The potential of nanomedicine therapies to treat neovascular disease in the retina

Neovascular disease in the retina is the leading cause of blindness in all age groups. Thus, there is a great need to develop effective therapeutic agents to inhibit and prevent neovascularization in the retina. Over the past decade, anti-VEGF therapeutic agents have entered the clinic for the treatment of neovascular retinal disease, and these agents have been effective for slowing and preventing the progression of neovascularization. However, the therapeutic benefits of anti-VEGF therapy can be diminished by the need for prolonged treatment regimens of repeated intravitreal injections, which can lead to complications such as endophthalmitis, retinal tears, and retinal detachment. Recent advances in nanoparticle-based drug delivery systems offer the opportunity to improve bioactivity and prolong bioavailability of drugs in the retina to reduce the risks associated with treating neovascular disease. This article reviews recent advances in the development of nanoparticle-based drug delivery systems which could be utilized to improve the treatment of neovascular disease in the retina

Characterization of a renoprotective AATF peptide in models of diabetic nephropathy

Inflammation and cell death play central roles in diabetic kidney complications. Identification of novel renoprotective molecules is essential for developing new therapies. We have identified an unconventional extrinsic renoprotective pathway mediated by a 12-amino acid peptide (SAP-12) derived from extracellularly secreted AATF (apoptosis antagonizing transcription factor) in blocking renal damage in models of diabetic nephropathy (DN). SAP-12 (secreted AATF peptide of 12 amino acids, SALKNSHKALKA) is conserved among human, mouse, and rat AATF proteins, and confers potent renoprotective properties at femtomolar concentrations with a broad effective range in renal tubular epithelial cells (RTECs) following exposure to high levels of glucose. We reported previously that AATF was a highly effective in protecting against renal damage and it rescues renal tubular epithelial cells from both apoptotic and necrotic death. The rationale for the current study was based on our recent observation that the renoprotective actions of AATF seemed to be accomplished in a highly unusual manner in diabetic kidneys. As a transcription factor, AATF often functions as an intracellular protein located in cytoplasmic and/or nuclear compartments. However, we have unexpectedly noted that a significant amount of intracellular AATF protein was secreted extracellularly by RTECs under diabetic conditions. Furthermore, secreted AATF (sAATF) functions, at least in part, as a specific ligand and antagonist of the cell surface receptor TLR4 (Toll-like receptor-4). Of importance, TLR4-mediated signaling has been shown to be critically involved in the inflammation and cell death in DN. A region corresponding to the amino acid sequence between AATF179 and AATF279 was responsible for interacting with TLR-4. Based on these observations, several small AATF core peptides derived from this region of AATF were synthesized and tested for their renoprotective properties and their ability to interact with TLR4. One of these peptides, SAP-12, was identified at the interface of AATF/TLR4 interaction. Surprisingly, SAP-12 had a much greater potency and broader effective dose range than the full length sAATF in protecting RTECs in models of diabetic nephropathy. The extrinsic pathway mediated by sAATF and SAP-12 provides strong support for the existence of non-classical secretory pathways where cytoplasmic and nuclear proteins can be secreted extracellularly without a classical N-terminal signal peptide. The region(s) in the extracellular ectodomain of TLR4 involved in interacting with SAP-12 and the potential therapeutic applications of SAP-12 in DN will be discussed. By studying the structure-activity relationships of SAP-12, it may also be possible to develop additional novel versatile peptides with even greater renoprotective capacity and specificity. This study is therefore highly innovative and significant. This work supported in part by an award from Harold Hamm Diabetes Center at the University of Oklahoma. # To whom correspondence should be addressed: Dept. of Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104. Tel.: 405-271-2226; Fax: 405-271-3181; E-mail: [email protected]

Renormalization group improved pQCD prediction for Υ(1S)\Upsilon(1S) leptonic decay

The complete next-to-next-to-next-to-leading order short-distance and bound-state QCD corrections to $\Upsilon(1S)$ leptonic decay rate $\Gamma(\Upsilon(1S)\to \ell^+\ell^-)$ has been finished by Beneke {\it et al.} \cite{Beneke:2014qea}. Based on those improvements, we present a renormalization group (RG) improved pQCD prediction for $\Gamma(\Upsilon(1S)\to \ell^+\ell^-)$ by applying the principle of maximum conformality (PMC). The PMC is based on RG-invariance and is designed to solve the pQCD renormalization scheme and scale ambiguities. After applying the PMC, all known-type of $\beta$-terms at all orders, which are controlled by the RG-equation, are resummed to determine optimal renormalization scale for its strong running coupling at each order. We then achieve a more convergent pQCD series, a scheme- independent and more accurate pQCD prediction for $\Upsilon(1S)$ leptonic decay, i.e. $\Gamma_{\Upsilon(1S) \to e^+ e^-}|_{\rm PMC} = 1.270^{+0.137}_{-0.187}$ keV, where the uncertainty is the squared average of the mentioned pQCD errors. This RG-improved pQCD prediction agrees with the experimental measurement within errors.Comment: 11 pages, 4 figures. Numerical results and discussions improved, references updated, to be published in JHE

The cGAS-STING Pathway in Diabetic Retinopathy and Age-Related Macular Degeneration

Diabetic retinopathy and age-related macular degeneration are common retinal diseases with shared pathophysiology, including oxidative stress-induced inflammation. Cellular mechanisms responsible for converting oxidative stress into retinal damage are ill-defined but have begun to clarify. One common outcome of retinal oxidative stress is mitochondrial damage and subsequent release of mitochondrial DNA into the cytosol. This leads to activation of the cGAS-STING pathway, resulting in interferon release and disease-amplifying inflammation. This review summarizes the evolving link between aberrant cGAS-STING signaling and inflammation in common retinal diseases and provides prospective for targeting this system in diabetic retinopathy and age-related macular degeneration. Further defining the roles of this system in the retina is expected to reveal new disease pathology and novel therapeutic approaches

Analysis of influence factors of free cataract surgery in suburban district of one city in middle China

AIM:To investigate the reasons of the barriers to free cataract surgery in suburban area of one city in middle China. <p>METHODS: From 2008 to 2009, in Sight Rehabilitation Programme of Cataract in suburban district of one city in middle China, all visually significant cataract patients screened were questioned about why he/she did not accept free cataract surgery. The answers were recorded and analyzed. <p>RESULTS: Of 892 screened patients, only 387 patients(43.39%)wanted a free cataract surgery at first. At last 490 patients(54.93%)accepted free surgery. The main reasons for patients who did not accept free surgery include: be afraid of surgery and wanting other treatments(193, 21.64%), thinking the eyesight was enough for daily life(148, 16.59%), worrying about that the result would not be good as those paid for surgery(147, 16.48%), and other reasons(17, 1.91%).<p>CONCLUSION: The reasons of the barriers to free cataract surgery include patients' ignorance, surgery outcome of patients around, and working mode of designated surgical hospital

Therapeutic Effects of PPAR α

Peroxisome-proliferator activated receptor-alpha (PPARα) is a broadly expressed nuclear hormone receptor and is a transcription factor for diverse target genes possessing a PPAR response element (PPRE) in the promoter region. The PPRE is highly conserved, and PPARs thus regulate transcription of an extensive array of target genes involved in energy metabolism, vascular function, oxidative stress, inflammation, and many other biological processes. PPARα has potent protective effects against neuronal cell death and microvascular impairment, which have been attributed in part to its antioxidant and anti-inflammatory properties. Here we discuss PPARα’s effects in neurodegenerative and microvascular diseases and also recent clinical findings that identified therapeutic effects of a PPARα agonist in diabetic microvascular complications

Knockdown of GBP5 alleviates lipid accumulation and inflammation in alcoholic fatty liver through inhibition of NF-κB pathway in mice

Alcoholic liver disease (ALD) is a global liver disease that manifests in a variety of forms, including alcoholic hepatitis, liver inflammation, fatty liver, and liver cirrhosis. One of the early stages of ALD is alcoholic fatty liver (AFL) disease, which is primarily characterized by the accumulation of lipids and inflammation in hepatocytes. Guanylate binding protein 5 (GBP5) has been investigated for its involvement in disease progression. The regulatory effects of GBP5 on the progression of AFL disease are still not well understood. This study aims to investigate the impact of GBP5 on AFL progression and its underlying mechanism of action. To achieve this, gene expression was evaluated using western blot and reverse transcription quantitative polymerase chain reaction (RT-qPCR) methods. Lipid accumulation was confirmed using the Oil Red O staining assay, while the levels of Triglyceride (TG), aspartate aminotransferases (AST), and alanine aminotransferases (ALT) were measured using commercial kits. The levels of inflammatory cytokines were assessed using enzyme-linked immuno sorbent assay (ELISA) assay. Finally, cell apoptosis was evaluated using flow cytometry. Cell apoptosis was evaluated through flow cytometry. Our work demonstrated that GBP5 expression was up-regulated in the Ethyl Alcohol (EtOH) group. Additionally, lipid accumulation was increased after EtOH inducement, but this change was attenuated by silencing GBP5. Silencing of GBP5 reduced EtOH-mediated inflammation and cell apoptosis. Finally, it was discovered that knockdown of GBP5 retarded the EtOH-stimulated nuclear factor kappa-B (NF-κB) pathway. Knockdown of GBP5 alleviated lipid accumulation and inflammation in AFL through inhibition of NF-κB pathway. This finding suggested that GBP5 may be a useful bio-target for AFL treatment