Pirfenidone restricts Th2 differentiation in vitro and limits Th2 response in experimental liver fibrosis

Polarized T helper type 2 (Th2) response is linked with fibrosis. Here, we evaluated the effect of the anti-fibrotic agent pirfenidone on Th type 1 (Th1) and Th2 responses. For in vivo testing; Wistar rats were made cirrhotic by intraperitoneal administration of thioacetamide. Once hepatic damage was established, pirfenidone was administered intragastrically on a daily basis during three weeks. Gene expression of Th marks was evaluated by RT-PCR and Western blot assays from liver homogenates. Pirfenidone therapy induced down-regulation of Th2 transcripts and proteins (GATA3 and IL-4), without affecting significantly Th1 genes expression (T-bet and IFN-γ). We found that the activated form of p38 MAPK (identified by Western blot) was reduced by pirfenidone treatment, which is consistent with the anti-Th2 activity observed. Pirfenidone reduced GATA3 nuclear localization without modifying its DNA binding activity (evaluated by electrophoretic mobility shift assay). For in vitro testing; human naive CD4+ T cells were cultured in either Th1 or Th2 polarizing conditions in the presence of pirfenidone and flow cytometric analysis of intracellular synthesis of IFN-γ and IL-4 was conducted. Pirfenidone impaired development of Th2 subpopulation. In conclusion, pirfenidone is capable of impairing Th2 differentiation and limits Th2 profibrogenic response. The mechanism involves p38 inhibition and regulation of GATA3 expression and translocation. © 2011 Elsevier B.V. All rights reserved

Ethylenediaminetetraacetic acid induces antioxidant and anti-inflammatory activities in experimental liver fibrosis

Background: Experimental liver fibrosis induced by carbon tetrachloride (CCl4) is associated with oxidative stress, lipid peroxidation, and inflammation. This work was focused on elucidating the anti-inflammatory and antioxidant effects of ethylenediaminetetraacetic acid (EDTA) in this model of hepatotoxicity Methods: Wistar male rats were treated with CCl4 and EDTA (60, 120, or 240 mg/kg). Morphometric analyses were carried out in Masson's stained liver sections to determine fibrosis index. Coagulation tests prothrombin time (PT) and partial thromboplastin time (PTT) were also determined. Gene expression for transforming growth factor beta (TGF-beta1), alpha1(I) procollagen gene (alpha1 Col I), tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and superoxide dismutase (SOD) was monitored by real-time PCR. Antioxidant effect of EDTA was measured by its effects on lipid peroxidation; biological activity of ceruloplasmin (Cp), SOD, and catalase (Cat) were analyzed by zymography assays. Results: Animals with CCl4-hepatic injury that received EDTA showed a decrement in fibrosis (20%) and lipid peroxidation (22%). The mRNA expression for TNF-alpha (55%), TGF-beta1 (50%), IL-6 (52%), and alpha1 Col I (60%) was also decreased. This group of animals showed increased Cp (62%) and SOD (25%) biological activities. Coagulation blood tests, Cat activity, and gene expression for SOD were not modifiedby EDTA treatment. Conclusion: This study demonstrates that EDTA treatment induces the activity of antioxidant enzymes, decreases lipid peroxidation, hepatic inflammation, and fibrosis in experimental liver fibrosis induced by CCl4. © W.S. Maney & Son Ltd

Polymeric Implants for the Treatment of Intraocular Eye Diseases: Trends in Biodegradable and Non-Biodegradable Materials

Intraocular/Intravitreal implants constitute a relatively new method to treat eye diseases successfully due to the possibility of releasing drugs in a controlled and prolonged way. This particularity has made this kind of method preferred over other methods such as intravitreal injections or eye drops. However, there are some risks and complications associated with the use of eye implants, the body response being the most important. Therefore, material selection is a crucial factor to be considered for patient care since implant acceptance is closely related to the physical and chemical properties of the material from which the device is made. In this regard, there are two major categories of materials used in the development of eye implants: non-biodegradables and biodegradables. Although non-biodegradable implants are able to work as drug reservoirs, their surgical requirements make them uncomfortable and invasive for the patient and may put the eyeball at risk. Therefore, it would be expected that the human body responds better when treated with biodegradable implants due to their inherent nature and fewer surgical concerns. Thus, this review provides a summary and discussion of the most common non-biodegradable and biodegradable materials employed for the development of experimental and commercially available ocular delivery implants

Lipid-Based Nanocarriers as Topical Drug Delivery Systems for Intraocular Diseases

Effective drug delivery to intraocular tissues remains a great challenge due to complex anatomical and physiological barriers that selectively limit the entry of drugs into the eye. To overcome these challenges, frequent topical application and regular intravitreal injections are currently used to achieve the desired drug concentrations into the eye. However, the repetitive installation or recurrent injections may result in several side effects. Recent advancements in the field of nanoparticle-based drug delivery have demonstrated promising results for topical ophthalmic nanotherapies in the treatment of intraocular diseases. Studies have revealed that nanocarriers enhance the intraocular half-life and bioavailability of several therapies including proteins, peptides and genetic material. Amongst the array of nanoparticles available nowadays, lipid-based nanosystems have shown an increased efficiency and feasibility in topical formulations, making them an important target for constant and thorough research in both preclinical and clinical practice. In this review, we will cover the promising lipid-based nanocarriers used in topical ophthalmic formulations for intraocular drug delivery