Melanocortin receptors (MCRs) and their accessory proteins (MRAPs) evolutionarily first appear in the genome of sea lamprey. The most ancient melanocortin system consists of only two melanocortin receptors (slMCa and slMCb) and one MRAP2 (slMRAP2) protein, but the physiological roles have not been fully explored in this primitive species. Here, we synthesize and characterize the pharmacological features of slMRAP2 protein on two slMCRs. Our results show that the slMRAP2 protein lacks the long carboxyl terminus; it directly interacts and decreases the surface expression but enhances the α-MSH-induced agonism of slMCa and slMCb. In comparison with higher organisms such as elephant shark and zebrafish, we also demonstrate the constantly evolving regulatory function of the carboxyl terminus of MRAP2 protein, the unique antiparallel topology of slMRAP2 dimer and the homo- and hetero-dimerization of two slMCRs. This study elucidates the presence and modulation of melanocortin receptor by the accessory protein of the agnathans for the first time, which provides a better insight of the melanocortin system in ancient species of chordates.
Ming Zhu, Bingxin Xu, Meng Wang, Shangyun Liu, Yue Zhang and Chao Zhang
Chao-bin He, Yu Zhang, Zhi-yuan Cai and Xiao-jun Lin
The role of surgery in the treatment of metastatic pancreatic neuroendocrine tumors (PNETs) was controversial. The objectives of this study were to illustrate the impact of surgery in improving the prognosis of patients with metastatic PNETs and build nomograms to predict overall survival (OS) and cancer-specific survival (CSS) based on a large population-based cohort.
Patients diagnosed with metastatic PNETs between 2004 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database were retrospectively collected. Nomograms for estimating OS and CSS were established based on Cox regression model and Fine and Grey’s model. The precision of the nomograms was evaluated and compared using concordance index (C-index) and the area under receiver operating characteristic (ROC) curve (AUC).
The study cohort included 1966 patients with metastatic PNETs. It was shown that the surgery provided survival benefit for all groups of patients with metastatic PNETs. In the whole study cohort, 1-, 2- and 3-year OS and CSS were 51.5, 37.1 and 29.4% and 53.0, 38.9 and 31.1%, respectively. The established nomograms were well calibrated, and had good discriminative ability, with C-indexes of 0.773 for OS prediction and 0.774 for CSS prediction.
Patients with metastatic PNETs could benefit from surgery when the surgery tolerance was acceptable. The established nomograms could stratify patients who were categorized as tumor-node-metastasis (TNM) IV stage into groups with diverse prognoses, showing better discrimination and calibration of the established nomograms, compared with 8th TNM stage system in predicting OS and CSS for patients with metastatic PNETs.
Chao Xu, Xiang-Fei Li, Hong-Yan Tian, Hua-Juan Shi, Ding-Dong Zhang, Kenneth Prudence Abasubong and Wen-Bin Liu
After a 12-week feeding trial, the glucose tolerance test was performed in Megalobrama amblycephala to evaluate the effects of metformin on the metabolic responses of glycolipids. Plasma insulin peaked at 2 h, then decreased to the basal value at 8–12 h post-injection. Plasma triglyceride levels and liver glycogen contents of the control group was decreased significantly during the first 2 and 1 h, respectively. Then, they returned to basal values at 12 h. During the whole sampling period, the high-carbohydrate groups had significantly higher levels of plasma metabolites and liver glycogen than those of the control group, and metformin supplementation enhanced these changes (except insulin levels). Glucose administration lowered the transcriptions of ampk α1, ampk α2, pepck, g6pase, fbpase, cpt IA and aco, the phosphorylation of Ampk α and the activities of the gluconeogenic enzymes during the first 2–4 h, while the opposite was true of glut 2, gs, gk, pk, accα and fas. High-carbohydrate diets significantly increased the transcriptions of ampk α1, ampk α2, glut 2, gs, gk, pk, accα and fas, the phosphorylation of Ampk α and the activities of the glycolytic enzymes during the whole sampling period, while the opposite was true for the remaining indicators. Furthermore, metformin significantly upregulated the aforementioned indicators (except accα and fas) and the transcriptions of cpt IA and aco. Overall, metformin benefits the glucose homeostasis of Megalobrama amblycephala fed high-carbohydrate diets through the activation of Ampk and the stimulation of glycolysis, glycogenesis and fatty acid oxidation, while depressing gluconeogenesis and lipogenesis.
Peng Fan, Chao-Xia Lu, Di Zhang, Kun-Qi Yang, Pei-Pei Lu, Ying Zhang, Xu Meng, Su-Fang Hao, Fang Luo, Ya-Xin Liu, Hui-Min Zhang, Lei Song, Jun Cai, Xue Zhang and Xian-Liang Zhou
Liddle syndrome (LS), a monogenetic autosomal dominant disorder, is mainly characterized by early-onset hypertension and hypokalemia. Clinically, misdiagnosis or missing diagnosis is common, since clinical phenotypes of LS are variable and nonspecific. We report a family with misdiagnosis of primary aldosteronism (PA), but identify as LS with a pathogenic frameshift mutation of the epithelial sodium channel (ENaC) β subunit. DNA samples were collected from a 32-year-old proband and 31 other relatives in the same family. A designed panel including 41 genes associated with monogenic hypertension was screened using next-generation sequencing. The best candidate disease-causing variants were verified by Sanger sequencing. Genetic analysis of the proband revealed a novel frameshift mutation c.1838delC (p.Pro613Glnfs*675) in exon 13 of SCNN1B. This heterozygous mutation involved the deletion of a cytosine from a string of three consecutive cytosines located at codons 612 to 613 and resulted in deletion of the crucial PY motif and elongation of the β-ENaC protein. The identical mutation was also found in 12 affected family members. Amiloride was effective in alleviating LS for patients. There were no SCNN1A or SCNN1G mutations in this family. Our study emphasizes the importance of considering LS in the differential diagnosis of early-onset hypertension. The identification of a novel frameshift mutation of SCNN1B enriches the genetic spectrum of LS and has allowed treatment of this affected family to prevent severe complications.
Zeming Liu, Di Hu, Yihui Huang, Sichao Chen, Wen Zeng, Ling Zhou, Wei Zhou, Min Wang, Haifeng Feng, Wei Wei, Chao Zhang, Danyang Chen and Liang Guo
Controversies regarding factors associated with distant metastasis in pediatric thyroid cancer remain among the scientific community. The aim of this study was to investigate factors influencing distant metastasis in pediatric thyroid cancer.
We reviewed 1376 patients (aged 2 to 18 years) with thyroid cancer treated between 2003 and 2014. Data collected and analyzed included sex, race, age at diagnosis, year of diagnosis, pathological type, number of tumor foci, tumor extension, T-stage, N-stage, surgical procedure and radiation. Univariate and multivariate analyses were conducted to evaluate factors influencing distant metastasis of pediatric thyroid cancer.
In the univariate analysis, factors influencing distant metastasis of thyroid cancer were age at diagnosis (P < 0.001), N-stage (P < 0.001), number of tumor foci (P = 0.003), tumor extension (P < 0.001) and T-stage (T1 vs T2 (P = 0.803), T3 (P < 0.001) and T4 (P < 0.001)). In multivariate analysis, factors influencing distant metastasis of thyroid cancer were age at diagnosis (P = 0.001), N-stage (P < 0.001) and T-stage (T1 vs T3 (P = 0.036) and T4 (P < 0.001)). Sex, race, year of diagnosis, pathological type, number of tumor foci, tumor extension, surgical procedure and radiation had no significant influence on distant metastasis (all P > 0.05). Furthermore, according to chi-squared test, younger pediatric thyroid cancer patients with higher T- and N-stages are more likely to have distant metastasis.
Age at diagnosis, T-stage and N-stage influence distant metastasis of thyroid cancer patients aged 2 to 18 years; accordingly, more radical treatments may need to be used for patients with those risk elements.
Min Li, Ying Chen, Jingjing Jiang, Yan Lu, Zhiyi Song, Shengjie Zhang, Chao Sun, Hao Ying, Xiaofang Fan, Yuping Song, Jialin Yang and Lin Zhao
Recent studies have shown that neuregulin 4 (Nrg4), a member of the epidermal growth factor (EGF) family of extracellular ligands, plays an important role in the prevention of obesity, insulin resistance and nonalcoholic fatty liver disease (NAFLD). Considering that thyroid hormone (TH) has profound effects on whole-body energy metabolism, we speculate that circulating Nrg4 levels might be altered in patients with hyperthyroidism.
Design and methods
A total of 129 hyperthyroid patients and 100 healthy subjects were recruited. Of them, 39 hyperthyroid patients received thionamide treatment for 3 months until euthyroidism. Serum Nrg4 levels were determined using the ELISA method. To further confirm the relationship between TH and Nrg4, C57BL/6 mice were treated with T3 and quantitative real-time PCR was performed to detect Nrg4 gene expression.
Serum Nrg4 levels were significantly elevated in hyperthyroid patients as compared with normal controls (3.84 ± 1.63 vs 2.21 ± 1.04 ng/mL, P < 0.001). After achieving euthyroidism by thionamide treatment, serum Nrg4 levels dropped markedly from 3.57 ± 1.26 to 1.94 ± 0.72 ng/ml (P < 0.001). After adjustment for potential confounders, serum Nrg4 levels were independently associated with hyperthyroidism. The upregulation of Nrg4 expression in the livers and white adipose tissues by T3 was further confirmed by animal and cell culture experiments.
Serum Nrg4 levels were increased in patients with hyperthyroidism. The liver and white adipose tissue might be primary sources contributing to elevated serum Nrg4 concentrations.