Melanocortin subtype 4 receptor agonists: structure-activity relationships about the 4-alkyl piperidine core

SAR about the piperidine core in a series of MC4R agonists is described. A number of alkyl substituents that furnish compounds with good affinity and functional potency are reported.     

Hidden in plain sight: Borrelia burgdorferi and the extracellular matrix

Borrelia burgdorferi, the tick-transmitted etiologic agent of Lyme borreliosis, can colonize and persist in multiple tissue sites despite vigorous host immune responses. The extracellular matrix appears to provide a protective niche for the spirochete. Recent studies in mice suggest that B. burgdorferi interacts in various ways with collagen and its associated molecules, exploiting molecular and structural features to establish microcolonial refugia. Better knowledge of the genetic and structural bases for these interactions of B. burgdorferi with the extracellular matrix will be required before an understanding of the persistence of B. burgdorferi in the tissues and development of chronic infections can be achieved.     

Occurrence of Apristurus species in the Galicia Bank Seamount (NE Atlantic)

The aim of this study was to identify some of the Apristurus species by combining morphometric and genetic tools. Several specimens of the genus Apristurus were caught on the Galicia Bank Seamount (NE Atlantic), between 1460 and 1809 m depths, during a multidisciplinary survey carried out in 2011 within the framework of the INDEMARES Project. Morphometric and genetic analyses were conducted to aid the identification of the specimens collected. A total of 20 specimens were identified, of which 18 corresponded to Apristurus aphyodes (Nakaya and Stehmann, 1998 ), one to A. profundorum (Goode and Bean, 1896 ) and one to A. melanoasper Iglesias, Nakaya & Stehmann, 2004 . Genetic results based on the mtDNA COI sequences (682–690 bp fragment of the COI gene) support the identification of A. profundorum and A. melanoasper, with a bootstrap of 99 and 96%, respectively. The identification of A. aphyodes was also performed using a 499 bp fragment of the 16S mitochondrial gene. These are the first records of the Apristurus species from Galician waters, which extends their known area of distribution and provides more information on different biological and ecological aspects of this complex taxonomic group.     

Analysis of gene expression for studying tumor progression: the case of glucocorticoid administration

Background

Glucocorticoids are commonly used as adjuvant treatment for side-effects and have anti-proliferative activity in several tumors but, on the other hand, their proliferative effect has been reported in several studies, some of them involving the spread of cancer. We shall attempt to reconcile these incongruities from the genomic and tissue-physiology perspectives with our findings.

Methods

An accurate phenotype analysis of microarray data can help to solve multiple paradoxes derived from tumor-progression models. We have developed a new strategy to facilitate the study of interdependences among the phenotypes defined by the sample clusters obtained by common clustering methods (HC, SOTA, SOM, PAM). These interdependences are obtained by the detection of non-linear expression-relationships where each fluctuation in the relationship implies a phenotype change and each relationship typology implies a specific phenotype interdependence. As a result, multiple phenotypic changes are identified together with the genes involved in the phenotype transitions. In this way, we study the phenotypic changes from microarray data that describe common phenotypes in cancer from different tissues, and we cross our results with biomedical databases to relate the glucocorticoid activity to the phenotypic changes.

Results

11,244 significant non-linear expression relationships, classified into 11 different typologies, have been detected from the data matrix analyzed. From them, 415 non-linear expression relationships were related to glucocorticoid activity. Studying them, we have found the possible reason for opposite effects of some stressor agents like dexamethasone on tumor progression and it has been confirmed by literature. This hidden reason has resulted in being linked with the type of tumor progression of the tissues. In the first type of tumor progression found, new cells can be stressed during proliferation and stressor agents increase tumor proliferation. In the second type, cell stress and tumor proliferation are antagonists so, therefore, stressor agents stop tumor proliferation in order to stress the cells. The non-linear expression relationships among DUSP6, FERMT2, FKBP5, EGFR, NEDD4L and CITED2 genes are used to synthesize these findings.     

Effects of Piper hispidinervum on spermatogenesis and histochemistry of ovarioles of Spodoptera frugiperda

The fall armyworm, Spodoptera frugiperda (J. E. Smith) (Lepidoptera: Noctuidae), not only damages crops, but controlling its population also requires synthetic insecticides, which leads to selection of resistant populations and environmental contamination. Essential oils are an alternative for controlling this insect. There are few studies of the effects of these oils on the insect's reproductive system. We evaluated the effects of the long pepper, Piper hispidinervum, essential oil on the gonads of the armyworm and tested its possible influence on the fertility of this insect. Dosages of 30 and 50 mg/ml were tested in 3^rd instar caterpillars using the leaf immersion method. Testes and ovarioles were collected, fixed with 10% formalin and embedded in Historesin. The sections were stained with toluidine blue and Mallory trichrome to detect connective tissue, periodic acid-Schiff to detect neutral carbohydrates, and bromophenol blue to detect proteins. We found that the long pepper essential oil affected negatively the spermatogenesis and altered the histochemistry of the ovarioles of S. frugiperda. The effects of long pepper oil suggest that it is a promising tool for controlling the armyworm pest.     

Guidelines for diagnosis and treatment of Hunter Syndrome for clinicians in Latin America

This review aims to provide clinicians in Latin America with the most current information on the clinical aspects, diagnosis, and management of Hunter syndrome, a serious and progressive disease for which specific treatment is available. Hunter syndrome is a genetic disorder where iduronate-2-sulfatase (I2S), an enzyme that degrades glycosaminoglycans, is absent or deficient. Clinical manifestations vary widely in severity and involve multiple organs and tissues. An attenuated and a severe phenotype are recognized depending on the degree of cognitive impairment. Early diagnosis is vital for disease management. Clinical signs common to children with Hunter syndrome include inguinal hernia, frequent ear and respiratory infections, facial dysmorphisms, macrocephaly, bone dysplasia, short stature, sleep apnea, and behavior problems. Diagnosis is based on screening urinary glycosaminoglycans and confirmation by measuring I2S activity and analyzing I2S gene mutations. Idursulfase (recombinant I2S) (Elaprase^®, Shire) enzyme replacement therapy (ERT), designed to address the underlying enzyme deficiency, is approved treatment and improves walking capacity and respiratory function, and reduces spleen and liver size and urinary glycosaminoglycan levels. Additional measures, responding to the multi-organ manifestations, such as abdominal/inguinal hernia repair, carpal tunnel surgery, and cardiac valve replacement, should also be considered. Investigational treatment options such as intrathecal ERT are active areas of research, and bone marrow transplantation is in clinical practice. Communication among care providers, social workers, patients and families is essential to inform and guide their decisions, establish realistic expectations, and assess patients’ responses.     

Cyclic analogs of alpha-melanocyte-stimulating hormone (alphaMSH) with high agonist potency and selectivity at human melanocortin receptor 1b

Alpha-melanotropin (alphaMSH), Ac-Ser1-Tyr2-Ser3-Met4-Glu5-His6-Phe7-Arg8-Trp9-Gly10-Lys11-Pro12-Val13-NH2,(1) has been long recognized as an important physiological regulator of skin and hair pigmentation in mammals. Binding of this peptide to the melanocortin receptor 1 (MC1R) leads to activation of tyrosinase, the key enzyme of the melanin biosynthesis pathway. In this study, interactions of the human MC1bR (an isoform of the receptor 1a) with the synthetic cyclic analogs of alphaMSH were studied. These ligands were analogs of MTII, Ac-Nle4-cyclo-(Asp5-His6-D-Phe7-Arg8-Trp9-Lys10)-NH2, a potent pan-agonist at the human melanocortin receptors (hMC1,3-5R). In the structure of MTII, the His6-D-Phe7-Arg8-Trp9 segment has been recognized as "essential" for molecular recognition at the human melanocortin receptors (hMC1,3-5R). Herein, the role of the Trp9 in the ligand interactions with the hMC1b,3-5R has been reevaluated. Analogs with various amino acids in place of Trp9 were synthesized and tested in vitro in receptor affinity binding and cAMP functional assays at human melanocortin receptors 1b, 3, 4 and 5 (hMC1b,3-5R). Several of the new peptides were high potency agonists (partial) at hMC1bR (EC50 from 0.5 to 20 nM) and largely inactive at hMC3-5R. The bulky aromatic side chain in position 9, such as that in Trp, was found not to be essential to agonism (partial) of the studied peptides at hMC1bR.     

Aspects of peridomiciliary ecotopes in rural areas of northeastern Brazil associated to triatomine (Hemiptera, Reduviidae) infestation, vectors of chagas disease

Artificial ecotopes of 121 peridomiciliary environments in four rural localities in the state of Ceará, Brazil, were studied and the type of material of the ecotopes was identified as triatomine infestation. Two thousand two hundred and four Triatoma brasiliensis Neiva, 340 Triatoma pseudomaculata Corrêa and Espínola, 121 Rhodnius nasutus Stall, and 5 Panstrongylus lutzi (Neiva and Pinto) were captured. Out of the 323 ecotopes found (X = 2.0 +/- 1.8 per dwelling) - such as pigpens, henhouses, corrals, perches, dovecotes, piles of roofing tiles, bricks, wood, and straw - 30.3% were infested by triatomines in all different developmental stages, including eggs. A substantial number of triatomines were found in perches, however the largest infestation took place in roofing materials used in the construction of goat/sheep corrals, henhouses, and pigpens, where 98% of them were captured: 1372 triatomines were located in the roofing tile covers, 285 in the straw, 187 in the perches, 77 in the coverings of roofing tiles and straw, and 13 in the straw and wood Among all the different pile of materials, roofing tiles were the most infested (50%) followed by bricks (38.9%) and woods (36.1%). T. brasiliensis colonized mainly brick piles (chi-squared = 16.539; p < 0.05) and roofing tiles (chi-squared = 5,090.58; p < 0.05); T. pseudomaculata preferred wood perches (chi-squared = 472.39; p < 0.05) and woodpiles (chi-squared = 126.0 p < 0.05), and R. nasutus was principally found in roofing straw (chi-squared = 384.43; p < 0.05). These findings suggest that triatomines tend to colonize peridomiciliary ecotopes similar to their original habitats.