• diabetic retinopathy (dr)
• retinal ischemia
• photoreceptors
• ischemia reperfusion (ir)
• retinal degeneration

• Animals
• Reperfusion Injury/metabolism
• Mice
• Mice, Inbred C57BL
• Diabetes Mellitus, Experimental/complications
• Diabetic Retinopathy/etiology
• Diabetic Retinopathy/metabolism
• In Situ Nick-End Labeling
• Photoreceptor Cells, Vertebrate/pathology
• Photoreceptor Cells, Vertebrate/drug effects
• Male
• Phlorhizin/pharmacology
• Capillary Permeability
• Diabetes Mellitus, Type 2/complications
• Apoptosis

• R01 EY012021 NEI NIH HHS
• S10 OD028612 NIH HHS
• R01 EY031961 NEI NIH HHS
• P30 DK020572 NIDDK NIH HHS
• P30 EY007003 NEI NIH HHS
• R01 EY029349 NEI NIH HHS

• Antioxidants
• Eye
• Ocular diseases
• Oxidative stress
• Pathophysiology
• Reactive oxygen species

• Antioxidants/metabolism
• Reactive Oxygen Species/metabolism
• Eye/metabolism
• Eye/pathology
• Oxidative Stress
• Lens, Crystalline/metabolism
• Lens, Crystalline/pathology

• ferroptosis
• inhibitors
• neurovascular unit (NVU)
• stroke
• therapeutic target

• Natural Science Foundation of Henan Province
• Henan Medical Science and Technique Foundation
• National Natural Science Foundation of China

• PANoptosis
• acute ocular hypertension
• melatonin
• microglia/macrophage
• retinal ganglion cell

• Animals
• Mice
• Apoptosis
• bcl-2-Associated X Protein/metabolism
• Caspase 3/metabolism
• Caspase 8/metabolism
• DNA Nucleotidylexotransferase/metabolism
• Glaucoma
• Interleukin-1beta/metabolism
• Melatonin/pharmacology
• Melatonin/therapeutic use
• Neuroprotective Agents/pharmacology
• Neuroprotective Agents/therapeutic use
• NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
• Ocular Hypertension/drug therapy
• Ocular Hypertension/metabolism
• Proto-Oncogene Proteins c-bcl-2/metabolism

The mammalian retina contains approximately 30 neuropeptides that are synthetized by different neuronal cell populations, glia, and the pigmented epithelium. The presence of these neuropeptides leaves a mark on normal retinal molecular processes and physiology, and they are also crucial in fighting various pathologies (e.g., diabetic retinopathy, ischemia, age-related pathologies, glaucoma) because of their protective abilities. Retinal pathologies of different origin (metabolic, genetic) are extensively investigated by genetically manipulated in vivo mouse models that help us gain a better understanding of the molecular background of these pathomechanisms. These models offer opportunities to manipulate gene expression in different cell types to help reveal their roles in the preservation of retinal health or identify malfunction during diseases. In order to assess the current status of transgenic technologies available, we have conducted a literature survey focused on retinal disorders of metabolic origin, zooming in on the role of retinal neuropeptides in diabetic retinopathy and ischemia. First, we identified those neuropeptides that are most relevant to retinal pathologies in humans and the two clinically most relevant models, mice and rats. Then we continued our analysis with metabolic disorders, examining neuropeptide-related pathways leading to systemic or cellular damage and rescue. Last but not least, we reviewed the available literature on genetically modified mouse strains to understand how the manipulation of a single element of any given pathway (e.g., signal molecules, receptors, intracellular signaling pathways) could lead either to the worsening of disease conditions or, more frequently, to substantial improvements in retinal health. Most attention was given to studies which reported successful intervention against specific disorders. For these experiments, a detailed evaluation will be given and the possible role of converging intracellular pathways will be discussed. Using these converging intracellular pathways, curative effects of peptides could potentially be utilized in fighting metabolic retinal disorders.

• apoptosis
• diabetic retinopathy
• inflammation
• ischemia
• neuropeptides
• oxidative stress

• gene expression
• ischemia-reperfusion
• ischemic conditioning
• myocardial infarction
• somatostatin
• somatostatin receptor
• translational research

• Adult
• Aged
• Case-Control Studies
• Cell Line
• Cell Survival/drug effects
• Female
• Fibroblasts/cytology
• Fibroblasts/drug effects
• Fibroblasts/metabolism
• Gene Expression Regulation/drug effects
• Graves Ophthalmopathy/drug therapy
• Graves Ophthalmopathy/genetics
• Graves Ophthalmopathy/metabolism
• Humans
• Insulin-Like Growth Factor I/genetics
• Insulin-Like Growth Factor I/metabolism
• Male
• Middle Aged
• NF-kappa B/metabolism
• Octreotide/pharmacology
• Orbit/cytology
• Orbit/drug effects
• Orbit/metabolism
• Receptors, Somatostatin/metabolism
• Signal Transduction/drug effects
• Up-Regulation/drug effects
• Young Adult

• Basic Science Research Program through the National Research Foundation of Korea (NRF)

• AMPK
• Autophagy
• Hepatic ischemia-reperfusion
• Melatonin
• Nrf2
• Octreotide

• Hepatic ischemia/reperfusion injury
• Melatonin
• NLRP3
• Octreotide
• Pyroptosis
• TLR4

Many retinal diseases, such as diabetic retinopathy, glaucoma, and age-related macular (AMD) degeneration, are associated with elevated reactive oxygen species (ROS) levels. ROS are important intracellular signaling molecules that regulate numerous physiological actions, including vascular reactivity and neuron function. However, excessive ROS formation has been linked to vascular endothelial dysfunction, neuron degeneration, and inflammation in the retina. ROS can directly modify cellular molecules and impair their function. Moreover, ROS can stimulate the production of inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) causing inflammation and cell death. However, there are various compounds with direct or indirect antioxidant activity that have been used to reduce ROS accumulation in animal models and humans. In this review, we report on the physiological and pathophysiological role of ROS in the retina with a special focus on the vascular system. Moreover, we present therapeutic approaches for individual retinal diseases targeting retinal signaling pathways involving ROS.

• oxidative stress
• reactive oxygen species
• retinal disease
• vascular endothelium

• ischemia-reperfusion injury
• lanreotide
• octreotide
• oxidative stress
• peroxynitrite
• rat ovarian torsion

• RPE cells
• perinatal hypoxia–ischemia
• reoxygenation
• retina
• thioredoxin 1

• antioxidants
• blood-retina barrier
• neuropeptides
• nutraceuticals
• vascular endothelial growth factor

Pituitary adenylate cyclase-activating polypeptide (PACAP1-38) is a highly conserved member of the secretin/glucagon/VIP family. The repressive effect of PACAP1-38 on the apoptotic machinery has been an area of active research conferring a significant neuroprotective potential onto this peptide. A remarkable number of studies suggest its importance in the etiology of neurodegenerative disorders, particularly in relation to retinal metabolic disorders. In our review, we provide short descriptions of various pathological conditions (diabetic retinopathy, excitotoxic retinal injury and ischemic retinal lesion) in which the remedial effect of PACAP has been well demonstrated in various animal models. Of all the pathological conditions, diabetic retinopathy seems to be the most intriguing as it develops in 75% of patients with type 1 and 50% of patients with type 2 diabetes, with concomitant progression to legal blindness in about 5%. Several animal models have been developed in recent years to study retinal degenerations and out of these glaucoma and age-related retina degeneration models bear human recapitulations. PACAP neuroprotection is thought to operate through enhanced cAMP production upon binding to PAC1-R. However, the underlying signaling network that leads to neuroprotection is not fully understood. We observed that (i) PACAP is not equally efficient in the above conditions; (ii) in some cases more than one signaling pathways are activated; (iii) the coupling of PAC1-R and signaling is stage dependent; and (iv) PAC1-R is not the only receptor that must be considered to interpret the effects in our experiments. These observations point to a complex signaling mechanism, that involves alternative routes besides the classical cAMP/protein kinase A pathway to evoke the outstanding neuroprotective action. Consequently, the possible contribution of the other two main receptors (VPAC1-R and VPAC2-R) will also be discussed. Finally, the potential medical use of PACAP in some retinal and ocular disorders will also be reviewed. By taking advantage of, low-cost synthesis technologies today, PACAP may serve as an alternative to the expensive treatment modelities currently available in ocular or retinal conditions.

• PACAP
• metabolic origin
• neuroprotection
• retina degeneration
• signaling

In the pathogenesis of many disorders, neuronal death plays a key role. It is now assumed that neurodegeneration is caused by multiple and somewhat converging/overlapping death mechanisms, and that neurons are sensitive to unique death styles. In this respect, major advances in the knowledge of different types, mechanisms, and roles of neurodegeneration are crucial to restore the neuronal functions involved in neuroprotection. Several novel concepts have emerged recently, suggesting that the modulation of the neuropeptide system may provide an entirely new set of pharmacological approaches. Neuropeptides and their receptors are expressed widely in mammalian retinas, where they exert neuromodulatory functions including the processing of visual information. In multiple models of retinal diseases, different peptidergic substances play neuroprotective actions. Herein, we describe the novel advances on the protective roles of neuropeptides in the retina. In particular, we focus on the mechanisms by which peptides affect neuronal death/survival and the vascular lesions commonly associated with retinal neurodegenerative pathologies. The goal is to highlight the therapeutic potential of neuropeptide systems as neuroprotectants in retinal diseases.

• cell death
• neuropeptides
• neuroprotection
• receptors
• retina neurodegeneration
• retinal neurons
• retinal vessels
• vertebrate retina

Age-related macular degeneration (AMD) affects the retinal macula and results in loss of vision, and AMD is the primary cause of blindness and severe visual impairment among elderly people worldwide. AMD is characterized by the accumulation of drusen in the Bruch's membrane and dysfunction of retinal pigment epithelial (RPE) cells and photoreceptors. The pathogenesis of AMD remains unclear, and no effective treatment exists. Accumulating evidence indicates that oxidative stress plays a critical role in RPE cell degeneration and AMD. Melatonin is an antioxidant that scavenges free radicals, and it has anti-inflammatory, antitumor, and antiangiogenic effects. This study investigated the antioxidative, antiapoptotic, and autophagic effects of melatonin on oxidative damage to RPE cells. We used hydrogen peroxide (H₂O₂) to stimulate reactive oxygen species production to cause cell apoptosis in ARPE-19 cell lines. Our findings revealed that treatment with melatonin significantly inhibited H₂O₂-induced RPE cell damage, decreased the apoptotic rate, increased the mitochondrial membrane potential, and increased the autophagy effect. Furthermore, melatonin reduced the Bax/Bcl-2 ratio and the expression levels of the apoptosis-associated proteins cytochrome c and caspase 7. Additionally, melatonin upregulated the expression of the autophagy-related proteins LC3-II and Beclin-1 and downregulated the expression of p62. Thus, melatonin's effects on autophagy and apoptosis can protect against H₂O₂-induced oxidative damage in human RPE cells. Melatonin may have multiple protective effects on human RPE cells against H₂O₂-induced oxidative damage.

• Retina
• magnetic nanoparticles
• octreotide
• ocular disease
• somatostatin
• topical administration.

• Animals
• Diabetic Retinopathy/drug therapy
• Drug Delivery Systems
• Humans
• Nanoparticles
• Neuroprotective Agents/administration & dosage

• High-mobility group Box-1
• N-methyl-d-aspartic acid
• Nuclear factor kappa B
• Retina

• Ischemia reperfusion
• Penehyclidine hydrochloride (PubChem CID: 177923)
• Pharmacological postconditioning
• Time-window

• high glucose
• neuropilin 1
• occludin
• somatostatin receptor 2
• vascular endothelial growth factor

• Functional property
• Ischemia-reperfusion injury
• Mechanism of action
• Modification strategy
• Peptide

• NF-κB pathway
• Quercetin
• ischemia-reperfusion injury
• myocardium
• peroxisome proliferator-activated receptor γ

• Epac-1
• Rap-1
• Vitexin
• aortic rings
• apoptosis
• myocardial ischemia/reperfusion injury

To investigate the impacts and related mechanisms of penehyclidine hydrochloride (PHC) on ischemia/reperfusion (I/R)-induced myocardial injury. A rat model of myocardial I/R injury was established by the ligation of left anterior descending coronary artery for 30 min followed by 3 h perfusion. Before I/R, the rats were pretreated with or without PHC. Cardiac function was measured by echocardiography. The activities/levels of myocardial enzymes, oxidants and antioxidant enzymes were detected. Evans blue/TTC double staining was performed to assess infarct size. Cardiomyocyte apoptosis was evaluated by TUNEL assay. The release of inflammatory cytokines and inflammatory mediators was detected by ELISA. Western blot was performed to analyze the expression of COX-2, IκB, p-IκB and NF-κB. Meanwhile, the rats were given a single injection of H-PHC before I/R. The effects of PHC on myocardial infarct and cardiac function were investigated after 7 days post-reperfusion. We found that PHC remarkably improved cardiac function, alleviated myocardial injury by decreasing myocardial enzyme levels and attenuated oxidative stress in a dose-dependent manner. Additionally, PHC preconditioning significantly reduced infarct size and the apoptotic rate of cardiomyocytes. Administration of PHC significantly decreased serum TNF-α, IL-1β, IL-6 and PGE₂ levels and myocardium COX-2 level. Meanwhile, the expression levels of p-IκB and NF-κB were downregulated, while IκB expression was upregulated. H-PHC also exerted long-term cardioprotection in a rat model of I/R injury by decreasing infarct size and improving cardiac function. These results suggest that PHC can efficiently protect the rats against I/R-induced myocardial injury.

• Animals
• Apoptosis
• Cardiotonic Agents/pharmacology
• Cytokines/metabolism
• Disease Models, Animal
• Inflammation Mediators/metabolism
• Ischemic Preconditioning
• Male
• Myocardial Reperfusion Injury/prevention & control
• Myocytes, Cardiac/pathology
• Oxidative Stress
• Quinuclidines/pharmacology
• Rats
• Rats, Wistar