This work aims to summarize the current knowledge about Mannose--Phosphate/ Insulin-like Growth Factor Receptor M P/IGF -R in the regulation of growth and development, and its involvement in tumor progression. M P/IGF -R binds both molecules sharing M P signals and IGF . The studies showed that M P/IGF -R is involved in the traicking of mannnose--phosphorylated enzymes from the TransGolgi Network TGN to lysosomes and the uptake of secreted proenzymes from the plasma membrane to the lysosomes via clathrin-coated vesicles for their maturation. The M P/IGF -R acts as a scavenger that binds IGF and transports it to lysosomes for its degradation since IGF exerts its biological efects on cell proliferation and development by binding with lower ainity on IGF receptor, which is structurally similar to insulin receptor and diferent from the M P/IGF -R. The M P/IGF -R has also been studied in human cancer, and frequent losses of heterozygosity LOH at the q -gene region with mutations in the remaining allele have been described. These results led to consider M P/IGF -R gene as a putative tumor suppressor and its potential prognostic value has been suggested.
Peptide Nucleic Acid (PNAs) and small noncoding RNAs including small interfering RNAs (siRNAs) represent a new class of oligonucleotides considered as an alternative therapeutic strategy in the chronic hepatitis B treatment. Indeed, chronic hepatitis B virus (HBV) infection remains a major public health problem worldwide, despite the availability of an effective prophylactic vaccine. Current therapeutic approaches approved for chronic HBV treatment are pegylated-interferon alpha (IFN)-α and nucleos(t)ide analogues (NAs). Both therapies do not completely eradicate viral infection and promote severe side effects. In this context, the development of new effective treatments is imperative. This review focuses on antiviral activity of both PNAs and siRNAs targeting hepatitis B virus. Thus, we briefly present our results on the ability of PNAs to decrease hepadnaviral replication in duck hepatitis B virus (DHBV) model. Interestingly, other oligonucleotides as siRNAs could significantly inhibit HBV antigen expression in transient replicative cell culture. Because the application of these oligonucleotides as new antiviral drugs has been hampered by their poor intracellular bioavailability, we also discuss the benefits of their coupling to different molecules such as the cell penetrating peptides (CPPs), which were used as vehicles to deliver therapeutic agents into the cells.
Central administration of angiotensin (Ang) II stimulates thirst and sodium intake via the AT-1 receptor. Mineralocorticoid pretreatment enhances Ang II-induced drinking of hypertonic salt solutions (i.e. the synergy theory) in Wistar and Sprague-Dawley rats. Electrophysiological experiments using iontophoretic application of Ang II, and the AT-1 receptor specific nonpeptide antagonist losartan, have shown excitation of neurones in the preoptic/medial septum region of urethane anaesthetised male Wistar rats. Deoxycorticosterone acetate (DOCA) pretreatment further enhanced this neuronal excitation to Ang II and reduced the responses to losartan. This generated the hypothesis that DOCA-enhanced Ang II-induced neuronal excitation was necessary for the enhanced salt intake of synergy theory. We tested this hypothesis in Fischer 344 rats that are known to have a low basal salt appetite and reduced sensitivity for i.c.v. Ang II. We compared the effect of DOCA pretreatment on i.c.v. Ang II-induced water and 2% NaCl intake in behaving adult male, Fischer rats, as well as preoptic/medial septum region neuronal responses to Ang II and losartan, using a seven-barrelled micro-iontophoretic electrode sealed to a recording electrode in urethane anaesthetised, male Fischer rats. Two groups were used: one pretreated with DOCA (0.5 mg/day for 3 days) and the other comprising controls, treated with isotonic saline. Ang II applied iontophoretically increased activity in 31% of the spontaneously active neurones. Following DOCA pretreatment, the responsiveness to Ang II (when applied after aldosterone) was increased. By contrast, in the behaving animals, water and 2% NaCl intake in response to i.c.v. Ang II were not enhanced by DOCA pretreatment. These results do not support the working hypothesis but could be interpreted as evidence for the existence of two separately modulated central Ang II systems: one responding to mineralocorticoids with increased neuronal activity and the other responsible for the Ang II-induced sodium appetite in conscious rats.
Central angiotensin II (AngII) stimulates water and salt solution intake. Pretreatment with low-dose mineralocorticoid (DOCA) enhances this AngII-induced intake of salt solutions (the synergy theory) in Wistar and Sprague Dawley rats but not in Fischer rats. This response is mediated via the AT-1 receptor. Electrophysiological experiments using iontophoretic application of AngII and the AT-1 receptor-specific non-peptide antagonist losartan showed excitation of neurons in the preoptic/medial septum region of urethane-anesthetized male Wistar rats. DOCA pretreatment further enhances this neuronal excitation in response to AngII and reduces the responses to losartan. This generated the hypothesis that DOCA-enhanced AngIIinduced neuronal excitation is the neural support for the synergy theory. AT-2 receptors modulate these intake responses depending on sodium in the diet, and diuretic-induced dehydration during pregnancy produces a higher salt intake in the offspring. AngII-induced salt and water intakes were tested in offspring from Sprague Dawley mothers with only 1.8% NaCl to drink in which half were treated with furosemide. The important observations were a) the AT-1 antagonist alone suppressed intakes in offspring from mothers not treated with furosemide, b) both AT-1 and AT-2 antagonists suppressed intakes in offspring from furosemide-treated mothers, and c) combined administration of AT-1 and AT-2 antagonists greatly suppressed water intake in offspring from mothers not treated with furosemide. These results suggest that AT-1 and AT-2 receptors have variable properties (receptor number and/or second messengers). Furthermore, the activity and function of these central AngII receptors depend on the background mineralocorticoid levels. The exact mechanism of this influence, however, remains to be determined. Correspondence
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