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The complexity of parathyroid hormone-related peptide (PTHrP) signalling
No full textOur understanding of the mode of action of parathyroid hormone-related protein (PTHrP) has changed profoundly during the last decade. Most PTHrP activities are mediated by membrane receptors through autocrine/paracrine pathways. However, both endogenous and exogenous PTHrP also appear to have intracrine effects through translocation into the nucleus. The present review proposes unconventional PTHrP signalling, based on novel clues. First, PTHrP binding to its membrane receptor triggers internalization of the whole complex, mediated by beta-arrestin. There is growing evidence that the receptor and arrestin are the effectors of biological responses, rather than the ligand (or in addition to the ligand). Second, the existence of putative PTHrP targets within the cytoplasm is beginning to be supported. Recent findings of interactions between a COOH-terminus of PTHrP and beta-arrestin and between the PTHrP receptor and 14-3-3 proteins represent the starting point for identification of intracellular partners of both the hormone and its receptor
Can the apparent conflicting roles of PKC delta on cell proliferation and survival be reconciled?
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Rottlerin: bases for a possible usage in psoriasis
No full textRottlerin is a natural polyphenolic compound, which was initially indicated and marketed as a PKC delta inhibitor and recently proposed and patented as an anti-hypertensive drug. In vitro results from our Laboratory and data from the literature suggest a potential use of Rottlerin in the treatment/control of psoriasis, a skin disease characterized by abnormal cellular proliferation, abnormal angiogenesis and inflammation. Rottlerin, indeed, is an antioxidant and a potent inhibitor of the transcription factor NFkappaB, a key mediator of immune responses and a crucial regulator of cell cycle and apoptosis in immune cells, endothelial cells and keratinocytes. Herein, we will review the multiple activities of Rottlerin (antioxidant, antiproliferative, antiangiogenic and anti-inflammatory) that give to the drug the potential to be used as a new therapeutic approach against psoriasis
Antiproliferative Effect of Rottlerin on Sk-Mel-28 Melanoma Cells
Full text linkMelanoma is the most aggressive and chemoresistant form of skin cancer. Mutated, constitutively active B-RAF is believed to play a crucial role, although the selective B-RAF inhibition has shown poor clinical success, since phenomena of resistance usually occur, likely arising from additional genetic aberrations, such as loss of function of p53 and PTEN, overexpression of cyclin D1, hyperactivation of NF-κB, and downregulation of p21/Cip1. Since all of them are present in the Sk-Mel-28 melanoma cells, this cell line could be an ideal, albeit hard to study, model to develop new therapeutic strategies. In the current study, we tested the cytostatic action of Rottlerin on Sk-Mel-28 melanoma cells, on the basis of the known Rottlerin effects on the main proliferative signaling pathways. We presented evidence that the drug inhibits cell growth by an Akt- and p21/Cip1-independent mechanism, involving the dual inhibition of ERK and NF-κB and downregulation of cyclin D1. In addition, we found that Rottlerin increases ERK phosphorylation, but, surprisingly, this resulted in decreased ERK activity. Pull-down experiments, using Rottlerin-CNBr-conjugated Sepharose beads, revealed that Rottlerin binds to ERK, independently from its phosphorylation status. This direct interaction could in part explain the paradoxical blockage of ERK downstream signaling and growth arrest. We would like to dedicate this paper to the memory of our friend and colleague, prematurely deceased, Claudia Torricelli, who actively contributed to this project
Cutaneous MMPs are differently modulated by environmental stressors in old and young mice
No full textSkin is frequently exposed to pro-oxidative insults such as UV light, ozone (O(3)) and cigarette smoke (CS), which are able to deplete antioxidants and induce oxidation products affecting skin pathophysiology. Skin turnover and regeneration are largely dependent on extracellular matrix metabolism, which is under the control of matrix metalloproteinases, MMPs. The present study evaluated cutaneous MMPs activity upon environmental pollutants exposure and analyzed the response of old and young animals. For this purpose, SKH-1 hairless mice (8 weeks and 18 months old) were exposed for 6h/day to 0.25ppm of O(3) or to UV radiation (0.3 MED) or to CS for 4 days. Gelatin zymography revealed an increase of MMP-2 in both young and old animals, after exposure to pollutants, while MMP-9, undetectable in unexposed subjects, was strongly induced only in old mice. Casein zymography and Western blot analysis showed an increase of MMP-12 in the aged group after environmental stressors exposure. TIMP-1 and -2 expression levels did not change. The current study demonstrates the ability of certain environmental pollutants to affect the ECM turnover through modulation of specific MMPs, and confirms the higher susceptibility of old subjects to exogenous pro-oxidant insults
Parathyroid hormone-related protein in preeclampsia: a linkage between maternal and fetal failures
No full textPreeclampsia is a disorder associated with pregnancy that affects both the mother and the fetus. Typical features of the disease are maternal hypertension, proteinuria, and edema as well as fetal growth retardation. Although the etiological details are still being debated, a consensus exists that the starting point is deficient placentation in the first half of pregnancy. The crucial early steps are reduced trophoblast invasiveness and enhanced apoptotic death. In the present review, we demonstrate that parathyroid hormone-related protein is involved not only in the maternal and fetal failures but also in the etiological aspects of the disease. We hypothesize that reduced local production of the peptide is a major causative event
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