Nanotherapies for the Treatment of Age-Related Macular Degeneration (AMD) Disease: Recent Advancements and Challenges.

Age-related Macular Degeneration (AMD) is one of the common diseases affecting the posterior part of the eye, of a large population above 45 years old. Anti-Vascular Endothelial Growth Factor- A (Anti-VEGF-A) agents have been considered and approved as therapeutic agents for the treatment of AMD. Due to the large molecular weight and poor permeability through various eye membranes, VEGF-A inhibitors are given through an intravitreal injection, even though the delivery of small therapeutic molecules by topical application to the posterior part of the eye exhibits challenges in the treatment. To overcome these limitations, nanocarrier based delivery systems have been utilized to a large extent for the delivery of therapeutics. Nanocarriers system offers prodigious benefits for the delivery of therapeutics to the posterior part of the eye in both invasive and non-invasive techniques. The nano size can improve the permeation of therapeutic agent across the biological membranes. They provide protection from enzymes present at the site, targeted delivery or binding with the disease site and extend the release of therapeutic agents with prolonged retention. This leads to improved therapeutic efficacy, patient compliance, and cost effectiveness of therapy with minimum dose associated side-effects. This review has summarized various nanocarriers explored for the treatment of AMD and challenges in translation.

Pattern recognition by pentraxins.

Pentraxins are a family of evolutionarily conserved pattern-recognition proteins that are made up of five identical subunits. Based on the primary structure of the subunit, the pentraxins are divided into two groups: short pentraxins and long pentraxins. C-reactive protein (CRP) and serum amyloid P-component (SAP) are the two short pentraxins. The prototype protein of the long pentraxin group is pentraxin 3 (PTX3). CRP and SAP are produced primarily in the liver while PTX3 is produced in a variety of tissues during inflammation. The main functions of short pentraxins are to recognize a variety of pathogenic agents and then to either eliminate them or neutralize their harmful effects by utilizing the complement pathways and macrophages in the host. CRP binds to modified low-density lipoproteins, bacterial polysaccharides, apoptotic cells, and nuclear materials. By virtue of these recognition functions, CRP participates in the resolution of cardiovascular, infectious, and autoimmune diseases. SAP recognizes carbohydrates, nuclear substances, and amyloid fibrils and thus participates in the resolution of infectious diseases, autoimmunity, and amyloidosis. PTX3 interacts with several ligands, including growth factors, extracellular matrix component and selected pathogens, playing a role in complement activation and facilitating pathogen recognition by phagocytes. In addition, data in gene-targeted mice show that PTX3 is essential in female fertility, participating in the assembly of the cumulus oophorus extracellular matrix. PTX3 is therefore a nonredundant component of the humoral arm of innate immunity as well as a tuner of inflammation. Thus, in conjunction with the other components of innate immunity, the pentraxins use their pattern-recognition property for the benefit of the host.

A novel RBP-J kappa-dependent switch from C/EBP beta to C/EBP zeta at the C/EBP binding site on the C-reactive protein promoter.

Regulation of basal and cytokine (IL-6 and IL-1beta)-induced expression of C-reactive protein (CRP) in human hepatoma Hep3B cells occurs during transcription. A critical transcriptional regulatory element on the CRP promoter is a C/EBP binding site overlapping a NF-kappaB p50 binding site. In response to IL-6, C/EBPbeta and p50 occupy the C/EBP-p50 site on the CRP promoter. The aim of this study was to identify the transcription factors occupying the C/EBP-p50 site in the absence of C/EBPbeta. Accordingly, we treated Hep3B nuclear extract with a C/EBP-binding consensus oligonucleotide to generate an extract lacking active C/EBPbeta. Such treated nuclei contain only C/EBPzeta (also known as CHOP10 and GADD153) because the C/EBP-binding consensus oligonucleotide binds to all C/EBP family proteins except C/EBPzeta. EMSA using this extract revealed formation of a C/EBPzeta-containing complex at the C/EBP-p50 site on the CRP promoter. This complex also contained RBP-Jkappa, a transcription factor known to interact with kappaB sites. RBP-Jkappa was required for the formation of C/EBPzeta-containing complex. The RBP-Jkappa-dependent C/EBPzeta-containing complexes were formed at the C/EBP-p50 site on the CRP promoter in the nuclei of primary human hepatocytes also. In luciferase transactivation assays, overexpressed C/EBPzeta abolished both C/EBPbeta-induced and (IL-6 + IL-1beta)-induced CRP promoter-driven luciferase expression. These results indicate that under basal conditions, C/EBPzeta occupies the C/EBP site, an action that requires RBP-Jkappa. Under induced conditions, C/EBPzeta is replaced by C/EBPbeta and p50. We conclude that the switch between C/EBPbeta and C/EBPzeta participates in regulating CRP transcription. This process uses a novel phenomenon, that is, the incorporation of RBP-Jkappa into C/EBPzeta complexes solely to support the binding of C/EBPzeta to the C/EBP site.

Oxidative stress and antioxidant status in cancer patients and healthy subjects, a case-control study.

Since raised oxidative stress (OS) or weak antioxidant defence or both are considered to be important players in multimechanistic pathogenesis of cancer, the present study was undertaken to evaluate their possible involvement in the pathogenesis of this disease in the local population. Levels of plasma vitamin C, vitamin E, total antioxidant activity (TAA) and thiobarbituric acid reacting substances (TBARS) as a marker of OS were measured in 20 cancer patients (Mean age 63.1 + 9.3 yr.) and 20 age, sex and socioeconomically matched healthy subjects (Mean age 63.7+7.8 yr.). Significantly low level of vitamin C (p <0.001), vitamin E (p <0.001) and TAA (p <0.003) were observed in cancer patients, whereas OS was significantly increased in patients as compared to control (p <0.003). Smokers had significantly lowered TAA and significantly raised OS than non-smokers, in both case and control groups. Tobacco chewer patients had raised OS as compared to control. This study supports the thesis that OS is a risk factor in carcinogenesis and that smoking, an established risk factor in cancer, at least partly appears through it.