β-Aminopropionitrile   中文名称: β-氨基丙腈

Lysyl oxidase (LOX)

β-氨基丙腈 (BAPN)/β-Aminopropionitrile 可增强体外胰岛素抵抗模型中的葡萄糖吸收，并使 GLUT4 和脂联素的表达正常化 [1]。 β-氨基丙腈（500 μM；72 h）可抑制体外宫颈癌细胞的侵袭和迁移，同时抑制缺氧诱导的 EMT 形态和标志蛋白变化[2]。

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BAPN/β-氨基丙腈抑制低氧诱导的宫颈癌症细胞侵袭[2]
癌症转移过程的第一步是细胞侵袭。为了研究LOX抑制对宫颈癌细胞行为的影响，我们在体外检测了HeLa和SiHa细胞的侵袭性。在有或没有500μM BAPN（一种LOX抑制剂）的情况下，在常氧或缺氧条件下，将两种细胞系在Matrigel涂层的透孔滤膜上孵育48小时。孵育后，对跨膜（侵袭）细胞进行染色（图2A和B）并计数（图2C和D）。如图所示，与常氧相比，两种细胞系在缺氧条件下表现出强烈的侵袭现象。值得注意的是，在两种细胞模型中，灭活LOX活性的BAPN显著降低了缺氧诱导的细胞侵袭（图2A和B）。侵袭细胞数量的计数进一步说明了形态学结论。如图所示（图2C和D），在500μM BAPN的存在下，缺氧使癌症细胞的侵袭增强到对照的220和250%，在HeLa和SiHa细胞中分别抑制到对照的50%和60%。因此，LOX在宫颈癌细胞侵袭的发展中起着关键作用。

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BAPN/β-氨基丙腈消除HeLa和SiHa细胞中的EMT形态改变[2]
为了回答BAPN是否抑制癌症细胞模型中低氧诱导的EMT，我们用相差显微镜检查了BAPN对低氧条件下宫颈癌细胞形态变化的影响。暴露于缺氧48小时的HeLa和SiHa细胞显示出向间充质样外观的形态变化（图5）。缺氧的HeLa和SiHa细胞不再能够形成上皮细胞典型的“鹅卵石”簇，而是获得了更细长的纺锤状形态，这是EMT的关键标志。这些形态学变化与缺氧下宫颈癌细胞的侵袭和迁移有关（33）。这是基于BAPN抑制肿瘤细胞侵袭和迁移的研究结果（图2和图3）在低氧条件下拮抗癌症细胞的形态学变化，并逆转与常氧条件下相似的细胞表型。因此，BAPN阻止了HeLa和SiHa细胞向EMT方向缺氧诱导的形态变化。

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BAPN/β-氨基丙腈拮抗缺氧诱导的HeLa和SiHa细胞EMT标志物蛋白的变化[2]
最后，我们检测了BAPN对暴露于缺氧48小时的HeLa和SiHa细胞中E-cadherin、α-SMA、波形蛋白、MMP-2和MMP-9蛋白（EMT标志物）表达的影响。如图所示，BAPN有效地阻止了缺氧诱导的E-cadherian下调（图6A和B），并强烈抑制了缺氧诱导了α-SMA和波形蛋白的上调（图6C和D）。尽管在缺氧或缺氧加BAPN的情况下，HeLa和SiHa细胞中的MMP-2没有显著变化，但两种细胞系中的MMP-9在实验条件（缺氧和BAPN处理）下都发生了显著变化。缺氧使SiHa细胞中MMP-9的表达增加，高达对照组的1.65倍（47.5密度单位），在500μM BAPN的存在下，MMP-9的表达变为对照组的0.88倍（47.5%密度单位）。此外，BAPN还将HeLa细胞中MMP-9的表达降低到对照组的0.41（128密度单位），以应对缺氧。BAPN对EMT标记蛋白影响的密度测量数据如表I所示。这些结果与BAPN对肿瘤细胞侵袭和迁移的影响一致，有力地支持LOX是调节低氧诱导的EMT、宫颈癌症细胞侵袭和转移的重要因素的结论。

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BAPN/β-Aminopropionitrile/β-氨基丙腈使GLUT4和脂联素的表达正常化，并改善胰岛素抵抗体外模型中的葡萄糖摄取[1]
为了确定BAPN是否直接影响脂肪细胞功能，我们在分化的3T3-L1脂肪细胞中进行了TNFα诱导的胰岛素抵抗模型的体外实验。如图5所示和之前所述（Stephens等人，1997；Sethi和Hotamisligil，1999），TNFα降低了这些细胞中GLUT4和脂联素的表达，并增加了SOCS3蛋白水平。有趣的是，BAPN阻止了这些影响（图5A-C）。因此，BAPN使分化的3T3-L1脂肪细胞中观察到的TNFα诱导的胰岛素刺激葡萄糖摄取减少正常化（图5D）。

在饮食引起的肥胖大鼠中，β-氨基丙腈 /β-Aminopropionitrile(BAPN)（100 毫克/公斤/天；口服；6 周）可改善代谢状况并减少体重增加[1]。 C57BL/6 小鼠给予 β-氨基丙腈单富马酸盐（1 g/kg/天；口服；4 周）以诱导胸主动脉夹层[3]。

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BAPN/β-氨基丙腈改善HFD喂养大鼠的体重增加、肥胖和脂肪组织纤维化[1]
为了研究LOX是否会导致与肥胖相关的脂肪组织功能障碍，对患有HFD的大鼠进行了BAPN治疗，BAPN是一种不可逆的LOX活性特异性抑制剂。如图3A所示，HFD导致体重显著增加，从第三周开始达到显著差异。经过三周的治疗，BAPN显著阻止了HFD大鼠体重的增加，但在喂食标准饮食的动物中则没有（图3A）。这些差异一直持续到研究结束（表1，图3A）。同样，BAPN减少了肥胖动物白色脂肪组织（附睾和腰椎）重量的增加（表1），并减轻了其增强的肥胖（表1。应该指出的是，在喂食HFD的大鼠中，BAPN引发的体重变化与食物摄入量的差异无关（表1）。

β-氨基丙腈/β-Aminopropionitrile引起的HFD喂养大鼠脂肪组织质量的变化促使我们确定LOX抑制是否可以调节脂肪细胞面积。附睾脂肪组织的组织学分析显示，HFD组脂肪细胞面积增加。在接受BAPN治疗的肥胖动物中观察到该参数衰减的趋势（图3B，C）。此外，与喂食HFD的大鼠相比，在BAPN治疗的肥胖动物中检测到向较小脂肪细胞的转变（图3D）。有趣的是，通过Picrosirius红染色分析，LOX抑制阻止了肥胖大鼠细胞周胶原含量的增加（图3E，F）。

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BAPN/β-氨基丙腈改善肥胖大鼠体内观察到的代谢变化[1]
接下来，我们研究了抑制LOX活性是否会改变肥胖动物的代谢参数。BAPN治疗改善了HFD组的空腹血糖和胰岛素水平，从而降低了HOMA指数（表1）。LOX抑制也降低了肥胖动物的血浆甘油三酯，但总胆固醇水平没有显著差异（表1）。

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BAPN/β-氨基丙腈改善肥胖动物脂肪组织中的胰岛素信号传导[1]
为了了解BAPN如何改善肥胖动物的胰岛素敏感性，我们分析了附睾脂肪组织中参与控制胰岛素敏感性的蛋白质水平。HFD组中观察到的葡萄糖转运蛋白4（GLUT4）和脂联素表达的减少通过抑制LOX活性而恢复正常（图4A，B）。此外，BAPN完全阻止了HFD引发的DPP4和细胞因子信号传导抑制因子3（SOCS3）蛋白水平的增加（图4C，D）。

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β-氨基丙腈/β-Aminopropionitrile治疗小鼠的基础特征，有或没有Ang II[3]
据报道，用LOX抑制剂BAPN加Ang II治疗FVB小鼠可诱导TAD 8。我们最近发现，在C57BL/6背景下，相同剂量的BAPN在Ang II给药前导致约56%的小鼠突然死亡，这是由胸主动脉破裂引起的4。因此，我们比较了BAPN对具有两种遗传背景的小鼠的影响。FVB或C57BL/6背景的雄性小鼠（3周龄）在饮用水中以1 每公斤体重g，持续4周。BAPN治疗降低了舒张压（图1a），对收缩压（图1b）没有影响，表明主动脉僵硬度增加。BAPN治疗还减轻了FVB和C57BL/6小鼠的体重增加（图1c，d），并显著降低了血浆甘油三酯和胆固醇水平（图1e，f）。

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BAPN/β-氨基丙腈治疗诱发TAD[3]
接下来，我们研究了BAPN治疗对TAD发病率的影响。为了确定血管紧张素II是否也是TAD发展所必需的，在BAPN治疗4周后处死小鼠进行尸检，有或没有24周 h的Ang II输注。与之前的报告8一致，BAPN加Ang II给药在所有小鼠中都诱导了TAD，而单独用BAPN治疗的FVB小鼠中约有75%没有发生TAD（图2a和表1）。然而，仅用BAPN治疗的C57BL/6小鼠的TAD发生率达到87%（图2a和表1），该组45%的小鼠死于主动脉破裂。在所有用BAPN加Ang II治疗的C57BL/6小鼠中也观察到TAD，其中50%在24小时内发生主动脉破裂 h的Ang II输注。给予BAPN（含或不含Ang II输注）的C57BL/6小鼠的主动脉从根部扩大到胸段，在某些情况下，腹部也受到影响。病变中观察到血肿，表明血栓形成（图2a）。

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BAPN/β-氨基丙腈诱导TAD的剂量优化[3]
为了进一步研究内侧变性对TAD形成的因果关系，我们通过给3周龄的C57BL/6雄性小鼠喂食含有0、0.4、1.0或1.5的饮食，应用了不同剂量的BAPN g每100个BAPN g小鼠进食4周。体重随着BAPN剂量的增加而降低（图3a）。所有六只喂食0.4的小鼠 g每100个BAPN g在BAPN给药后2至4周，饮食发生TAD，5人死于夹层破裂。在六只喂食1.0的小鼠中 g BAPN饮食，两名患者在治疗结束时出现TAD，但未出现破裂。最令人惊讶的是，在喂食1.5的小鼠中没有观察到TAD的形成 g BAPN饮食（图3b）。

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β-氨基丙腈/β-Aminopropionitrile诱导的TAD的分子表型特征[3]
由于BAPN诱导的TAD表现出人类疾病的典型组织学特征，我们接下来检查了主动脉培养基中TAD相关基因的表达是否也发生了变化。选择了一组已知在TAD形成的中间降解过程中失调的基因进行分析。这些是基质金属蛋白酶（MMPs，MMP2/3/9）5,8,11,12和组织蛋白酶（组织蛋白酶S/K/L）13（降解细胞外基质），I型胶原α1（COL1α1）和结缔组织生长因子（CTGF）（指示LDS中TGF-β信号通路激活的靶基因）14，α-平滑肌肌动蛋白（α-SMA）和β-肌球蛋白重链（β-MHC）（与家族性胸主动脉瘤和夹层综合征有关）15。在对照组和BAPN处理的C57BL/6小鼠中比较这些基因的表达。在BAPN治疗组中，与对照组相比，MMP2显著上调（图4a），而MMP3和MMP9下调（图4b，c）。组织蛋白酶S和组织蛋白酶K水平在两组中没有差异（图4d，e），而组织蛋白酶L在BAPN组中显著降低（图4f）。经BAPN处理后，COL1α1和α-SMA的表达均显著降低（图4g，h），而CTGF和β-MHC水平没有变化（图4i，j）。这些结果表明，BAPN诱导的TAD与典型的ECM降解有关，可能是通过MMP2，SMC的损失导致α-SMA降低，这与之前在人类和小鼠模型中的观察结果一致。

葡萄糖摄取测量[1]
完全分化的3T3-L1脂肪细胞被剥夺胰岛素，并在TNFα存在或不存在的情况下用β-氨基丙腈预处理24小时 h.脂肪细胞被血清剥夺3 h在添加有或不添加TNFα和β-Aminopropionitrile/BAPN的2%无脂肪酸牛血清白蛋白（BSA）的DMEM中。然后去除无血清培养基，用1 ml克雷布斯-林格HEPES（KRH）缓冲液pH 7.4加0.2%BSA。葡萄糖摄取从0.9开始 ml含100的KRH缓冲液 mM胰岛素30 min，然后加100 µM 2-脱氧-d-葡萄糖和1 μCi/ml[3H]-2-脱氧-d-葡萄糖/ml。10 min，用50℃的冰冷溶液洗涤细胞 mM d-葡萄糖在PBS中三次。用含有0.5 使用液体闪烁计数器测量细胞裂解物保留的放射性。测量一式三份，并校正非特异性扩散。[3H]-2-脱氧葡萄糖的计数被标准化为蛋白质水平。

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LOX活性测定[2]
将无酚红DMEM中的宫颈癌细胞在常氧或缺氧条件下孵育。收集条件培养基，在Amplex Red荧光测定中使用二氨基戊烷作为底物测定LOX活性。反应混合物由1.2 mol/l尿素、0.05 mol/l硼酸钠（pH 8.2）、10 mmol/l二氨基戊烷、10μmol/l Amplex red和1 U/ml辣根过氧化物酶组成，最终体积为1 ml。在存在或不存在0.5 mmol/lβ-氨基丙腈（BAPN）的情况下，将条件培养基（500μl）加入反应混合物中，BAPN是LOX的活性位点抑制剂。样品在37°C下孵育30分钟，置于冰上，然后在563nm的激发波长和587nm的发射波长下记录（31）。所有酶活性均计算为荧光单位高于BAPN对照背景水平的增加，并归一化为总细胞蛋白。

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体外侵袭和迁移试验[2]
细胞被血清剥夺24小时，以50000个细胞/孔的密度接种在Matrigel涂层过滤器的顶部，转移到含有600μl 10%FBS作为化学引诱剂的腔室中，并在常氧或缺氧条件下孵育48小时。在缺氧前24小时向培养物中加入β-Aminopropionitrile/β-氨基丙腈（500μM），并在整个实验过程中继续。同时，将相等的细胞铺入96孔板中进行细胞数量测定（MTT）。将细胞（经处理和未经处理）在常氧或缺氧条件下在37°C下孵育48小时，然后用棉签取出Matrigel。将侵入的细胞固定，用苏木精染色并计数。宫颈癌细胞的侵袭性由侵袭评分的百分比（侵袭细胞数/总细胞数100%）决定。实验重复了三次。体外细胞迁移试验基于所述的膜侵袭培养系统，但在使用未涂覆Matrigel的过滤器方面有所不同。

蛋白质印迹分析[1]
细胞类型： 3T3-L1 脂肪细胞
测试浓度： 200 μM，含 1.15 nM 和 2.87 nM TNFα
孵育时间：72 小时
实验结果：TNFα 降低了这些细胞中 GLUT4 和脂联素的表达，并增加了 SOCS3 蛋白水平。这些影响都被阻止了。细胞侵袭测定[2]
细胞类型： HeLa 和 SiHa 细胞
测试浓度： 500 μM
孵育时间： 72 小时
实验结果：两种细胞模型中缺氧引起的细胞侵袭均显着减少。

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细胞迁移测定 [2]
细胞类型： HeLa 和 SiHa 细胞
测试浓度： 500 μM
孵育时间： 72 小时
实验结果： HeLa 和 SiHa 细胞中缺氧诱导的迁移分别从 180% 和 240% 减少到 60% 和 70%。

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蛋白质印迹分析[2]
细胞类型： HeLa 和 SiHa 细胞
测试浓度： 500 μM
孵育时间：72小时
实验结果：有效阻止缺氧引起的E-cadherin下调，并强烈抑制缺氧引起的α-SMA和vimentin上调。

Animal/Disease Models: Male Wistar rats of 150 g, high-fat diet (HFD) model[1]
Doses: 100 mg/kg/day
Route of Administration: In the drinking water, 6 weeks
Experimental Results: Dramatically prevented the rise in body weight in HFD rats, but not in animals that were fed a standard diet. decreased the increase in the weight of white adipose tissue (both epididymal and lumbar) in obese animals and attenuated their enhanced adiposity. Improved fasted glucose and insulin levels and consequently decreased HOMA index in the HFD group. Improved insulin signaling in adipose tissue from obese animals.

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Animal/Disease Models: C57BL/6 mice[3]
Doses: 1 g/kg/day
Route of Administration: In the drinking water, 4 weeks
Experimental Results: Induce thoracic aortic dissection (TAD) in all mice with 24 h of Ang II infusion. Caused 87% of C57BL/6 mice to develop TAD without Ang II.

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Male Wistar rats of 150 g were fed either a HFD (33.5% fat) or a standard diet (3.5% fat) for 6 weeks. Half of the animals of each group received the irreversible inhibitor of LOX activity β-Aminopropionitrile/BAPN (100 mg/kg/day) in the drinking water for the same period, as previously described (Brasselet et al., 2005). The amount of β-Aminopropionitrile/BAPN effectively taken daily per animal was calculated from the amount of water consumed on a daily basis. Animal weight was periodically controlled to adjust the target dose of BAPN. Food and water intake were determined throughout the experimental period. Animals were fasted the day before euthanasia by anaesthesia with a cocktail of ketamine (70 mg/kg; intraperitoneal) and xilacine (Rompun 2%, 6 mg/kg). Serum and plasma were collected and abdominal adipose tissue was dissected for further analysis. Adiposity index was calculated as: sum of fat pads/[(body weight-fat pad weight)×100]. [1]

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Animal model and ethics statement [3]
Three-week-old male mice were fed a normal diet and administered freshly prepared β-Aminopropionitrile/BAPN solution dissolved in the drinking water (1 g/kg/d) for 4 wk, as described previously8. Blood pressure was measured before and after BAPN administration for 4 wk, using the tail-cuff method. Interventions lasted 4 wk and body weights were measured weekly. As previously reported, at 7 wk old, osmotic mini pumps administering 1 μg/kg per min Ang II were implanted subcutaneously and mice were euthanized 24 h after implantation17. All mice died before expected end time of the experiment were autopsied immediately, and Blood clots were found in the thoracic cavities of these mice. Mice surviving at the end of the experiment were sacrificed by an overdose of sodium pentobarbital and their blood and tissue samples were collected for further analyses. Histopathological analysis [3]
Complete gross and histopathological evaluations were performed with samples from control and β-Aminopropionitrile/BAPN-treated mice. After euthanasia, normal and dissected aortas were harvested from the ascending aorta to the iliac artery and were fixed in 10% buffered formalin, as were human tissues. Fixed, paraffin-embedded tissues were cut at 5 μm thickness, stained with haematoxylin and eosin following standard procedures and examined under light microscopy, as previously described4.

Absorption, Distribution and Excretion
BETA-AMINOPROPIONITRILE (BAPN) WAS FOUND IN URINE WITHIN 1 HR OF ORAL ADMIN. ORAL 250 MG BAPN AT 6 HR INTERVALS EACH DAY FOR 21 DAYS RESULTED IN URINARY BAPN RECOVERIES APPROXIMATING 16% OF TOTAL DOSE. BAPN WAS NOT DETECTED IN SPECIMENS COLLECTED LATER THAN 7 HR AFTER CESSATION OF BAPN DOSAGE. URINARY CYANOACETIC ACID APPEARED MORE SLOWLY THAN BAPN & INCR GRADUALLY TO APPROX 3 TIMES THAT OF URINARY BAPN. AFTER BAPN WAS DISCONTINUED, THERE WAS PROLONGED URINARY EXCRETION OF BAPN-DERIVED CYANOACETIC ACID.
AFTER APPLICATION TO THE SKIN OF RATS, (14)C-BAPN FREE BASE WAS ABSORBED MORE RAPIDLY AND TO A GREATER EXTENT THAN THE FUMARATE SALT. SIX HOURS AFTER TOPICAL ADMINISTRATION OF THE FREE BASE ONLY TRACES OF (14)C WERE FOUND ON THE SKIN AND LESS THAN 1% OF THE DOSE WITHIN THE SKIN SECTION SUGGESTING RAPID DRUG ABSORPTION.

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Metabolism / Metabolites
...BETA-AMINOPROPIONITRILE /IS METABOLIZED/ INTO CYANOACETIC ACID...
BETA-AMINOPROPIONITRILE (BAPN) WAS FOUND IN URINE WITHIN 1 HR OF ORAL ADMIN. ORAL 250 MG BAPN AT 6 HR INTERVALS EACH DAY FOR 21 DAYS RESULTED IN URINARY BAPN RECOVERIES APPROXIMATING 16% OF TOTAL DOSE. BAPN WAS NOT DETECTED IN SPECIMENS COLLECTED LATER THAN 7 HR AFTER CESSATION OF BAPN DOSAGE. URINARY CYANOACETIC ACID APPEARED MORE SLOWLY THAN BAPN & INCR GRADUALLY TO APPROX 3 TIMES THAT OF URINARY BAPN. AFTER BAPN WAS DISCONTINUED, THERE WAS PROLONGED URINARY EXCRETION OF BAPN-DERIVED CYANOACETIC ACID.
Organic nitriles are converted into cyanide ions through the action of cytochrome P450 enzymes in the liver. Cyanide is rapidly absorbed and distributed throughout the body. Cyanide is mainly metabolized into thiocyanate by either rhodanese or 3-mercaptopyruvate sulfur transferase. Cyanide metabolites are excreted in the urine. (L96)

Toxicity Summary
Organic nitriles decompose into cyanide ions both in vivo and in vitro. Consequently the primary mechanism of toxicity for organic nitriles is their production of toxic cyanide ions or hydrogen cyanide. Cyanide is an inhibitor of cytochrome c oxidase in the fourth complex of the electron transport chain (found in the membrane of the mitochondria of eukaryotic cells). It complexes with the ferric iron atom in this enzyme. The binding of cyanide to this cytochrome prevents transport of electrons from cytochrome c oxidase to oxygen. As a result, the electron transport chain is disrupted and the cell can no longer aerobically produce ATP for energy. Tissues that mainly depend on aerobic respiration, such as the central nervous system and the heart, are particularly affected. Cyanide is also known produce some of its toxic effects by binding to catalase, glutathione peroxidase, methemoglobin, hydroxocobalamin, phosphatase, tyrosinase, ascorbic acid oxidase, xanthine oxidase, succinic dehydrogenase, and Cu/Zn superoxide dismutase. Cyanide binds to the ferric ion of methemoglobin to form inactive cyanmethemoglobin. (L97)

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Interactions
USE OF BAPN (1 G/KG/DAY) FOR PERIOD OF 8 WK CAUSED SIMULTANEOUS CHANGES IN SKIN & AORTIC CONNECTIVE TISSUES OF RATS. IN SKIN, COLLAGEN TISSUE WAS DISLOCATED & BROKEN INTO FRAGMENTS, ELASTIC TISSUE DISAPPEARED & FIBROBLASTS WERE VACUOLIZED. ADDITION OF PYRIDINOL CARBAMATE (PDC) TO BAPN PREVENTS FORMATION OF LESIONS OF ELASTIC TISSUE & OF FIBROBLASTS. WHEN GIVEN AFTER CESSATION OF LATHYROGEN TREATMENT, PDC ARRESTED FORMATION OF LESIONS & ACCELERATED THEIR REGRESSION.
A DOSE OF 2,500 MG/KG BAPN GIVEN BY GAVAGE ON DAY 11 TO PREGNANT HAMSTERS PRODUCED 69.5% SKELETAL ANOMALIES IN THE OFFSPRING. ADMINISTRATION OF BETA-HYDROXYETHYLRUTOSIDES (WHICH PROTECT AGAINST COLLAGEN DAMAGE FROM LATHYROGENS) IMMEDIATELY AFTER BAPN TO THE PREGNANT ANIMALS RESULTED IN SIGNIFICANTLY DECREASED TERATOGENIC RESPONSE. THIS SUPPORTS THE VIEW THAT THE MECHANISM FOR BAPN-INDUCED SKELETAL DYSMORPHOGENESIS IS THE INHIBITION OF CROSS-LINKING DURING THE MATURATION OF COLLAGEN FIBERS.

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Non-Human Toxicity Values
LD50 Mouse ip 1152 mg/kg

[1]. The lysyl oxidase inhibitor β-aminopropionitrile reduces body weight gain and improves the metabolic profile in diet-induced obesity in rats. Dis Model Mech. 2015 Jun;8(6):543-51.
[2]. Inactivation of lysyl oxidase by β-aminopropionitrile inhibits hypoxia-induced invasion and migration of cervical cancer cells. Oncol Rep. 2013 Feb;29(2):541-8.
[3]. β-Aminopropionitrile monofumarate induces thoracic aortic dissection in C57BL/6 mice. Sci Rep. 2016 Jun 22;6:28149.

Beta-aminopropionitrile is an aminopropionitrile carrying an amino group at the beta-position. It has a role as a plant metabolite, an antineoplastic agent, an antirheumatic drug and a collagen cross-linking inhibitor. It is a conjugate base of a beta-ammoniopropionitrile.
beta-Aminopropionitrile is a metabolite found in or produced by Escherichia coli (strain K12, MG1655).
3-Aminopropanenitrile has been reported in Euglena gracilis with data available.
beta-Aminopropionitrile is a toxic amino-acid derivative. On an unusual case of the Cantrell-sequence in a premature infant with associated dysmelia, aplasia of the right kidney, cerebellar hypoplasia and circumscribed aplasia of the cutis, maternal history suggested an occupational exposure to aminopropionitriles prior to pregnancy. The characteristic features of the Cantrell-sequence--anterior thoraco-abdominal wall defect with ectopia cordis and diaphragm, sternum, pericardium, and heart defects--have been observed in animals following maternal administration of beta-aminopropionitrile. Some species of lathyrus (chickling pea, Lathyrus sativus- related), notably Lathyrus odoratus, are unable to induce human lathyrism but contain beta-aminopropionitrile, that induces pathological changes in bone (osteolathyrism) and blood vessels (angiolathyrism) of experimental animals without damaging the nervous system. The administration of beta-aminopropionitrile has been proposed for pharmacological control of unwanted scar tissue in human beings. beta-Aminopropionitrile is a reagent used as an intermediate in the manufacture of beta-alanine and pantothenic acid. (A11439, A11440, A11441)
Reagent used as an intermediate in the manufacture of beta-alanine and pantothenic acid.
See also: ... View More ...

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Mechanism of Action
The mechanism of the effect is unknown, but it is thought to be by some action on growth of certain mesodermal tissues. It is not due to one of its major metabolites, cyanoacetic acid, and both the free amino group and the cyano group seem essential for activity. It is not produced if the amino group is in the alpha position, or if in the gamma position in butyronitrile.
IT HAS BEEN SUGGESTED THAT LATHYROGENIC AGENTS ACT BY BLOCKING CERTAIN CARBONYL GROUPS NORMALLY PRESENT IN COLLAGEN, & THUS INTERFERING WITH FORMATION OF CROSS LINKAGES. THEIR ACTION MAY BE RETARDED BY RESERPINE OR BY CALCIUM SALTS. /LATHYROGENIC AGENTS/

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Therapeutic Uses
EXPTL USE: ADMIN OF LYSYL OXIDASE INHIBITOR, BAPN, PREVENTED DEVELOPMENT OF HYPERTENSION & DECR AMT OF VASCULAR COLLAGEN IN RATS IN WHICH HYPERTENSION HAD BEEN INDUCED. HISTOLOGICAL EXAM REVEALED THAT ARTERIOSCLEROTIC CHANGES WERE PREVENTED BY BAPN.
EXPTL USE: IN YOUNG HYPERTENSIVE RATS, BAPN (20 MG, IP DAILY, FOR 2 WK) PREVENTED DEVELOPMENT OF HYPERTENSION. IN ADULT SPONTANEOUS HYPERTENSIVE RATS (50 MG, IP, DAILY FOR 2 WK) DECR BLOOD PRESSURE.
EXPTL USE: RATS WITH SC IMPLANTED POLYVINYL ALCOHOL SPONGES AND WITH INFLICTED SKIN INCISION WOUNDS RECEIVED A SINGLE INJECTION OF β-Aminopropionitrile (BAPN) AT 4 DOSAGES RANGING FROM 1-40 MG/100 G. EVEN THE LOWEST DOSE OF BAPN INHIBITED LYSYL OXIDASE ACTIVITY FOR 6 HOURS; WITH LARGER DOSAGES THE INHIBITION LASTED LONGER, AT 40 MG BAPN, AT LEAST 48 HOURS. THE MAGNITUDE AND DURATION OF INHIBITION WERE REFLECTED IN THE EXTRACTABILITY OF COLLAGEN AND BURSTING STRENGTH OF THE WOUND. THE DATA SUGGEST THAT A MINIMAL DOSE OF BAPN WOULD BE CLINICALLY EFFECTIVE IF EITHER THE METABOLISM OF THE DRUG WERE REDUCED (BY MONOAMINE OXIDASE INHIBITORS) OR A SUSTAINED-RELEASE PREPARATION OF BAPN WERE USED.
EXPTL USE: BETA-AMINOPROPIONITRILE (BAPN) WAS TESTED FOR ABILITY TO PREVENT EXCESS COLLAGEN FORMATION IN BLEOMYCIN-INDUCED PULMONARY FIBROSIS IN THE HAMSTER. TWO GROUPS RECEIVED 1 ENDOTRACHEAL DOSE OF BLEOMYCIN; ONE OF THESE WAS INJECTED WITH BAPN TWICE DAILY FOR 30 DAYS. A 3RD GROUP RECEIVED SALINE AND BAPN. THE BLEOMYCIN INCREASED COLLAGEN CONTENT, DECREASED LUNG VOLUME, AND PRODUCED FIBROSIS AND A MORTALITY RATE OF 51%. ADMINISTRATION OF BAPN TO BLEOMYCIN-TREATED ANIMALS PREVENTED EXCESS COLLAGEN ACCUMULATION, PRODUCED LESS FIBROSIS, AND LESSENED MORTALITY RATE TO 24%; BAPN ALONE HAD NO EFFECT ON LUNG MECHANICS OR COLLAGEN CONTENT.

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Extracellular matrix (ECM) remodelling of the adipose tissue plays a pivotal role in the pathophysiology of obesity. The lysyl oxidase (LOX) family of amine oxidases, including LOX and LOX-like (LOXL) isoenzymes, controls ECM maturation, and upregulation of LOX activity is essential in fibrosis; however, its involvement in adipose tissue dysfunction in obesity is unclear. In this study, we observed that LOX is the main isoenzyme expressed in human adipose tissue and that its expression is strongly upregulated in samples from obese individuals that had been referred to bariatric surgery. LOX expression was also induced in the adipose tissue from male Wistar rats fed a high-fat diet (HFD). Interestingly, treatment with β-Aminopropionitrile (BAPN), a specific and irreversible inhibitor of LOX activity, attenuated the increase in body weight and fat mass that was observed in obese animals and shifted adipocyte size toward smaller adipocytes. BAPN also ameliorated the increase in collagen content that was observed in adipose tissue from obese animals and improved several metabolic parameters - it ameliorated glucose and insulin levels, decreased homeostasis model assessment (HOMA) index and reduced plasma triglyceride levels. Furthermore, in white adipose tissue from obese animals, BAPN prevented the downregulation of adiponectin and glucose transporter 4 (GLUT4), as well as the increase in suppressor of cytokine signaling 3 (SOCS3) and dipeptidyl peptidase 4 (DPP4) levels, triggered by the HFD. Likewise, in the TNFα-induced insulin-resistant 3T3-L1 adipocyte model, BAPN prevented the downregulation of adiponectin and GLUT4 and the increase in SOCS3 levels, and consequently normalised insulin-stimulated glucose uptake. Therefore, our data provide evidence that LOX plays a pathologically relevant role in the metabolic dysfunction induced by obesity and emphasise the interest of novel pharmacological interventions that target adipose tissue fibrosis and LOX activity for the clinical management of this disease. [1]

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Tumor invasion and migration are major causes of mortality in patients with cervical carcinoma. Tumors under hypoxic conditions are more invasive and have a higher metastasic activity. Lysyl oxidase (LOX) is a hypoxia-responsive gene. LOX has been shown to be essential for hypoxia-induced metastasis in breast cancer. However, the direct impact of LOX on cervical cancer cell motility remains poorly understood. Our study revealed that LOX expression at protein and catalytic levels is upregulated in cervical cancer cells upon exposure to hypoxia. Hypoxia induced mesenchymal-like morphological changes in HeLa and SiHa cells which were accompanied by upregulation of α-SMA and vimentin, two mesenchymal markers, and downregulation of E-cadherin, an epithelial marker, indicating the epithelial-mesenchymal transition (EMT) of cervical cancer cells occurred under hypoxic conditions. Treatment of tumor cells with β-Aminopropionitrile (BAPN), an active site inhibitor of LOX, blocked the hypoxia-induced EMT morphological and marker protein changes, and inhibited invasion and migration capacities of cervical carcinoma cells in vitro. Collectively, these findings suggest LOX enhances hypoxia-induced invasion and migration in cervical cancer cells mediated by the EMT which can be inhibited by BAPN. [2]

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Thoracic aortic dissection (TAD) is a catastrophic disease with high mortality and morbidity, characterized by fragmentation of elastin and loss of smooth muscle cells. However, the underlying pathological mechanisms of this disease remain elusive because there are no appropriate animal models, limiting discovery of effective therapeutic strategies. We treated mice on C57BL/6 and FVB genetic backgrounds with β-Aminopropionitrile monofumarate (BAPN), an irreversible inhibitor of lysyl oxidase, for 4 wk, followed by angiotensin II (Ang II) infusion for 24 h. We found that the BAPN plus Ang II treatment induced formation of aortic dissections in 100% of mice on both genetic backgrounds. BAPN without Ang II caused dissections in few FVB mice, but caused 87% of C57BL/6 mice to develop TAD, with 37% dying from rupture of the aortic dissection. Moreover, a lower dose of BAPN induced TAD formation and rupture earlier with fewer effects on body weight. Therefore, we have generated a reliable and convenient TAD model in C57BL/6 mice for studying the pathological process and exploring therapeutic targets of TAD.[3]

C₃H₆N₂

70.09

70.053

151-18-8

1647

Colorless to light yellow Liquid

0.9±0.1 g/cm3

186.3±13.0 °C at 760 mmHg

< 25 °C

66.5±19.8 °C

0.7±0.4 mmHg at 25°C

1.430

-1.02

49.81

1

2

1

5

49.2

0

C(CN)C#N

AGSPXMVUFBBBMO-UHFFFAOYSA-N

InChI=1S/C3H6N2/c4-2-1-3-5/h1-2,4H2

3-aminopropanenitrile

β-Aminopropionitrile; 3-aminopropionitrile; 3-Aminopropanenitrile; 151-18-8; 2-Cyanoethylamine; Aminopropionitrile; BETA-AMINOPROPIONITRILE; Propanenitrile, 3-amino-; beta-Cyanoethylamine; β Aminopropionitrile

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： (1). 本产品在运输和储存过程中需避光。  (2). 请将本产品存放在密封且受保护的环境中（例如氮气保护），避免吸湿/受潮。

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~1426.74 mM)
H2O : ~50 mg/mL (~713.37 mM)

配方 1 中的溶解度: ≥ 3.25 mg/mL (46.37 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 32.5 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 3.25 mg/mL (46.37 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 32.5 mg/mL 澄清 DMSO 储备液加入 900 μL 20% SBE-β-CD 生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 3.25 mg/mL (46.37 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 32.5 mg/mL 澄清 DMSO 储备液加入900 μL 玉米油中，混合均匀。

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配方 4 中的溶解度: 100 mg/mL (1426.74 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶.

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。