Effects by daily long term provision of ghrelin to unselected weight‐losing cancer patients

Lundholm, Kent; Gunnebo, Lena; Körner, Ulla; Iresjö, Britt‐Marie; Engström, Christer; Hyltander, Anders; Smedh, Ulrika; Bosæus, Ingvar

doi:10.1002/cncr.24917

Cited by 94 publications

(46 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…It is concluded that piperidine-constrained wFw-Isn-NH 2 is a functionally biased ghrelin receptor agonist that activates classical G␣ q pathways, internalization, and ERK1/2 phosphorylation; but in contrast to all previously reported ghrelin receptor agonists, it is unable to stimulate SRE-mediated transcriptional activity, which conceivably is mediated through the G␣ 13 pathway. The biased signaling of wFw-Isn-NH 2 is also observed in cell lines naturally expressing the ghrelin receptor, suggesting a physiological relevance and that it is not an artifact due to receptor expression levels.…”

Section: C-terminal Modification Of the D-trp-phe-d-trp Motif-inmentioning

confidence: 76%

“…However, these compounds never reached the market, mainly because of a lack of efficacy (11,12). Today non-peptide ghrelin receptor agonists and ghrelin analogues are being developed in attempts to treat, for example, various forms of cachexia and malnourishment in hospitalized patients (13). Antagonists or inverse agonists of the ghrelin receptor have been proposed as a potential treatment for obesity, diabetes, and also more recently alcohol abuse; but these are still in early development (14).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Unique Interaction Pattern for a Functionally Biased Ghrelin Receptor Agonist

Sivertsen

Lang

Frimurer

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

]substance P, a series of novel, small, peptidemimetic agonists for the ghrelin receptor were generated. By using various simple, ring-constrained spacers connecting the D-Trp-Phe-D-Trp motif with the important C-terminal carboxyamide group, 40 nM agonism potency was obtained and also in one case (wFw-Isn-NH 2 , where Isn is isonipecotic acid) ϳ80% efficacy. However, in contrast to all previously reported ghrelin receptor agonists, the piperidine-constrained wFw-Isn-NH 2 was found to be a functionally biased agonist. Thus, wFw-Isn-NH 2 mediated potent and efficacious signaling through the G␣ q and ERK1/2 signaling pathways, but in contrast to all previous ghrelin receptor agonists it did not signal through the serum response element, conceivably the G␣ 12/13 pathway. The recognition pattern of wFw-Isn-NH 2 with the ghrelin receptor also differed significantly from that of all previously characterized unbiased agonists. Most importantly, wFw-Isn-NH 2 was not dependent on GluIII:09 (Glu3.33), which otherwise is an obligatory TM III anchor point residue for ghrelin agonists. Molecular modeling and docking experiments indicated that wFw-Isn-NH 2 binds in the classical agonist binding site between the extracellular segments of TMs III, VI, and VII, interacting closely with the aromatic cluster between TMs VI and VII, but that it does so in an opposite orientation as compared with, for example, the wFw peptide agonists. It is concluded that the novel peptide-mimetic ligand wFw-Isn-NH 2 is a biased ghrelin receptor agonist and that the selective signaling pattern presumably is due to its unique receptor recognition pattern lacking interaction with key residues especially in TM III.Ghrelin is a neuroendocrine hormone that differs from other peptide hormones by a fatty acid modification, which is crucial for both the binding and activation of its receptor (1). Ghrelin is synthesized mainly in the gastrointestinal tract, where the gene coding for the peptide sequence is expressed together with the enzyme responsible for the acylation of the fatty acid to the ghrelin peptide sequence (2, 3). Multiple functions have been described for ghrelin since it was discovered. Initially it was believed that growth hormone secretion induced by ghrelin receptors in the hypothalamus and the pituitary was the primary function of ghrelin (4). However, the function of ghrelin in the hypothalamus, and in particular in the arcuate nucleus, has become the focus of attention over the last decade. In the arcuate nucleus, ghrelin is responsible for increased activity in the NPY (neuropeptide Y) and AGRP (Agouti-related protein) neurones leading to increased appetite, decreased energy expenditure, and fat accumulation (5, 6). High receptor expression is also observed in the ventromedial nucleus of the hypothalamus, and the function in this area has been proposed to be orexigenic based on the regulation of fatty acid metabolism (7). More recently it has been demonstrated that ghrelin is also involved in reward-seeking behavior such as alcohol and ...

show abstract

Section: C-terminal Modification Of the D-trp-phe-d-trp Motif-inmentioning

confidence: 76%

mentioning

confidence: 99%

Unique Interaction Pattern for a Functionally Biased Ghrelin Receptor Agonist

Sivertsen

Lang

Frimurer

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…They include mainly appetite stimulants and anabolic agents such as prednisolone [15,51] and progesterone [12,42,43,77] and ghrelin, a ligand which stimulates growth hormone release [44,59]. Anecdotally, the use of α-3 omega fatty acids (eicosapentaenoic acid) [52] and thalidomide (potent anti-TNF activity) have been reported [48].…”

Section: Discussionmentioning

confidence: 99%

Selective Inhibition of NF-kappa-B with NBD Peptide Reduces Tumor- Induced Wasting in a Murine Model of Cancer Cachexia In vivo

Wysong¹,

Asher

Yin

et al. 2011

JCST

View full text Add to dashboard Cite

Cancer cachexia is a severe wasting syndrome characterized by the progressive loss of lean body mass and systemic inflammation, which is seen in as many as 80% of patients with advanced malignancy. It accounts for an estimated 20-30% of all cancer-related deaths. The mechanism by which cancer induces skeletal muscle atrophy in cachexia involves tumor-derived cytokines, including TNFα, IL-1, and IL-6. Upon interaction with their unique receptors on skeletal muscle, these cytokines activate NF-kappaB, a transcription factor crucial for atrophy related sarcomere proteolysis to occur. The significance of NF-κB is highlighted in studies demonstrating that genetic inhibition of NF-κB ameliorates cancer-induced muscle loss in vivo. In the present study, we evaluate a selective NF-kappaB inhibitor (NBD peptide) which targets the IkappaB complex to prevent cancer-induced skeletal muscle atrophy in an established mouse model (C26 adenocarcinoma). We identified for the first time that NBD peptide can directly inhibit tumor-induced NFkappaB activation in skeletal muscle, resulting in a decrease loss of lean muscle. We also identified that NBD peptide reduces the expression of the tumor induced ubiquitin ligases MuRF-1 and MAFbx/Atrogin-1 necessary for atrophy. These findings highlight that NBD peptide may be a potential selective therapeutic agent for the treatment of cancer cachexia.

show abstract

“…Otros estudios experimentales no han demostrado disminución de los niveles de ghrelina post gastrectomía vertical tubular y la posible explicación es la producción extragástrica de ghrelina 23,36 . De acuerdo a los resultados del presente estudio, se confirma que la GTV presenta buenos resultados a mediano plazo, con baja de peso comparable con otras publicaciones [26][27][28][29][30][31] y se ha constatado la disminución de la liberación de ghrelina secundaria a la resección del fondo gástrico en un importante número de pacientes, lo que no ocurre después de otras operaciones bariátricas en las que no se reseca el fondo gástrico. En un estudio efectuado en nuestro Departamento se demostró también disminución de la ghrelina plasmática después de resección gástrica 32 .…”

Section: Discussionunclassified