Transwell小室检测肝癌细胞的侵袭能力,RT-PCR、Western blotting实验检测CXCR4 mRNA及蛋白表达的变化。结果花姜酮处理人肝癌细胞48 h后,对照组细胞透膜数为(56.8±7.8)个/视野,10μmol/L组透膜数为(41.4±4.8)个/视野,20μmol/L组透膜数为(23.2±5.6)个/视野,随花姜酮浓度增加,细胞侵袭人工基底膜的能力显著降低(P<0.05),RT-PCR及Western blotting结果显示CXCR4 mRNA及蛋白表达随花姜酮浓度的增加而降低(P<0.05)。结论花姜酮可能通过降低CXCR4的表达抑制人肝癌SMMC-7721细胞的生长和侵袭能力。     

Zerumbone induces gastric cancer cells apoptosis: Involving cyclophilin A

Gastric cancer is one of the leading causes for cancer death. There is an urgent need to develop new therapeutic approaches targeting metastatic gastric cancer. It has been reported that zerumbone has the anti-cancer effects in various malignant cells. However, the effect and the mechanism of zerumbone on melanoma cells is still largely unknown. In the study, we determined the actions of zerumbone on the human gastric cancer cell line SGC-7901.We also observed the mechanism by which zerumbone induced gastric cancer cell apoptosis. Our data indicated that zerumbone significantly inhibited the growth of human gastric cancer cells in a dose-dependent manner and apoptosis was the main cause of decreased cell viability in zerumbone −treated cells. The treatment with zerumbone downregulated Cyp A and Bcl-2 levels, upregulated Bax levels, and caused Cytochrome c (Cyt-C) to release, activating Caspase-3. In summary, our study suggests that zerumbone mightinduced human gastric cancer cells apoptosis through down-regulating Cyp A and mitochondria-mediated pathways.     

花姜酮通过抑制氧化应激减轻MPP~+诱导的SH-SY5Y细胞损伤

目的:探讨花姜酮(zerumbone,ZER)对1-甲基-4-苯基-吡啶鎓离子(1-methyl-4-phenylpyridinium,MPP~+)诱导的人神经母细胞瘤SH-SY5Y细胞损伤的作用及其可能的分子机制。方法:采用CCK-8法检测MPP~+对SH-SY5Y细胞的毒性作用以及ZER的保护作用,采用流式细胞术检测活性氧簇(reactive oxygen species,ROS)含量和细胞凋亡情况,采用短发夹RNA(short hairpin RNA,shRNA)干扰技术抑制人帕金森病蛋白7(Parkinson disease protein 7,PARK7)基因的表达,采用Western blot法检测PARK7、核因子E2相关因子2(nuclear factor E2-related factor 2,Nrf2)和血红素氧合酶1(heme oxygenase-1,HO-1)的蛋白表达水平。结果:MPP~+可显著抑制SH-SY5Y细胞活力(P0.05),并呈剂量和时间依赖性;ZER可使经600μmol/L MPP~+处理24 h的SH-SY5Y细胞活力升高,PARK7和Nrf2蛋白表达水平显著升高(P0.05),ROS含量和细胞凋亡明显减少(P0.05),抗氧化剂N-乙酰-L-半胱氨酸(N-acetyl-L-cysteine,NAC)具有相似的作用;沉默PARK7基因后,Nrf2和HO-1蛋白的表达水平明显下降(P0.05),ROS含量和细胞凋亡显著增加(P0.05)。结论:ZER可在体外剂量依赖性地减轻MPP~+对SH-SY5Y细胞的毒性作用,这可能与ZER激活PARK7/Nrf2/HO-1通路,继而抑制MPP~+诱导的ROS生成和细胞凋亡有关。     

Healing potential of zerumbone ointment on experimental full-thickness excision cutaneous wounds in rat

Zerumbone is a monocyclic sesquiterpene compound. Based on report, it is the predominant bioactive compound from the rhizomes of Zingiber zerumbet. The study was undertaken to evaluate the therapeutic effects of topical zerumbone on excision wounds in rats. A 1% (w/w) simple ointment containing zerumbone was applied topically (100 mg ointment per rat) once a day on full-thickness excision wounds created on rats. The wound tissue was removed and used for estimation of antioxidant activity and to observe histopathological changes. Immunohistochemical staining was performed to study the expression pattern of vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-β1 and collagen IV. Zerumbone exhibited antimicrobial activity against Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Candida albicans and Candida tropicali. Zerumbone ointment has potent wound healing capacity as evident from the wound contraction on 15th post wounding day. The histopathological examinations of healed wound sections showed greater tissue regeneration, more fibroblasts and angiogenesis in zerumbone ointment-treated group. VEGF, TGF-β1 and collagen IV expression were also correlative with the healing pattern observed. Zerumbone possesses potent antioxidant activity by increasing superoxide dismutase, catalase, glutathione and decreased lipid peroxidation. The synergistic effects of both antimicrobial and antioxidant activities in zerumbone are deduced to have accelerated the wound repair. The results demonstrate that zerumbone possessed strong wound healing potential and can be exploited to accelerate excision wound healing.     

花姜酮对重症急性胰腺炎大鼠肝损伤的保护作用及机制

目的 观察花姜酮对重症急性胰腺炎大鼠肝损伤的作用,并探讨其机制.方法 雄性56只Wistar大鼠,随机分为4组.正常对照组(SO组,n=8);重症急性胰腺炎组(SAP组)按时间分1、3、6、12h亚组(n =8);花姜酮预处理组(ZER组,n=8);花姜酮药物对照组(ZER-CON组,n=8).留取血清,固定及冻存胰腺及肝脏.血清检测血淀粉酶(AMY)、谷丙转氨酶(ALT)、谷草转氨酶(AST)以及磷脂酶A2(PLA2)水平,病理学检测胰腺与肝脏评分.提取各组大鼠新鲜肝脏组织核蛋白行凝胶电泳迁移实验(EMSA),免疫组织化学法检测各组大鼠肝脏核因子-κB p65(NF-κBp65)表达水平,提取各组大鼠肝脏组织浆蛋白检测白细胞介素-1β(IL-1β)水平.结果 SAP组大鼠血清AMY、ALT、AST、PLA2以及胰腺病理评分、肝脏病理分级较正常与药物对照组升高明显(P＜0.05);使用花姜酮后上述指标有明显下降(P＜0.05).SO、SAP 1、3、6、12 h、ZER、ZER-CON组、AMY[(U/L)1 485.6±130.5、2865.5±536.9、4 858.0±707.3、5702.3±885.2、7072.6±868.2、4 367.3±811.4、1 833.4±216.9],PLA2[(nmol/min· ml) 493.6±86.1、522.5±102.3、992.3±97.8、1 144.7±94.4、825.9±87.8、653.5±92.3、552.4±86.2],ALT[(U/L) 87.3±8.5、92.7±10.4、166.9±21.7、188.3±26.6、267.4±30.4、179.4±27.9、96.6±15.0],AST[(U/L) 103.5±11.7、230.8±48.4、381.0 ±76.0、510.7±84.3、484.1±74.5、317.1±66.2、120.3±35.1],胰腺病理评分[(分)0.40±0.39、3.45±0.93、6.70±1.40、9.35±1.68、10.85±1.89、6.96±1.21、0.52 ±0.15].SAP组大鼠肝脏NF-κB水平以及活性、IL-1β水平较正常组与药物对照组升高明显(P＜0.05),在使用花姜酮干预后,上述指标均有明显下降(P＜0.05).结论 花姜酮可以通过减少重症急性胰腺炎大鼠肝脏组织NF-κB蛋白表达,并进一步抑制下游炎性分子IL-1β,对胰腺炎肝损伤起到保护作用.     

Zerumbone induces apoptosis in T-acute lymphoblastic leukemia cells

Zerumbone (ZER) is a potential anticancer natural compound, isolated from Zingiber zerumbet Smith. In this investigation, the anticancer properties of ZER were evaluated on cancer cells of T-acute lymphoblastic leukemia, CEM-ss. The results showed that ZER has cytotoxic effect against CEM-ss cells with an IC₅₀ of 8.4 ± 1.9 μg/ml (coefficient of variation < 30%). Comparatively, 5-fluorouracil (positive control), imposed an inhibitory effect on CEM-ss cells with an IC₅₀ of 1.94 ± 0.06 μg/ml. Scanning electron microscopy (SEM) results revealed abnormalities such as membrane blebbing, holes and cytoplasmic extrusions, all of which are characteristics of apoptosis. In addition, ZER has increased the number of TUNEL-positive stain and the cellular level of caspase-3, the hallmarks of apoptosis, on treated CEM-ss cells. It could be concluded that, ZER was able to produce apoptosis on T-acute lymphoblastic leukemia, CEM-ss. The current findings suggest that ZER might be helpful for improving the usefulness of anticancer agents in the therapy of leukemia.