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N-acetyl-L-cysteine for the treatment of endometriosis
No full textit has previously been proposed that NAC could be used in new therapeutic strategies for endometriosis, based on its use as an antioxidant and a ROS scavenger. The inventors of the present disclosure show that NAC induces molecular and cellular changes that not only inhibit proliferation but also induce differentiation of the diseased tissue towards normal tissueThese findings have led the inventors of the present invention to propose a new prescription of NAC in the treatment of endometriosis and of indications associated with endometriosis, in a human or mammalian animal patient. ln addition an effective dose range of NAC in the treatment of endometriosis is proposed. In one embodiment of the present invention the prescribed treatment regimen may be used e.g in order to control the frequency and the intensity of pain symptoms (dysmenorrhea, dyspareunia and acyckic chronic pelvic pain), to reduce the size of endometriotic lesions eventually up to their disappearance, to reduce recurrences after surgery and/or to improve fertility. Side effects of this treatment are virtually absent and, in particular, this treatment does not hinder pregnancy.
The present invention provides a pharmaceutical composition for the treatment of endometriosis comprising N-acetyl-L-cysteine
Abrupt modification of phospholipid bilayer properties at critical cholesterol concnetrations
No full textThe fluorescence generalized polarization (GP) of 2-dimethylamino-6-lauroylnaphthalene (Laurdan) reveals different effects of cholesterol on the phase behavior of phospholipid bilayers. Phospholipid vesicles composed of gel, liquid-crystalline, and coexisting domains of the two phases have been studied at temperatures from 1 to 65 degrees C, without cholesterol and with cholesterol concentrations of 3-50 mol %. Laurdan GP measurements show the general effect of cholesterol of increasing the molecular dynamics of the gel and of decreasing the molecular dynamics of the liquid-crystalline phase. In the liquid-crystalline phase, the increased order yields Laurdan GP values close to those obtained in the gel phase. At cholesterol concentrations >15 mol % a phase transition cannot be detected. Using the wavelength dependence of the excitation and emission GP spectra we determine that differences between the two phospholipid phases cannot be detected. In particular, in vesicles composed of coexisting gel and liquid-crystalline phases the GP wavelength dependence characteristic of coexisting domains cannot be observed at cholesterol concentrations greater than or equal to 15 mol %. Cholesterol causes the decrease in both the polarity and the dipolar relaxation effects on the neighborhood of the fluorescent naphthalene moiety of Laurdan. Probably because of a cholesterol-induced increase in the bilayer packing, these effects do not occur continuously with the increase of cholesterol concentration in the bilayer. Cholesterol concentrations inducing higher Laurdan GP values have been determined at about 5, 10, 15, 30, and 45 mol % with respect to phospholipids. We propose that the formation of ordered molecular microdomains at critical cholesterol concentrations can explain the occurrence of the observed discontinuities
Two-photon fluorescence imaging of aorta fibres reveals a new mechanism for vascular damage induced by LDL hydroperoxides
No full textCell membrane lipid molecular dynamics in a solenoid versus a magnetically shielded room
No full textThe generalized polarization function of the fluorescent probe 2-dimethylamino-6-lauroylnaphthalene has been used to evaluate the lipid dynamics in Friend erythroleukemia cell membrane. The values of this function varied during the culture growth cycle, showing decreased lipid dynamics 24-48 h from the cell seeding. When the cycle occurred in a solenoid producing a magnetic field of 70 mu T at 50 Hz in addition to the 45 mu T DC of the earth (short-term 4-day exposure), the membrane lipid dynamics during this same time-period decreased by about 10% (P < .04). After long-term (184 days) or extremely long-term (395 days) exposure of the cells to the magnetic field, little additional variation in the membrane lipid dynamics was observed, suggesting an adaptation phenomenon. A variation of membrane lipid dynamics was also observed due to in vitro cell differentiation (P < .02). Nevertheless, the exposure of both undifferentiating and differentiating cells to a highly attenuated magnetic field in a magnetically shielded room (20 nT DC plus 2.5 pT AC) did not induce any modification of membrane lipid dynamics. (C) 1998 Wiley-Liss, Inc
Atheroscleorosis: another protein misfolding disease
No full textThe secondary structure and conformation of apo-B 100 in low-density lipoproteins (LDL) are imposed by lipid–protein interactions and dynamics, and affected by the introduction or removal of lipids during the course of lipoprotein metabolism. Following an alteration of the water–lipid interface as a result of, for example, oxidation of lipids, the supramolecular structure becomes destabilized and apoB can misfold. These events have been observed in LDL−, a fraction of oxidatively modified LDL isolated in vivo. This modified lipoprotein possesses several atherogenic properties and represents an in vivo counterpart of in vitro modified LDL that is implicated in atherosclerosis. The misfolding of apoB, its aggregation, resistance to proteolysis, and cytotoxicity are common motifs shared by LDL− and amyloidogenic proteins. Based on these analogies, we propose that atherogenesis could be considered as a disease produced by the accumulation of cytotoxic and pro-inflammatory misfolded lipoproteins
Misfolding of apoprotein B-100, LDL aggregation and 17-β -estradiol in atherogenesis.
No full textThe long quest for a missing mechanistic rationale accounting for the correlation between plasma cholesterol levels and cardiovascular disease (CVD) has been focused on various possible modifications of low density lipoprotein (LDL), turning this physiological cholesterol carrier into a damaging agent able to trigger atherogenesis and later the onset of the disease. In addition to the debated oxidized LDL (oxLDL), a modified LDL with a misfolded apoprotein B-100, called electronegative LDL(-) for its negative charge due to an increased amount of free fatty acids, is commonly present in plasma. LDL(-) is generated by the action of secretory calcium dependent phospholipase A2. LDL(-) primes LDL aggregation and amyloid formation according to mechanisms very similar to those observed in other misfolding diseases. The LDL particle aggregates recall the structure and size of the subendothelial lipid droplets described in early atherogenesis and elicit a powerful inflammatory response. The use of 17-β-estradiol (E2) confirmed that the suggested atherogenicity of LDL (-) is mostly dependent on the misfolded character of its apoprotein. E2 binding to the apoprotein of native LDL, through a specific and saturable receptor, inhibits misfolding phenomenon despite an unaffected production of LDL (-) by phospholipase A2, ultimately preventing LDL aggregation. The apoprotein misfolding in LDL(-) emerges as a possible significant trigger mechanism of atherogenesis. Potential implications for the development of novel therapeutic approaches might be hypothesized in perspective. The existing evidence is discussed and reported in this review
Human cell membrane oxidative damage induced by single and fractionated doses of ionizing radiation: a fluorescence spectroscopy study
No full textPurpose: To investigate the production and repair of lipid oxidative damage in two human cell lines exposed to acute and fractionated dose of ionizing radiation. Radiation dose was in the range from 0.1 to 44 Gy. Materials and Methods: K562 and HL60 human cell lines have been used, 24 and 96 h after seeding. Membrane lipid oxidative damage has been detected by the measurement of the fluorescence decay of 1,6-diphenyl-1,3,5-hexatriene (DPH), its polarization value and the conjugated dienes concentration. The modification of DPH decay has been previously reported to be directly related to the lipid hydroperoxide concentration. Results: A modification of the DPH decay has been observed as a linear function of the logarithm of the radiation dose and only when the irradiation was performed in the presence of oxygen. The amount of the damage is related to the time after the cell medium change. By exposing the cells to fractionated radiation doses for several days (10 cGy day(-1)), the oxidative damage has been found to be cumulative. After a single acute dose, evidence of repair of the lipid oxidative damage was not obtained. Conclusions: Following a previously developed method, the membrane damage was attributed to the production of hydroperoxide residues in the lipid acyl chains with the consequence of water penetration into the external portion of the bilayer, from the aqueous environment to the position of hydroperoxides. This damage is not repaired. The results obtained by measuring the DPH fluorescence decay have been compared with those obtained using other current optical and biochemical methods. None of these techniques could detect membrane oxidative damage at doses <10Gy. Finally, the different sensitivity of 'young' and 'old' cells to the oxidative damage can be related to different cholesterol concentrations
Tecniche di fluorescenza per l’osservazione di danni ossidativi prodotti da basse dosi di radiazioni ionizzanti su lipidi di membrana
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