Dysregulation of RNA-Exosome machinery is directly linked to major cancer hallmarks in prostate cancer: Oncogenic role of PABPN1.

Novel biomarkers and therapeutic strategies for prostate-cancer (PCa) are required to overcome its lethal progression. The dysregulation/implication of the RNA-Exosome-complex (REC; cellular machinery controlling the 3'-5'processing/degradation of most RNAs) in different cancer-types, including PCa, is poorly known. Herein, different cellular/molecular/preclinical approaches with human PCa-samples (tissues and/or plasma of 7 independent cohorts), and in-vitro/in-vivo PCa-models were used to comprehensively characterize the REC-profile and explore its role in PCa. Moreover, isoginkgetin (REC-inhibitor) effects were evaluated on PCa-cells. We demonstrated a specific dysregulation of the REC-components in PCa-tissues, identifying the Poly(A)-Binding-Protein-Nuclear 1 (PABPN1) factor as a critical regulator of major cancer hallmarks. PABPN1 is consistently overexpressed in different human PCa-cohorts and associated with poor-progression, invasion and metastasis. PABPN1 silencing decreased relevant cancer hallmarks in multiple PCa-models (proliferation/migration/tumourspheres/colonies, etc.) through the modulation of key cancer-related lncRNAs (PCA3/FALEC/DLEU2) and mRNAs (CDK2/CDK6/CDKN1A). Plasma PABPN1 levels were altered in patients with metastatic and tumour-relapse. Finally, pharmacological inhibition of REC-activity drastically inhibited PCa-cell aggressiveness. Altogether, the REC is drastically dysregulated in PCa, wherein this novel molecular event/mechanism, especially PABPN1 alteration, may be potentially exploited as a novel prognostic and therapeutic tool for PCa.

Alternative splicing in bladder cancer: potential strategies for cancer diagnosis, prognosis, and treatment.

Bladder cancer is the most common malignancy of the urinary tract worldwide. The therapeutic options to tackle this disease comprise surgery, intravesical or systemic chemotherapy, and immunotherapy. Unfortunately, a wide number of patients ultimately become resistant to these treatments and develop aggressive metastatic disease, presenting a poor prognosis. Therefore, the identification of novel therapeutic approaches to tackle this devastating pathology is urgently needed. However, a significant limitation is that the progression and drug response of bladder cancer is strongly associated with its intrinsic molecular heterogeneity. In this sense, RNA splicing is recently gaining importance as a critical hallmark of cancer since can have a significant clinical value. In fact, a profound dysregulation of the splicing process has been reported in bladder cancer, especially in the expression of certain key splicing variants and circular RNAs with a potential clinical value as diagnostic/prognostic biomarkers or therapeutic targets in this pathology. Indeed, some authors have already evidenced a profound antitumor effect by targeting some splicing factors (e.g., PTBP1), mRNA splicing variants (e.g., PKM2, HYAL4-v1), and circular RNAs (e.g., circITCH, circMYLK), which illustrates new possibilities to significantly improve the management of this pathology. This review represents the first detailed overview of the splicing process and its alterations in bladder cancer, and highlights opportunities for the development of novel diagnostic/prognostic biomarkers and their clinical potential for the treatment of this devastating cancer type. This article is categorized under: RNA Processing > Splicing Regulation/Alternative Splicing RNA in Disease and Development > RNA in Disease.

Truncated variants of pig somatostatin receptor subtype 5 (sst5) act as dominant-negative modulators for sst2-mediated signaling.

Somatostatin (SST) and its related peptide cortistatin (CORT) exert their multiple actions through binding to the SST receptor (sst) family, generally considered to comprise five G protein-coupled receptors with seven transmembrane domains (TMD), named sst1-sst5, plus a splice sst2B variant. However, we recently discovered that human and rodent sst5 gene expression also generates, through noncanonical alternative splicing, novel truncated albeit functional sst5 variants with less than seven TMD. Here, we cloned and characterized for the first time the porcine wild-type sst5 (psst5, full-length) and identified two novel truncated psst5 variants with six and three TMD, thus termed psst5TMD6 and psst5TMD3, respectively. In line with that observed in human and rodent truncated sst5 variants, psst5TMD6 and psst5TMD3 are functional (e.g., activate calcium signaling), selectively respond to SST and CORT, respectively, and exhibit specific tissue expression profiles that differ from full-length psst5 and often overlaps with psst2 expression. Moreover, fluorescence resonance energy transfer analysis shows that psst5 truncated variants physically interact with psst2, thereby altering their localization at the plasma membrane and specifically disrupting the cellular response to SST and/or CORT. These results represent the first characterization of a key porcine SST receptor, psst5, and, together with our previous results, provide strong evidence that alternative splicing-derived, truncated sst5 variants with distinct functional capacities exist in the mammalian lineage, where they can act as dominant-negative receptors, by interacting directly with long, seven TMD variants, potentially contributing to modulate normal and pathological SST and CORT signaling.

Genomic insights into the early peopling of the Caribbean.

The Caribbean was one of the last regions of the Americas to be settled by humans, but where they came from and how and when they reached the islands remain unclear. We generated genome-wide data for 93 ancient Caribbean islanders dating between 3200 and 400 calibrated years before the present and found evidence of at least three separate dispersals into the region, including two early dispersals into the Western Caribbean, one of which seems connected to radiation events in North America. This was followed by a later expansion from South America. We also detected genetic differences between the early settlers and the newcomers from South America, with almost no evidence of admixture. Our results add to our understanding of the initial peopling of the Caribbean and the movements of Archaic Age peoples in the Americas.

In vivo and in vitro structure-activity relationships and structural conformation of Kisspeptin-10-related peptides.

Kisspeptins, the natural ligands of the G protein-coupled receptor KISS1R, comprise a family of related peptides derived from the proteolytic processing of a common precursor encoded by the KISS1 gene. Among those, Kisspeptin-10 (Kp-10) contains the basic residues to retain full functional activity and exhibits higher receptor affinity and biopotency than longer forms of the peptide. Although kisspeptins were first characterized by their ability to inhibit tumor metastasis, recent studies have revealed that the KISS1/KISS1R system plays an essential role in the neuroendocrine control of the reproductive axis. In this context, development and functional analysis of Kp-10 analogs may help in the search for new agonists and antagonists as valuable tools to manipulate the KISS1/KISS1R system and hence fertility. We report herein functional and structural analyses of a series of Ala-substituted rat kp-10 analogs, involving [Ca(2+)](i) responses in rat kiss1r-transfected Chinese hamster ovary cells, dynamic luteinizing hormone (LH) responses in vivo, and NMR structural studies. In vitro assays revealed that Ala substitutions in positions 6 or 10 of kp-10 resulted in a significant increase in EC(50) values (>6.46 x 10(-6) M versus 1.54 to 2.6 x 10(-8) M for rat and human Kp-10, respectively) and a substantial decrease in the proportion of responsive cells coupled to a marked increase in the time required to reach maximal response. In vivo assays showed that Ala(6) substitution diminished and Ala(10) substitution eliminated LH secretory responses, whereas coadministration of each analog failed to affect the LH-releasing ability of kp-10. Molecular modeling under NMR restraints revealed that kp-10 exhibits a helicoidal structure between the Asn(4) and Tyr(10) residues, with mixed alpha- and 3(10)-helix characteristics. Ala(6) substitution induced limited destabilization of the helix around the position of the substitution. Ala(10) substitution was found to totally disrupt the helical structure in the C-terminal region of the molecule. Taken together, our results indicate that positions 6 and 10 are critical for kp-10 action at kiss1r and suggest that modifications in these positions could lead to the generation of new kisspeptin agonists and/or antagonists with altered functional and perhaps binding properties. Furthermore, they emphasize the importance of using combined, multidisciplinary approaches, including in vivo studies, to reliably evaluate structure function properties of novel kisspeptin analogs.

Intracellular signaling pathways activated by kisspeptins through GPR54: do multiple signals underlie function diversity?

Kisspeptins, a family of peptide products derived from the KiSS-1 gene, activate their cognate receptor GPR54 in various target tissues to exert disparate functions, including inhibition of tumor metastasis and control of reproductive function. In contrast to the plethora of studies that have analyzed in recent years the regulatory functions of the KiSS-1/GPR54 system, only a limited number of reports have been primarily focused on delineating the intracellular signaling pathways involved. Nevertheless, there is solid evidence indicating that kisspeptin can activate a wide variety of signals via GPR54. These include typical G-protein (Galphaq/11)-coupled cascades, such as activation of phospholipase C (PLC), and subsequent accumulation of inositol-(1,4,5)-triphosphate (IP3), intracellular Ca(2+) mobilization, and activation of protein kinase C. However, kisspeptin also activates pathways related to mitogen activated protein kinases (MAPK), especially ERK1/2, and p38 and phosphatidylinositol-3-kinase (PI3K)/Akt. Additionally, the kisspeptin/GPR54 pair can also influence cell signaling by interacting with other receptors, such as chemokine receptor CXCR4, and GnRH receptor. Kisspeptin can also affect other signaling events, like expression of matrix metalloproteinase 9 (via NFkappaB), and that of calcineurin. The information gathered hitherto clearly indicates that activation of a specific set of interconnected signals is selectively triggered by kisspeptin via GPR54 in a cell type-dependent manner to precisely regulate functions as distinct as hormone release and cell migration. In this scenario, it will be important to decipher kisspeptin/GPR54 signaling mechanisms in reproductive and non-reproductive tissues by studying additional models, especially on natural kisspeptin targets expressing endogenous GPR54.

Rab18 is reduced in pituitary tumors causing acromegaly and its overexpression reverts growth hormone hypersecretion.

CONTEXT: Rab proteins regulate the sequential steps of intracellular membrane transport. Alterations of these GTPases and their associated proteins are emerging as the underlying cause for several human diseases involving dysregulated secretory activities. OBJECTIVE: Herein we investigated the role of Rab18, which negatively regulates hormone secretion by interacting with secretory granules, in relation to the altered functioning of tumoral pituitary somatotropes causing acromegaly. PATIENTS: A total of 18 patients diagnosed with pituitary tumors causing acromegaly (nine patients) or nonfunctioning adenomas (nine patients) underwent endoscopic transsphenoidal surgery. Adenomas were subsequently processed to evaluate Rab18 production in relation to GH secretion. RESULTS: We found that somatotropinoma cells are characterized by a high secretory activity concomitantly with a remarkably reduced Rab18 expression (15%) and protein content levels (30%), as compared with cells from nonfunctioning pituitary adenomas derived from patients with normal or reduced GH plasma levels (100%). Furthermore, immunoelectron microscopy revealed that Rab18 association with the surface of GH-containing secretory granules was significantly lower in somatotropes from acromegalies than nonfunctioning pituitary adenomas. Finally, we provide evidence that modulation of Rab18 gene expression can revert substantially the hypersecretory activity of cells because Rab18 overexpression reduced by 40% the capacity of cells from acromegalies to respond to GHRH stimulation. CONCLUSION: These results suggest that molecular alterations affecting individual components of the secretory granule traffic machinery can contribute to maintain a high level of GH in plasma. Accordingly, Rab18 constitutes a valuable target as a diagnostic, prognostic, and/or therapeutic tool for human acromegaly.

Urotensin II and urotensin II-related peptide activate somatostatin receptor subtypes 2 and 5.

The UII and urotensin II-related peptide (URP) genes belong to the same superfamily as the somatostatin gene. It has been previously shown that somatostatin activates the UII-receptor (UTR). In contrast, the possible interaction between UII and URP and somatostatin receptors has remained scarcely analyzed. Herein, we have investigated the effects of UII and URP on cell proliferation and free cytosolic Ca2+ concentration ([Ca2+]i) in CHO-K1 cells stably expressing the porcine somatostatin receptor subtypes sst2 and sst5. Results show that both UII and URP induce stimulation of cell proliferation mediated by sst2 receptors and UII provokes inhibition of cell proliferation mediated by sst5 receptors. UII and URP also provoked an increase of [Ca2+]i in both sst2- and sst5-transfected cells. Together, our present data demonstrate that UII and URP directly activate sst2 and sst5 and thus mimic the effect of somatostatin on its cognate receptors.

Ghrelin-O-Acyltransferase (GOAT) Enzyme as a Novel Potential Biomarker in Gastroenteropancreatic Neuroendocrine Tumors.

OBJECTIVES: The association between the presence and alterations of the components of the ghrelin system and the development and progression of neuroendocrine tumors (NETs) is still controversial and remains unclear. METHODS: Here, we systematically evaluated the expression levels (by quantitative-PCR) of key ghrelin system components of in gastroenteropancreatic (GEP)-NETs, as compared to non-tumor adjacent (NTA; n = 42) and normal tissues (NT; n = 14). Then, we analyzed their putative associations with clinical-histological characteristics. RESULTS: The results indicate that ghrelin and its receptor GHSR1a are present in a high proportion of normal tissues, while the enzyme ghrelin-O-acyltransferase (GOAT) and the splicing variants In1-ghrelin and GHSR1b were present in a lower proportion of normal tissues. In contrast, all ghrelin system components were present in a high proportion of tumor and NTA tissues. GOAT was significantly overexpressed (by quantitative-PCR (qPCR)) in tumor samples compared to NTA, while a trend was found for ghrelin, In1-ghrelin and GHSR1a. In addition, expression of these components displayed significant correlations with key clinical parameters. The marked overexpression of GOAT in tumor samples compared to NTA regions was confirmed by IHC, revealing that this enzyme is particularly overexpressed in gastrointestinal NETs, where it is directly correlated with tumor diameter. CONCLUSIONS: These results provide novel information on the presence and potential pathophysiological implications of the ghrelin system components in GEP-NETs, wherein GOAT might represent a novel diagnostic biomarker.

Regulation of pituitary cell function by adiponectin.

Adiponectin is a member of the family of adipose tissue-related hormones known as adipokines, which exerts antidiabetic, antiatherogenic, antiinflammatory, and antiangiogenic properties. Adiponectin actions are primarily mediated through binding to two receptors expressed in several tissues, AdipoR1 and AdipoR2. Likewise, adiponectin expression has been detected in adipocytes as well as in a variety of extra-adipose tissues, including the chicken pituitary. Interestingly, adiponectin secretion and adiponectin receptor expression in adipocytes have been shown to be regulated by pituitary hormones. These observations led us to investigate whether adiponectin, like the adipokine leptin, regulates pituitary hormone production. Specifically, we focused our analysis on somatotrophs and gonadotrophs because of the relationship between the control of energy metabolism, growth and reproduction. To this end, the effects of adiponectin on both GH and LH secretion as well as its interaction with major stimulatory regulators of somatotrophs (ghrelin and GHRH) and gonadotrophs (GnRH) and with their corresponding receptors (GHS-R, GHRH-R, and GnRH-R), were evaluated in rat pituitary cell cultures. Results show that adiponectin inhibits GH and LH release as well as both ghrelin-induced GH release and GnRH-stimulated LH secretion in short-term (4 h) treated cell cultures, wherein the adipokine also increases GHRH-R and GHS-R mRNA content while decreasing that of GnRH-R. Additionally, we demonstrate that the pituitary expresses both adiponectin and adiponectin receptors under the regulation of the adipokine. In sum, our data indicate that adiponectin, either locally produced or from other sources, may play a neuroendocrine role in the control of both somatotrophs and gonadotrophs.

Porcine somatostatin receptor 2 displays typical pharmacological sst2 features but unique dynamics of homodimerization and internalization.

Somatostatin (SRIF) exerts its multiple actions, including inhibition of GH secretion and of tumoral growth, through a family of five receptor subtypes (sst1-sst5). We recently reported that an sst2-selective agonist markedly decreases GH release from pig somatotropes, suggesting important roles for this scarcely explored receptor, psst2. Here, functional expression of psst2 in Chinese hamster ovary-K1 and human embryonic kidney-293-AD cell lines was employed to determine its pharmacological features and functional ability to reduce cAMP, and to examine its homodimerization and internalization dynamics in real time in single living cells. Results show that psst2 is a high-affinity receptor (dissociation constant = 0.27 nM) displaying a typical sst2 profile (nM affinity for SRIF-14> or =SRIF-28>cortistatin>MK678>octreotide) and high selectivity (EC(50) = 1.1 nM) for the sst2 agonist l-779,976, but millimolar or undetectable affinity to other sst-specific agonists (sst3>sst1>sst5>>>sst4). Accordingly, SRIF dose-dependently inhibited forskolin-stimulated cAMP with high potency (EC(50) = 6.55 pm) and modest efficacy (maximum 29.1%) via psst2. Cotransfection of human embryonic kidney-293 and Chinese hamster ovary-K1 cells with two receptor constructs modified with distinct fluorescent tags (psst2-YFP/psst2-CFP) enabled fluorescence resonance energy transfer measurement of physical interaction between psst2 receptors and also receptor internalization in single living cells. This revealed that under basal conditions, psst2 forms constitutive homodimers/homomultimers, which dissociate immediately (11 sec) upon SRIF binding. Interestingly, contrary to human sst2, psst2 rapidly reassociates (110.5 sec) during a subsequent process that temporally overlaps with receptor internalization (half-maximal = 95.1 sec). Therefore, psst2 is a potent inhibitory receptor displaying a unique set of interrelated dynamic features of agonist-dependent dimerization, dissociation, internalization, and reassociation, a cascade of events that might be critical for receptor function.

Ghrelin is produced by and directly activates corticotrope cells from adrenocorticotropin-secreting adenomas.

CONTEXT: In Cushing's disease, ACTH hypersecretion by pituitary corticotrope adenoma cells and resulting hypercortisolism is accompanied by a severely blunted GH secretory response. Interestingly, in Cushing's disease, ghrelin markedly increases plasma ACTH, whereas its stimulatory action on GH secretion is reduced. Although the reported expression of ghrelin receptors (GHS-R) in corticotrope tumors offers a potential mechanism for ghrelin-induced ACTH hypersecretion, studies on the direct effects of synthetic GH secretagogues on corticotropinoma cells offered contradictory results. OBJECTIVE AND DESIGN: To evaluate the direct action of ghrelin on corticotropinoma cells from two patients with Cushing's disease, we measured its effect on free cytosolic calcium concentration ([Ca(2+)](i)). Additionally, expression of GHS-R and its ligand ghrelin was examined in these cells and in five additional corticotropinomas. RESULTS: Ghrelin (10(-6) m) induced a marked [Ca(2+)](i) increase in 89.5% (case 1; n = 19 cells) and 85% (case 2; n = 13 cells) of corticotropinoma cells. Moreover, RT-PCR showed that expression of GHS-R isoforms is accompanied by that of ghrelin in all seven corticotrope adenomas examined. Importantly, double immunogold electron microscopy revealed that ghrelin is costored within ACTH secretory vesicles in densely granulated adenomatous corticotropes. CONCLUSIONS: These results constitute the first demonstration that ghrelin acts directly on corticotrope tumor cells derived from patients with Cushing's disease. The presence of ghrelin and GHS-R suggests that pituitary ghrelin may play an autocrine/paracrine role in regulating ACTH release in Cushing's disease. Our findings provide a plausible cellular basis for the exaggerated ACTH response to ghrelin in Cushing's disease and suggest novel research strategies to develop medical treatments for this disease.

Role of the Kiss1/Kiss1r system in the regulation of pituitary cell function.

Kisspeptin (Kiss1) is an amidated neurohormone that belongs to the RF-amide peptide family, which has a key role in the control of reproduction. Specifically, kisspeptin regulates reproductive events, including puberty and ovulation, primarily by activating the surface receptor Kiss1r (aka GPR54), at hypothalamic gonadotropin-releasing hormone (GnRH) neurons. More recently, it has been found that kisspeptin peptide is present in the hypophyseal portal circulation and that the Kiss1/Kiss1r system is expressed in pituitary cells, which suggest that kisspeptin could exert an endocrine, paracrine or even autocrine role at the pituitary gland level. Indeed, mounting evidence is pointing towards a direct role of kisspeptin in the control of not only gonadotropins but also other pituitary secretions such as growth hormone or prolactin. In this review, we summarize the most recent advances in the study of the role that the Kiss/Kiss1r system plays in the control of pituitary gland function, paying special attention to the direct role of this neuropeptide on pituitary cells and its interactions with other relevant regulators.

Gonadotropin-releasing hormone (GnRH) receptor expression and membrane signaling in early embryonic GnRH neurons: role in pulsatile neurosecretion.

The characteristic pulsatile secretion of GnRH from hypothalamic neurons is dependent on an autocrine interaction between GnRH and its receptors expressed in GnRH-producing neurons. The ontogeny and function of this autoregulatory process were investigated in studies on the properties of GnRH neurons derived from the olfactory placode of the fetal rat. An analysis of immunocytochemically identified, laser-captured fetal rat hypothalamic GnRH neurons, and olfactory placode-derived GnRH neurons identified by differential interference contrast microscopy, demonstrated coexpression of mRNAs encoding GnRH and its type I receptor. Both placode-derived and immortalized GnRH neurons (GT1-7 cells) exhibited spontaneous electrical activity that was stimulated by GnRH agonist treatment. This evoked response, as well as basal neuronal firing, was abolished by treatment with a GnRH antagonist. GnRH stimulation elicited biphasic intracellular calcium ([Ca2+]i) responses, and both basal and GnRH-stimulated [Ca2+]i levels were reduced by antagonist treatment. Perifused cultures released GnRH in a pulsatile manner that was highly dependent on extracellular Ca2+. The amplitude of GnRH pulses was increased by GnRH agonist stimulation and was diminished during GnRH antagonist treatment. These findings demonstrate that expression of GnRH receptor, GnRH-dependent activation of Ca2+ signaling, and autocrine regulation of GnRH release are characteristics of early fetal GnRH neurons and could provide a mechanism for gene expression and regulated GnRH secretion during embryonic migration.

Regulation of cyclic adenosine 3',5'-monophosphate signaling and pulsatile neurosecretion by Gi-coupled plasma membrane estrogen receptors in immortalized gonadotropin-releasing hormone neurons.

Immortalized GnRH neurons (GT1-7) express receptors for estrogen [estrogen receptor-alpha and -beta(ERalpha and ERbeta)] and progesterone (progesterone receptor A) and exhibit positive immunostaining for both intracellular and plasma membrane ERs. Exposure of GT1-7 cells to picomolar estradiol concentrations for 5-60 min caused rapid, sustained, and dose-dependent inhibition of cAMP production. In contrast, treatment with nanomolar estradiol concentrations for 60 min increased cAMP production. The inhibitory and stimulatory actions of estradiol on cAMP formation were abolished by the ER antagonist, ICI 182,780. The estradiol-induced inhibition of cAMP production was prevented by treatment with pertussis toxin, consistent with coupling of the plasma membrane ER to an inhibitory G protein. Coimmunoprecipitation studies demonstrated an estradiol-regulated stimulatory interaction between ERalpha and Galphai3 that was prevented by the ER antagonist, ICI 182,780. Exposure of perifused GT1-7 cells and hypothalamic neurons to picomolar estradiol levels increased the GnRH peak interval, shortened peak duration, and increased peak amplitude. These findings indicate that occupancy of the plasma membrane-associated ERs expressed in GT1-7 neurons by physiological estradiol levels causes activation of a Gi protein and modulates cAMP signaling and neuropeptide secretion.

Regulation of cyclic adenosine 3',5'- monophosphate signaling and pulsatile neurosecretion by Gi-coupled plasma membrane estrogen receptors in immortalized gonadotrophin-releasing hormone neurons.

Immortalized GnRH neurons (GT1-7) express receptors for estrogen [estrogen receptor-alpha and-13(ERa and ERI3)] and progesterone (progesterone receptor A) and exhibit positive immunostaining for both intracellular and plasma membrane ERs. Exposure of GT1-7 cells to picomolar estradiol concentrations for 5-60 min caused rapid, sustained,and dose-dependent inhibition of cAMP production. In contrast, treatment with nanomolar estradiol concentrations for 60 min increased cAMP production. The inhibitory and stimulatory actions of estradiol on cAMP formation were abolished by the ER antagonist, ICI 182,780. The estradiol-induced inhibition of cAMP production was prevented by treatment with pertussis toxin, consistent with coupling of the plasma membrane ER to an inhibitory G protein. Coimmunoprecipitation studies demonstrated an estradiol-regulated stimulatory interaction between ERa and G,3 that was prevented by the ER antagonist, ICI 182,780. Exposure of perifused GT1-7 cells and hypothalamic neurons to picomolar estradiol levels increased the GnRH peak interval, shortened peak duration, and increased peak amplitude. These findings indicate that occupancy of the plasma membrane-associated ERs expressed in GT1-7 neurons by physio-logical estradiol levels causes activation of a G, protein and modulates cAMP signaling and neuropeptide secretion.

The race concept in six regions: variation without consensus.

Race, once the central concept in physical anthropology worldwide, now varies in the degree of support it receives in different regions. We present the currently available information on the status of the concept in the United States, the Spanish language areas, Poland, Europe, Russia, and China. Rejection of race ranges from high to low with the highest rejection occurring among anthropologists in the United States (and Canada). Rejection of race is moderate in Europe, sizeable in Poland and Cuba, and lowest in Russia and China. A discussion on the scientific and contextual reasons influencing these variations is presented. The tension between scientific evidence and social influences varies from region to region. The methods used in the studies reported here included questionnaires and content analysis. Response rates to questionnaires were often around 50 percent (with exception of the Polish studies). We discuss reasons for the low rates. Although a uniform method of data gathering is desirable, it may not suit scientists working in different traditions of theory and research. We conclude that it is once again timely to discuss the race concept in international meetings where all scientific and political changes occurring throughout the world in recent past decades are taken into account.

Ghrelin gene products, receptors, and GOAT enzyme: biological and pathophysiological insight.

Ghrelin is a 28-amino acid acylated hormone, highly expressed in the stomach, which binds to its cognate receptor (GHSR1a) to regulate a plethora of relevant biological processes, including food intake, energy balance, hormonal secretions, learning, inflammation, etc. However, ghrelin is, in fact, the most notorious component of a complex, intricate regulatory system comprised of a growing number of alternative peptides (e.g. obestatin, unacylated ghrelin, and In1-ghrelin, etc.), known (GHSRs) and, necessarily unknown receptors, as well as modifying enzymes (e.g. ghrelin-O-acyl-transferase), which interact among them as well as with other regulatory systems in order to tightly modulate key (patho)-physiological processes. This multiplicity of functions and versatility of the ghrelin system arise from a dual, genetic and functional, complexity. Importantly, a growing body of evidence suggests that dysregulation in some of the components of the ghrelin system can lead to or influence the development and/or progression of highly concerning pathologies such as endocrine-related tumors, inflammatory/cardiovascular diseases, and neurodegeneration, wherein these altered components could be used as diagnostic, prognostic, or therapeutic targets. In this context, the aim of this review is to integrate and comprehensively analyze the multiple components and functions of the ghrelin system described to date in order to define and understand its biological and (patho)-physiological significance.

Role of endogenous cortistatin in the regulation of ghrelin system expression at pancreatic level under normal and obese conditions.

Ghrelin-system components [native ghrelin, In1-ghrelin, Ghrelin-O-acyltransferase enzyme (GOAT) and receptors (GHS-Rs)] are expressed in a wide variety of tissues, including the pancreas, where they exert different biological actions including regulation of neuroendocrine secretions, food intake and pancreatic function. The expression of ghrelin system is regulated by metabolic conditions (fasting/obesity) and is associated with the progression of obesity and insulin resistance. Cortistatin (CORT), a neuropeptide able to activate GHS-R, has emerged as an additional link in gut-brain interplay. Indeed, we recently reported that male CORT deficient mice (cort-/-) are insulin-resistant and present a clear dysregulation in the stomach ghrelin-system. The present work was focused at analyzing the expression pattern of ghrelin-system components at pancreas level in cort-/- mice and their control littermates (cort +/+) under low- or high-fat diet. Our data reveal that all the ghrelin-system components are expressed at the mouse pancreatic level, where, interestingly, In1-ghrelin was expressed at higher levels than native-ghrelin. Thus, GOAT mRNA levels were significantly lower in cort-/- mice compared with controls while native ghrelin, In1-ghrelin and GHS-R transcript levels remained unaltered under normal metabolic conditions. Moreover, under obese condition, a significant increase in pancreatic expression of native-ghrelin, In1-ghrelin and GHS-R was observed in obese cort+/+ but not in cort-/- mice. Interestingly, insulin expression and release was elevated in obese cort+/+, while these changes were not observed in obese cort-/- mice. Altogether, our results indicate that the ghrelin-system expression is clearly regulated in the pancreas of cort+/+ and cort -/- under normal and/or obesity conditions suggesting that this system may play relevant roles in the endocrine pancreas. Most importantly, our data demonstrate, for the first time, that endogenous CORT is essential for the obesity-induced changes in insulin expression/secretion observed in mice, suggesting that CORT is a key regulatory component of the pancreatic function.

Role of SST, CORT and ghrelin and its receptors at the endocrine pancreas.

Somatostatin (SST), cortistatin (CORT), and its receptors (sst1-5), and ghrelin and its receptors (GHS-R) are two highly interrelated neuropeptide systems with a broad range of overlapping biological actions at central, cardiovascular, and immune levels among others. Besides their potent regulatory role on GH release, its endocrine actions are highlighted by SST/CORT and ghrelin influence on insulin secretion, glucose homeostasis, and insulin resistance. Interestingly, most components of these systems are expressed at the endocrine pancreas and are actively involved in the modulation of pancreatic islet function and, consequently influence glucose homeostasis. In addition, some of them also participate in islet survival and regeneration. Furthermore, under severe metabolic condition as well as in endocrine pathologies, their expression profile is severely deregulated. These findings suggest that SST/CORT and ghrelin systems could play a relevant role in pancreatic function under metabolic and endocrine pathologies. Accordingly, these systems have been therapeutically targeted for the prevention or amelioration of certain metabolic conditions (obesity) as well as for tumor growth inhibition and/or hormonal regulation in endocrine pathologies (neuroendocrine tumors). This review focuses on the interrelationship between SST/CORT and ghrelin systems and their role in severe metabolic conditions and some endocrine disorders.