Multiple bronchial carcinoids associated with Cowden syndrome.

Cowden syndrome (CS) is a rare genetic condition due to the various germline mutations in the phosphatase and tensin homologue on chromosome ten (PTEN) tumour suppressor gene. As a result, CS is characterised by an increased risk of developing various benign and malignant tumours, such as thyroid, breast, endometrial and urogenital neoplasms, as well as gastrointestinal tract tumours. However, the neuroendocrine tumour association with CS is not elucidated yet. We present a case of a 46-year-old male patient diagnosed with testicular seminoma and follicular thyroid cancer in his medical history. Our patient met the clinical diagnostic criteria of Cowden syndrome. Genetic analysis established the clinical diagnosis; a known heterozygous PTEN mutation was detected [PTEN (LRG_311t1)c.388 C > T (p.Arg130Ter)]. Incidentally, he was also seen with multiple pulmonary lesions during his oncological follow-up. A video-assisted thoracoscopic left lingula wedge resection and later resections from the right lung were performed. Histological findings revealed typical pulmonary carcinoid tumours and smaller tumorlets. Somatostatin receptor SPECT-CT, 18F-FDG-PET-CT and 18F-FDOPA-PET-CT scans and endoscopy procedures could not identify any primary tumours in other locations. Our patient is the first published case of Cowden syndrome, associated with multifocal pulmonary carcinoids. Besides multiple endocrine neoplasia type 1, we propose Cowden syndrome as another hereditary condition predisposing to multiple pulmonary tumorlets and carcinoid tumours.

Surprising genetic and pathological findings in a patient with giant bilateral periadrenal tumours: PEComas and mutations of PTCH1 in Gorlin-Goltz syndrome.

Gorlin-Goltz syndrome (GGS) or nevoid basal cell carcinoma syndrome is a rare tumour-overgrowth syndrome associated with multiple developmental anomalies and a wide variety of tumours. Here, we describe a case of a man aged 23 years with GGS with bilateral giant tumours adjacent to both adrenals that raised the suspicion of malignancy on imaging. Histological analysis of both surgically resected tumours revealed perivascular epitheloid cell tumours (PEComas) that were independent of the adrenals. Exome sequencing of the patient's blood sample revealed a novel germline heterozygous frameshift mutation in the PTCH1 gene. As a second hit, a somatic five nucleotide long deletion in the PTCH1 gene was demonstrated in the tumour DNA of both PEComas. To the best of our knowledge, this is the first report on PEComa in GGS, and this finding also raises the potential relevance of PTCH1 mutations and altered sonic hedgehog signalling in PEComa pathogenesis. The presence of the same somatic mutation in the bilateral tumours might indicate the possibility of a postzygotic somatic mutation that along with the germline mutation of the same gene could represent an intriguing genetic phenomenon (type 2 segmental mosaicism).

Serum- and glucocorticoid-induced kinase drives hepatic insulin resistance by directly inhibiting AMP-activated protein kinase.

A hallmark of type 2 diabetes (T2D) is hepatic resistance to insulin's glucose-lowering effects. The serum- and glucocorticoid-regulated family of protein kinases (SGK) is activated downstream of mechanistic target of rapamycin complex 2 (mTORC2) in response to insulin in parallel to AKT. Surprisingly, despite an identical substrate recognition motif to AKT, which drives insulin sensitivity, pathological accumulation of SGK1 drives insulin resistance. Liver-specific Sgk1-knockout (Sgk1Lko) mice display improved glucose tolerance and insulin sensitivity and are protected from hepatic steatosis when fed a high-fat diet. Sgk1 promotes insulin resistance by inactivating AMP-activated protein kinase (AMPK) via phosphorylation on inhibitory site AMPKαSer485/491. We demonstrate that SGK1 is dominant among SGK family kinases in regulation of insulin sensitivity, as Sgk1, Sgk2, and Sgk3 triple-knockout mice have similar increases in hepatic insulin sensitivity. In aggregate, these data suggest that targeting hepatic SGK1 may have therapeutic potential in T2D.

Unusual onset of thyroid associated orbitopathy during pregnancy: case report and review of literature.

BACKGROUND: Thyroid associated orbitopathy (TAO) is the most common extrathyroidal complication of Graves' disease. The disease course ranges from mild, where symptomatic therapy is sufficient, to severe, where high dose steroid administration or orbital decompression surgery is required. Women of their reproductive age are more likely to be affected. Although pregnancy is a state of enhanced immune tolerance, TAO may develop or worsen in 0.2-0.4% of pregnant women. CASE PRESENTATION: We present the case of a 19-year-old woman who has developed hyperthyroidism and progressive TAO during the second trimester of her third pregnancy, which has improved postpartum. The possible mechanisms and the importance of follow up in pregnancy is discussed. CONCLUSIONS: Expectant mothers with Graves' disease require follow up of eye signs throughout pregnancy, preferably in the setting of a thyroid-eye clinic.

WS2 and MoS2 thin film gas sensors with high response to NH3 in air at low temperature.

Transition metal dichalcogenides (TMDs) have received immense research interest in particular for their outstanding electrochemical and optoelectrical properties. Lately, chemical gas sensor applications of TMDs have been recognized as well owing to the low operating temperatures of devices, which is a great advantage over conventional metal oxide based sensors. In this work, we elaborate on the gas sensing properties of WS2 and MoS2 thin films made by simple and straightforward thermal sulfurization of sputter deposited metal films on silicon chips. The sensor response to H2, H2S, CO and NH3 analytes in air at 30 °C has been assessed and both MoS2 and WS2 were found to have an excellent selectivity to NH3 with a particularly high sensitivity of 0.10 ± 0.02 ppm-1 at sub-ppm concentrations in the case of WS2. The sensing behavior is explained on the bases of gas adsorption energies as well as carrier (hole) localization induced by the surface adsorbed moieties having reductive nature.

True MEN1 or phenocopy? Evidence for geno-phenotypic correlations in MEN1 syndrome.

PURPOSE: Multiple endocrine neoplasia type 1 is a rare tumor syndrome caused by germline mutations of MEN1 gene. Phenotype varies widely, and no definitive correlation with the genotype has been observed. Mutation-negative patients with MEN1-associated tumors represent phenocopies. By comparing mutation-positive and mutation-negative patients, we aimed to identify phenotype features predictive for a positive genetic test and to evaluate the role of MEN1 mutations in phenotype modulation. METHODS: Mutation screeening of MEN1 gene by Sanger sequencing and assessment of clinical data of 189 consecutively enrolled probands and relatives were performed at our national and European Reference Center. Multiple ligation probe amplification analysis of MEN1 gene and Sanger sequencing of CDKN1B were carried out in clinically suspicious but MEN1-negative cases. RESULTS: Twenty-seven probands and twenty family members carried MEN1 mutations. Five mutations have not been described earlier. Pronouncedly high number of phenocopies (>70%) was observed. Clinical suspicion of MEN1 syndrome emerged at significantly earlier age in MEN1-positive compared to MEN1-negative probands. Gastroenteropancreatic neuroendocrine tumors developed significantly earlier and more frequently in carriers compared to non-carriers. Probands with high-impact (frameshift, nonsense, large deletions) mutations, predicted to affect menin function significantly, developed GEP-NETs more frequently compared to low-impact (inframe and missense) mutation carriers. CONCLUSIONS: MEN1 phenocopy is common and represents a significant confounder for the genetic testing. GEP-NET under 30 years best predicted a MEN1 mutation. The present study thus confirmed a previous proposal and suggested that GEP-NET under 30 years should be considered as a part of the indication criteria for MEN1 mutational analysis.

SGK1/FOXO3 Signaling in Hypothalamic POMC Neurons Mediates Glucocorticoid-Increased Adiposity.

Although the central nervous system has been implicated in glucocorticoid-induced gain of fat mass, the underlying mechanisms are poorly understood. The aim of this study was to investigate the possible involvement of hypothalamic serum- and glucocorticoid-regulated kinase 1 (SGK1) in glucocorticoid-increased adiposity. It is well known that SGK1 expression is induced by acute glucocorticoid treatment, but it is interesting that we found its expression to be decreased in the arcuate nucleus of the hypothalamus, including proopiomelanocortin (POMC) neurons, following chronic dexamethasone (Dex) treatment. To study the role of SGK1 in POMC neurons, we produced mice that developed or experienced adult-onset SGK1 deletion in POMC neurons (PSKO). As observed in Dex-treated mice, PSKO mice exhibited increased adiposity and decreased energy expenditure. Mice overexpressing constitutively active SGK1 in POMC neurons consistently had the opposite phenotype and did not experience Dex-increased adiposity. Finally, Dex decreased hypothalamic α-melanocyte-stimulating hormone (α-MSH) content and its precursor Pomc expression via SGK1/FOXO3 signaling, and intracerebroventricular injection of α-MSH or adenovirus-mediated FOXO3 knockdown in the arcuate nucleus largely reversed the metabolic alterations in PSKO mice. These results demonstrate that POMC SGK1/FOXO3 signaling mediates glucocorticoid-increased adiposity, providing new insights into the mechanistic link between glucocorticoids and fat accumulation and important hints for possible treatment targets for obesity.

[Hereditary phaeochromocytoma in twins]. / Ikerpárban eloforduló örökletes phaeochromocytoma.

Phaeochromocytoma is a tumor of the catecholamine-producing cells of the adrenal gland. Extraadrenal phaeochromocytomas are frequently called paragangliomas. The majority of phaeochromocytomas are sporadic, however, about 25-30% are caused by genetic mutation. These tumor are frequently referred as hereditary phaeochromocytomas/paragangliomas. Their incidence increases continuously which can be attributed to availability of genetic examination and to the discovery of novel genes. The 47-year-old female patient underwent abdominal computed tomography which revealed bilateral adrenal gland enlargement. Abdominal magnetic resonance imaging, the 131-I- metaiodobenzylguanidine scintigraphy, urinary catecholamines and serum chomogranin A measurements confirmed the diagnosis of bilateral phaeochromocytomas. The genetically identical twin sister of the patient was also diagnosed with hormonally active bilateral phaechromocytoma, suggesting the genetic origin of phaeochromocytoma. Mutation screening confirmed a germline mutation of the transmembrane protein 127 tumorsupressor gene in both patients. Both patients underwent cortical-sparing adrenalectomy. The adrenal gland with the larger tumor was totally resected, while in the opposite side only the tumor was resected and a small part of the cortex was saved. After the operation urinary catecholamines and serum chromogranin A returned to normal in both patients. Adrenocortical deficiency was absent in the first patient, but her sister developed adrenal insufficiency requiring glucocorticoid replacement. To the best of the authors' knowledge phaeochromocytoma affecting twins has never been described earlier. Genetic examination performed in siblings confirmed the presence of the mutant gene through four generations. Orv. Hetil., 2016, 157(33), 1326-1330.

Mineralocorticoid Receptor Deficiency in Macrophages Inhibits Neointimal Hyperplasia and Suppresses Macrophage Inflammation Through SGK1-AP1/NF-κB Pathways.

OBJECTIVE: Restenosis after percutaneous coronary intervention remains to be a serious medical problem. Although mineralocorticoid receptor (MR) has been implicated as a potential target for treating restenosis, the cellular and molecular mechanisms are largely unknown. This study aims to explore the functions of macrophage MR in neointimal hyperplasia and to delineate the molecular mechanisms. APPROACH AND RESULTS: Myeloid MR knockout (MMRKO) mice and controls were subjected to femoral artery injury. MMRKO reduced intima area and intima/media ratio, Ki67- and BrdU-positive vascular smooth muscle cells, expression of proinflammatory molecules, and macrophage accumulation in injured arteries. MMRKO macrophages migrated less in culture. MMRKO decreased Ki67- and BrdU-positive macrophages in injured arteries. MMRKO macrophages were less Ki67-positive in culture. Conditioned media from MMRKO macrophages induced less migration, Ki67 positivity, and proinflammatory gene expression of vascular smooth muscle cells. After lipopolysaccharide treatment, MMRKO macrophages had decreased p-cFos and p-cJun compared with control macrophages, suggesting suppressed activation of activator protein-1 (AP1). Nuclear factor-κB (NF-κB) pathway was also inhibited by MMRKO, manifested by decreased p-IκB kinase-ß and p-IκBα, increased IκBα expression, decreased nuclear translocation of p65 and p50, as welll as decreased phosphorylation and expression of p65. Finally, overexpression of serum-and-glucocorticoid-inducible-kinase-1 (SGK1) attenuated the effects of MR deficiency in macrophages. CONCLUSIONS: Selective deletion of MR in myeloid cells limits macrophage accumulation and vascular inflammation and, therefore, inhibits neointimal hyperplasia and vascular remodeling. Mechanistically, MR deficiency suppresses migration and proliferation of macrophages and leads to less vascular smooth muscle cell activation. At the molecular level, MR deficiency suppresses macrophage inflammatory response via SGK1-AP1/NF-κB pathways.

Novel SDHB and TMEM127 Mutations in Patients with Pheochromocytoma/Paraganglioma Syndrome.

Pheochromocytomas (Pheo) and paragangliomas (PGL) are rare tumors, with heterogeneous genetic background. In up to 30 % of all, apparently sporadic Pheo/PGL cases germline mutations can be identified in one of the 15 genes representing genetic susceptibility for Pheo/PGL. Malignancy is rare but it frequently associates with SDHB mutations. Our aim was to determine the prevalence of germline SDHx, SDHAF2, MAX and TMEM127 mutations in Hungarian patients with apparently sporadic Pheo/PGLs. Mutation screening of the SDHx, SDHAF2, MAX and TMEM127 genes was performed in 82 Hungarian patients with apparently sporadic Pheo/PGL using PCR and bidirectional Sanger sequencing. Disease-causing germline mutations were identified in 11 patients, of which 4 SDHB and 2 TMEM127 mutations were novel. Earlier development of Pheo/PGL, more malignant phenotype and multiple tumors were observed in genetically positive cases especially in those with SDHB mutations. The presence of bilateral or multiple tumors was the most predictive for identification of a pathogenic mutation. Together with cases harboring germline RET, VHL and NF1 mutations, Hungarian patients with Pheo/PGL exhibit a heterogeneous mutation spectrum, indicating that all of the Pheo/PGL susceptibility genes should be tested. Novel genotype-phenotype associations revealed by our study may contribute to improvement of diagnostic approaches and may help to achieve a better clinical follow up for patients with Pheo/PGL.

Hepatic serum- and glucocorticoid-regulated protein kinase 1 (SGK1) regulates insulin sensitivity in mice via extracellular-signal-regulated kinase 1/2 (ERK1/2).

Insulin resistance is a major hallmark of metabolic syndromes, including Type 2 diabetes. Although numerous functions of SGK1 (serum- and glucocorticoid-regulated kinase 1) have been identified, a direct effect of SGK1 on insulin sensitivity has not been previously reported. In the present study, we generated liver-specific SGK1-knockout mice and found that these mice developed glucose intolerance and insulin resistance. We also found that insulin signalling is enhanced or impaired in Hep1-6 cells infected with adenoviruses expressing SGK1 (Ad-SGK1) or shRNA directed against the coding region of SGK1 (Ad-shSGK1) respectively. In addition, we determined that SGK1 inhibits ERK1/2 (extracellular-signal-regulated kinase 1/2) activity in liver and Ad-shERK1/2-mediated inhibition of ERK1/2 reverses the attenuated insulin sensitivity in Ad-shSGK1 mice. Finally, we found that SGK1 functions are compromised under insulin-resistant conditions and overexpression of SGK1 by Ad-SGK1 significantly ameliorates insulin resistance in both glucosamine-treated HepG2 cells and livers of db/db mice, a genetic model of insulin resistance.

The AGC kinase SGK1 regulates TH1 and TH2 differentiation downstream of the mTORC2 complex.

SGK1 is an AGC kinase that regulates the expression of membrane sodium channels in renal tubular cells in a manner dependent on the metabolic checkpoint kinase complex mTORC2. We hypothesized that SGK1 might represent an additional mTORC2-dependent regulator of the differentiation and function of T cells. Here we found that after activation by mTORC2, SGK1 promoted T helper type 2 (TH2) differentiation by negatively regulating degradation of the transcription factor JunB mediated by the E3 ligase Nedd4-2. Simultaneously, SGK1 repressed the production of interferon-γ (IFN-γ) by controlling expression of the long isoform of the transcription factor TCF-1. Consistent with those findings, mice with selective deletion of SGK1 in T cells were resistant to experimentally induced asthma, generated substantial IFN-γ in response to viral infection and more readily rejected tumors.

In vitro pharmacological evaluation of the radiolabeled C-terminal substance P analogue Lys-Phe-Phe-Gly-Leu-Met-NH2: Does a specific binding site exist?

In the present paper, we report the synthesis, radiolabeling and comprehensive pharmacological evaluation of a C-terminally truncated tachykinin derivative, 3H-KFFGLM-NH2. The C-terminal fragments of endogenous tachykinins are pharmacophores responsible for interaction with the tachykinin receptors NK1, NK2 and NK3. The N-terminal fragments are responsible for modulation of receptor selectivity and interactions with other receptor systems. To evaluate and separate the function of an NK-pharmacophore from the activity of its parent neurokinin, KFFGLM-NH2 was synthesized in both tritiated and unlabeled forms. It has been proposed that the obtained NK-binding profiles of specific reference ligands and KFFGLM-NH2 differentiate monomeric and dimeric forms of NK receptors. We hypothesize that dimers of NK receptors could be specific receptor(s) for C-terminal fragments of all neurokinins as well as their C-terminal fragments, including H-KFFGLM-NH2. Dissociation of dimers into monomers opens access to additional allosteric binding sites. Fully elongated undecapeptide substance P interacts with both the "tachykinin pocket" and the "allosteric pocket" on the monomeric NK1 receptor, resulting in high and selective activation. However, C-terminal hexapeptide fragment analogues, recognizing only the "tachykinin pocket", may have less specific interactions with all tachykinin receptors in both monomeric and dimeric forms.

[3H]IVDE77, a novel radioligand with high affinity and selectivity for the insulin-regulated aminopeptidase.

The hexapeptide angiotensin IV (Ang IV) induces diverse biological effects such as memory enhancement and protection against ischemic stroke. Studies on the mechanism of Ang IV however are hampered by its instability and its lack of selectivity. The high-affinity binding site for Ang IV is the insulin-regulated aminopeptidase (IRAP, EC 3.4.11.3), but Ang IV also acts as a weak agonist for the Ang II-receptor (AT1), implying the need for stable and highly selective Ang IV-analogues. Here we present the screening of novel Ang IV-analogues, selected on basis of high affinity for IRAP, high selectivity (compared to aminopeptidase N and the AT1 receptor) and resistance against proteases. The selected compound IVDE77 possesses a number of advantages compared to Ang IV: (i) it has a 40 times higher affinity for IRAP (Ki 1.71 nM), (ii) it does not activate the AT1 receptor, (iii) it is easily radiolabeled with tritium and (iv) it is resistant to proteolysis, even in human plasma. In addition, pre-treatment of intact CHO-K1 cells with IVDE77 led to a virtually complete inhibition of subsequent intracellular accumulation of [(3)H]IVDE77-IRAP complexes. IVDE77 thus represents the first Ang IV-analogue able to abolish IRAP-availability completely at the cell surface in vitro. In summary, IVDE77 is a useful tool for the detection of IRAP under physiological conditions, and may contribute to elucidating the mechanism of Ang IV to ascertain which functions are IRAP-dependent.

Angiotensin IV displays only low affinity for native insulin-regulated aminopeptidase (IRAP).

Radioligand binding studies revealed that Ang IV binds to insulin-regulated aminopeptidase (IRAP)/'AT(4) receptors' with high affinity. Yet, as these experiments were routinely carried out in the presence of chelators, only the catalytic zinc-depleted apo-form of IRAP was labelled. While the chelators remove the catalytic zinc from IRAP and protect Ang IV from proteolytic degradation, the aminopeptidase N selective inhibitor '7B' only exerts the latter effect. By using 7B along with the new stable Ang IV-analog [(3) H]AL-11, we here show that the native enzyme is only a low-affinity target for Ang IV.

Asymmetric synthesis and conformational analysis by NMR spectroscopy and MD of Aba- and α-MeAba-containing dermorphin analogues.

Dermorphin analogues, containing a (S)- and (R)-4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one scaffold (Aba) and the α-methylated analogues as conformationally constrained phenylalanines, were prepared. Asymmetric phase-transfer catalysis was unable to provide the (S)-α-Me-o-cyanophenylalanine precursor for (S)-α-MeAba in acceptable enantiomeric purity. However, by using a Schöllkopf chiral auxiliary, this intermediate was obtained in 88 % ee. [(S)-Aba 3-Gly 4]dermorphin retained µ-opioid affinity but displayed an increased δ-affinity. The corresponding R epimer was considerably less potent. In contrast, the [(R)-α-MeAba 3-Gly 4]dermorphin isomer was more potent than its S epimer. Tar-MD simulations of both non-methylated [Aba 3-Gly 4]dermorphin analogues showed a degree of folding at the C-terminal residues toward the N terminus of the peptide, without however, adopting a stabilized ß-turn conformation. The α-methylated analogues, on the other hand, exhibited a type I/I' ß-turn conformation over the α-MeAba 3 and Gly 4 residues, which was stabilized by a hydrogen bond involving Tyr 5-HN and D-Ala 2-CO.

Serum- and glucocorticoid-induced kinase 3 in recycling endosomes mediates acute activation of Na+/H+ exchanger NHE3 by glucocorticoids.

Na(+)/H(+) exchanger 3 (NHE3) is the major Na(+) transporter in the intestine. Serum- and glucocorticoid-induced kinase (SGK) 1 interacts with NHE regulatory factor 2 (NHERF2) and mediates activation of NHE3 by dexamethasone (Dex) in cultured epithelial cells. In this study, we compared short-term regulation of NHE3 by Dex in SGK1-null and NHERF2-null mice. In comparison to wild-type mice, loss of SGK1 or NHERF2 significantly attenuated regulation of NHE3 by Dex but did not completely obliterate the effect. We show that transfection of SGK2 or SGK3 in PS120 cells resulted in robust activation of NHE3 by Dex. However, unlike SGK1 or SGK2, SGK3 rapidly activated NHE3 within 15 min of Dex treatment in both PS120 and Caco-2bbe cells. Immunofluorescence analysis showed that SGK3 colocalized with NHE3 in recycling endosomes, whereas SGK1 and SGK2 were diffusely distributed. Mutation of Arg-90 of SGK3 disrupted the endosomal localization of SGK3 and delayed NHE3 activation. Activation of SGK3 and NHE3 by Dex was dependent on phosphoinositide 3-kinase (PI3K) and phosphoinositide-dependent kinase 1 (PDK1), and Dex induced translocation of PDK1 to endosomes. Our study identifies SGK3 as a novel endosomal kinase that acutely regulates NHE3 in a PI3K-dependent mechanism.

Binding of "AT4 receptor" ligands to insulin regulated aminopeptidase (IRAP) in intact Chinese hamster ovary cells.

Insulin regulated aminopeptidase (IRAP) recognises "AT(4)-receptor" ligands like angiotensin IV (Ang IV) and peptidomimetics like AL-11. The metabolic stability and high affinity of [(3)H]AL-11 for catalytically active IRAP allowed its detection in Chinese hamster ovary (CHO-K1) cell membranes in the absence of chelators (Demaegdt et al., 2009). Here, we show that, contrary to [(3)H]Ang IV, [(3)H]AL-11 displays high affinity and specificity for IRAP in intact CHO-K1 cells as well. After binding to IRAP at the surface, [(3)H]AL-11 is effectively internalized by an endocytotic process. Unexpectedly, surface binding and internalization of [(3)H]AL-11 was not affected by pretreating the cells with Ang IV but declined with AL-11. In the latter case surface expression of IRAP even increased. After elimination of simpler explanations, it is proposed that metabolically stable "AT(4)-receptor" ligands undergo semi-continuous cycling between the cell surface and endosomal compartments. The in vivo efficacy of stable and unstable "AT(4)-receptor" ligands could therefore differ.

Recent advances in endomorphin engineering.

Recent statistics from the World Health Organization indicate that a high percentage of people worldwide suffer from a wide variety of acute or cancer-associated chronic pain. At present, with a few exceptions, the treatment of severe pain relies upon oral administration of the mu-opioid receptor-targeting opiate morphine and its surrogates under strict clinical control. In spite of the powerful in vivo efficacy of these drugs, their long-term use is limited by antinociceptive tolerance, physical dependence, and respiratory depression that evolve. As no analgesics with moderate side effect profiles are currently available for the therapy of different types of pain and stages of cancer, considerable efforts must be made in the search for opiate substitutes. Following the recognition that endogenous peptide ligands of the opioid receptors exert striking effects in various pain models, and with the recent advances in chemical synthesis methods, research interest has steadily moved toward peptide-based compounds as potential opioid analgesics. The endomorphins are an attractive set of endogenous opioid peptides that may meet the requirements of opioid-based pain management. By virtue of their excellent mu-opioid receptor labeling and favorable analgesic properties, these tetrapeptides have gained attention in recent years as potential lead compounds. The ever-increasing number of publications in this field strongly suggests that modified analogues of endomorphins could serve as potent substitutes for opiates, with a lower propensity to induce side effects. This review surveys the main results achieved over the past decade regarding the design, radiolabeling, pharmacological characterization, and structure-activity features of a large body of endomorphin derivatives.