Circulating integrin alpha4/beta7+ lymphocytes targeted by vedolizumab have a pro-inflammatory phenotype

Publication date: Available online 26 May 2018
Source:Clinical Immunology
Author(s): James D. Lord, S. Alice Long, Donna M. Shows, Jerill Thorpe, Katherine Schwedhelm, Janice Chen, Mariko Kita, Jane H. Buckner
Integrin alpha4/beta7 on circulating lymphocytes identifies them as gut-tropic, and can be targeted by the humanized antibody vedolizumab to treat inflammatory bowel disease (IBD). We found lymphocytes expressing alpha4/beta7 were significantly more responsive to the pro-inflammatory cytokines IL-6, IL-7, and IL-21, and less responsive to the regulatory T cell (Treg)-supporting cytokine IL-2. Alpha4/beta7 was expressed by a smaller percent of FOXP3 + Helios+ thymically-derived Tregs (tTregs) than FOXP3 + Helios- peripherally-derived Tregs (pTregs) or FOXP3- effector T cells. Integrin alpha4/beta7+ CD4 T cells were also rare among cells expressing the Th2 marker CRTh2, but enriched in cells bearing the circulating T follicular helper cell marker CXCR5. Thus the effect of this anti-integrin therapy on the mucosal immune system may be more qualitative than quantitative, and selectively replace pro-inflammatory effector cells with Tregs and Th2 cells to facilitate immune tolerance in the mucosa without globally depleting lymphocytes from the intestinal mucosa.



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Combination of anti-citrullinated protein antibodies and rheumatoid factor is associated with increased systemic inflammatory mediators and more rapid progression from preclinical to clinical rheumatoid arthritis

Publication date: Available online 26 May 2018
Source:Clinical Immunology
Author(s): Nithya Lingampalli, Jeremy Sokolove, Lauren J. Lahey, Jess D. Edison, William R. Gilliland, V. Michael Holers, Kevin D. Deane, William H. Robinson
The development of rheumatoid factor (RF) and/or anti-citrullinated protein antibodies (ACPAs) can be observed years prior to clinical diagnosis of rheumatoid arthritis (RA). Nevertheless, the interaction between these two autoantibodies and their combined effect on development of RA is unclear. We measured RF, cytokines, and ACPA subtypes in serial pre-clinical serum samples collected from 83 US veterans who all developed RA. Levels of cytokines and ACPAs were compared between the following groups: anti-cyclic citrullinated peptide (anti-CCP)-/RF- (double negative), anti-CCP+/RF-, anti-CCP-/RF+, or anti-CCP+/RF+ (double-positive). The double-positive subgroup had significantly higher levels of 20 inflammatory cytokines and 29 ACPA reactivities, and the shortest interval, 1.3 years, between the preclinical sample timepoint and diagnosis of RA. Thus, the combined presence of ACPAs and RF is associated with a more rapid progression to RA, suggesting that anti-CCP+/RF+ individuals have a more advanced preclinical disease state and that the onset of RA may be imminent.



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Impaired spatial processing in a mouse model of fragile X syndrome

Publication date: 17 September 2018
Source:Behavioural Brain Research, Volume 350
Author(s): Mohamed Ghilan, Luis E.B. Bettio, Athena Noonan, Patricia S. Brocardo, Joana Gil-Mohapel, Brian R. Christie
Fragile X syndrome (FXS) is the most common form of inherited intellectual impairment. The Fmr1^−/y mouse model has been previously shown to have deficits in context discrimination tasks but not in the elevated plus-maze. To further characterize this FXS mouse model and determine whether hippocampal-mediated behaviours are affected in these mice, dentate gyrus (DG)-dependent spatial processing and Cornu ammonis 1 (CA1)-dependent temporal order discrimination tasks were evaluated. In agreement with previous findings of long-term potentiation deficits in the DG of this transgenic model of FXS, the results reported here demonstrate that Fmr1^−/y mice perform poorly in the DG-dependent metric change spatial processing task. However, Fmr1^−/y mice did not present deficits in the CA1-dependent temporal order discrimination task, and were able to remember the order in which objects were presented to them to the same extent as their wild-type littermate controls. These data suggest that the previously reported subregional-specific differences in hippocampal synaptic plasticity observed in the Fmr1^−/y mouse model may manifest as selective behavioural deficits in hippocampal-dependent tasks.



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The increase in fiber size in male rat gastrocnemius after chronic central leptin infusion is related to activation of insulin signaling

Publication date: 15 July 2018
Source:Molecular and Cellular Endocrinology, Volume 470
Author(s): Emma Burgos-Ramos, Sandra Canelles, Amaia Rodríguez, Laura M. Frago, Javier Gómez-Ambrosi, Julie A. Chowen, Gema Frühbeck, Jesús Argente, Vicente Barrios
Insulin potentiates leptin effects on muscle accrual and glucose homeostasis. However, the relationship between leptin's central effects on peripheral insulin sensitivity and the associated structural changes remain unclear. We hypothesized that central leptin infusion modifies muscle size through activation of insulin signaling. Muscle insulin signaling, enzymes of fatty acid metabolism, mitochondrial respiratory chain complexes, proliferating cell nuclear antigen (PCNA) and fiber area were analyzed in the gastrocnemius of chronic central infused (L), pair-fed (PF) and control rats. PCNA-positive nuclei, fiber area, GLUT4 and glycogen levels and activation of Akt and mechanistic target of rapamycin were increased in L, with no changes in PF. Acetyl-CoA carboxylase-β mRNA levels and non-esterified fatty acid and triglyceride content were reduced and carnitine palmitoyltransferase-1b expression and mitochondrial complexes augmented in L. These results suggest that leptin promotes an increase in muscle size associated with improved insulin signaling favored by lipid profile.



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Editorial Board

Publication date: 15 July 2018
Source:Molecular and Cellular Endocrinology, Volume 470





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Effects of metformin on cell growth and AMPK activity in pituitary adenoma cell cultures, focusing on the interaction with adenylyl cyclase activating signals

Publication date: 15 July 2018
Source:Molecular and Cellular Endocrinology, Volume 470
Author(s): Lara Faggi, Andrea Giustina, Giovanni Tulipano
For a few years we have been investigating AMP-activated protein kinase (AMPK) as a target for drug therapy of GH-secreting pituitary adenomas. Aim of this study was to investigate the direct effects of metformin, which causes AMPK activation in different cell types, on rat pituitary adenoma cell growth and on related cell signalling pathways. Our results suggest that metformin can exert a growth-inhibitory activity in rat pituitary tumor cells mediated by AMPK activation, although multiple mechanisms are most likely involved. Membrane proteins, including growth factor receptors, are valuable targets of AMPK. The inhibition of the mTOR-p70S6 kinase signalling pathway plays a role in the suppressive effect of metformin on pituitary tumor cell growth. Metformin did not affect the MTT reduction activity in energetic stress conditions. Finally, metformin was still able to induce AMPK activation and to inhibit cell growth in cells treated with forskolin and in transfected cells overexpressing GHRH-receptor and treated with GHRH. Hence, adenylyl cyclase over-activation does not account for the lack of response of some human pituitary tumors to AMPK-activating compounds in vitro.



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Editorial Board

Publication date: 5 July 2018
Source:Molecular and Cellular Endocrinology, Volume 469





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Molecular profiles of oxyphilic and chief cell parathyroid adenoma

Publication date: 15 July 2018
Source:Molecular and Cellular Endocrinology, Volume 470
Author(s): Ming Lu, Hanna Kjellin, Omid Fotouhi, Linkiat Lee, Inga-Lena Nilsson, Felix Haglund, Anders Höög, Janne Lehtiö, Catharina Larsson
ContextParathyroid adenomas may be composed of chief cells (conventional or water-clear), oxyphilic cells or a mixture of both cells. The molecular background is rarely studied.ObjectiveTo molecularly characterize parathyroid adenomas of different cell type composition.Design: Chief and oxyphilic cell adenomas were compared in a cohort of 664 sporadic cases. Extensive analyses of parathyroid tissues were performed in subgroup. Gene expressions of known parathyroid-related genes were quantified by qRT-PCR. Protein expression profiles determined by liquid chromatography – tandem mass spectrometry (LC-MS/MS) were compared between each type of parathyroid adenomas. Selected proteins were analysed by Western blot and immunohistochemistry.ResultsPatients with oxyphilic cell adenoma were found to be older at the time of operation than chief cell adenoma cases but did not differ in gender, serum calcium or tumor weight. The gene expression of CASR, VDR, FGFR1, CYP27B1, CYP24A1, PTHLH, GCM2, NDUFA13, CDKN1B, MEN1 and CNND1 did not differ between the groups. VDR protein levels were weaker in oxyphilic adenomas. The proteomic studies identified a set of novel dysregulated proteins of interest such as nuclear receptor subfamily 2 group C member 2 (TR4), LIM domain only protein 3 (LMO3) and calcium-binding protein B (S100B). LMO3 and S100B showed higher expression in oxyphilic adenoma and may be involve in parathyroid tumorgenesis through the p53 pathway. TR4 showed different subcellular localisation between adenoma and normal rim.ConclusionChief and oxyphilic cell parathyroid adenomas have partly overlapping but also distinct molecular profiles. The calmodulin-eEF2K, TR4 and p53 pathways may be involved in the tumor development.



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Activation of Nrf2 might reduce oxidative stress in human granulosa cells

Publication date: 15 July 2018
Source:Molecular and Cellular Endocrinology, Volume 470
Author(s): Nana Akino, Osamu Wada-Hiraike, Hiromi Terao, Harunori Honjoh, Wataru Isono, Houju Fu, Mana Hirano, Yuichiro Miyamoto, Michihiro Tanikawa, Miyuki Harada, Tetsuya Hirata, Yasushi Hirota, Kaori Koga, Katsutoshi Oda, Kei Kawana, Tomoyuki Fujii, Yutaka Osuga
Nuclear factor-E2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1)-antioxidant response element (ARE) signaling pathway is one of the most important defense mechanisms against oxidative stress (OS). It is well documented that equilibration status of OS plays fundamental roles in human reproductive medicine, and the physiological role of Nrf2 in ovarian granulosa cells (GCs) has not been determined yet. Herein we aimed to study the function of Nrf2 in GCs.Human ovarian tissues were subjected to immunohistochemistry to localize Nrf2 and Keap1 and we detected the expression of Nrf2 and Keap1 in the human GCs. Human luteinized GCs were isolated and cultured, and hydrogen peroxide (H2O2) or Dimethylfumarates (DMF), an activator of Nrf2, were added to GCs to analyze the relationship between Nrf2 and antioxidants by quantitative RT-PCR. The mRNA levels of Nrf2, catalase, superoxide dismutase 1 (SOD1), and 8-Oxoguanine DNA glycosylase (OGG1) were elevated by H2O2, and DMF treatment showed similar but pronounced effects through activation of Nrf2. To determine the relationship of Nrf2 and the generation of antioxidants, siRNAs were used and quantitative RT-PCR were conducted. Decreased expression of Nrf2 resulted in a decreased level of these antioxidant mRNA. Intracellular levels of ROS were investigated by fluorescence of 8-hydroxy-2′-deoxyguanosine and fluorescent dye, 2′,7′-dichlorodihydrofluorescein diacetate after H2O2 and/or DMF treatment, and DMF treatment quenched intracellular ROS generation by H2O2.These results show that activation of Nrf2 might lead to alleviate OS in human GCs, and this could provide novel insight to conquer the age-related fertility decline that is mainly attributed to the accumulation of aberrant OS.



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Corticotropin releasing hormone can selectively stimulate glucose uptake in corticotropinoma via glucose transporter 1

Publication date: 15 July 2018
Source:Molecular and Cellular Endocrinology, Volume 470
Author(s): Jie Lu, Blake K. Montgomery, Grégoire P. Chatain, Alejandro Bugarini, Qi Zhang, Xiang Wang, Nancy A. Edwards, Abhik Ray-Chaudhury, Marsha J. Merrill, Russell R. Lonser, Prashant Chittiboina
BackgroundPre-operative detection of corticotropin (ACTH) secreting microadenomas causing Cushing's disease (CD) improves surgical outcomes. Current best magnetic resonance imaging fails to detect up to 40% of these microadenomas. ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography (PET) is specific, but not sensitive in detecting corticotropinomas. Theoretically, secretagogue stimulation with corticotropin releasing hormone (CRH) could improve detection of adenomas with ¹⁸F-FDG PET. Previous attempts with simultaneous CRH stimulation have failed to demonstrate increased ¹⁸F-FDG uptake in corticotropinomas. We hypothesized that CRH stimulation leads to a delayed elevation in glucose uptake in corticotropinomas.MethodsClinical data was analyzed for efficacy of CRH in improving ¹⁸FDG-PET detection of corticotropinomas in CD. Glucose transporter 1 (GLUT1) immunoreactivity was performed on surgical specimens. Ex-vivo, viable cells from these tumors were tested for secretagogue effects (colorimetric glucose uptake), and for fate of intracellular glucose (glycolysis stress analysis). Validation of ex-vivo findings was performed with AtT-20 cells.ResultsCRH increased glucose uptake in human-derived corticotroph tumor cells and AtT-20, but not in normal murine or human corticotrophs (p < 0.0001). Continuous and intermittent (1 h) CRH exposure increased glucose uptake in AtT-20 with maximal effect at 4 h (p = 0.001). Similarly, CRH and 8-Br-cAMP led to robust GLUT1 upregulation and increased membrane translocation at 2 h, while fasentin suppressed baseline (p < 0.0001) and CRH-mediated glucose uptake. Expectedly, intra-operatively collected corticotropinomas demonstrated GLUT1 overexpression. Lastly, human derived corticotroph tumor cells demonstrated increased glycolysis and low glucose oxidation.ConclusionIncreased and delayed CRH-mediated glucose uptake differentially occurs in adenomatous corticotrophs. Delayed secretagogue-stimulated ¹⁸F-FDG PET could improve microadenoma detection.



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The impact of new technologies in our understanding of testis formation and function

Publication date: 15 June 2018
Source:Molecular and Cellular Endocrinology, Volume 468
Author(s): Serge Nef, Dagmar Wilhelm




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Dysregulation of Δ4-3-oxosteroid 5β-reductase in diabetic patients: Implications and mechanisms

Publication date: 15 July 2018
Source:Molecular and Cellular Endocrinology, Volume 470
Author(s): Leila Valanejad, Mwlod Ghareeb, Stephanie Shiffka, Christina Nadolny, Yuan Chen, Liangran Guo, Ruchi Verma, Sangmin You, Fatemeh Akhlaghi, Ruitang Deng
Aldo-keto reductase family 1 member D1 (AKR1D1) is a Δ⁴-3-oxosteroid 5β-reductase required for bile acid synthesis and steroid hormone metabolism. Both bile acids and steroid hormones, especially glucocorticoids, play important roles in regulating body metabolism and energy expenditure. Currently, our understanding on AKR1D1 regulation and its roles in metabolic diseases is limited. We found that AKR1D1 expression was markedly repressed in diabetic patients. Consistent with repressed AKR1D1 expression, hepatic bile acids were significantly reduced in diabetic patients. Mechanistic studies showed that activation of peroxisome proliferator-activated receptor-α (PPARα) transcriptionally down-regulated AKR1D1 expression in vitro in HepG2 cells and in vivo in mice. Consistently, PPARα signaling was enhanced in diabetic patients. In summary, dysregulation of AKR1D1 disrupted bile acid and steroid hormone homeostasis, which may contribute to the pathogenesis of diabetes. Restoring bile acid and steroid hormone homeostasis by modulating AKR1D1 expression may represent a new approach to develop therapies for diabetes.



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Mathematical modeling of gonadotropin-releasing hormone signaling

Publication date: 15 July 2018
Source:Molecular and Cellular Endocrinology, Volume 470
Author(s): George Fink




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Retraction notice to: "Role of Mammalian sirtuin 1 (SIRT1) in lipids metabolism and cell proliferation of goose primary hepatocytes" MCE Volume 382, Issue 1, 25 January 2014, Pages 282-291

Publication date: 15 July 2018
Source:Molecular and Cellular Endocrinology, Volume 470
Author(s): Chunchun Han, Huofu Wan, Shuang Ma, Dandan Liu, Fang He, Jiwen Wang, Zhixiong Pan, Hehe Liu, Liang Li, Hua He, Hongyong Xu, Shouhai Wei, Feng Xu




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Editorial - Endocrine Tumor

Publication date: 5 July 2018
Source:Molecular and Cellular Endocrinology, Volume 469
Author(s): Shioko Kimura, Anthony Glover




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MENIN loss as a tissue-specific driver of tumorigenesis

Publication date: 5 July 2018
Source:Molecular and Cellular Endocrinology, Volume 469
Author(s): Janet W.Y. Li, Xianxin Hua, Diane Reidy-Lagunes, Brian R. Untch
The MEN1 gene encodes MENIN, a tumor suppressor that plays a role in multiple cellular processes. Germline and somatic mutations in MEN1 have been identified in hereditary and sporadic tumors of neuroendocrine origins suggesting context-specific functions. In this review, we focus on the development of mutational Men1 in vivo models, the known cellular activities of MENIN and efforts to identify vulnerabilities in tumors with MENIN loss.



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Editorial Board

Publication date: 15 June 2018
Source:Molecular and Cellular Endocrinology, Volume 468





https://ift.tt/2KYafRc

Targeting RAW 264.7 macrophages (M1 type) with Withaferin-A decorated mannosylated liposomes induces repolarization via downregulation of NF-κB and controlled elevation of STAT-3

Publication date: August 2018
Source:International Immunopharmacology, Volume 61
Author(s): Manoj Kumar Neog, Farhath Sultana, Mahaboobkhan Rasool
In the present study, we intend to gain an insight into the mechanism of Withaferin-A (WA), a steroidal lactone with reference to repolarization of RAW 264.7 macrophages (M1 to M2 type). We found that successful internalization of WA via mannosylated liposomal delivery system (ML-WA) reduced the RAW 264.7 macrophage (M1) mediated pro-inflammatory cytokines (IL-1β, IL-6, IL-23, and TNF-α) through the attenuation of transcription factor NF-κB-p65 expression. Whereas, ML-WA treatment induced a controlled upregulation of p-STAT3, and ablated the key oxidative stress markers (NO, iNOS, and ROS) in M1 → M2 RAW 264.7 macrophage repolarization, which suggested the recalibration of M1 macrophage metabolic function. Further, the elevated expression of M2 macrophage associated CD163 over the M1 macrophage related CD86 concluded that ML-WA induces an anti-inflammatory response by repolarizing the M1 → M2 RAW 264.7 macrophage.



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Predicted miRNA-mRNA-mediated posttranscriptional control associated with differences in cervical and thoracic thymus function

Publication date: July 2018
Source:Molecular Immunology, Volume 99
Author(s): Amanda F. Assis, Jie Li, Paula B. Donate, Janaína A. Dernowsek, Nancy R. Manley, Geraldo A. Passos
A secondary cervical thymus (CT) is present in the neck region in about 50% of human and mice. CT in mice is an independent and functional organ, which can be colonized by T lymphocyte progenitors and generate thymocytes that are selected by the T cell receptor repertoire following the positive and negative selection. However, CT and the main thoracic thymus (TT) have been shown in mice to have significant functional differences. In this study, we use transcriptional profiling to compare mRNA or miRNAs expression patterns in murine CT and TT. We used these data to perform functional enrichment of the expression signatures and reconstruction of posttranscriptional miRNA-mRNA interaction networks. For this purpose, we compared the transcriptome profiling of paired RNA samples of whole CTs, TTs and parathyroid gland (PT), which was used as an external group, from Foxn1-GFP;Pth-Cre;R26dTomato transgenic mice that differentially label CT and TT. As expected, CT and TT featured comprehensive transcriptome similarity and this suggests that these organs are subjected to correlated transcriptional control. Nevertheless, significant differences were also observed between TT and CT, characterized by 107 differentially expressed (DE) mRNAs, and in 13 DE miRNAs, that in turn established interactions. These results suggest that functional similarity between TT and CT is reflected in their transcriptional activity and that CT functional uniqueness might be under posttranscriptional control.



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Genomic organization and adaptive evolution of IGHC genes in marine mammals

Publication date: July 2018
Source:Molecular Immunology, Volume 99
Author(s): Lili Li, Xinghua Rong, Guiting Li, Yingying Wang, Bingyao Chen, Wenhua Ren, Guang Yang, Shixia Xu
Immunoglobulins are important elements of the adaptive immune system that bind to an immense variety of microbial antigens to neutralize infectivity and specify effector functions. In the present study, the immunoglobulin heavy chain constant region (IGHC) genes from marine mammals were identified and compared with those of their terrestrial relatives to explore their genomic organization and evolutionary characteristics. The genomic organization of marine mammal IGHC genes was shown to be conservative with other eutherian mammals. Stronger signals of positive selection on IGHC were revealed in terrestrial mammals than that in marine mammals with the branch-site model, displaying different selective pressure, which might suggest their divergent adaptations to contrasted environments.



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