Early postnatal pulmonary failure and primary hypothyroidism in mice with combined TPST-1 and TPST-2 deficiency

Protein-tyrosine sulfation is a post-translational modification of an unknown number of secreted and membrane proteins mediated by two known Golgi tyrosylprotein sulfotransferases (TPST-1 and TPST-2). Tpst double knockouts were generated to investigate the importance of tyrosine sulfation in vivo. Double knockouts were born alive at the expected frequency, were normal in size, and their tissues do not synthesize sulfotyrosine. However, most pups die in the early postnatal period with signs of cardiopulmonary insufficiency. A combination of clinical, magnetic resonance imaging, and histological data indicated that lungs of Tpst double knockouts fail to expand at birth resulting in acute pulmonary hypertension, right-to-left shunting, and death by asphyxia in the early postnatal period. Some double knockouts survive the postnatal period, but fail to thrive and display delayed growth that is due in part to hypothyroidism. In addition, we find that Tpst2-/- mice have primary hypothyroidism, but that Tpst1-/- mice are euthyroid. This suggests that a protein(s) required for thyroid hormone production is sulfated and cannot be sulfated in the absence of TPST-2. Thus, Tpst1 and Tpst2 are the only Tpst genes in mice, tyrosine sulfation is required for normal pulmonary function at birth, and TPST-2 is required for normal thyroid gland function.     

红景天苷在大鼠体内的代谢途径研究

目的研究红景天苷在大鼠体内的代谢物谱,分析其代谢途径。方法大鼠ig给予红景天苷200 mg/kg后,收集胆汁、尿液、粪便和血浆,应用高分辨质谱技术鉴定可能的代谢产物,分析红景天苷在大鼠体内的代谢途径。结果共检测到除原型药物外的20个代谢产物,提示红景天苷在大鼠体内的主要代谢途径为葡萄糖化、乙酰化、硫酸化和甲基化。结论红景天苷在大鼠体内经历了广泛的Ⅰ相和Ⅱ相代谢,代谢物主要通过尿液排出。应用峰面积归一化法计算主要代谢产物相对生成量,提示红景天苷在大鼠尿、粪、胆汁中的主要代谢途径为Ⅱ相代谢,血浆中红景天苷原型药物为体循环系统中主要暴露物质。     

硫酸酯化天麻多糖的制备及其抗氧化活性

目的：研究硫酸酯化天麻多糖（Sulfated Gastrodia elata polysaccharides,GEPs）的制备和GEPs抗氧化活性。方法：采用氨基磺酸-甲酰胺法制备GEPs,测量其硫酸根取代度,并采用红外光谱（FT-IR）和核磁共振法（¹HNMR）鉴定其结构。测定GEPs对二苯代苦味酰肼（DPPH）、羟基自由基（OH·）、超氧阴离子（O₂^-·）的清除作用,以及GEPs的还原力。结果：将所得的粗天麻多糖用DEAE-52纤维素柱层析分离,得到两个产物GEP和GEPⅡ,分别将GEP和GEPⅡ经Sephadex G-100凝胶柱纯化,发现GEP和GEPⅡ为纯天麻多糖,且相对分子质量分别为12 882和4 120。将GEP和GEPⅡ进行硫酸酯化修饰后,经FT-IR和¹HNMR检测鉴定分析,结果表明修饰成功。GEP、GEPⅡ、GEPs和GEPⅡs都有清除DPPH、OH·和O₂^-·的能力以及较强的还原力,并且表现出浓度依赖性。将结构修饰前后的多糖抗氧化活性进行对比,发现GEPs和GEPⅡs对DPPH、OH·和O₂^-·的清除率和还原力都要强于GEP和GEPⅡ。结论：天麻多糖经硫酸酯化修饰后,抗氧化活性有所提高,为研究GEPs的生物活性提供了实验依据。     

Biallelic variants in the SLC13A1 sulfate transporter gene cause hyposulfatemia with a mild spondylo-epi-metaphyseal dysplasia

Sulfate is the fourth most abundant anion in human plasma but is not measured in clinical practice and little is known about the consequences of sulfate deficiency. Nevertheless, sulfation plays an essential role in the modulation of numerous compounds, including proteoglycans and steroids. We report the first patient with a homozygous loss-of-function variant in the SLC13A1 gene, encoding a renal and intestinal sulfate transporter, which is essential for maintaining plasma sulfate levels. The homozygous (Arg12Ter) variant in SLC13A1 was found by exome sequencing performed in a patient with unexplained skeletal dysplasia. The main clinical features were enlargement of joints and spondylo-epi-metaphyseal radiological abnormalities in early childhood, which improved with age. In addition, autistic features were noted. We found profound hyposulfatemia due to complete loss of renal sulfate reabsorption. Cholesterol sulfate was reduced. Intravenous N-acetylcysteine administration temporarily restored plasma sulfate levels. We conclude that loss of the SLC13A1 gene leads to profound hypersulfaturia and hyposulfatemia, which is mainly associated with abnormal skeletal development, possibly predisposing to degenerative bone and joint disease. The diagnosis might be easily missed and more frequent.