Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China.
Guangzhou University of Chinese Medicine, Guangzhou, 510405, China.
BMC Complement Altern Med. 2018 Sep 10;18(1):250. doi: 10.1186/s12906-018-2309-3.
Angiogenesis is a pathobiological hallmark of gastric cancer. However, rare studies focus on angiogenesis in gastric precancerous lesions (GPL). Weipixiao (WPX), a Chinese herbal preparation, is proved clinically effective in treating GPL. Here, we evaluated WPX's anti-angiogenic potential for GPL, and also investigated the possibility of its anti-angiogenic mechanisms.
HPLC analysis was applied to screen the major chemical components of WPX. After modeling N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced GPL in male Sprague-Dawley rats, different doses of WPX were administrated orally for 10 weeks. Next, we performed histopathological examination using routine H&E staining and HID-AB-PAS staining. In parallel, we assessed angiogenesis revealed by microvessel density (MVD) using CD34 immunostaining, and subsequently observe microvessel ultrastructure in gastric mucosa under Transmission Electron Microscope. Finally, we detect expression of angiogenesis-associated markers VEGF and HIF-1α using immunohistochemistry. Moreover, mRNA expressions of ERK1, ERK2, Cylin D1 as well as HIF-1α in gastric mucosa were determined by quantitative real-time reverse transcription- polymerase chain reaction.
We observed the appearance of active angiogenesis in GPL rats, and demonstrated that WPX could reduce microvascular abnormalities and attenuate early angiogenesis in most of GPL specimens with a concomitant regression of most intestinal metaplasia (IM) and a portion of gastric epithelial dysplasia (GED). In parallel, WPX could suppress HIF-1α mRNA expression (P < 0.01) as well as protein expression (although without statistical significance), and could markedly inhibit VEGF protein expression in GPL rats. Mechanistically, WPX intervention, especially at low dose, caused a significant decrease in the ERK1 and Cylin D1 mRNA levels. However, WPX might probably have no regulatory effect on ERK2 amplification.
WPX could attenuate early angiogenesis and temper microvascular abnormalities in GPL rats. This might be partly achieved by inhibiting on the angiogenesis-associated markers HIF-1α and VEGF, and on the ERK1/Cylin D1 aberrant activation.
血管生成是胃癌的一个病理生物学标志。然而，很少有研究关注胃癌前病变（GPL）中的血管生成。胃痞消（WPX）是一种中药制剂，已被临床证明在治疗 GPL 方面有效。在这里，我们评估了 WPX 对 GPL 的抗血管生成潜力，并研究了其抗血管生成机制的可能性。
采用高效液相色谱法（HPLC）分析 WPX 的主要化学成分。在雄性 Sprague-Dawley 大鼠中建模 N-甲基-N'-硝基-N-亚硝基胍（MNNG）诱导的 GPL 后，给予不同剂量的 WPX 口服 10 周。接下来，我们使用常规 H&E 染色和 HID-AB-PAS 染色进行组织病理学检查。同时，我们使用 CD34 免疫染色评估血管生成情况，并用透射电子显微镜观察胃黏膜下的微血管超微结构。最后，我们使用免疫组织化学检测血管生成相关标志物 VEGF 和 HIF-1α的表达。此外，我们还通过定量实时逆转录聚合酶链反应（qRT-PCR）测定胃黏膜中 ERK1、ERK2、Cylin D1 和 HIF-1α 的 mRNA 表达。
我们观察到 GPL 大鼠出现活跃的血管生成，WPX 可减少微血管异常，并在大多数 GPL 标本中减轻早期血管生成，同时大多数肠上皮化生（IM）和部分胃上皮异型增生（GED）消退。同时，WPX 可抑制 HIF-1α mRNA 表达（P<0.01）和蛋白表达（尽管无统计学意义），并可显著抑制 GPL 大鼠的 VEGF 蛋白表达。机制上，WPX 干预，特别是低剂量，可显著降低 ERK1 和 Cylin D1 mRNA 水平。然而，WPX 可能对 ERK2 扩增没有调节作用。
WPX 可减轻 GPL 大鼠的早期血管生成和调节微血管异常。这可能部分是通过抑制血管生成相关标志物 HIF-1α和 VEGF 以及 ERK1/Cylin D1 的异常激活来实现的。
