Programmed longevity, youthspan, and juventology.

The identification of conserved genes and pathways that regulate lifespan but also healthspan has resulted in an improved understanding of the link between nutrients, signal transduction proteins, and aging but has also provided evidence for the existence of multiple "longevity programs," which are selected based on the availability of nutrients. Periodic fasting and other dietary restrictions can promote entry into a long-lasting longevity program characterized by cellular protection and optimal function but can also activate regenerative processes that lead to rejuvenation, which are independent of the aging rate preceding the restricted period. Thus, a "juventology"-based strategy can complement the traditional gerontology approach by focusing not on aging but on the longevity program affecting the life history period in which mortality is very low and organisms remain youthful, healthy, and fully functional.

Magnetoelectric nanoparticles for delivery of antitumor peptides into glioblastoma cells by magnetic fields.

AIM: We studied externally controlled anticancer effects of binding tumor growth inhibiting synthetic peptides to magnetoelectric nanoparticles (MENs) on treatment of glioblastomas. METHODS: Hydrothermally synthesized 30-nm MENs had the core-shell composition of CoFe2O4@BaTiO3. Molecules of growth hormone-releasing hormone antagonist of the MIA class (MIA690) were chemically bound to MENs. In vitro experiments utilized human glioblastoma cells (U-87MG) and human brain microvascular endothelial cells. RESULTS: The studies demonstrated externally controlled high-efficacy binding of MIA690 to MENs, targeted specificity to glioblastoma cells and on-demand release of the peptide by application of d.c. and a.c. magnetic fields, respectively. CONCLUSION: The results support the use of MENs as an effective drug delivery carrier for growth hormone-releasing hormone antagonists in the treatment of human glioblastomas.

Rapid increase in fibroblast growth factor 21 in protein malnutrition and its impact on growth and lipid metabolism.

Protein malnutrition promotes hepatic steatosis, decreases insulin-like growth factor (IGF)-I production and retards growth. To identify new molecules involved in such changes, we conducted DNA microarray analysis on liver samples from rats fed an isoenergetic low-protein diet for 8 h. We identified the fibroblast growth factor 21 gene (Fgf21) as one of the most strongly up-regulated genes under conditions of acute protein malnutrition (P<0·05, false-discovery rate<0·001). In addition, amino acid deprivation increased Fgf21 mRNA levels in rat liver-derived RL-34 cells (P<0·01). These results suggested that amino acid limitation directly increases Fgf21 expression. FGF21 is a polypeptide hormone that regulates glucose and lipid metabolism. FGF21 also promotes a growth hormone-resistance state and suppresses IGF-I in transgenic mice. Therefore, to determine further whether Fgf21 up-regulation causes hepatic steatosis and growth retardation after IGF-I decrease in protein malnutrition, we fed an isoenergetic low-protein diet to Fgf21-knockout (KO) mice. Fgf21-KO did not rescue growth retardation and reduced plasma IGF-I concentration in these mice. Fgf21-KO mice showed greater epididymal white adipose tissue weight and increased hepatic TAG and cholesterol levels under protein malnutrition conditions (P<0·05). Overall, the results showed that protein deprivation directly increased Fgf21 expression. However, growth retardation and decreased IGF-I were not mediated by increased FGF21 expression in protein malnutrition. Furthermore, FGF21 up-regulation rather appears to have a protective effect against obesity and hepatic steatosis in protein-malnourished animals.

Integrated Transcriptional and Proteomic Analysis of Growth Hormone Suppression Mediated by Trichothecene T-2 Toxin in Rat GH3 Cells.

Chronic exposure to trichothecenes is known to disturb insulin-like growth factor 1 and signaling of insulin and leptin hormones and causes considerable growth retardation in animals. However, limited information was available on mechanisms underlying trichothecene-induced growth retardation. In this study, we employed an integrated transcriptomics, proteomics, and RNA interference (RNAi) approach to study the molecular mechanisms underlying trichothecene cytotoxicity in rat pituitary adenoma GH3 cells. Our results showed that trichothecenes suppressed the synthesis of growth hormone 1 (Gh1) and inhibited the eukaryotic transcription and translation initiation by suppressing aminoacyl-tRNA synthetases transcription, inducing eukaryotic translation initiation factor 2-alpha kinase 2 (EIF2AK2) and reducing eukaryotic translation initiation factor 5 a. The sulfhydryl oxidases , protein disulfide isomerase,and heat shock protein 90 (were greatly reduced, which resulted in adverse regulation of protein processing and folding. Differential genes and proteins associated with a decline in energy metabolism and cell cycle arrest were also found in our study. However, use of RNAi to interfere with hemopoietic cell kinase (Hck) and EIF2AK2 transcriptions or use of chemical inhibitors of MAPK, p38, Ras, and JNK partially reversed the reduction of Gh1 levels induced by trichothecenes. It indicated that the activation of MAPKs, Hck, and EIF2AK2 were important for trichothecene-induced growth hormone suppression. Considering the potential hazards of exposure to trichothecenes, our findings could help to improve our understanding regarding human and animal health implications.

ß-Hydroxybutyric sodium salt inhibition of growth hormone and prolactin secretion via the cAMP/PKA/CREB and AMPK signaling pathways in dairy cow anterior pituitary cells.

ß-hydroxybutyric acid (BHBA) regulates the synthesis and secretion of growth hormone (GH) and prolactin (PRL), but its mechanism is unknown. In this study, we detected the effects of BHBA on the activities of G protein signaling pathways, AMPK-α activity, GH, and PRL gene transcription, and GH and PRL secretion in dairy cow anterior pituitary cells (DCAPCs). The results showed that BHBA decreased intracellular cAMP levels and a subsequent reduction in protein kinase A (PKA) activity. Inhibition of PKA activity reduced cAMP response element-binding protein (CREB) phosphorylation, thereby inhibiting GH and PRL transcription and secretion. The effects of BHBA were attenuated by a specific Gαi inhibitor, pertussis toxin (PTX). In addition, intracellular BHBA uptake mediated by monocarboxylate transporter 1 (MCT1) could trigger AMPK signaling and result in the decrease in GH and PRL mRNA translation in DCAPCs cultured under low-glucose and non-glucose condition when compared with the high-glucose group. This study identifies a biochemical mechanism for the regulatory action of BHBA on GH and PRL gene transcription, translation, and secretion in DCAPCs, which may be one of the factors that regulate pituitary function during the transition period in dairy cows.

Growth hormone pathways signaling for cell proliferation and survival in hippocampal neural precursors from postnatal mice.

BACKGROUND: Accumulating evidence suggests that growth hormone (GH) may play a major role in the regulation of postnatal neurogenesis, thus supporting the possibility that it may be also involved in promoting brain repair after brain injury. In order to gain further insight on this possibility, in this study we have investigated the pathways signaling the effect of GH treatment on the proliferation and survival of hippocampal subgranular zone (SGZ)-derived neurospheres. RESULTS: Our results demonstrate that GH treatment promotes both proliferation and survival of SGZ neurospheres. By using specific chemical inhibitors we have been also able to demonstrate that GH treatment promotes the activation of both Akt-mTOR and JNK signaling pathways, while blockade of these pathways either reduces or abolishes the GH effects. In contrast, no effect of GH on the activation of the Ras-ERK pathway was observed after GH treatment, despite blockade of this signaling path also resulted in a significant reduction of GH effects. Interestingly, SGZ cells were also capable of producing GH, and blockade of endogenous GH also resulted in a decrease in the proliferation and survival of SGZ neurospheres. CONCLUSIONS: Altogether, our findings suggest that GH treatment may promote the proliferation and survival of neural progenitors. This effect may be elicited by cooperating with locally-produced GH in order to increase the response of neural progenitors to adequate stimuli. On this view, the possibility of using GH treatment to promote neurogenesis and cell survival in some acquired neural injuries may be envisaged.

Identification of the receptors for somatostatin (SST) and cortistatin (CST) in chickens and investigation of the roles of cSST28, cSST14, and cCST14 in inhibiting cGHRH1-27NH2-induced growth hormone secretion in cultured chicken pituitary cells.

Somatostatin receptors (SSTRs) are proposed to mediate the actions of somatostatin (SST) and its related peptide, cortistatin (CST), in vertebrates. However, the identity, functionality, and tissue expression of these receptors remain largely unknown in most non-mammalian vertebrates including birds. In this study, five SSTRs (named cSSTR1, cSSTR2, cSSTR3, cSSTR4, cSSTR5) were cloned from chicken brain by RT-PCR. Using a pGL3-CRE-luciferase reporter system, we demonstrated that activation of each cSSTR expressed in CHO cells by cSST28, cSST14 and cCST14 treatment could inhibit forskolin-induced luciferase activity of CHO cells, indicating the functional coupling of all cSSTRs to Gi protein(s). Interestingly, cSSTR1-4 expressed in CHO cells could be activated by cSST28, cSST14 and cCST14 with high potencies, suggesting that they may function as the receptors common for these peptides. In contrast, cSSTR5 could be potently activated by cSST28 only, indicating that it is a cSST28-specific receptor. Using RT-PCR, wide expression of cSSTRs was detected in chicken tissues including pituitary. In accordance with their expression in pituitary, cSST28, cSST14, and cCST14 were demonstrated to inhibit basal and novel cGHRH1-27NH2-induced GH secretion in cultured chicken pituitary cells dose-dependently (0-10nM) by Western blot analysis, suggesting the involvement of cSSTR(s) common for these peptides in mediating their inhibitory actions. Collectively, our study establishes a molecular basis to elucidate the roles of SST/CST in birds and provide insights into the roles of SST/CST in vertebrates, such as their conserved actions on pituitary.

Short-chain fatty acids inhibit growth hormone and prolactin gene transcription via cAMP/PKA/CREB signaling pathway in dairy cow anterior pituitary cells.

Short-chain fatty acids (SCFAs) play a key role in altering carbohydrate and lipid metabolism, influence endocrine pancreas activity, and as a precursor of ruminant milk fat. However, the effect and detailed mechanisms by which SCFAs mediate bovine growth hormone (GH) and prolactin (PRL) gene transcription remain unclear. In this study, we detected the effects of SCFAs (acetate, propionate, and butyrate) on the activity of the cAMP/PKA/CREB signaling pathway, GH, PRL, and Pit-1 gene transcription in dairy cow anterior pituitary cells (DCAPCs). The results showed that SCFAs decreased intracellular cAMP levels and a subsequent reduction in PKA activity. Inhibition of PKA activity decreased CREB phosphorylation, thereby inhibiting GH and PRL gene transcription. Furthermore, PTX blocked SCFAs- inhibited cAMP/PKA/CREB signaling pathway. These data showed that the inhibition of GH and PRL gene transcription induced by SCFAs is mediated by Gi activation and that propionate is more potent than acetate and butyrate in inhibiting GH and PRL gene transcription. In conclusion, this study identifies a biochemical mechanism for the regulation of SCFAs on bovine GH and PRL gene transcription in DCAPCs, which may serve as one of the factors that regulate pituitary function in accordance with dietary intake.

Comparative inhibition of the GH/IGF-I axis obtained with either the targeted secretion inhibitor SXN101959 or the somatostatin analog octreotide in growing male rats.

Abnormally high GH/IGF-I levels, most often caused by adenomas arising from pituitary somatotrophs, generate deleterious effects. We recently described a targeted secretion inhibitor (SXN101742) comprising a GHRH domain and the endopeptidase domain of botulinum toxin serotype D (GHRH-light chain endopeptidase type D domain [LC/D] associated to a heavy chain translocation domain [HN]) able to down-regulate the GH/IGF-I axis. In the present study, we compared the effect of a single iv bolus of a related molecule developed for clinical studies (SXN101959, 1 mg/kg) with a sc infusion of the somatostatin analog octreotide (SMS201-995, 10 µg/kg · h) to lower GH/IGF-I activity in growing male rats. Ten days after administration of SXN101959 or initiation of the octreotide infusion, body and pituitary weights, body length, GH peaks, and IGF-I production were reduced by both treatments but to a greater extent with SXN101959. In contrast to unaltered GH gene expression and increased GH storage in pituitaries from octreotide-treated rats, the inhibition of GH secretion was associated with a collapse of both GH mRNA and protein level in pituitaries from SXN101959-treated rats, in line with a specific decrease in hypothalamic GHRH production, not observed with octreotide. SXN101959 did not induce major apoptotic events in anterior pituitary and exhibited a reversible mode of action with full recovery of somatotroph cell functionality 30 days after treatment. Octreotide infusion permanently decreased ghrelin levels, whereas SXN101959 only transiently attenuated ghrelinemia. Both treatments limited bone mass acquisition and altered specifically tissues development. In conclusion, SXN101959 exerts a powerful and reversible inhibitory action on the somatotropic axis. Specific features of SXN101959, including long duration of action coupled to a strong inhibition of pituitary GH synthesis, represent advantages when treating overproduction of GH.

Critical aspects to be considered prior to large-scale production of peptides.

Numerous peptides are available on the market as therapeutic drugs for regulating tumor growth, microorganism proliferation, immune response and/or metabolic disorders. Peptides are produced either by chemical synthesis or heterologous expression. Independent of the method chosen, there are challenges to transferring its production from the bench (~mg/L) to the industrial (~g/L) scale. Thus, the main scale-up pitfalls for the two methods of peptide production are reviewed here, including the advantages of each. Moreover, there will be a special focus on the main challenges for large-scale, heterologous production systems. Peptides that are currently available on the market are also described with an emphasis on how their process optimization has been designed in order to develop a cost-effective product.

A crucial role of activin A-mediated growth hormone suppression in mouse and human heart failure.

Infusion of bone marrow-derived mononuclear cells (BMMNC) has been reported to ameliorate cardiac dysfunction after acute myocardial infarction. In this study, we investigated whether infusion of BMMNC is also effective for non-ischemic heart failure model mice and the underlying mechanisms. Intravenous infusion of BMMNC showed transient cardioprotective effects on animal models with dilated cardiomyopathy (DCM) without their engraftment in heart, suggesting that BMMNC infusion improves cardiac function via humoral factors rather than their differentiation into cardiomyocytes. Using conditioned media from sorted BMMNC, we found that the cardioprotective effects were mediated by growth hormone (GH) secreted from myeloid (Gr-1(+)) cells and the effects was partially mediated by signal transducer and activator of transcription 3 in cardiomyocytes. On the other hand, the GH expression in Gr-1(+) cells was significantly downregulated in DCM mice compared with that in healthy control, suggesting that the environmental cue in heart failure might suppress the Gr-1(+) cells function. Activin A was upregulated in the serum of DCM models and induced downregulation of GH levels in Gr-1(+) cells and serum. Furthermore, humoral factors upregulated in heart failure including angiotensin II upregulated activin A in peripheral blood mononuclear cells (PBMNC) via activation of NFκB. Similarly, serum activin A levels were also significantly higher in DCM patients with heart failure than in healthy subjects and the GH levels in conditioned medium from PBMNC of DCM patients were lower than that in healthy subjects. Inhibition of activin A increased serum GH levels and improved cardiac function of DCM model mice. These results suggest that activin A causes heart failure by suppressing GH activity and that inhibition of activin A might become a novel strategy for the treatment of heart failure.

Reduction of circulating soluble fms-like tyrosine kinase-1 plays a significant role in renal dysfunction-associated aggravation of atherosclerosis.

BACKGROUND: Renal dysfunction is commonly accompanied by a worsening of atherosclerosis; however, the underlying molecular mechanism is not fully understood. We examined the role played by soluble fms-like tyrosine kinase-1 (sFlt-1), an endogenous antagonist of the proatherogenic cytokine placental growth factor (PlGF), in the worsening of atherosclerosis in patients with renal dysfunction and in an animal model of renal failure. METHODS AND RESULTS: In this study, 329 patients who received cardiac catheterization and 76 patients who underwent renal biopsy were enrolled. Both plasma sFlt-1 levels and renal sFlt-1 mRNA expression were positively correlated with estimated glomerular filtration rate (P<0.01). The PlGF/sFlt-1 ratio was negatively correlated with estimated glomerular filtration rate (P<0.01), whereas plasma PlGF levels were not affected by it. The PlGF/sFlt-1 ratio was significantly higher in patients with multivessel coronary artery disease than in patients with single-vessel or no coronary artery disease. The reduction of circulating sFlt-1 and renal sFlt-1 mRNA levels was confirmed in five-sixths (5/6)-nephrectomized apolipoprotein E-deficient mice that developed experimental renal dysfunction. Atherosclerotic plaque area and macrophage infiltration into the plaque were significantly higher in 5/6-nephrectomized apolipoprotein E-deficient mice than in control mice, but replacement therapy with recombinant sFlt-1 significantly reduced both plaque formation and macrophage infiltration. CONCLUSIONS: The present study demonstrates that a reduction in the circulating levels of sFlt-1 is associated with the worsening of atherosclerosis that accompanies renal dysfunction.

Growth hormone and insulin-like growth factor-I in the transition from normal mammary development to preneoplastic mammary lesions.

Adult female mammary development starts at puberty and is controlled by tightly regulated cross-talk between a group of hormones and growth factors. Although estrogen is the initial driving force and is joined by luteal phase progesterone, both of these hormones require GH-induced IGF-I in the mammary gland in order to act. The same group of hormones, when experimentally perturbed, can lead to development of hyperplastic lesions and increase the chances, or be precursors, of mammary carcinoma. For example, systemic administration of GH or IGF-I causes mammary hyperplasia, and overproduction of IGF-I in transgenic animals can cause the development of usual or atypical hyperplasias and sometimes carcinoma. Although studies have clearly demonstrated the transforming potential of both GH and IGF-I receptor in cell culture and in animals, debate remains as to whether their main role is actually instructive or permissive in progression to cancer in vivo. Genetic imprinting has been shown to occur in precursor lesions as early as atypical hyperplasia in women. Thus, the concept of progression from normal development to cancer through precursor lesions sensitive to hormones and growth factors discussed above is gaining support in humans as well as in animal models. Indeed, elevation of estrogen receptor, GH, IGF-I, and IGF-I receptor during progression suggests a role for these pathways in this process. New agents targeting the GH/IGF-I axis may provide a novel means to block formation and progression of precursor lesions to overt carcinoma. A novel somatostatin analog has recently been shown to prevent mammary development in rats via targeted IGF-I action inhibition at the mammary gland. Similarly, pegvisomant, a GH antagonist, and other IGF-I antagonists such as IGF binding proteins 1 and 5 also block mammary gland development. It is, therefore, possible that inhibition of IGF-I action, or perhaps GH, in the mammary gland may eventually play a role in breast cancer chemoprevention by preventing actions of both estrogen and progesterone, especially in women at extremely high risk for developing breast cancer such as BRCA gene 1 or 2 mutations.

Growth hormone inhibitors in prostate cancer: a systematic analysis.

OBJECTIVE: Despite initial therapeutic success through androgen ablation in patients with advanced prostate cancer, the vast majority progress to androgen independence. Somatostatin (SST) analogs are a viable therapeutic modality before resorting to chemotherapy or immunotherapy. Their mechanism of action is related to a reduction in the IGF-1 (survival factor, reaction on neuroendocrine cells) appearing incrementally after long-term androgen deprivation and a possible suppression of GnRH receptors in prostate cancer following exposure to LHRH agonists. METHODS: The computerized databases Medline, NCBI and OMIM were searched for the terms, somatostatin and prostate cancer, in parallel with printed bibliographic references. Forty-two studies were included and 267 patients with androgen-independent prostate cancer (AIPC) who were treated with SST analogs alone or in combination with other medications, e.g. dexamethasone, were analyzed. RESULTS: In 42 studies with 267 AIPC patients, SST analogs were found to be effective, particularly when combined with estrogens or corticosteroids. The side effects are mild and related to the gastrointestinal tract. CONCLUSIONS: It would be interesting to study SST analogs in randomized trials including patients with well-defined AIPC. Whether SST analogs could be given earlier during sequential hormonal therapy remains to be studied.

The contribution of growth hormone to mammary neoplasia.

While the effects of growth hormone (GH) on longitudinal growth are well established, the observation that GH contributes to neoplastic progression is more recent. Accumulating literature implicates GH-mediated signal transduction in the development and progression of a wide range malignancies including breast cancer. Recently autocrine human GH been demonstrated to be an orthotopically expressed oncogene for the human mammary gland. This review will highlight recent evidence linking GH and mammary carcinoma and discuss GH-antagonism as a potential therapeutic approach for treatment of breast cancer.

Activation of growth hormone receptors by growth hormone and growth hormone antagonist dimers: insights into receptor triggering.

GH binds dimerized GH receptors (GHRs) to form a trimolecular complex and induces downstream signaling events. The mechanism by which GH binding converts the inactive predimerized GHR to its active signaling conformation is uncertain. GH has no axis of symmetry. Its interaction with GHR is mediated by two asymmetric binding sites on GH, each with distinct affinity. Site 1 is of high affinity and is thought to mediate the first binding step. Mutation of binding site 2 (as in the human GH mutant, G120R) disrupts the second binding but leaves site 1 binding intact. G120R is a GH antagonist; it binds only one GHR and thus fails to signal, and it prevents productive GHR binding by normal GH. We previously demonstrated that prolactin receptor signaling was achieved by a dimeric version of a prolactin antagonist. We now employ assays of cellular signaling and receptor conformational changes to examine whether GH molecules harboring two site 1 regions can trigger GHR activation. We used recombinantly produced GH-GH and G120R-G120R dimers in which monomers in tandem are connected by a short linker peptide. Rabbit GHR-expressing human fibrosarcoma cells (C14) were treated with GH, G120R, GH-GH, or G120R-G120R. As expected, GH and GH-GH, but not G120R, induced GHR disulfide linkage, as assessed by anti-GHR blotting of cell extracts resolved by SDS-PAGE under nonreducing conditions. Disulfide linkage of GHRs reflects attainment of the active signaling conformation. Likewise, GH and GH-GH, but not G120R, caused Janus kinase 2 (JAK2) and signal transducer and activator of transcription 5 (STAT5) activation. Notably, G120R-G120R, despite its lack of an intact site 2 in either dimer partner, also promoted GHR disulfide linkage and JAK2 and STAT5 activation, albeit less potently than either GH or GH-GH. Time-course responses of the three agonists were similar in terms of JAK2 and STAT5 activation. Pretreatment of cells with our conformation-sensitive inhibitory monoclonal antibody, anti-GHR ext-mAb, prevented ligand-induced receptor activation for all three agonists. GHR was also rendered less immunoprecipitable by anti-GHR ext-mAb after treatment with these agonists. These results are important in that they indicate that a ligand with two intact binding sites 1 causes GHR to adopt similar conformational changes as does GH and thus triggers activation of JAK2 and downstream signaling. Furthermore, we infer that there is substantial flexibility in the GHR extracellular domain, such that it productively accommodates GH dimers that are much larger than GH.

DNMT3A and DNMT3B mediate autocrine hGH repression of plakoglobin gene transcription and consequent phenotypic conversion of mammary carcinoma cells.

Directed by microarray analyses, we report that autocrine human growth hormone (hGH) increased the mRNA and protein expression of DNA methyltransferase 1 (DNMT1), DNMT3A and DNMT3B in mammary carcinoma cells. Autocrine hGH stimulation of DNMT3A and DNMT3B expression was mediated by JAK2 and Src kinases, and treatment of mammary carcinoma cells with the DNMT inhibitor, 5'-aza-2'-deoxycytidine (AZA), abrogated autocrine hGH-stimulated cellular proliferation, apoptosis and anchorage-independent growth. AZA reversed the epitheliomesenchymal transition of mammary carcinoma cells induced by autocrine hGH, to an epithelioid morphology and abrogated cell migration stimulated by autocrine hGH. Autocrine hGH-stimulated hypermethylation of the first exon of the PLAKOGLOBIN gene and AZA abrogated the ability of autocrine hGH to repress plakoglobin gene transcription. Small interfering RNA (siRNA)-mediated depletion of the individual DNMT molecules did not release autocrine hGH repression of PLAKOGLOBIN promoter activity nor did individual DNMT depletion affect autocrine hGH-stimulated migration. However, concomitant siRNA-mediated depletion of both DNMT3A and DNMT3B abrogated hypermethylation of the PLAKOGLOBIN gene stimulated by autocrine hGH and subsequent repression of plakoglobin gene transcription and increased cell migration. Thus, the autocrine hGH-stimulated increases in DNMT3A and DNMT3B expression mediate repression of plakoglobin gene transcription by direct hypermethylation of its promoter and consequent phenotypic conversion of mammary carcinoma cells. Autocrine hGH, therefore, utilizes DNA methylation as a mechanism to exert its oncogenic effects in mammary carcinoma cells.

Pasireotide (SOM230): development, mechanism of action and potential applications.

Pasireotide (SOM230) is a multi-receptor ligand somatostatin analogue with high binding affinity for somatostatin receptor subtypes sst(1,2,3) and sst(5). Pasireotide potently suppresses GH, IGF-I and ACTH secretion, indicating potential efficacy in acromegaly and Cushing's disease. The prolonged inhibition of hormone secretion by pasireotide in animal models and expression of multiple sst receptors in carcinoid tumors suggests that pasireotide may have clinical advantages over octreotide in patients with carcinoid tumors. Direct and indirect antitumor activity has been observed in vitro with pasireotide, including sst receptor-mediated apoptosis and antiangiogenesis, suggesting a possible role for pasireotide in antineoplastic therapy. In summary, preclinical evidence, as well as preliminary results from clinical studies suggests that pasireotide is a promising new treatment for patients with symptoms of metastatic carcinoid tumors refractory or resistant to octreotide, de novo or persistent acromegaly, and that pasireotide has the potential to be the first directed medical therapy for Cushing's disease.

Cardiac expression of adenine nucleotide translocase-1 in transgenic mice overexpressing bovine GH.

Heart hypertrophy is a common finding of acromegaly, a syndrome due to GH excess. Impairment of adenine nucleotide translocase-1 (ANT-1) gene, the main mitochondrial ADP/ATP exchanger, leads to cardiac hypertrophy. The aim of the study was to evaluate cardiac expression and the functional role of ANT-1 in 1- to 12-month-old transgenic mice overexpressing bovine GH (acromegalic mice, Acro) and littermate controls (wild-type mice, Wt). GH specificity of protein degree variation was assessed treating Acro with pegvisomant, a GH receptor competitor. Tissue levels of ANT-1, NF-kappaB, ATP, and lactic acid were evaluated by western blot, bioluminescence, and Fourier transform infrared spectroscopy respectively. The degree of ANT-1 expression was higher in 1-month-old Acro than in Wt (47+/-5% OD vs 33+/-4% OD, P<0 01). On the contrary, ANT-1 expression was lower in 3- to 12-month-old Acro than in Wt (P<0 03). Changes in ANT-1 expression were associated with consistent changes of cellular ATP content, increasing at 1 month (P<0 05) and reducing thereafter in Acro when compared with Wt (P<0 04). Treatment with pegvisomant abolished ANT-1 and ATP changes observed in 1- and 3-month-old Acro, thus supporting a GH-dependent mechanism. Reduced ATP generation in hypertrophied hearts of older Acro was associated with increased lactic acid levels suggesting that part of energy was due to glycolysis. Variations in ANT-1 expression were linked to GH through changes in NF-kappaB, the levels of which changed accordingly. In conclusion, 1-month-old acromegalic mice had increased ANT-1 expression and higher degree of ATP production. Long-standing disease was associated with a consistent reduction of ANT-1 and ATP tissue levels, which became GH-independent in older animals. This study demonstrated a direct effect of GH on key proteins involved in energy metabolism of acromegalic hearts.