B lymphocytes are the source of autoantibodies against the thyroid-stimulating hormone receptor (TSHR) in Graves’ disease (GD). Characterization of autoimmune B-cell expression profiles might enable a better understanding of GD pathogenesis. To reveal this, the expression levels of long noncoding RNAs (lncRNAs) and mRNAs (genes) in purified B cells from patients with newly diagnosed GD and healthy individuals were compared using microarrays, which elucidated 604 differentially expressed lncRNAs (DE-lncRNAs) and 410 differentially expressed genes (DEGs). GO and pathway analyses revealed that the DEGs are mainly involved in immune response. A protein–protein interaction network presented experimentally validated interactions among the DEGs. Two independent algorithms were used to identify the DE-lncRNAs that regulate the DEGs. Functional annotation of the deregulated lncRNA–mRNA pairs identified 14 pairs with mRNAs involved in cell proliferation. The lncRNAs TCONS_00022357-XLOC_010919 and n335641 were predicted to regulate TCL1 family AKT coactivator A (TCL1A), and the lncRNA n337845 was predicted to regulate SH2 domain containing 1A (SH2D1A). TCL1A and SH2D1A are highly involved in B-cell proliferation. The differential expression of both genes was validated by qRT-PCR. In conclusion, lncRNA and mRNA expression profiles of B cells from patients with GD indicated that the lncRNA–mRNA pairs n335641–TCL1A, TCONS_00022357-XLOC_010919–TCL1A, and n337845–SH2D1A may participate in GD pathogenesis by modulating B-cell proliferation and survival. Therefore, the identified lncRNA and mRNA may represent novel biomarkers and therapeutic targets for GD.
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Xuechao Jiang, Yonghui Wang, Xiaoying Li, Leqi He, Qian Yang, Wei Wang, Jun Liu and Bingbing Zha
Yuan Zhou, ShengNan Wang, Jing Wu, Jianjun Dong and Lin Liao
Aims: Heterozygous inactivating mutations in the GCK gene cause the familial, mild fasting hyperglycaemia named MODY2. Many patients with MODY2 in Asia have delayed timely treatment because they did not receive the correct diagnosis. This study aims to analyze the clinical characteristics and GCK mutations in Asian MODY2.
Methods: We have collected 110 Asian patients with MODY2 from the Pubmed, Embase, Medline, Web of Science, CNKI, and Wanfang with the following search terms: "Maturity-Onset Diabetes of the Young" OR "MODY" OR "Maturity-Onset Diabetes of the Young type 2" OR "MODY2" OR "GCK-DM" OR "GCK-MODY". Both mutations of GCK and clinical characteristics of MODY2 were analyzed.
Results: There were 96 different mutations occurred in coding regions and non-coding regions. Exon 5 and 7 were the most common location in coding regions, and missense was the primarily mutation type. The proportion of probands younger than 25 was 81.8%, and 81.4% of the probands had family history of hyperglycaemia. Ninety percent and 93% of Asian MODY2 probands exhibited the mild elevating in FPG (5.4-8.3 mmol/L) and HbA1c (5.6-7.6%), respectively.
Conclusions: Most Asian MODY2 patients were due to GCK mutation in coding region, and exon 5 and 7 were the most common locations. FPG, HbA1c, and familial diabetes were important reference indicators for diagnosing MODY2. Altogether, the study indicates that for the young onset of diabetes with mild elevated blood glucose and HbA1c, and family history of hyperglycaemia, molecular genetic testing is suggested in order to differ MODY2 from other types of diabetes earlier.
Rajae Talbi and Victor M Navarro
Kiss1 neurons are essential regulators of the hypothalamic–pituitary–gonadal (HPG) axis by regulating gonadotropin-releasing hormone (GnRH) release. Compelling evidence suggests that Kiss1 neurons of the arcuate nucleus (Kiss1ARC), recently identified as the hypothalamic GnRH pulse generator driving fertility, also participate in the regulation of metabolism through kisspeptinergic and glutamatergic interactions with, at least, proopiomelanocortin (POMC) and agouti-related peptide (AgRP)/neuropeptide Y (NPY) neurons, located in close apposition with Kiss1ARC. This review offers a comprehensive overview of the recent developments, mainly derived from animal models, on the role of Kiss1 neurons in the regulation of energy balance, including food intake, energy expenditure and the influence of circadian rhythms on this role. Furthermore, the possible neuroendocrine pathways underlying this effect, and the existing controversies related to the anorexigenic action of kisspeptin in the different experimental models, are also discussed.
Thomas Couronne, Paul Girot, Julien Hadoux, Thierry Lecomte, Alice Durand, Caroline Fine, Katia Vandevoorde, Catherine Lombard-Bohas and Thomas Walter
Objective: First-line chemotherapy in metastatic neuroendocrine carcinomas (NEC) is based on etoposide and platinum. However, there is no standard concerning second-line treatment. The objective of this study was to evaluate efficacy and tolerance of dacarbazine or temozolomide in metastatic digestive NEC as post first-line treatment.
Material and Methods: This study included patients with a metastatic NEC of digestive or unknown primary site. All patients received platinum-etoposide as first-line chemotherapy. Primary endpoint was progression-free survival (PFS). Secondary endpoints were: clinical/morphological responses, toxicity, and overall survival (OS).
Results: 27 patients were included: 17 received dacarbazine and 10 temozolomide as post-first line treatments. Median PFS was 3.0 (95%CI [2.2;3.7]) months. There was no significant difference between dacarbazine and temozolomide on PFS. Clinical and morphological responses were found in 46% and 33% of patients, respectively. Median OS was 7.2 (95%CI [2.2;12.2]) months. The toxicity profile was that expected with such treatments.
Conclusion: This study confirms a poor prognosis of metastatic NEC during post first-line treatment. LV5FU2-Dacarbazine or temozolomide-capecitabine chemotherapies allow a temporary clinical response for half of patients and/or a morphological response for a third of patients.
Elizabeth M Winter, Alex Ireland, Natalie Clare Butterfield, Melanie Haffner-Luntzer, Marie-Noelle Horcajada, Annegreet Veldhuis-Vlug, Ling Oei, Graziana Colaianni and Nicolas Bonnet
In this review we discuss skeletal adaptations to the demanding situation of pregnancy and lactation. Calcium demands are increased during pregnancy and lactation, and this is effectuated by a complex series of hormonal changes. The changes in bone structure at the tissue and whole bone level observed during pregnancy and lactation appear to largely recover over time. The magnitude of the changes observed during lactation may relate to the volume and duration of breastfeeding and return to regular menses. Studies examining long-term consequences of pregnancy and lactation suggest that there are small, site-specific benefits to bone density, and that bone geometry may also be affected. Pregnancy- and lactation-induced osteoporosis (PLO) is a rare disease for which the pathophysiological mechanism is as yet incompletely known; here we discuss and speculate on the possible roles of genetics, oxytocin, sympathetic tone and bone marrow fat. Finally, we discuss fracture healing during pregnancy and lactation and the effects of estrogen on this process.
Louise Vølund Larsen, Delphine Mirebeau-Prunier, Tsuneo Imai, Cristina Alvarez-Escola, Kornelia Hasse-Lazar, Simona Censi, Luciana A Castroneves, Akihiro Sakurai, Minoru Kihara, Kiyomi Horiuchi, Véronique Dorine Barbu, Françoise Borson-Chazot, Anne-Paule Gimenez-Roqueplo, Pascal Pigny, Stephane Pinson, Nelson Wohllk, Charis Eng, Berna İmge Aydoğan, Dhananjaya Saranath, Sarka Dvorakova, Frederic Castinetti, Patocs Attila, Damijan Bergant, Thera P. Links, Mariola Peczkowska, Ana O Hoff, Caterina Mian, Trisha Dwight, Barbara Jarzab, Hartmut P H Neumann, Mercedes Robledo, Shinya Uchino, Anne Barlier, Christian Godballe and Jes Sloth Mathiesen
OBJECTIVE: Multiple endocrine neoplasia type 2A (MEN 2A) is a rare syndrome caused by RET germline mutations, and have been associated with primary hyperparathyroidism (PHPT) in up to 30% of cases. Recommendations on RET screening in patients with apparently sporadic PHPT are unclear. We aimed to estimate the prevalence of cases presenting with PHPT as first manifestation among MEN 2A index cases and to characterize the former cases.
DESIGN AND METHODS: An international retrospective multicenter study of 1085 MEN 2A index cases. Experts from MEN 2 centres all over the world were invited to participate. A total of 19 centers in 17 different countries provided registry data of index cases followed from 1974 to 2017.
RESULTS: Ten cases presented with PHPT as their first manifestation of MEN 2A, yielding a prevalence of 0.9% (95% CI: 0.4-1.6). 9/10 cases were diagnosed with medullary thyroid carcinoma (MTC) in relation to parathyroid surgery and 1/10 was diagnosed 15 years after parathyroid surgery. 7/9 cases with full TNM data were node-positive at MTC diagnosis.
CONCLUSIONS: Our data suggest that the prevalence of MEN 2A index cases that present with PHPT as their first manifestation is very low. The majority of index cases presenting with PHPT as first manifestation, have synchronous MTC, often node-positive. Thus, our observations suggest that not performing RET mutation analysis in patients with apparently sporadic PHPT would result in an extremely low false negative rate, if no other MEN 2A component, specifically MTC, are found during work up or resection of PHPT.
Emmely M de Vries, Hermina C van Beeren, Albert C.w.a. van Wijk, Andries Kalsbeek, Johannes A Romijn, Eric Fliers and Anita Boelen
Fasting induces profound changes in the hypothalamus-pituitary-thyroid axis and peripheral thyroid hormone (TH) metabolism, ultimately leading to lower serum thyroid hormone (TH) concentrations. In the present study, we aimed to investigate the regulation of type 3 deiodinase (D3) during fasting in two metabolic tissues: liver and white adipose tissue (WAT). To this end, we studied the effect of modulation of the mammalian target of rapamycin (mTOR) and hypoxia inducible factor 1α (HIF1α) on D3 expression in a primary rat hepatocytes and in 3T3-L1 adipocytes. In addition, we studied the role of the constitutive androstane receptor (CAR) on liver TH metabolism using primary hepatocytes and CAR-/- mice. Twenty-four hour fasting increased liver D3 expression in mice. Inhibition of mTOR using mTOR inhibitors markedly induced D3 mRNA expression in primary hepatocytes; this increase was accompanied by a small increase in D3 activity. Stimulation of these cells with a CAR agonist induced both D3 mRNA expression and activity. Fasting increased hepatic D3 expression in WT but not in CAR-/- mice. In WAT, D3 mRNA expression increased 5-fold after 48h fasting. Treatment of 3T3-L1 adipocytes with mTOR inhibitors induced D3 mRNA expression, whereas stimulation of these cells with cobalt chloride, a compound that mimics hypoxia and stabilizes HIF1α, did not induce D3 mRNA expression. In conclusion, our results indicate an important role of mTOR in the upregulation of D3 in WAT and liver during fasting. Furthermore, CAR plays a role in the fasting induced D3 increase in the liver.
Lianghui You, Yan Wang, Yao Gao, Xingyun Wang, Xianwei Cui, Yanyan Zhang, Lingxia Pang, Chenbo Ji, Xirong Guo and Xia Chi
Enhanced brown adipose tissue (BAT) mass and activity have been demonstrated to promote the expenditure of excess stored energy and reduce prevalence of obesity. Cold is known as a potent stimulator of BAT and activates BAT primarily through the β3-adrenergic-cAMP signaling. Here, we performed RNA-sequencing to identify differential miRNAs in mouse BAT upon cold exposure and a total of 20 miRNAs were validated. With the treatment of CL-316,243 (CL) and forskolin (Fsk) in mouse and human differentiated brown adipocyte cells in vitro, miR-23b-5p, miR-133a-3p, miR-135-5p, miR-491-5p, and miR-150-3p expression decreased and miR-455-5p expression increased. Among these deferentially expressed miRNAs, miR-23b-5p expression was differentially regulated in activated and aging mouse BAT and negatively correlated with Ucp1 expression. Overexpression of miR-23b-5p in the precursor cells from BAT revealed no significant effects on lipid accumulation, but diminished mitochondrial function and decreased expression of BAT specific markers. Though luciferase reporter assays did not confirm the positive association of miR-23b-5p with the 3′UTRs of the predicted target Ern1, miR-23b-5p overexpression may affect brown adipocyte thermogenic capacity mainly through regulating genes expression involving in lipolysis and fatty acid β-oxidation pathways. Our results suggest that miRNAs are involved in cold-mediated BAT thermogenic activation and further acknowledged miR-23b-5p as a negative regulator in controlling thermogenic programs, further providing potential molecular therapeutic targets to increase surplus energy and treat obesity.
Ulrik Ø Andersen, Dijana Terzic, Nicolai Jacob Wewer Albrechtsen, Peter Dall Mark, Peter Plomgaard, Jens F Rehfeld, Finn Gustafsson and Jens P Goetze
Neprilysin degrades natriuretic peptides in circulation and is also suggested to degrade the gut hormones gastrin and cholecystokinin. Neprilysin inhibition has become a therapeutic strategy and thus a regimen in need of further testing in terms of other hormonal axes besides natriuretic peptides. The aim of this study was to examine whether acute inhibition of neprilysin affects meal-induced responses in gastrin and cholecystokinin concentrations in healthy individuals.
Methods and results
Nine healthy young men were included in an open-labelled, randomized cross-over clinical trial. The participants received a standardized meal (25 g fat, 26 g protein, 42 g carbohydrate) on two separate days with or without a one-time dosage of sacubitril ((194 mg)/valsartan (206 mg)). Blood pressure, heart rate and blood samples were measured and collected during the experiment. Statistical differences between groups were assessed using area under the curve together with an ANOVA with a Bonferroni post hoc test. Sacubitril/valsartan increased the postprandial plasma concentrations of both gastrin and cholecystokinin (80% (AUC0-270 min, P = 0.004) and 60% (AUC0-270 min, P = 0.003), respectively) compared with the control meal. No significant hemodynamic effects were noted (blood pressure, AUC0-270 min, P = 0.86, heart rate, AUC0-270 min, P = 0.96).
Our study demonstrates that sacubitril/valsartan increases the postprandial plasma concentrations of gastrin and cholecystokinin in healthy individuals. The results thus suggest that neprilysin-mediated degradation of gastrin and cholecystokinin is physiologically relevant and may have a role in heart failure patients treated with sacubitril/valsartan.
Teresa Vilariño-García, Antonio Pérez-Pérez, Esther Santamaría-López, Nicolás Prados, Manuel Fernández-Sánchez and Victor Sanchez-Margalet
INTRODUCTION: Polycystic ovary syndrome (PCOS) is a complex metabolic disorder associated with ovulatory dysfunction, hyperandrogenism, obesity, and insulin resistance, that leads to subfertility. Sam68 is an RNA-binding protein with signaling functions that is ubiquitously expressed, including gonads. Sam68 is recruited to leptin signaling, mediating different leptin actions.
OBJECTIVE: We aimed to investigate the role of Sam68 in leptin signaling mediating the effect on aromatase expression in granulosa cells, and the posible implication of Sam68 in the leptin resistance in PCOS.
MATERIALS AND METHODS: Granulosa cells were from healthy donor (n=25) and women with PCOS (n=25), within age range 20-40 years old, from Valencian Infertility Institute (IVI), Seville, Spain. Sam68 expression was inhibited by siRNA method and overexpressed by expression vector. Expression level was analysed by qPCR and immunoblot. Statistical significance was assessed by ANOVA followed by different post hoc tests. A P value <0.05 was considered statistically significant.
RESULTS: We have found that leptin stimulation increases phosphorylation, and expression level of Sam68, and aromatase in granulosa cells. Downregulation of Sam68 expression resulted in a lower activation of MAPK and PI3K pathways in response to leptin, whereas overexpression of Sam68 increased leptin stimulation of signaling, enhancing aromatase expression. Granulosa cells from women with PCOS presented lower expression of Sam68 and were resistant to the leptin effect on aromatase expression.
CONCLUSIONS: These results suggest the participation of Sam68 in leptin receptor signaling, mediating the leptin effect on aromatase expression in granulosa cells, and points to a new target in leptin resistance in PCOS.