salicylates and Fibrosis

Renal fibrosis is the common pathway in chronic kidney diseases progression to end-stage renal disease, but to date, no clinical drug for its treatment is approved. It has been demonstrated that the inhibitor of proto-oncogene Ras, farnesylthiosalicylic acid (FTS), shows therapeutic potential for renal fibrosis, but its application was hindered by the water-insolubility and low bioavailability. Hence, in this study, we improved these properties of FTS by encapsulating it into bovine serum albumin nanoparticles (AN-FTS) and tested its therapeutic effect in renal fibrosis.. AN-FTS was developed using a classic emulsification-solvent ultrasonication. The pharmacokinetics of DiD-loaded albumin nanoparticle were investigated in SD rats. The biodistribution and therapeutic efficacy of AN-FTS was assessed in a mouse model of renal fibrosis induced by unilateral ureteral obstruction (UUO).. AN-FTS showed a uniform spherical shape with the size of 100.6 ± 1.12 nm and PDI < 0.25. In vitro, AN-FTS displayed stronger inhibitory effects on the activation of renal fibroblasts cells NRK-49F than free FTS. In vivo, AN-FTS showed significantly higher peak concentration and area under the concentration-time curve. After intravenous administration to UUO-induced renal fibrosis mice, AN-FTS accumulated preferentially in the fibrotic kidney, and alleviated renal fibrosis and inflammation significantly more than the free drug. Mechanistically, the improved anti-fibrosis effect of AN-FTS was associated with greater inhibition in renal epithelial-to-mesenchymal transformation process via Ras/Raf1/p38 signaling pathway.. The study reveals that AN-FTS is capable of delivering FTS to fibrotic kidney and showed superior therapeutic efficacy for renal fibrosis.

Topics: Albumins; Animals; Farnesol; Fibrosis; Mice; Nanoparticles; Proto-Oncogene Proteins c-raf; Rats; Rats, Sprague-Dawley; Salicylates; Signal Transduction; Tissue Distribution

Protein modification by small ubiquitin-like modifier (SUMO) plays a critical role in the pathogenesis of heart diseases. The present study was designed to determine whether ginkgolic acid (GA) as a SUMO-1 inhibitor exerts an inhibitory effect on cardiac fibrosis induced by myocardial infarction (MI).. GA was delivered by osmotic pumps in MI mice. Masson staining, electron microscopy (EM) and echocardiography were used to assess cardiac fibrosis, ultrastructure and function. Expression of SUMO-1, PML, TGF-β1 and Pin1 was measured with Western blot or Real-time PCR. Collagen content, cell viability and myofibroblast transformation were measured in neonatal mouse cardiac fibroblasts (NMCFs). Promyelocytic leukemia (PML) protein was over-expressed by plasmid transfection.. GA improved cardiac fibrosis and dysfunction, and decreased SUMO-1 expression in MI mice. GA (>20 μM) inhibited NMCF viability in a dose-dependent manner. Nontoxic GA (10 μM) restrained angiotensin II (Ang II)-induced myofibroblast transformation and collagen production. GA also inhibited expression of TGF-β1 mRNA and protein in vitro and in vivo. GA suppressed PML SUMOylation and PML nuclear body (PML-NB) organization, and disrupted expression and recruitment of Pin1 (a positive regulator of TGF-β1 mRNA), whereas over-expression of PML reversed that.. Inhibition of SUMO-1 by GA alleviated MI-induced heart dysfunction and fibrosis, and the SUMOylated PML/Pin1/TGF-β1 pathway is crucial for GA-inhibited cardiac fibrosis.

Topics: Animals; Animals, Newborn; Cell Survival; Dose-Response Relationship, Drug; Fibrosis; Male; Mice; Myocardial Infarction; Salicylates; Stroke Volume; SUMO-1 Protein

Radiation-induced normal tissue toxicity is closely linked to endothelial cell (EC) damage and dysfunction (acute effects). However, the underlying mechanisms of radiation-induced adverse late effects with respect to the vascular compartment remain elusive, and no causative radioprotective treatment is available to date.. The importance of injury to EC for radiation-induced late toxicity in lungs after whole thorax irradiation (WTI) was investigated using a mouse model of radiation-induced pneumopathy. We show that WTI induces EC loss as long-term complication, which is accompanied by the development of fibrosis. Adoptive transfer of mesenchymal stem cells (MSCs) either derived from bone marrow or aorta (vascular wall-resident MSCs) in the early phase after irradiation limited the radiation-induced EC loss and fibrosis progression. Furthermore, MSC-derived culture supernatants rescued the radiation-induced reduction in viability and long-term survival of cultured lung EC. We further identified the antioxidant enzyme superoxide dismutase 1 (SOD1) as a MSC-secreted factor. Importantly, MSC treatment restored the radiation-induced reduction of SOD1 levels after WTI. A similar protective effect was achieved by using the SOD-mimetic EUK134, suggesting that MSC-derived SOD1 is involved in the protective action of MSC, presumably through paracrine signaling.. In this study, we explored the therapeutic potential of MSC therapy to prevent radiation-induced EC loss (late effect) and identified the protective mechanisms of MSC action.. Adoptive transfer of MSCs early after irradiation counteracts radiation-induced vascular damage and EC loss as late adverse effects. The high activity of vascular wall-derived MSCs for radioprotection may be due to their tissue-specific action. Antioxid. Redox Signal. 26, 563-582.

Topics: Animals; Disease Models, Animal; Endothelial Cells; Fibroblasts; Fibrosis; Gene Expression; Lung; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Organometallic Compounds; Phenotype; Radiation Injuries; Radiation Injuries, Experimental; Salicylates; Superoxide Dismutase-1

The Ras superfamily of guanosine-triphosphate (GTP)-binding proteins regulates a diverse spectrum of intracellular processes involved in inflammation and fibrosis. Farnesythiosalicylic acid (FTS) is a unique and potent Ras inhibitor which decreased inflammation and fibrosis in experimentally induced liver cirrhosis and ameliorated inflammatory processes in systemic lupus erythematosus, neuritis and nephritis animal models. FTS effect on Ras expression and activity, muscle strength and fibrosis was evaluated in the dy(2J)/dy(2J) mouse model of merosin deficient congenital muscular dystrophy. The dy(2J)/dy(2J) mice had significantly increased RAS expression and activity compared with the wild type mice. FTS treatment significantly decreased RAS expression and activity. In addition, phosphorylation of ERK, a Ras downstream protein, was significantly decreased following FTS treatment in the dy(2J)/dy(2J) mice. Clinically, FTS treated mice showed significant improvement in hind limb muscle strength measured by electronic grip strength meter. Significant reduction of fibrosis was demonstrated in the treated group by quantitative Sirius Red staining and lower muscle collagen content. FTS effect was associated with significantly inhibition of both MMP-2 and MMP-9 activities. We conclude that active RAS inhibition by FTS was associated with attenuated fibrosis and improved muscle strength in the dy(2J)/dy(2J) mouse model of congenital muscular dystrophy.

Topics: Animals; Base Sequence; Blotting, Western; Disease Models, Animal; DNA Primers; Farnesol; Fibrosis; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Muscle Strength; Muscular Dystrophies; ras Proteins; Salicylates

Chemical peels are an effective treatment for wrinkles, but their use is limited because of the associated risk of scarring, hypopigmentation, and the inability to accurately control the depth of tissue injury. High energy, pulsed, or computer scanned continuous wave carbon dioxide (CO2) lasers cause minimal thermal injury, decrease the risk of scarring, and allow for precise control of tissue vaporization to predictable depths.. To compare the effectiveness and side effect profile of a medium-depth chemical peel to that of the SilkTouch CO2 laser in the treatment of periorbital wrinkles.. Twenty-four subjects (nine male, 15 female) with moderate to severe periorbital wrinkles were assigned a wrinkle score (1 = mild through 5 = severe) before treatment and 6 months after treatment. Each subject was treated with Jessner's solution and 35% trichloroacetic acid on one side and the SilkTouch CO2 laser on the other side.. The average periorbital wrinkle score decreased from 4.00 +/- 0.78 before laser treatment to 1.75 +/- 0.68 6 months after treatment. The chemical peel wrinkle score decreased from 4.13 +/- 0.85 to 3.29 +/- 0.99. The degree in which the wrinkle score improved after laser treatment compared with after chemical peel treatment was statistically significant. Posttreatment erythema lasted an average of 4.5 months for the laser-treated areas and 2.5 months for the chemical peel-treated areas.. Treatment of periorbital wrinkles with the SilkTouch CO2 laser resulted in a greater degree of improvement than treatment with a medium-depth chemical peel but had longer lasting posttreatment erythema.

Topics: Administration, Cutaneous; Adult; Aged; Carbon Dioxide; Chemexfoliation; Cicatrix; Drug Combinations; Erythema; Ethanol; Female; Fibrosis; Follow-Up Studies; Forecasting; Humans; Hypopigmentation; Lactic Acid; Laser Therapy; Male; Middle Aged; Orbit; Resorcinols; Rhytidoplasty; Risk Factors; Salicylates; Skin; Skin Aging; Time Factors; Trichloroacetic Acid; Wound Healing