Sepiapterin reverses the changes in gastric nNOS dimerization and function in diabetic gastroparesis.
Sepiapterin reverses the changes in gastric nNOS dimerization and function in diabetic gastroparesis.
复制标题
DOI：
10.1111/j.1365-2982.2010.01588.x
复制
发表时间：
2010-12
影响因子：
3.5
通讯作者：
Ravella K
中科院分区：
文献类型：
--
作者：
Gangula PR;Mukhopadhyay S;Pasricha PJ;Ravella K
我们之前已经证明，体内补充四氢生物蝶呤（BH4）；神经元一氧化氮合酶（nNOS）的辅助因子显著恢复糖尿病大鼠胃排空延迟和氮能松弛减弱。在这项研究中，我们研究了补充sepapterin （SEP）是否能恢复雌性糖尿病大鼠的胃排空和氮能系统。sepapterin是通过挽救途径生物合成BH4的前体。糖尿病大鼠（链脲佐菌素诱导）补充BH4或SEP （20 mg kg - 1体重）。采用电场刺激法测定高糖和SEP存在或不存在时胃氮能松弛的情况。健康或糖尿病雌性大鼠的胃肌条在高糖、SEP和/或甲氨蝶呤（MTX）存在或不存在的情况下孵育。采用NO比色法测定一氧化氮释放量。Western blot检测nNOSα的表达及二聚化程度。体外胃肌肉组织研究表明，MTX作为一种通过挽救途径合成BH4的抑制剂，可显著降低NO的释放。体内MTX治疗可降低胃氮能松弛和nNOSα二聚体。补充SEP可显著减轻糖尿病大鼠胃排空延迟。此外，补充SEP可恢复糖尿病大鼠受损的氮能松弛、胃nNOSα蛋白表达和二聚体。上述数据表明，添加SEP可加速胃排空，减轻胃nNOSα表达和二聚体的减少。因此，SEP补充是女性糖尿病性胃轻瘫患者的潜在治疗选择。
We have demonstrated previously that in vivo supplementation of tetrahydrobiopterin (BH4); a co-factor for neuronal nitric oxide synthase (nNOS) significantly restored delayed gastric emptying and attenuated nitrergic relaxation in diabetic rat. In this study, we have investigated whether supplementation of sepiapterin (SEP), a precursor for BH4 biosynthesis via salvage pathway restores gastric emptying and nitrergic system in female diabetic rats. Diabetic rats (streptozotocin-induced) were supplemented with BH4 or SEP (20 mg kg−1 body weight). Gastric nitrergic relaxation in the presence or absence of high glucose and SEP were measured by electric field stimulation. Gastric muscular strips from healthy or diabetic female rats were incubated in the presence or absence of high glucose, SEP and/or methotrexate (MTX). Nitric oxide release was measured colorimetrically by NO assay kit. The expression of nNOSα and dimerization was detected by Western blot. In vitro studies on gastric muscular tissues showed that MTX, an inhibitor of BH4 synthesis via salvage pathway, significantly decreased NO release. In vivo treatment with MTX reduced both gastric nitrergic relaxation and nNOSα dimerization. Supplementation of SEP significantly attenuated delayed gastric emptying in diabetic rats. In addition, SEP supplementation restored impaired nitrergic relaxation, gastric nNOSα protein expression and dimerization in diabetic rats. The above data suggests that supplementation of SEP accelerated gastric emptying and attenuated reduced gastric nNOSα expression, and dimerization. Therefore, SEP supplementation is a potential therapeutic option for female patients of diabetic gastroparesis.
登录
查看更多内容
影响因子：
168.9
作者：
Levy, Harvey L.;Milanowski, Andrzej;Dorenbaum, Alex
通讯作者：
Dorenbaum, Alex
影响因子：
3.8
作者：
Fiege, B;Ballhausen, D;Blau, N
通讯作者：
Blau, N
影响因子：
3
作者：
Ishii, M;Shimizu, S;Yamamoto, T
通讯作者：
Yamamoto, T
影响因子：
4.8
作者：
Reif, A;Fröhlich, LG;Schmidt, HHHW
通讯作者：
Schmidt, HHHW
影响因子：
4.7
作者：
Pall, Martin L.
通讯作者：
Pall, Martin L.