APE1/Ref-1 as a Novel Target for Retinal Diseases

APE1/Ref-1 (also called Ref-1) has been extensively studied for its role in DNA repair and reduction-oxidation (redox) signaling. The review titled: “The multifunctional APE1 DNA repair-redox signaling protein as a drug target in human disease” by Caston et. al. summarizes the molecular functions of Ref-1 and the role it plays in a number of diseases, with a specific focus on various types of cancer [1]. Previous studies have demonstrated that Ref-1 plays a critical role in regulating specific transcription factors (TFs) involved in a number of pathways, not only in cancer, but other disease indications as well. Disease indications of particular therapeutic interest include retinal vascular diseases such as diabetic retinopathy (DR), diabetic macular edema (DME), and neovascular agerelated macular degeneration (nvAMD). While Ref-1 controls a number of TFs that are under redox regulation, three have been found to directly link cancer studies to retinal diseases; HIF-1α, NF-κB and STAT3. HIF-1α controls the expression of VEGF for angiogenesis while NF-κB and STAT3 regulate a number of known cytokines and factors involved in inflammation. These pathways are highly implicated and validated as major players in DR, DME and AMD. Therefore, findings in cancer studies for Ref-1 and its inhibition may be translated to these ocular diseases. This report discusses the path from cancer to the potential treatment of retinal disease, the Ref-1 redox signaling function as a possible target, and the current small molecules which have been identified to block this activity. One molecule, APX3330, is in clinical trials, while the others are in preclinical development. Inhibition of Ref-1 and its effects on inflammation and angiogenesis makes it a potential new therapeutic target for the treatment of retinal vascular diseases. This commentary summarizes the retinal-relevant research that built on the results summarized in the review by Caston et. al. [1]

Hunger Artists: Yeast Adapted to Carbon Limitation Show Trade-Offs under Carbon Sufficiency

As organisms adaptively evolve to a new environment, selection results in the improvement of certain traits, bringing about an increase in fitness. Trade-offs may result from this process if function in other traits is reduced in alternative environments either by the adaptive mutations themselves or by the accumulation of neutral mutations elsewhere in the genome. Though the cost of adaptation has long been a fundamental premise in evolutionary biology, the existence of and molecular basis for trade-offs in alternative environments are not well-established. Here, we show that yeast evolved under aerobic glucose limitation show surprisingly few trade-offs when cultured in other carbon-limited environments, under either aerobic or anaerobic conditions. However, while adaptive clones consistently outperform their common ancestor under carbon limiting conditions, in some cases they perform less well than their ancestor in aerobic, carbon-rich environments, indicating that trade-offs can appear when resources are non-limiting. To more deeply understand how adaptation to one condition affects performance in others, we determined steady-state transcript abundance of adaptive clones grown under diverse conditions and performed whole-genome sequencing to identify mutations that distinguish them from one another and from their common ancestor. We identified mutations in genes involved in glucose sensing, signaling, and transport, which, when considered in the context of the expression data, help explain their adaptation to carbon poor environments. However, different sets of mutations in each independently evolved clone indicate that multiple mutational paths lead to the adaptive phenotype. We conclude that yeasts that evolve high fitness under one resource-limiting condition also become more fit under other resource-limiting conditions, but may pay a fitness cost when those same resources are abundant

Multiple Signals Converge on a Differentiation MAPK Pathway

An important emerging question in the area of signal transduction is how information from different pathways becomes integrated into a highly coordinated response. In budding yeast, multiple pathways regulate filamentous growth, a complex differentiation response that occurs under specific environmental conditions. To identify new aspects of filamentous growth regulation, we used a novel screening approach (called secretion profiling) that measures release of the extracellular domain of Msb2p, the signaling mucin which functions at the head of the filamentous growth (FG) MAPK pathway. Secretion profiling of complementary genomic collections showed that many of the pathways that regulate filamentous growth (RAS, RIM101, OPI1, and RTG) were also required for FG pathway activation. This regulation sensitized the FG pathway to multiple stimuli and synchronized it to the global signaling network. Several of the regulators were required for MSB2 expression, which identifies the MSB2 promoter as a target “hub” where multiple signals converge. Accessibility to the MSB2 promoter was further regulated by the histone deacetylase (HDAC) Rpd3p(L), which positively regulated FG pathway activity and filamentous growth. Our findings provide the first glimpse of a global regulatory hierarchy among the pathways that control filamentous growth. Systems-level integration of signaling circuitry is likely to coordinate other regulatory networks that control complex behaviors

CLIPing the brain:studies of protein-RNA interactions important for neurodegenerative disorders

The fate of an mRNA is largely determined by its interactions with RNA binding proteins (RBPs). Post-transcriptional processing, RNA stability, localisation and translation are some of the events regulated by the plethora of RBPs present within cells. Mutations in various RBPs cause several diseases of the central nervous system, including frontotemporal lobar degeneration, amyotrophic lateral sclerosis and fragile X syndrome. Here we review the studies that integrated UV-induced cross-linked immunoprecipitation (CLIP) with other genome-wide methods to comprehensively characterise the function of diverse RBPs in the brain. We discuss the technical challenges of these studies and review the strategies that can be used to reliably identify the RNAs bound and regulated by an RBP. We conclude by highlighting how CLIP and related techniques have been instrumental in addressing the role of RBPs in neurologic diseases. This article is part of a Special Issue entitled: RNA and splicing regulation in neurodegeneration. © 2013

The possessions of Lavra on the island of Saint Eustratios until the Turkish attack at the beginning of the 14th century

 At the beginning of the 14th century and particularly before December of 1305, the Turks carried out an attack against the island of St Eustratios (of Neoi), which was a possession of the Athonite monastery of Great Lavra. The abbot of the monastery, monk Gerasimos, required from the archbishop of Lemnos and Imbros to provide in his archbishopric a kathedra, i.e. an agricultural piece of land with residence for the monks of St Eustratios in order to settle there and save themselves from the Turkish danger. The archbishop granted the monks of St Eustratios and generally Lavra the little monastery of Theotokos Kakaviotissa, which is still existing on the southwest part of the island of Lemnos.In this study is offered a short review of the history of St Eustratios (of Neoi) during the Byzantine period; the origin of the name of the island is specified and it is emphasized that the island is attested from the second half of the 9th century onwards. At that time the island of St Eustratios (of Neoi) was uninhabited and for a short period of time (865/866) served as a place of ascetic living for St Efthymios the Younger († 15.10.898) and the hermits John Kolovos and Symeon.About 976-984 the island of Neoi (St Eustratios) was donated by the emperor Basileios II (976-1025) to John Iberian († 14.6.1005), a nobleman from Iberia (nowadays Georgia). The latter donated the island to Lavra because of his friendship with St Athanasios the Athonite († 5.7.1001 or 1004), the foun­der of the monastery of Great Lavra. According to the Vita of St Athana­sios, the island was donated directly from the emperor Basileios II to the monastery of Lavra.Since then the island of Neoi (St Eustratios) was a place of solitary life for the younger monks of Lavra. In addition, Byzantine emperors such as Ro­ma­nos  III Argyros (1031), Nicephoros III Botaneiates (1079), Michael VIII Palaeologos (1259), Andronikos II Palaeologos (1298) and Andronikos III Pa­laeologos (1329) confirmed with chrysobulls the rights of possession of the Lavra monastery upon the island.In conclusion, since the time that St Eustratios became a dependency of Lavra on the last quarter of the 10th century and until the beginning of the 14th century, the island was continually under the possession of Lavra and life went on peacefully and undisturbed.At the beginning of the 14th century the Byzantine Εmpire being in a state of decline was unable to resist against Turkish danger. The Turkish tribes had conquered almost the whole Asia Minor –with exception of some cities and ports– and they had founded small and expanding states (emirates). The Εmirate of Mentese and the one of Aydin were the first ones which started piracy into the Aegean sea. Perhaps the first or the latter attacked the island of St Eustratios. It is at that time that the monks of the island found shelter in the little monastery of Kakaviotissa on the island of Lemnos.During the same period similar cases appeared: monks from northwest Asia Minor abandoned their monasteries or monastic centers because of the Turkish danger and sought shelter in the monasteries of Thrace in the European region

Gsh levels affect weight loss in individuals with metabolic syndrome and obesity following dietary therapy

This study examined the effects of redox status markers on metabolic syndrome (MetS) and obesity before and after dietary intervention and exercise for weight loss. A total of 103 adults suffering from MetS and obesity participated in this study and followed a personalized diet plan for 6 months. Body weight, body fat (BF) percentage (BF%), respiratory quotient (RQ) and the redox status markers, reduced glutathione (GSH), thiobarbituric acid reactive substances (TBARS) and protein carbonyls (CARB), were measured twice in each individual, before and after intervention. Dietary intervention resulted in weight loss, a reduction in BF% and a decrease in RQ. The GSH levels were significantly decreased following intervention, while the levels of TBARS and CARB were not affected. Based on the initial GSH levels, the patients were divided into 2 groups as follows: The high GSH group (GSH, >3.5 µmol/g Hb) and the low GSH group (GSH <3.5 µmol/g Hb). Greater weight and BF loss were observed in patients with high GSH levels. It was observed that patients with MetS and obesity with high GSH values responded better to the dietary therapy, exhibiting more significant changes in weight and BF%. This finding underscores the importance of identifying redox status markers, particularly GSH, in obese patients with MetS. Knowing the levels of GSH may aid in developing a better design of an individualized dietary plan for individuals who wish to lose weight. © 2018, Spandidos Publications. All rights reserved