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Background Predatory attacks on horses can become a problem in some parts of the world, particularly when considering the recovering gray wolf populations. The issue studied was whether horses transformed by humans and placed in stable-pasture environments had retained their natural abilities to respond to predation risk. The objective of the study was to determine the changes in cardiac activity, cortisol concentrations, and behavior of horses in response to the vocalizations of two predators: the gray wolf (Canis lupus), which the horses of the breed studied had coevolved with but not been exposed to recently, and Arabian leopard (Panthera pardus nimr), from which the horses had been mostly isolated. In addition, we hypothesized that a higher proportion of Thoroughbred (TB) horse ancestry in the pedigree would result in higher emotional excitability in response to predator vocalizations. Nineteen horses were divided into groups of 75%, 50% and 25% TB ancestry. The auditory test conducted in a paddock comprised a 10-min prestimulus period, a 5-min stimulus period when one of the predators was heard, and a 10-min poststimulus period without any experimental stimuli. Results The increase in heart rate and saliva cortisol concentration in response to predator vocalizations indicated some level of stress in the horses. The lowered beat-to-beat intervals revealed a decrease in parasympathetic nervous system activity. The behavioral responses were less distinct than the physiological changes. The responses were more pronounced with leopard vocalizations than wolf vocalizations. Conclusions The horses responded with weak signs of anxiety when exposed to predator vocalizations. A tendency towards a stronger internal reaction to predators in horses with a higher proportion of TB genes suggested that the response intensity was partly innate. The more pronounced response to leopard than wolf may indicate that horses are more frightened of a threatening sound from an unknown predator than one known by their ancestors. The differing response can be also due to differences in the characteristic of the predators’ vocalizations. Our findings suggested that the present-day horses’ abilities to coexist with predators are weak. Hence, humans should protect horses against predation, especially when introducing them into seminatural locations.

The current predation threat of domestic horses is generally low, and horses do not know predators' frightening cues. We studied whether horses still recognise predation threats. The aim of the study was to analyse the emotional response of purebred Arabian horses (Arabian) and Polish Konik horses (Konik) to an Arabian panther (Panthera pardus nimr) (panther) growl and a grey wolf (Canis lupus) (wolf) howl. Panther vocalisation was known to Arabian ancestors, whereas ancestors of Konik knew wolf vocalisation. The response to the howls of golden jackals (Canis aureus) (jackal), which did not prey on equids, was also studied comparatively. Two groups of 10 adult horses of each breed were subject to predator sounds of one predator daily for 5 min during a turn out on pasture. The test was performed for 18 days in total. The sound of each predator was interchangeably featured from one loudspeaker for 3 days followed by four loudspeakers simultaneously to imitate a group of predators for 3 days. The horses' emotional agitation in response to the sounds was measured based on the parameters of heart rate variability (HRV) using telemetric devices. The results showed that the predators' sounds were identified by horses as stressful or neutral. Horses generally retained their anti-predator responses even in the current habitat, which typically lacks predation cues. The results are not always coherent and may demonstrate that the response is somewhat attenuated. The wolf howl elicited a stronger response in Koniks. The panther growl more strongly influenced Arabians, whereas the jackal howl minimally elicited an agitation in the horses. The differentiated response of the two horse breeds to the three predator species suggests that the response is an innate adaptation to the predation risk in the habitat of the breed ancestors. This response occurs regardless of the emotional arousal specific to a breed, and the frightening cue is not the sound per se but the possible attack of predators. Horses display a type of understanding of the sound meaning. Their HRV response seems to be adequate for the threat signalised by the sound.

Melanopsin, a G family coupled receptor, found within the ganglion cell layer in the retina, plays an important role in non-image-forming visual functions, including hormone secretion, entrainment of circadian rhythms, cognitive and affective processes. Diffuse projections of melanopsin-containing cells to many brain areas suggest that different responses may involve different neural projections, thus different melanopsin cells. Considering the complexity of the melanopsin system, its contribution to so many different biological functions is not surprising. In this review, we summarize the current knowledge about melanopsin in terms of its photophysics, photochemistry, mechanisms of activation, cell signaling, morphology, and physiology. In the last part, the role of melanopsin in image and non-image forming processes and cognitive and affective functioning of animals and humans, are discussed. Although in recent years considerable insight has been gained into the melanopsin system, it still remains an open question of how one protein expressed by several thousand cells in the retina, could be responsible for so many diverse functions and what activation mechanism(s) it uses.

The aim of the study was to evaluate physiological changes in hematological and biochemical parameters in mares in perinatal period. Blood samples were collected from 24 pregnant Polish Konik breed mares which were divided into two groups. The first group (Group – I, n=12) comprised mares living in the wild, in the reserve. The second group (Group – II, n=12) consisted of mares kept in stables. The blood was collected 2 weeks prior to the parturition, then 24 hours after the delivery, and then at the 7th and 21st day after foaling. When comparing the two groups before the parturition, no significant differences in terms of WBC, RBC, and Hb were found, however, there was a significant difference in MCV, MCH, LYM, NEU and SEG NEU (p≤0.05). In Group II, 24 hours after the parturition and at the 21st day after foaling, a significant raise in WBC, NEU and SEG NEU (p≤0.05) was detected. No significant differences in serum concentrations of proteins such as TP, Alb or Glb were observed. As to acute phase proteins, significant rise in SAA and Hp (p≤0.05) was found in the two examined groups 24 hours after the parturition. Yet, this rise remained within physiological range. The study revealed a certain degree of fluctuations in hematological parameters, in serum concentrations of acute-phase proteins and total proteins in the mares in the perinatal period. However, these changes remained still within physiological ranges and thus they do not indicate potential susceptibility to disorders of perinatal period.

Melanopsin is a G protein-coupled receptor with a peak sensitivity in the blue part of the spectrum, which plays a key role in nonvisual light-mediated signaling. Recently, its importance in forming visual pathway as well as its role in blood vessels photorelaxation was also revealed. Melanopsin was discovered in 1998 in Xenopus leavis. Since then, the melanopsin presence was demonstrated across the species. The existence of two melanopsin genes (opn4m and opn4x) as well as melanopsin isoforms resulting from alternative splicing contributes to the variety in melanopsin-regulated processes. In this review, the diversity in melanopsin-induced signaling, regulation of melanopsin activity by phosphorylation and regulation of melanopsin mRNA are discussed.

Developmental changes that occur in the prefrontal cortex during adolescence alter behavior. These behavioral alterations likely stem from changes in prefrontal cortex neuronal activity, which may depend on the properties and expression of ion channels. Nav1.9 sodium channels conduct a Na

Touching the skin by gentle stroking is frequently used to reward horses. The objective of the study was to examine emotional excitability and behaviour of horses in response to stroking different regions of their bodies. The study included 15 adult warmbloods and 15 adult ponies, nine geldings and six mares within each type of horse. First, a novel-object test was conducted. For five successive days, one of five regions of the horse's body was stroked on each side for 5 min. Heart rate and heart rate variability were monitored at rest, during the test and stroking. Simultaneously, horse behaviour was assessed on a 1-5 scale. The data were analysed using analysis of variance GLM, Tukey's Honestly Significant Difference test and Spearman's correlation coefficient. When stroked, horses were more excited than when at rest. Differences in emotional excitability and behaviour while stroking various body regions depended on the type and sex of horses. Parameters studied indicated that both in warmbloods and ponies, stroking the head may be beneficial, whereas the trunk should be treated with caution. Stroking may have a more positive influence in horses of lower emotionality and highly estimated behaviour at rest and during the novel-object test.

Heme oxygenase-1 (HO-1), a heme-degrading enzyme, is suggested to play an important role in kidney pathophysiology, mostly due to its anti-fibrotic, anti-apoptotic and anti-oxidant properties. One of the mycotoxin, ochratoxin A (OTA) was previously shown to affect HO-1 expression, however, the mechanisms of OTA-induced nephrotoxicity during HO-1 deficiency are unknown. We have shown that OTA regulates the number of pro-fibrotic, pro-inflammatory, anti-oxidative and pro-apoptotic factors in HO-1 dependent manner, as the lack of HO-1 accelerates whereas the induction of HO-1 expression by cobalt protoporphyrin (CoPP) attenuates nephrotoxic effect of OTA. The down-regulation of the nuclear factor-erythroid-2- related factor 2 (Nrf2) transcription factor by OTA, observed in HO-1 knock-out animals, might be another mechanism of OTA toxicity. Moreover, HO-1 level and OTA treatment influences the expression of microRNAs. Namely, p53-regulated miR-34a and pro-fibrotic miR-21 were already increased in HO-1-/- kidneys and were further induced by OTA administration, whereas anti-fibrotic miR-29c was down-regulated by this mycotoxin. Our study indicates that complex mechanisms of OTA nephrotoxicity may be partially overcome by HO-1 induction.

Several mechanisms are postulated to be responsible for nephrotoxic and nephrocarcinogenic activities of mycotoxin and food contaminant, ochratoxin A (OTA). Although Nrf2 transcription factor was suggested to be involved in OTA-mediated renal injury, comprehensive study evaluating the effect of OTA toxicity in Nrf2 knock-out mice with special regard to sex-dependency has not been performed yet. Our results clearly show exacerbated OTA toxicity in porcine tubular epithelial cells after shRNA-mediated Nrf2 inhibition as well as in proximal tubular cells isolated from Nrf2-/- male mice in comparison to cells derived from their wild-type counterparts. In vivo study revealed that male mice are significantly more susceptible to OTA-mediated injury than females and this effect was further enhanced in mice lacking Nrf2. OTA increased the expression of pro-fibrotic, pro-inflammatory and pro-apoptotic factors, while concomitantly decreased the level of claudin-2 and vascular endothelial growth factor (VEGF). Importantly, miR-21, miR-34a and miR-382 were potently up-regulated after OTA delivery. Noteworthy, treatment with sulforaphane (SFN), diminished expression of OTA-induced inflammatory cytokines (IL-1β, IL-6), pro-apoptotic factors (c-myc, PUMA) and microRNAs (miR-382, miR-34a) in male mice. In summary, our data implies sex-dependent effect of OTA, with males being more sensitive. The lack of Nrf2 enhances susceptibility to mycotoxin-induced pathologies, suggesting that modulation of the Nrf2 pathway may provide a therapeutic approach to treat OTA-triggered renal diseases.

Highlights ► AAI increases whereas OTA decreases production of proangiogenic VEGF. ► The upregulation of VEGF expression by AAI is caused by induction of SP-1 and HIFs. ► Hypoxia prevents OTA-diminished VEGF production ► The effect of hypoxia on OTA-reduced VEGF is mediated by HIF-2α but not HIF-1α., Aristolochic acid I (AAI) and ochratoxin A (OTA) cause chronic kidney diseases. Recently, the contribution of hypoxic injuries and angiogenic disturbances to nephropathies has been suggested, but underlying mechanisms have not been fully clarified yet. In porcine kidney epithelial cell line, LLC-PK1 cells, treatment with non-toxic doses of AAI increased whereas with OTA decreased production of vascular endothelial growth factor (VEGF), the angiogenic factor with well-defined functions in kidney. Moreover, the activity of transcription factors regulating VEGF expression was differentially affected by examined compounds. Activity of hypoxia inducible factors (HIFs) and SP-1 was increased by AAI but diminished by OTA. Interestingly, AP-1 activity was inhibited while NFκB was not influenced by both toxins. Mithramycin A, a SP-1 inhibitor, as well as chetomin, an inhibitor of HIFs, reversed AAI-induced up-regulation of VEGF synthesis, indicating the importance of SP-1 and HIFs in this effect. Additionally, adenoviral overexpression of HIF-2α but not HIF-1α prevented OTA-diminished VEGF production suggesting the protective effect of this isoform towards the consequences exerted by OTA. These observations provide new insight into complex impact of AAI and OTA on angiogenic gene regulation. Additionally, it adds to our understanding of hypoxia influence on nephropathies pathology.

In the present study the effect of quercetin and its major metabolites quercetin-3-glucuronide (Q3G) and isorhamnetin on inflammatory gene expression was determined in murine RAW264.7 macrophages stimulated with lipopolysaccharide. Quercetin and isorhamnetin but not Q3G significantly decreased mRNA and protein levels of tumor necrosis factor alpha. Furthermore a significant decrease in mRNA levels of interleukin 1β, interleukin 6, macrophage inflammatory protein 1α and inducible nitric oxide synthase was evident in response to the quercetin treatment. However Q3G did not affect inflammatory gene expression. Anti-inflammatory properties of quercetin and isorhamnetin were accompanied by an increase in heme oxygenase 1 protein levels, a downstream target of the transcription factor Nrf2, known to antagonize chronic inflammation. Furthermore, proinflammatory microRNA-155 was down-regulated by quercetin and isorhamnetin but not by Q3G. Finally, anti-inflammatory properties of quercetin were confirmed in vivo in mice fed quercetin-enriched diets (0.1 mg quercetin/g diet) over 6 weeks.

Changes in the coat cover are important for mammalian thermoregulation. This is especially true where variable environmental conditions exist throughout the seasons. Coat cover shedding is the replacement of old coat hair with new hair. The process differs in various equids. The aim of the study was to examine the changes in the coat of primitive Polish Konik horses living on a reserve in southeast Poland (50.6319° N). The reserve is located in a temperate climate. The mean temperature is below 0°C in winter (December 8 to March 9) and over 15°C in summer (June 8 to September 8). Five adult mares were included in the study. The study used a specific methodical approach to quantitatively assess coat cover changes. Photos were taken once every 2 wk throughout the whole year to document the state of the mares' coat. MultiScanBase software was used to analyze 260 photos. The percentage of the skin surface covered with short hair in relation to the surface of the body (without the head, neck, and limbs; short hair body [SHB]) was determined. To assess the topography of coat changes, surface parts covered with short hair within 6 regions of the body (shoulder, back, chest, loins, belly, and hindquarters; short hair part [SHP]) were considered separately. The regression coefficient was calculated for the SHB and the air temperature. Correlations in SHP and SHB between the left and right sides of the body were determined. The correlations within the right side of the body concerned particular SHP. As the results show, the coat changes take place at the same time on both sides of the horse's body. In spring, the winter hair is shed, and in the fall, the winter hair grows in longer. High regression (0.901; < 0.0001) proved that air temperature strongly affected the coat changes. The most important increase of SHB occurs in April and the first half of May, whereas the main decrease of SHB takes place in September. Changes between SHP are highly correlated (0.967-0.994; < 0.05). Spring and fall coat changes demonstrate that the shoulders, back, and loins require the winter cover for a longer time than the chest and belly, whereas the hindquarters are the least demanding in this respect. The phenomenon may be associated with, among others, the stronger effect of rain and snow on the upper parts of the body.

The objective of this study was to assess the effect of relaxing massage on the heart rate (HR) and heart rate variability (HRV) in young racehorses during their first racing season. In the study, 72 Purebred Arabian racehorses were included. The study was implemented during the full race season. The horses from control and experimental groups were included in regular race training 6 days a week. The horses from the experimental group were additionally subject to the relaxing massage 3 days a week during the whole study. HR and HRV were assumed as indicators of the emotional state of the horses. The measurements were taken six times, every 4-5 weeks. The HRV parameters were measured at rest, during grooming and saddling the horse and during warm-up walking under a rider. The changes of the parameters throughout the season suggest that the relaxing massage may be effectively used to make the racehorses more relaxed and calm. Moreover, the horses from the experimental group had better race performance records.

Aims: Heme oxygenase-1 (HO-1) is a cytoprotective enzyme that can be down-regulated in diabetes. Its importance for mature endothelium has been described, but its role in proangiogenic progenitors is not well known. We investigated the effect of HO-1 on the angiogenic potential of bone marrow-derived cells (BMDCs) and on blood flow recovery in ischemic muscle of diabetic mice. Results: Lack of HO-1 decreased the number of endothelial progenitor cells (Lin−CD45−cKit-Sca-1+VEGFR-2+) in murine bone marrow, and inhibited the angiogenic potential of cultured BMDCs, affecting their survival under oxidative stress, proliferation, migration, formation of capillaries, and paracrine proangiogenic potential. Transcriptome analysis of HO-1−/− BMDCs revealed the attenuated up-regulation of proangiogenic genes in response to hypoxia. Heterozygous HO-1+/− diabetic mice subjected to hind limb ischemia exhibited reduced local expression of vascular endothelial growth factor (VEGF), placental growth factor (PlGF), stromal cell-derived factor 1 (SDF-1), VEGFR-1, VEGFR-2, and CXCR-4. This was accompanied by impaired revascularization of ischemic muscle, despite a strong mobilization of bone marrow-derived proangiogenic progenitors (Sca-1+CXCR-4+) into peripheral blood. Blood flow recovery could be rescued by local injections of conditioned media harvested from BMDCs, but not by an injection of cultured BMDCs. Innovation: This is the first report showing that HO-1 haploinsufficiency impairs tissue revascularization in diabetes and that proangiogenic in situ response, not progenitor cell mobilization, is important for blood flow recovery. Conclusions: HO-1 is necessary for a proper proangiogenic function of BMDCs. A low level of HO-1 in hyperglycemic mice decreases restoration of perfusion in ischemic muscle, which can be rescued by a local injection of conditioned media from cultured BMDCs. Antioxid. Redox Signal. 20, 1677–1692.

In vivo gene replacement is one of the most compelling concepts in modern medicine. Adeno-associated virus (AAV) vectors are currently among the most frequently used viral vectors for gene therapy and they have shown therapeutic efficacy in a range of animal models. The lack of pathogenicity of the virus, low immunogenicity, its stability, and many available serotypes have increased AAV's potential as a delivery vehicle for gene therapy applications. There are some limitations to the use of rAAV in gene therapy. The first is their size. Due to the small size of the vector, the ability to conduct a therapeutic gene expression cassette is limited. Another limitation is the common occurrence of neutralizing antibodies in human populations. This review will focus on the biology of AAV, its use as a vector for gene therapy and mechanisms of AAV/host cell interaction.

In this study attention was focused on gene preparations that stimulate angiogenesis in the skin. Angiogenesis was stimulated by gene preparations encoding angiogenic factors introduced into the skin by injection, and applied as ointments.The appropriate angiogenic formulations containing angiogenic nonviral vectors (pVEGF, pFGF, pSDF, pVIF), or viral vectors (rAAV/VEGF, rAAV/SDF) were prepared for the test. Cholesterol ointment was used as the vehicle for viral and non-viral vectors. The new vessels in the mouse skin were counted according to the criteria suggested by Sidky and Auerbach.Studies indicate that all non-viral (pVEGF, pFGF, pSDF, pVIF) and viral (rAAV/VEGF, rAAV/SDF) vectors strongly stimulate new vessel formation when administered into mouse skin as injections. The impact of angiogenic gene ointments for skin angiogenesis was about 3-4 times weaker than that observed for injection preparations.Angiogenic injection gene preparations strongly stimulate skin neovascularization. The clinical usefulness of gene ointments should stimulate further laboratory studies in the field of experimental skin gene therapy.

cope Ochratoxin A (OTA) is a mycotoxin exhibiting nephrotoxic and potential carcinogenic activity. We investigated the cross-talk between microRNAs, nuclear factor E2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) in ochratoxin A-mediated effects. Methods and results In porcine renal proximal tubular cells, OTA increased expression of profibrotic transforming growth factors β (TGFβ) while concomitantly decreasing expression of Nrf2, HO-1, and erythropoietin. Adenoviral overexpression of Nrf2 counteracted OTA-mediated reduction in HO-1 and erythropoietin expression and cell proliferation as well as increase in reactive oxygen species (ROS) generation and TGFβ expression. Additionally, inhibition of HO activity enhanced whereas adenoviral overexpression of HO-1 reduced expression of TGFβ. Moreover, antioxidants, N-acetyl-cysteine and desferioxamine, prevented OTA-mediated enhancement of ROS generation, and TGFβ expression. Finally, OTA modulated microRNA processing by upregulating LINeage protein 28 and DiGeorge syndrome critical region-8, increasing the total pool of cellular microRNAs and elevating the expression of miR-132 and miR-200c. Inhibition of miR-132 by specific antagomir restored the OTA-driven reduction in Nrf2 expression. Moreover, anti-miR-132 and anti-miR-200c counteracted OTA-mediated decrease in HO-1 levels as well as increase in ROS production and TGFβ expression. Conclusion We showed that attenuation of Nrf2 and HO-1 expression through induction of miR-132 and miR-200c by OTA elevates ROS levels and profibrotic TGFβ expression.

Studies on the mechanisms of adaptation to adverse hypoxic conditions led to the discovery of hypoxia inducible factors, HIF-1 and HIF-2. These factors regulate the expression of many genes which allow cells to adapt to changes in oxygen concentration and counteract the effects of oxidative stress developing in hypoxia. Regulation of HIF activity is dependent on the prolyl hydroxylases activity and results in its degradation under normoxic conditions by the ubiquitin-dependent proteasome pathway. Recent studies indicate a specific role of reactive oxygenspecies (ROS) generated by the mitochondrial respiratory chain in regulation of HIF stability. ROS affect also the level of nitric oxide (NO), leading to a reduction in its concentration by forming reactive nitrogen species (RNS), which may cause the increase in oxidative and nitrosative stress. Regulation of HIF activity by ROS, NO and RNS is currently the subject of many studies and seems to be a mechanism dependent on conditions (e.g., normoxia/hypoxia), or concentrations of individual stimulators (e.g. NO donor used).

This is an open-access article distributed under the terms of the Creative Commons Attribution License.-- et al., [Background]: The transcription factor Nrf2 (NF-E2-related factor 2) and its target gene products, including heme oxygenase-1 (HO-1), elicit an antioxidant response that may have therapeutic value for Parkinson's disease (PD). However, HO-1 protein levels are increased in dopaminergic neurons of Parkinson's disease (PD) patients, suggesting its participation in free-iron deposition, oxidative stress and neurotoxicity. Before targeting Nrf2 for PD therapy it is imperative to determine if HO-1 is neurotoxic or neuroprotective in the basal ganglia. [Methodology]: We addressed this question by comparing neuronal damage and gliosis in Nrf2- or HO-1-knockout mice submitted to intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for five consecutive days. Nrf2- knockout mice showed exacerbated gliosis and dopaminergic nigrostriatal degeneration, as determined by immunohistochemical staining of tyrosine hydroxylase in striatum (STR) and substantia nigra (SN) and by HPLC determination of striatal dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC). On the other hand, the severity of gliosis and dopaminergic degeneration in HO-1-null mice was neither increased nor reduced. Regarding free-iron deposition, both Nrf2- and HO-1-deficient mice exhibited similar number of deposits as determined by Perl's staining, therefore indicating that these proteins do not contribute significantly to iron accumulation or clearance in MPTP-induced Parkinsonism. [Conclusions]: These results suggest that HO-1 does not protect or enhance the sensitivity to neuronal death in Parkinson's disease and that pharmacological or genetic intervention on Nrf2 may provide a neuroprotective benefit as add on therapy with current symptomatic protocols., This work was supported by grant SAF2007-62646 from the Spanish Ministry of Science and Innovation. The Faculty of Biochemistry, Biophysics and Biotechnology of the Jagiellonian University is a beneficiary of the structural funds from the European Union (grant No: POIG.02.01.00-12-064/08 and 02.02.00-00- 014/08). N.I. is recipient of a FPU fellowship of Universidad Autónoma of Madrid.

Through hypoxia-inducible factor 1 (HIF-1), hypoxia regulates the expression of numerous genes and is a potent inducer of angiogenesis. However, interleukin-8 (IL-8), an important angiogenic mediator, has been reported to be downregulated by HIF-1, although the mechanisms have not been elucidated. HIF-1 was induced in human endothelial cells by hypoxia and dimethyloxaloylglycine (DMOG). Interestingly, both hypoxia and DMOG attenuated IL-8 expression, and a similar effect has been obtained by adenoviral overexpression of the stable form of HIF-1alpha. Heme oxygenase-1 (HO-1) expression was also downregulated by HIF-1 induction. This suggests similar mechanisms of regulation of IL-8 and HO-1, indicating the involvement of Nrf2, a transcription factor previously linked to hypoxia-mediated inhibition of HO-1. Indeed, HIF-1-mediated downregulation of both IL-8 and HO-1 was associated with both lowered Nrf2 expression and induction of Bach1, a repressor of Nrf2 transcriptional activity. Accordingly, overexpression of Nrf2 reversed the inhibitory effect of HIF-1 on IL-8 and HO-1 expression. However, neither overexpression of HO-1 nor HO-1 inhibition affected IL-8 synthesis. The data indicate that HIF-1-dependent inhibition of IL-8 expression is caused by downregulation of Nrf2. However, expression of IL-8 is independent of HO-1. Cross-talk between HIF-1 and Nrf2 may influence the outcome of anti-angiogenic therapies aimed at targeting HIF-1. Antioxid.