CX3CL1/CX3CR1 Signaling Mediated Neuroglia Activation Is Implicated in the Retinal Degeneration: A Potential Therapeutic Target to Prevent Photoreceptor Death.

Purpose: Retinal degeneration (RD) is a large cluster of retinopathies that is characterized by the progressive photoreceptor death and visual impairments. CX3CL1/CX3CR1 signaling has been documented to mediate the microglia activation and gliosis reaction during neurodegeneration. We intend to verify whether the CX3CL1/CX3CR1 signaling is involved in the RD pathology. Methods: A pharmacologically induced RD mice model was established. AZD8797, a CX3CR1 antagonist, was injected into the vitreous cavity of an RD model to modulate the neuroglia activation. Then, the experimental animals were subjected to functional, morphological, and behavioral analysis. Results: The CX3CL1/CX3CR1 signaling mediated neuroglia activation was implicated in the photoreceptor demise of an RD model. Intravitreal injection of AZD8797 preserved the retinal structure and enhanced the photoreceptor survival through inhibiting the CX3CL1/CX3CR1 expressions. Fundus photography showed that the distribution of retinal vessel was clear, and the severity of lesions was alleviated by AZD8797. In particular, these morphological benefits could be translated into remarkable functional improvements, as evidenced by the behavioral test and electroretinogram (mf-ERG) examination. A mechanism study showed that AZD8797 mitigated the microglia activation and migration in the degenerative retinas. The Müller cell hyper-reaction and secondary gliosis response were also suppressed by AZD8797. Conclusions: The neuroinflammation is implicated in the photoreceptor loss of RD pathology. Targeting the CX3CL1/CX3CR1 signaling may serve as an effective therapeutic strategy. Future refinements of these findings may cast light into the discovery of new medications for RD.

Ferroptosis in the ageing retina: A malevolent fire of diabetic retinopathy.

Ageing retina is prone to ferroptosis due to the iron accumulation and impaired efficiency of intracellular antioxidant defense system. Ferroptosis acts as a cell death modality that is characterized by the iron-dependent accumulation of lipid peroxidation. Ferroptosis is distinctively different from other types of regulated cell death (RCD) at the morphological, biochemical, and genetic levels. Diabetic retinopathy (DR) is a common microvascular complication of diabetes. Its prevalence and severity increase progressively with age. Recent reports have shown that ferroptosis is implicated in the pathophysiology of DR. Under hyperglycemia condition, the endothelial cell and retinal pigment epithelium (RPE) cell will undergo ferroptosis, which contributes to the increased vascular permeability and the disrupted blood retinal barrier (BRB). The underlying etiology of DR can be attributed to the impaired BRB integrity and subsequent damages of the neurovascular units. In the absence of timely intervention, the compromised BRB can ultimately cause profound visual impairments. In particular, the ageing retina is vulnerable to ferroptosis, and hyperglycemia will accelerate the progression of this pathological process. In this article, we discuss the contributory role of ferroptosis in DR pathogenesis, and summarize recent therapeutic trials that targeting the ferroptosis. Further study on the ferroptosis mediated damage would enrich our knowledge of DR pathology, and promote the development of clinical treatment for this degenerative retinopathy.

Intravitreal Injection of ZYAN1 Restored Autophagy and Alleviated Oxidative Stress in Degenerating Retina via the HIF-1α/BNIP3 Pathway.

Mitochondrial autophagy plays a contributary role in the pathogenesis of retina degeneration (RD). ZYAN1 is a novel proline hydroxylase domain (PHD) inhibitor that can enhance the expression of hypoxia-inducible factor 1-alpha (HIF-1α). This study investigated whether ZYAN1 could alleviate progressive photoreceptor loss and oxidative damage in a pharmacologically induced RD model via the modulation of mitophagy. ZYAN1 was injected into the vitreous body of the RD model, and the retinal autophagy level was analyzed. The therapeutic effects of ZYAN1 were evaluated via a function examination, a morphological assay, in situ reactive oxygen species (ROS) detection, and an immunofluorescence assay. It was shown that the thickness of the outer nuclear layer (ONL) increased significantly, and visual function was efficiently preserved via ZYAN1 treatment. The mitochondria structure of photoreceptors was more complete in the ZYAN1-treated mice, and the number of autophagosomes also increased significantly. Membrane disc shedding and ROS overproduction were alleviated after ZYAN1 treatment, and the axonal cilia were more structurally intact. A Western blot analysis showed that the expression levels of the autophagy-related proteins LC3-B, Beclin-1, and ATG5 increased significantly after ZYAN1 treatment, while the expression of P62 was down-regulated. Moreover, the expression levels of HIF-1α and BNIP3 were up-regulated after ZYAN1 treatment. Therefore, an intravitreal injection of ZYAN1 can act as part of the pharmacologic strategy to modulate mitophagy and alleviate oxidative stress in RD. These findings enrich our knowledge of RD pathology and provide insights for the discovery of a therapeutic molecule.

Crosstalk Between Microglia and Müller Glia in the Age-Related Macular Degeneration: Role and Therapeutic Value of Neuroinflammation.

Age-related macular degeneration (AMD) is a progressive neurodegeneration disease that causes photoreceptor demise and vision impairments. In AMD pathogenesis, the primary death of retinal neurons always leads to the activation of resident microglia. The migration of activated microglia to the ongoing retinal lesion and their morphological transformation from branching to ameboid-like are recognized as hallmarks of AMD pathogenesis. Activated microglia send signals to Müller cells and promote them to react correspondingly to damaging stimulus. Müller cells are a type of neuroglia cells that maintain the normal function of retinal neurons, modulating innate inflammatory responses, and stabilize retinal structure. Activated Müller cells can accelerate the progression of AMD by damaging neurons and blood vessels. Therefore, the crosstalk between microglia and Müller cells plays a homeostatic role in maintaining the retinal environment, and this interaction is complicatedly modulated. In particular, the mechanism of mutual regulation between the two glia populations is complex under pathological conditions. This paper reviews recent findings on the crosstalk between microglia and Müller glia during AMD pathology process, with special emphasis on its therapeutic potentials.

Small Molecule Pin1 Inhibitor Blocking NF-κB Signaling in Prostate Cancer Cells.

Prolyl-isomerase 1 (Pin1) is a conserved enzyme that regulates cell processes such as cell cycle progression, transcriptional regulation, and apoptosis. However, overexpression of Pin1 is correlated with a higher probability of prostate tumor recurrence. We utilized a molecular docking technique to identify Pin1 inhibitors from a database of natural product and natural product-like compounds. The action of the hit compounds against Pin1 activity was studied using multiple methods, including a fluorometric enzymatic assay, co-immunoprecipitation, western blotting, cell thermal shiftm, and other techniques. We have identified compound 1 as a natural-product-like inhibitor of Pin1 activity via structure-based virtual screening and showed that compound 1 could target Pin1 and disrupt the interaction between Pin1 and the p65 subunit of NF-κB in cells. Furthermore, compound 1 reduced nuclear p65 (Thr254) phosphorylation and attenuated NF-κB activity in cells. Finally, compound 1 induced apoptosis in prostate cancer cells. Compound 1 represents a natural product-like Pin1 inhibitor that acts via targeting the Pin1-NF-κB interaction.

A natural product-like JAK2/STAT3 inhibitor induces apoptosis of malignant melanoma cells.

The JAK2/STAT3 signaling pathway plays a critical role in tumorigenesis, and has been suggested as a potential molecular target for anti-melanoma therapeutics. However, few JAK2 inhibitors were being tested for melanoma therapy. In this study, eight amentoflavone analogues were evaluated for their activity against human malignant melanoma cells. The most potent analogue, compound 1, inhibited the phosphorylation of JAK2 and STAT3 in human melanoma cells, but had no discernible effect on total JAK2 and STAT3 levels. A cellular thermal shift assay was performed to identify that JAK2 is engaged by 1 in cell lysates. Moreover, compound 1 showed higher antiproliferative activity against human melanoma A375 cells compared to a panel of cancer and normal cell lines. Compound 1 also activated caspase-3 and cleaved PARP, which are markers of apoptosis, and suppressed the anti-apoptotic Bcl-2 level. Finally, compound 1 induced apoptosis in 80% of treated melanoma cells. To our knowledge, compound 1 is the first amentoflavone-based JAK2 inhibitor to be investigated for use as an anti-melanoma agent.

The control and surveillance of filariasis in Hainan Province, China.

Hainan is a single bancroftian filariasis endemic province where filariasis is prevalent in all 18 cities and counties. A program to control filariasis was started in 1953. The strategy of eliminating infection sources has been adopted as the principal intervention measure in filariasis control. Over 30 years, the sustained effort throughout the province reached the point of basic elimination of filariasis in 1987. After the basic elimination of filariasis, the patterns of filariasis transmission in residual microfilaremia cases in Hainan Province were studied so as to provide a scientific basis for formulating strategies to eliminate filariasis. According to the "Technical scheme for surveillance in areas where fialariasis has been basically eliminated" issued by the Ministry of Health, a longitudinal and cross-sectional and entomological surveillance of fialariasis was carried out using parasitological and entomological and serological methods in the whole province during 1983-2004. In the cross-sectional and entomological surveillances, the last microfilaremia case was found in 1999, no mosquitoes were found to be infected with filarial larvae. A total of 132 microfilaremia cases found in the longitudinal surveillance become negative by 10 years. Since 1997 no mosquitoes were found to be infected with filarial larvae in the longitudinal surveillance. Serological surveillance of the population showed the mean positive rate of IFAT dropped from 10.63% in 1990 to 0.28% in 2000, which being similar to that of nonendemic areas. The results show that residual sources of infection after basic elimination of filariasis were tending to be naturally eliminated and transmission of filariasis has been interrupted in Hainan Province.