Fair‐Weather Friends: Evidence of Lipoxin Dysregulation in Neurodegeneration

Lipoxins (LXs) are autacoids, specialized proresolving lipid mediators (SPMs) acting locally in a paracrine or autocrine fashion. They belong to a complex superfamily of dietary small polyunsaturated fatty acid (PUFA)–metabolites, which direct potent cellular responses to resolve inflammation and restore tissue homeostasis. Together, these SPM activities have been intensely studied in systemic inflammation and acute injury or infection, but less is known about LX signaling and activities in the central nervous system. LXs are derived from arachidonic acid, an omega‐6 PUFA. In addition to well‐established roles in systemic inflammation resolution, they have increasingly become implicated in regulating neuroinflammatory and neurodegenerative processes. In particular, chronic inflammation plays a central role in Alzheimer's disease (AD) etiology, and dysregulated LX production and activities have been reported in a variety of AD rodent models and clinical tissue samples, yet with complex and sometimes conflicting results. In addition, reduced LX production following retinal injury has been reported recently by the authors, and an intriguing direct neuronal activity promoting survival and homeostasis in retinal and cortical neurons is demonstrated. Here, the authors review and clarify this growing literature and suggest new research directions to further elaborate the role of lipoxins in neurodegeneration.     

The Potential Role of Small-Molecule PERK Inhibitor LDN-0060609 in Primary Open-Angle Glaucoma Treatment

Primary open-angle glaucoma (POAG) constitutes the most common type of glaucoma. Emerging evidence suggests that Endoplasmic Reticulum (ER) stress and the protein kinase RNA-like endoplasmic reticulum kinase (PERK)-mediated Unfolded Protein Response (UPR) signaling pathway play a key role in POAG pathogenesis. Thus, the main aim of the study was to evaluate the effectiveness of the PERK inhibitor LDN-0060609 in cellular model of glaucoma using primary human trabecular meshwork (HTM) cells. To evaluate the level of the ER stress marker proteins, Western blotting and TaqMan gene expression assay were used. The cytotoxicity was measured by XTT, LDH assays and Giemsa staining, whereas genotoxicity via comet assay. Changes in cell morphology were assessed by phase-contrast microscopy. Analysis of apoptosis was performed by caspase-3 assay and flow cytometry (FC), whereas cell cycle progression by FC. The results obtained have demonstrated that LDN-0060609 triggered a significant decrease of ER stress marker proteins within HTM cells with induced ER stress conditions. Moreover, LDN-0060609 effectively increased viability, reduced DNA damage, increased proliferation, restored normal morphology, reduced apoptosis and restored normal cell cycle distribution of HTM cells with induced ER stress conditions. Thereby, PERK inhibitors, such as LDN-0060609, may provide an innovative, ground-breaking treatment strategy against POAG.     

Neuroprotection,Growth Factors and BDNF-TrkB Signalling in Retinal Degeneration

Neurotrophic factors play key roles in the development and survival of neurons. The potent neuroprotective effects of neurotrophic factors, including brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), glial cell-line derived neurotrophic factor (GDNF) and nerve growth factor (NGF), suggest that they are good therapeutic candidates for neurodegenerative diseases. Glaucoma is a neurodegenerative disease of the eye that causes irreversible blindness. It is characterized by damage to the optic nerve, usually due to high intraocular pressure (IOP), and progressive degeneration of retinal neurons called retinal ganglion cells (RGCs). Current therapy for glaucoma focuses on reduction of IOP, but neuroprotection may also be beneficial. BDNF is a powerful neuroprotective agent especially for RGCs. Exogenous application of BDNF to the retina and increased BDNF expression in retinal neurons using viral vector systems are both effective in protecting RGCs from damage. Furthermore, induction of BDNF expression by agents such as valproic acid has also been beneficial in promoting RGC survival. In this review, we discuss the therapeutic potential of neurotrophic factors in retinal diseases and focus on the differential roles of glial and neuronal TrkB in neuroprotection. We also discuss the role of neurotrophic factors in neuroregeneration.     

Mechanisms of Pannexin 1 (PANX1) Channel Mechanosensitivity and Its Pathological Roles

Pannexins (PANX) were cloned based on their sequence homology to innexins (Inx), invertebrate gap junction proteins. Although there is no sequence homology between PANX and connexins (Cx), these proteins exhibit similar configurations. The PANX family has three members, PANX1, PANX2 and PANX3. Among them, PANX1 has been the most extensively studied. The PANX1 channels are activated by many factors, including high extracellular K⁺ ([K⁺]_e), high intracellular Ca²⁺ ([Ca²⁺]_i), Src family kinase (SFK)-mediated phosphorylation, caspase cleavage and mechanical stimuli. However, the mechanisms mediating this mechanosensitivity of PANX1 remain unknown. Both force-from-lipids and force-from-filaments models are proposed to explain the gating mechanisms of PANX1 channel mechanosensitivity. Finally, both the physiological and pathological roles of mechanosensitive PANX1 are discussed.     

Synthesis,Computational Studies and Assessment of in Vitro Activity of Squalene Derivatives as Carbonic Anhydrase Inhibitors

We report novel molecules incorporating the nontoxic squalene scaffold and different carbonic anhydrase inhibitors (CAIs). Potent inhibitory action, in the low-nanomolar range, was detected against isoforms hCA II for sulfonamide derivatives, which proved to be selective against this isoform over the tumor-associate hCA IX and XII isoforms. On the other hand, coumarin derivatives showed weak potency but high selectivity against the tumor-associated isoform CA IX. These compounds are interesting candidates for preclinical evaluation in glaucoma or various tumors in which the two enzymes are involved. In addition, an in silico study of inhibitor-bound hCA II revealed extensive interactions with the hydrophobic pocket of the active site and provided molecular insights into the binding properties of these new inhibitors.     

TrkB Receptor Signalling: Implications in Neurodegenerative,Psychiatric and Proliferative Disorders

The Trk family of receptors play a wide variety of roles in physiological and disease processes in both neuronal and non-neuronal tissues. Amongst these the TrkB receptor in particular has attracted major attention due to its critical role in signalling for brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT3) and neurotrophin-4 (NT4). TrkB signalling is indispensable for the survival, development and synaptic plasticity of several subtypes of neurons in the nervous system. Substantial evidence has emerged over the last decade about the involvement of aberrant TrkB signalling and its compromise in various neuropsychiatric and degenerative conditions. Unusual changes in TrkB signalling pathway have also been observed and implicated in a range of cancers. Variations in TrkB pathway have been observed in obesity and hyperphagia related disorders as well. Both BDNF and TrkB have been shown to play critical roles in the survival of retinal ganglion cells in the retina. The ability to specifically modulate TrkB signalling can be critical in various pathological scenarios associated with this pathway. In this review, we discuss the mechanisms underlying TrkB signalling, disease implications and explore plausible ameliorative or preventive approaches.     

原发性闭角型青光眼的临床表现及治疗

随着社会经济的发展和医疗水平的进步,我国呈现人口老龄化趋势,随之青光眼发病率也逐年增长。青光眼分为原发性、先天性及继发性,本文先叙述了原发性闭角型青光眼的基本知识,如分类及发病因素,然后结合医学实践中治疗的临床表现,详细列举了患者的发病特征及治疗阶段,最后对治疗手段加以叙述,并重点介绍了药物手术结合治疗青光眼的治疗方法及效果,旨在为原发性闭角型青光眼的治疗提供第一手资料。     

Exploring the Molecular Interactions of 7,8-Dihydroxyflavone and Its Derivatives with TrkB and VEGFR2 Proteins

7,8-Dihydroxyflavone (7,8-DHF) is a TrkB receptor agonist, and treatment with this flavonoid derivative brings about an enhanced TrkB phosphorylation and promotes downstream cellular signalling. Flavonoids are also known to exert an inhibitory effect on the vascular endothelial growth factor receptor (VEGFR) family of tyrosine kinase receptors. VEGFR2 is one of the important receptors involved in the regulation of vasculogenesis and angiogenesis and has also been implicated to exhibit various neuroprotective roles. Its upregulation and uncontrolled activity is associated with a range of pathological conditions such as age-related macular degeneration and various proliferative disorders. In this study, we investigated molecular interactions of 7,8-DHF and its derivatives with both the TrkB receptor as well as VEGFR2. Using a combination of molecular docking and computational mapping tools involving molecular dynamics approaches we have elucidated additional residues and binding energies involved in 7,8-DHF interactions with the TrkB Ig2 domain and VEGFR2. Our investigations have revealed for the first time that 7,8-DHF has dual biochemical action and its treatment may have divergent effects on the TrkB via its extracellular Ig2 domain and on the VEGFR2 receptor through the intracellular kinase domain. Contrary to its agonistic effects on the TrkB receptor, 7,8-DHF was found to downregulate VEGFR2 phosphorylation both in 661W photoreceptor cells and in retinal tissue.     

Detection of microscopic glaucoma through fundus images using deep transfer learning approach

Glaucoma disease in humans can lead to blindness if it progresses to the point where it affects the oculus' optic nerve head. It is not easily detected since there are no symptoms, but it can be detected using tonometry, ophthalmoscopy, and perimeter. However, advances in artificial intelligence approaches have permitted machine learning techniques to diagnose at an early stage. Numerous methods have been proposed using Machine Learning to diagnose glaucoma with different data sets and techniques but these are complex methods. Although, medical imaging instruments are used as glaucoma screening methods, fundus imaging specifically is the most used screening technique for glaucoma detection. This study presents a novel DenseNet and DarkNet combination to classify normal and glaucoma affected fundus image. These frameworks have been trained and tested on three data sets of high-resolution fundus (HRF), RIM 1, and ACRIMA. A total of 658 images have been used for healthy eyes and 612 images for glaucoma-affected eyes classification. It has also been observed that the fusion of DenseNet and DarkNet outperforms the two CNN networks and achieved 99.7% accuracy, 98.9% sensitivity, 100% specificity for the HRF database. In contrast, for the RIM1 database, 89.3% accuracy, 93.3% sensitivity, 88.46% specificity has been attained. Moreover, for the ACRIMA database, 99% accuracy, 100% sensitivity, 99% specificity has been achieved. Therefore, the proposed method is robust and efficient with less computational time and complexity compared to the literature available.