Role Of Hormones Research Articles

Orosomucoid secretion levels by epicardial adipose tissue as possible indicator of endothelial dysfunction in diabetes mellitus or inflammation in coronary artery disease

ObjectiveType 2 diabetes mellitus (T2DM) is associated with fat and autonomic system dysfunction. Epicardial adipose tissue (EAT) plays an endocrine role over the heart. Since orosomucoid (ORM) has local actions around the coronaries, our aim was to assess the relationship between its secretion profile by EAT and its catecholaminergic regulation in patients with T2DM and coronary artery disease (CAD). MethodsWe obtained EAT, subcutaneous adipose tissue (SAT) and plasma from 55 patients undergoing cardiac surgery. Fat explants were stimulated with isoproterenol (ISO) 1 μM for 6 h. After, the fat explants released-ORM and plasma levels were analyzed by ELISA. mRNA or protein expression was analyzed by real time PCR or western blot, respectively. The effects of ORM on endothelial cells were analyzed by impedance and wound healing assays. ResultsWe observed that EAT-released ORM levels were higher than SAT (328 ± 185 vs 58 ± 45 ng/mL; p < 0.001). Interestingly, EAT secretion was lower in patients with than those without T2DM (260 ± 141 vs 370 ± 194 ng/mL; p < 0.05) and this difference was enhanced after ISO stimulation (p < 0.01). However, plasma levels (412 ± 119 vs 594 ± 207 μg/mL) and EAT-released ORM levels were higher in patients with than those without CAD (384 ± 195 vs 279 ± 159 ng/mL; p < 0.05). ISO stimulation, also reduced the EAT released-ORM levels in patients with CAD. On human endothelial cells, ORM induced an increase of healing and proliferation in a dose-dependent manner. ConclusionEAT-released ORM levels in patients with T2DM or CAD and its regulation by catecholamines might be the mirror of local endothelium dysfunction or inflammatory process in different cardiovascular disorders.

IGF binding proteins in cancer: mechanistic and clinical insights.

The six members of the family of insulin-like growth factor (IGF) binding proteins (IGFBPs) were originally characterized as passive reservoirs of circulating IGFs, but they are now understood to have many actions beyond their endocrine role in IGF transport. IGFBPs also function in the pericellular and intracellular compartments to regulate cell growth and survival - they interact with many proteins, in addition to their canonical ligands IGF-I and IGF-II. Intranuclear roles of IGFBPs in transcriptional regulation, induction of apoptosis and DNA damage repair point to their intimate involvement in tumour development, progression and resistance to treatment. Tissue or circulating IGFBPs might also be useful as prognostic biomarkers.

Stimulation of androgen production by d-aspartate through the enhancement of StAR, P450scc and 3β-HSD mRNA levels in vivo rat testis and in culture of immature rat Leydig cells

Previous studies have shown a role of d-aspartic acid (d-Asp) in testicular steroidogenesis. Here, we evaluated the effects of d-Asp on androgen production and on expression levels of mRNAs encoding specific steroidogenic key molecules. d-Asp was endogenously present in adult rat testis and its content paralleled to serum luteinizing hormone (LH) and, local and circulating androstenedione and testosterone levels. In vivod-Asp administration induced serum LH release, causing an indirect increase of androstenedione and testosterone levels by enhancing steroidogenic acute regulatory protein (StAR), cytochrome P450 cholesterol side-chain cleavage enzyme (P450scc) and 3β-hydroxysteroid dehydrogenase/D5-D4 isomerases (3β-HSD) mRNA levels. The direct endocrine role of d-Asp was evaluated using cultured immature Leydig cells (ILCs) obtained from 35days old rats. Cytoplasm and nucleus of ILCs localized d-Asp, while StAR marked the cytoplasm only. After 12h from d-Asp in vitro administration, ILCs resulted intensely d-Asp stained, and StaR protein level, evaluated by Western blotting, significantly increased. After 24h, significant androstenedione and testosterone syntheses were induced. At molecular level, d-Asp administration significantly increased StAR, P450scc and 3β-HSD mRNAs at 2, 4 and 12h, respectively. The temporal shift on relative mRNA expression levels indicated that d-Asp exerted its physiological role through sequential gene cascade activation of those molecules implicated in the synthesis of androgens. Conclusively, our findings demonstrated that d-Asp is a local messenger in testis and give a contribution in understanding the complexity of local endocrine regulation as well as the molecular events leading the acquisition to a steroidogenic competence by ILCs.

From cytokine to myokine: the emerging role of interleukin‐6 in metabolic regulation

The lack of physical activity and overnutrition in our modern lifestyle culminates in what we now experience as the current obesity and diabetes pandemic. Medical research performed over the past 20 years identified chronic low-grade inflammation as a mediator of these metabolic disorders. Hence, finding therapeutic strategies against this underlying inflammation and identifying molecules implicated in this process is of significant importance. Following the observation of an increased plasma concentration of interleukin-6 (IL-6) in obese patients, this protein, known predominantly as a pro-inflammatory cytokine, came into focus. In an attempt to clarify its importance, several studies implicated IL-6 as a co-inducer of the development of obesity-associated insulin resistance, which precedes the development of type 2 diabetes. However, the identification of IL-6 as a myokine, a protein produced and secreted by skeletal muscle to fulfil paracrine or endocrine roles in the insulin-sensitizing effects following exercise, provides a contrasting and hence paradoxical identity of this protein in the context of metabolism. We review here the literature considering the complex, pleiotropic role of IL-6 in the context of metabolism in health and disease.

Endocrine Disorders in Adolescent and Young Female Athletes: Impact on Growth, Menstrual Cycles, and Bone Mass Acquisition

Puberty is a crucial period of dramatic hormonal changes, accelerated growth, attainment of reproductive capacity, and acquisition of peak bone mass. Participation in recreational physical activity is widely acknowledged to provide significant health benefits in this period. Conversely, intense training imposes several constraints, such as training stress and maintenance of very low body fat to maximize performance. Adolescent female athletes are therefore at risk of overtraining and/or poor dietary intake, which may have several consequences for endocrine function. The "adaptive" changes in the hypothalamic-pituitary-gonadal, -adrenal, and somatotropic axes and the secretory role of the adipose tissue are reviewed, as are their effects on growth, menstrual cycles, and bone mass acquisition. A systematic search on Medline between 1990 and 2013 was conducted using the following terms: "intense training," "physical activity," or "exercise" combined with "hormone," "endocrine," and "girls," "women," or "elite female athletes." All articles reporting on the endocrine changes related to intense training and their potential implications for growth, menstrual cycles, and bone mass acquisition were considered. Young female athletes present a high prevalence of menstrual disorders, including delayed menarche, oligomenorrhea, and amenorrhea, characterized by a high degree of variability according to the type of sport. Exercise-related reproductive dysfunction may have consequences for growth velocity and peak bone mass acquisition. Recent findings highlight the endocrine role of adipose tissue and energy balance in the regulation of homeostasis and reproductive function. A better understanding of the mechanisms whereby intense training affects the endocrine system may orient research to develop innovative strategies (ie, based on nutritional or pharmacological approaches and individualized modalities of training and competition) to improve the medical care of these adolescents and protect their reproductive function.

Osteocalcin Promotes β-Cell Proliferation During Development and Adulthood Through Gprc6a

Expanding β-cell mass through β-cell proliferation is considered a potential therapeutic approach to treat β-cell failure in diabetic patients. A necessary step toward achieving this goal is to identify signaling pathways that regulate β-cell proliferation in vivo. Here we show that osteocalcin, a bone-derived hormone, regulates β-cell replication in a cyclin D1–dependent manner by signaling through the Gprc6a receptor expressed in these cells. Accordingly, mice lacking Gprc6a in the β-cell lineage only are glucose intolerant due to an impaired ability to produce insulin. Remarkably, this regulation occurs during both the perinatal peak of β-cell proliferation and in adulthood. Hence, the loss of osteocalcin/Gprc6a signaling has a profound effect on β-cell mass accrual during late pancreas morphogenesis. This study extends the endocrine role of osteocalcin to the developmental period and establishes osteocalcin/Gprc6a signaling as a major regulator of β-cell endowment that can become a potential target for β-cell proliferative therapies.

Third trimester NG2-positive amniotic fluid cells are effective in improving repair in spinal cord injury

Spinal cord injury presents a significant therapeutic challenge since the treatments available are mostly vain. The use of stem cells to treat this condition represents a promising new therapeutic strategy; therefore, a variety of stem cell treatments have been recently examined in animal models of CNS trauma.In this work, we analyzed the effects of third trimester amniotic fluid cells in a mouse model of spinal cord injury. Among the different cultures used for transplantation, some were able to induce a significant improvement in motor recovery (cultures #3.5, #3.6 and #7.30), evaluated by means of open field free locomotion. All effective cell cultures expressed the surface marker nerve/glial antigen 2, ortholog of the human chondroitin sulfate proteoglycan 4, which is present on several types of immature progenitor cells. The improved motor functional recovery was correlated with higher myelin preservation in the ventral horn white matter and an increased vascularization in the peri-lesion area. Real-Time PCR analysis showed higher expression levels of vascular endothelial growth factor and hypoxia-inducible factor-1α mRNA two days after cells transplantation compared to PBS-treated animals, indicating that an angiogenic pathway might have been activated by these cells, possibly through the production of hepatocyte growth factor. This cytokine appears to be produced mostly in filtering organs, such as the lung, of the transplanted animals and is likely released in the blood suggesting an endocrine role of hepatocyte growth factor in targeting the injury site.

Adipocytokines in obesity and metabolic disease

The current global obesity pandemic is the leading cause for the soaring rates of metabolic diseases, especially diabetes, cardiovascular disease, hypertension, and non-alcoholic hepatosteatosis. Efforts devoted to find cures for obesity and associated disorders in the past two decades have prompted intensive interest in adipocyte biology, and have led to major advances in the mechanistic understanding of adipose tissue as an essential endocrine organ. Adipose tissue secretes an array of hormones (adipokines) that signal key organs to maintain metabolic homeostasis, and their dysfunction has been causally linked to a wide range of metabolic diseases. In addition, obesity induces production of inflammatory cytokines (often referred to together with adipokines as adipocytokines) and infiltration of immune cells into adipose tissue, which creates a state of chronic low-grade inflammation. Metabolic inflammation has been increasingly recognized as a unifying mechanism linking obesity to a broad spectrum of pathological conditions. This review focuses on classic examples of adipocytokines that have helped to form the basis of the endocrine and inflammatory roles of adipose tissue, and it also details a few newly characterized adipocytokines that provide fresh insights into adipose biology. Studies of adipocytokines in clinical settings and their therapeutic potential are also discussed.

The endocrine role between β cells and intra-islet endothelial cells [Review

The islets of Langerhans is the endocrine function region of pancreas, which exist in five cell types. The majority of endocrine cells are insulin-secreting β cells, mixed up with glucagon-secreting α-cells. The islets of Langerhans are highly vascularized, and the capillary network around the islet is about five times denser than that in the exocrine tissues. It guarantees endocrine cells adequately contact with the capillary networks. Above mentioned is the basis of deep study the interaction between β cells and capillary. Increasing number of studies contribute to the consensus that endothelial cells have positive effects in the islet microenvironment. Endothelial cells can act as endocrine cells which release many active substances, such as hepatocyte growth factors (HGF), thrombospondin-1(TSP-1), laminins, and collagens by means of different molecule pathways, inducing β cells differentiation, proliferation, survivor, and insulin release next to the vessels. Apart from the effect of endothelial cells on β cells by paracrine fashion, the islets can utilize VEGF-A, angiopoietin-1 and insulin signaling to increase the interaction with endothelial cells. As the endocrine role of endothelial cells to β cells, it may be a novel target to stimulate β cells regeneration, promote vascularization post islet transplantation strategy in the treatment of diabetes mellitus.

The many faces of estrogen signaling.

Estrogens have long been known as important regulators of the female reproductive functions; however, our understanding of the role estrogens play in the human body has changed significantly over the past years. It is now commonly accepted that estrogens and androgens have important functions in both female and male physiology and pathology. This is in part due to the local synthesis and action of estrogens that broadens the role of estrogen signaling beyond that of the endocrine system. Furthermore, there are several different mechanisms through which the three estrogen receptors (ERs), ERα, ERβ and G protein-coupled estrogen receptor 1 (GPER1) are able to regulate target gene transcription. ERα and ERβ are mostly associated with the direct and indirect genomic signaling pathways that result in target gene expression. Membrane-bound GPER1 is on the other hand responsible for the rapid non-genomic actions of estrogens that activate various protein-kinase cascades. Estrogen signaling is also tightly connected with another important regulatory entity, i.e. epigenetic mechanisms. Posttranslational histone modifications, microRNAs (miRNAs) and DNA methylation have been shown to influence gene expression of ERs as well as being regulated by estrogen signaling. Moreover, several coregulators of estrogen signaling also exhibit chromatin-modifying activities further underlining the importance of epigenetic mechanisms in estrogen signaling. This review wishes to highlight the newer aspects of estrogen signaling that exceed its classical endocrine regulatory role, especially emphasizing its tight intertwinement with epigenetic mechanisms.

Alterations of serum antioxidant trace elements (Se, Zn and Cu) status in patients with cutaneous leishmaniasis

ObjectiveTo assess the serum antioxidant trace elements selenium (Se), zinc (Zn) and copper (Cu) in cutaneous leishmaniasis patients. MethodsIn this study, serum Se, Zn and Cu was determined by using atomic absorption spectrometry in patients with cutaneous leishmaniasis (n=95). The values were statistically compared between patients and control group (n=100) using One-way analysis of variance (ANOVA). ResultsOur results showed that there was a significant difference in the values of Se and Zn between two groups (P<0.000 1 and P<0.01, respectively). Meanwhile, no significant difference in level of Cu was observed between patients and healthy subjects (P>0.05). Se and Zn levels were found to be (4.33±1.06) and (70.23±19.12) μg/dL in cutaneous leishmaniasis cases, and these values were found statistically lower compared to the controls (11.10±2.37) and (119.61±26.18) μg/dL, respectively. ConclusionsThe observations that host products are released from stimulated leukocytes and could induce metabolic changes similar to an acute-phase response revealed an endocrine role for the immune system. Characteristic changes in trace-mineral metabolism are an integral part of the acute-phase response. The changes are usually reflected in decreased serum Se and Zn concentrations.

Infant Crying, Colic, and Gastrointestinal Discomfort in Early Childhood

y the time their child is 4 months old, up to 20% of parentshave reported colicky symptoms in their infants. Is infantcolic a disorder? Is it related to the intestine, as the term colicimplies? Is any treatment other than reassurance of families regard-ing the transient nature of these symptoms indicated? In short, arewe stepping in an evidence-based arena or are we dealing with ‘‘gutfeelings’’?This supplement on infant crying, colic, and gastrointestinal(GI) disturbances in early childhood provides theoretical andclinical observations on this and other intriguing functional GItopics. The supplement provides the scientific and clinical evidencethat should guide current clinical practice and serve future studiesthat will enable better understanding and appropriate managementby physicians and families alike.Burns and Thapar review the embryonic and postnatal eventsrelated to the enteric nervous system (ENS), which is the regulatorof gut secretion, blood flow, sensation, and coordinated motility (1).They provide evidence that a significant amount of modification ofthe ENS occurs not only during the fetal period but also postnatally;thus the ENS can be altered in a number of ways: stress, infections,and changes in nutrition.Indrio et al focus on the non-nutritive pathophysiology ofcolic, looking at the relation of colic to gastroesophageal reflux(GER), GI motility disorders, the role of gut hormones, andintestinal microflora (2). Their review raises the old debate ofwhether colic is a functional disorder (eg, troubling GER or‘‘immature’’ motility) or should be regarded as a normal develop-mental occurrence. The authors correctly conclude that ‘‘littleevidence supports a substantial role of GER or GERD in themajority of infants with colic,’’ and observations for the role ofhormones such as ghrelin and motilin as well as the positive effectshown for probiotic supplementation should be studied further.Indrio and colleagues also elaborate on the role of probioticsin the management of infant colic and provide recent and excitingdata on the clinical benefit of the administration of probiotics intreating functional disorders and organic diseases (3). This reviewexplores the hypothesis that there is a window of time when the gutmicrobiota may affect the structure and the function of the brain.The review by Di Lorenzo on early life events brings uselegantly to the ‘‘vulnerable child,’’ summarizing what is knownabout factors that predispose an infant to become colicky (4). Muchof the available data refers to the possible link among infectious,inflammatory, and psychological noxious events that may causechanges in enteric nerve reactivity, as well as immune responses oralterations in intestinal microbiota composition that can then lead tofunctional GI disorders later in life. For example, there is evidencethat early pain experiences are associated with altered painresponses later in infancy. Although the genetic background cannotbe changed and the stressful events may be unavoidable, identifyingthe child at risk may provide an opportunity for interventions thatwill attenuate or prevent later functional disorders.Ha-Vinh Leuchter et al discuss the possibility that the peakshape of the crying behavior found in colicky as opposed to non-colicky babies, the circadian rhythm of the crying, and the obser-vation that these babies are not soothed by ordinary sensorystimulation reflect a difference in central nervous system function-ing (eg, differences in circadian rhythm maturation, differentresponse to stimuli) rather than GI dysfunction (5).Heine summarizes available data on the relation betweencow’s-milk allergy and infant colic (6). He notes that in breast-fedinfants, elimination of cow’s milk and other food proteins from thematernal diet was associated with a greater reduction in crying orfussiness duration, and that the treatment of formula-fed infantswith extensively hydrolysed formula was associated with reducedcrying in several clinical trials. The use of lactose-free formulaeprovides inconsistent results, however. A limited trial of an

Conditioned mesenchymal stem cells produce pleiotropic gut trophic factors

Although mounting evidence implicates mesenchymal stem cells (MSCs) in intestinal tissue repair, controversy remains regarding the engraftment, proliferation, and differentiation for repopulating MSCs in recipient tissues. Therefore, we investigated the paracrine and/or endocrine role of MSCs in experimental colitis. We analyzed the therapeutic effects of MSC-conditioned medium (MSC-CM) on dextran sulfate sodium (DSS)- or 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis. We investigated the effects of MSC-CM on the epithelial cell viability, mobility, cell cycle, and cytokine production in ex vivo lamina propria/mesenteric lymphocytes, a macrophage cell line, and the mixed lymphocyte reaction. An optimal regimen against colitis was explored. The contents of MSC-CM were analyzed using a WNT signaling pathway polymerase chain reaction array, an inflammatory cytokines antibody array, and liquid chromatography-tandem mass spectrometry analysis. Independent of the systemic administration route, MSC-CM concentrates were effective for the inductive phase of TNBS-induced colitis and for the recovery phase of DSS-induced colitis. Hypoxia appeared to be one of the optimal preconditioning factors assessed by cell motility and viability through activating the PI3K-Akt pathway in rat small intestine epithelial cells, IEC-6. Thus, Hypoxia had profound effects on the contents of MSC-CM, which comprised pleiotropic gut trophic factors involved in each wound healing process, including the anti-inflammatory, proliferative, and tissue remodeling phases. Identification and optimization of potential gut trophic factors in MSC-CM is urgently needed to form the basis for new drug discovery and for optimizing cell-based therapies for inflammatory bowel disease.

Allatotropin: An Ancestral Myotropic Neuropeptide Involved in Feeding

BackgroundCell-cell interactions are a basic principle for the organization of tissues and organs allowing them to perform integrated functions and to organize themselves spatially and temporally. Peptidic molecules secreted by neurons and epithelial cells play fundamental roles in cell-cell interactions, acting as local neuromodulators, neurohormones, as well as endocrine and paracrine messengers. Allatotropin (AT) is a neuropeptide originally described as a regulator of Juvenile Hormone synthesis, which plays multiple neural, endocrine and myoactive roles in insects and other organisms.MethodsA combination of immunohistochemistry using AT-antibodies and AT-Qdot nanocrystal conjugates was used to identify immunoreactive nerve cells containing the peptide and epithelial-muscular cells targeted by AT in Hydra plagiodesmica. Physiological assays using AT and AT- antibodies revealed that while AT stimulated the extrusion of the hypostome in a dose-response fashion in starved hydroids, the activity of hypostome in hydroids challenged with food was blocked by treatments with different doses of AT-antibodies.ConclusionsAT antibodies immunolabeled nerve cells in the stalk, pedal disc, tentacles and hypostome. AT-Qdot conjugates recognized epithelial-muscular cell in the same tissues, suggesting the existence of anatomical and functional relationships between these two cell populations. Physiological assays indicated that the AT-like peptide is facilitating food ingestion.SignificanceImmunochemical, physiological and bioinformatics evidence advocates that AT is an ancestral neuropeptide involved in myoregulatory activities associated with meal ingestion and digestion.

Serum omentin levels in patients with obstructive sleep apnea

Obstructive sleep apnea syndrome (OSAS) is associated with increased rates of cardiovascular diseases (CVD). The basic mechanisms involved in the increased cardiovascular risk of OSAS remain unclear. Recent discoveries of fat-secreted substances which serve endocrine roles improve our understanding of the relationship between OSAS, CVD, and the metabolic syndrome. In this study, we aimed to examine associations between omentin levels and OSA. Forty-six newly diagnosed OSA patients and 35 non-apneic controls were enrolled in this study. Demographical data, cigarette smoking status, previous history of chronic diseases including CVD and metabolic diseases and drugs, and habits were obtained using a standardized questionnaire. All patients underwent polysomnographic evaluation. Omentin was measured the following morning. The mean age was 48.1 ± 12.5 (24-74) years in the OSA group and 42.8 ± 14.1 (21-69) years in the control group. Of the 81 patients, 46 (34 males and 12 females) were classified as having OSA and 35 patients (20 males and 15 females) as control. Plasma levels of omentin were found to be markedly higher in OSA patients (570.8 ng/ml) than in the control group (432.0 ng/ml; p < 0.001). In addition, plasma levels of omentin were found to be high in all OSA subgroups than in controls. The plasma omentin levels were significantly correlated only with age in patients with OSA. We conclude that circulating omentin levels are elevated in OSA patients. To the best of our knowledge, this is the first clinical study that demonstrated the association between omentin and OSA.

An endocrine role for brown adipose tissue?

White adipose tissue is recognized as both a site of energy storage and an endocrine organ that produces a myriad of endocrine factors called adipokines. Brown adipose tissue (BAT) is the main site of nonshivering thermogenesis in mammals. The amount and activity of brown adipocytes are associated with protection against obesity and associated metabolic alterations. These effects of BAT are traditionally attributed to its capacity for the oxidation of fatty acids and glucose to sustain thermogenesis. However, recent data suggest that the beneficial effects of BAT could involve a previously unrecognized endocrine role through the release of endocrine factors. Several signaling molecules with endocrine properties have been found to be released by brown fat, especially under conditions of thermogenic activation. Moreover, experimental BAT transplantation has been shown to improve glucose tolerance and insulin sensitivity mainly by influencing hepatic and cardiac function. It has been proposed that these effects are due to the release of endocrine factors by brown fat, such as insulin-like growth factor I, interleukin-6, or fibroblast growth factor-21. Further research is needed to determine whether brown fat plays an endocrine role and, if so, to comprehensively identify which endocrine factors are released by BAT. Such research may reveal novel clues for the observed association between brown adipocyte activity and a healthy metabolic profile, and it could also enlarge a current view of potential therapeutic tools for obesity and associated metabolic diseases.

Osteocytes are not only mechanoreceptive cells

Osteocytes represent 95% of all bone cells. These cells are old osteoblasts occupying the lacunar space surrounded by the bone matrix. They possess cytoplasmic dendrites that form a canalicular network for communication between osteocytes and the bone surface. They have a mechanosensing role that is dependent upon the frequency, the intensity, and the duration of strain. The mechanical information transmitted into the cytoplasm also triggers a biological cascade, starting with nitric oxide and prostaglandin E 2 and followed by Wnt/ β-catenin signaling. This information is transmitted to the bone surface through the canalicular network, particularly to the lining cells, and is able to trigger bone remodeling by directing the osteoblast activity and the osteoclastic resorption. Furthermore, the osteocyte death seems to play an important role. The outcome of microcracks in the vicinity of osteocytes may interrupt the canalicular network and trigger cell apoptosis in the immediate surrounding environment thus transmitting a message to the bone surface and activate remodeling. This network also plays a recognized endocrine role, particularly concerning phosphate regulation and vitamin D metabolism.

Silencing of ghrelin receptor expression inhibits endometrial cancer cell growth in vitro and in vivo

Ghrelin is a 28-amino acid peptide hormone produced predominantly in the stomach but also in a range of normal cell types and tumors, where it has endocrine, paracrine, and autocrine roles. Previously, we have demonstrated that ghrelin has proliferative and antiapoptotic effects in endometrial cancer cell lines, suggesting a potential role in promoting tumor growth. In the present study, we investigated the effect of ghrelin receptor, GHSR, and gene silencing in vitro and in vivo and characterized ghrelin and GHSR1a protein expression in human endometrial tumors. GHSR gene silencing was achieved in the Ishikawa and KLE endometrial cancer cell lines, using a lentiviral short-hairpin RNA targeting GHSR. The effects of GHSR1a knockdown were further analyzed in vivo using the Ishikawa cell line in a NOD/SCID xenograft model. Cell proliferation was reduced in cultured GHSR1a knockdown Ishikawa and KLE cells compared with scrambled controls in the absence of exogenously applied ghrelin and in response to exogenous ghrelin (1,000 nM). The tumor volumes were reduced significantly in GHSR1a knockdown Ishikawa mouse xenograft tumors compared with scrambled control tumours. Using immunohistochemistry, we demonstrated that ghrelin and GHSR1a are expressed in benign and cancerous glands in human endometrial tissue specimens, although there was no correlation between the intensity of staining and cancer grade. These data indicate that downregulation of GHSR expression significantly inhibits endometrial cancer cell line and mouse xenograft tumour growth. This is the first preclinical evidence that downregulation of GHSR may be therapeutic in endometrial cancer.

INSL3 as a Biomarker of Leydig Cell Functionality

Insulin-like factor 3 (INSL3) is a small peptide hormone made and secreted uniquely by mature Leydig cells in the testes of all mammals. Importantly, this expression and secretion appears to be constitutive and therefore reflects the differentiation status and number of the Leydig cells present, differing thereby from testosterone, which is acutely and homeostatically regulated by the hormones of the hypothalamic-pituitary-gonadal axis. As a consequence, the measurement of INSL3 either as mRNA in the testis or as secreted peptide circulating in the blood provides an excellent assessment of Leydig cell differentiation, for example, during fetal development, puberty, or aging or following exposure to endocrine-disrupting agents. Whereas INSL3 is proving increasingly useful as a biomarker for testis status, less is known about its functions, particularly in the adult male. Current evidence points to autocrine, paracrine, and endocrine roles, acting through the G-protein-coupled receptor called RXFP2, although more research is required to characterize these functions in detail.

Abstract 1932: Association of genetic variants with prostate cancer risk.

Abstract Background: Genetic alterations can contribute to the malignant transformation and progression of prostate cancer. We have previously shown a strong association between specific leptin gene alleles, elevated serum leptin level, and body mass index in subjects with prostate and breast cancer. These studies showing association with leptin suggest a strong link with obesity as an increased risk factor. Studies have shown that adipose tissue TNFa and leptin, which are both overexpressed in obesity, induces the production of acute phase reactants through their autocrine or endocrine role. When GSTP1 is inactivated, prostate cells appear to become more vulnerable to somatic alterations upon chronic exposure to genome-damaging stresses such as oxidants and electrophiles that are contributed by environment and lifestyle. Studies also show that the methylation status of glutathione S-transferase p1 (GSTP1) could individually distinguish prostate cancer from benign prostatic hyperplasia. Based on prior studies, it is possible that multi gene analysis can provide better diagnostic or prognostic values for prostate cancer. Methods: In this study, we screened leptin gene markers, TNFa, GSTP1 and BCCIP(TOK-1A) in 126 prostate cancer and normal healthy age &amp; sex matched controls (Prostate cases: Age range 45-94, Mean age 73.3 Control males: Age range 65-98, Mean age 73.5). Polymerase chain reaction was used to amplify Leptin, TNF-308 and GSTP1 genes and the products are analyzed using 3130 Genetic analyzer and PCR-RFLP methods. Statistical analysis was performed using the SPSS/PC statistical program (version 10.0 for Windows; SPSS, Inc.,Chicago, IL). Relationships between two groups and genotype variables were assessed by Pearson's correlation coefficient. Conclusions: Prostate cancer is a complex, heterogeneous disease and there a variety of gene-based biomarkers that have been associated with prostate cancer. Our results show strong association of leptin (p&amp;lt;0.006), GSTP1 (p&amp;lt;0.023) with prostate cancer. Individually TNF and BCCIP showed a modest association but TNF/BCCIP gene interaction had a significant effect on prostate cancer risk and disease progression suggesting a multigene model for prostate cancer screening. Citation Format: Radhika G. Andavolu, Jean-Luc Cardenas, Ross Shore, Zach Rubin, James MacMurray, Krishna Kanth Chiravuri, Murthy VS Andavolu, Svetlana Rubakovic. Association of genetic variants with prostate cancer risk. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1932. doi:10.1158/1538-7445.AM2013-1932