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Ischemia is a common pathological condition present in many neurodegenerative diseases, including ischemic stroke, retinal vascular occlusion, diabetic retinopathy, and glaucoma, threatening the sight and lives of millions of people globally. Ischemia can trigger excessive oxidative stress, inflammation, and vascular dysfunction, leading to the disruption of tissue homeostasis and, ultimately, cell death. Current therapies are very limited and have a narrow time window for effective treatment. Thus, there is an urgent need to develop more effective therapeutic options for ischemia-induced neural injuries. With emerging reports on the pharmacological properties of natural flavonoids, these compounds present potent antioxidative, anti-inflammatory, and antiapoptotic agents for the treatment of ischemic insults. Three major active flavonoids, baicalein, baicalin, and wogonin, have been extracted from Scutellaria baicalensis Georgi (S. baicalensis); all of which are reported to have low cytotoxicity. They have been demonstrated to exert promising pharmacological capabilities in preventing cell and tissue damage. This review focuses on the therapeutic potentials of these flavonoids against ischemia-induced neurotoxicity and damage in the brain and retina. The bioactivity and bioavailability of baicalein, baicalin, and wogonin are also discussed. It is with hope that the therapeutic potential of these flavonoids can be utilized and developed as natural treatments for ischemia-induced injuries of the central nervous system (CNS).

Glaucoma is the leading cause of irreversible blindness. Primary open-angle glaucoma (POAG) is the most common form globally and has been linked to mitochondrial dysfunction and energy deficiency. Plasma was used to investigate the energy metabolomic profiles of patients with POAG and controls, and to determine the metabolite flux within the core interconnected energy pathways. Targeted liquid chromatography-mass spectrometry (LC-MS) was used to analyze plasma energy metabolism in POAG patients and controls. Differential metabolite expression analysis, correlation analysis, and pathway flux analysis were then conducted to elucidate the metabolic alterations and the mechanisms underlying POAG. Our findings reveal elevated levels of D-Glucose-6-phosphate(G6P), 6-Phosphogluconic acid(6PGA), Adenosine diphosphate(ADP), Adenosine monophosphate(AMP), Adenosine triphosphate(ATP), Guanosine diphosphate(GDP), Inosine monophosphate(IMP), Phosphoenolpyruvic acid(PEP), Phosphorylethanolamine(pEtN), and uridine diphosphate N-acetylglucosamine(UDP-GlcNAc) in POAG patients. Conversely, POAG patients showed reduced ratios of ATP/ADP, Glycerol-3-phosphate(G3P)/ Dihydroxyacetone phosphate(DHAP), 1,3-Bisphosphoglyceric acid(BPG)/DHAP, PYR/PEP, Fumarate/Succinate, Arginine/ASA, and Citrulline/Ornithine. These findings collectively suggest disrupted flux in glycolysis, the TCA cycle, urea cycle, and tyrosine metabolism, offering new insights into POAG mechanisms and potential therapeutic strategies targeting energy metabolic pathways.

Prolonged use of dexamethasone (DEX) increases intraocular pressure (IOP) and the risk of glaucoma. Recent studies have shown that DEX upregulates thrombospondin-1 ( THBS1 ) gene expression and induces dysregulation of macroautophagy/autophagy in primary human trabecular meshwork (hTM) cells. Trehalose, a natural disaccharide, activates autophagy and protects cells against environmental stresses. Here, we report that trehalose-induced autophagy enhanced outflow facility, reduced IOP, and protected against ocular hypertension in mice. We analyzed autophagy induction by trehalose in hTM cells. Our data demonstrated that trehalose transcriptionally upregulated prototypical autophagy related genes and activated autophagy through the downregulation of THBS1 . Consistent with prior findings, the results indicated that THBS1 silencing or inhibition is a key cellular event for the regulation of aqueous humor outflow and IOP homeostasis. In conclusion, this study identified trehalose-induced autophagy as a protective mechanism against ocular hypertension which may have therapeutic potential.

Secretion of melatonin, a natural hormone whose receptors are present in the ciliary epithelium, displays diurnal variation in the aqueous humor (AH), potentially contributing to the regulation of intraocular pressure. This study aimed to determine the effects of melatonin on AH secretion in porcine ciliary epithelium. The addition of 100 µM melatonin to both sides of the epithelium significantly increased the short-circuit current (Isc) by ~40%. Stromal administration alone had no effect on the Isc, but aqueous application triggered a 40% increase in Isc, similar to that of bilateral application without additive effect. Pre-treatment with niflumic acid abolished melatonin-induced Isc stimulation. More importantly, melatonin stimulated the fluid secretion across the intact ciliary epithelium by ~80% and elicited a sustained increase (~50–60%) in gap junctional permeability between pigmented ciliary epithelial (PE) cells and non-pigmented ciliary epithelial (NPE) cells. The expression of MT3 receptor was found to be >10-fold higher than that of MT1 and MT2 in porcine ciliary epithelium. Aqueous pre-treatment with MT1/MT2 antagonist luzindole failed to inhibit the melatonin-induced Isc response, while MT3 antagonist prazosin pre-treatment abolished the Isc stimulation. We conclude that melatonin facilitates Cl− and fluid movement from PE to NPE cells, thereby stimulating AH secretion via NPE-cell MT3 receptors.

Our previous research showed that increased phosphorylation of connexin (Cx)36 indicated extended  coupling of AII amacrine cells (ACs) in the rod-dominant mouse myopic retina. This research will determine whether phosphorylation at serine 276 of Cx35-containing gap junctions increased in the myopic chicken, whose retina is cone-dominant. Refractive errors and ocular biometric dimensions of 7-days-old chickens were determined following 12 h and 7 days induction of myopia by a −10D lens. The expression pattern and size of Cx35-positive plaques were examined in the early (12 h) and compensated stages (7 days) of lens-induced myopia (LIM). At the same time, phosphorylation at serine 276 (functional assay) of Cx35 in strata 5 (S5) of the inner plexiform layer was investigated. The axial length of the 7 days LIM eyes was significantly longer than that of non-LIM controls (P < 0.05). Anti-phospho-Ser276 (Ser276-P)-labeled plaques were significantly increased in LIM retinas at both 12 h and 7 days. The density of Ser276-P of Cx35 was observed to increase after 12 h LIM. In the meanwhile, the areas of existing Cx35 plaques did not change. As there was more phosphorylation of connexin35 at Ser276 at both the early and late stages (12 h) and 7 days of LIM chicken retinal activity, the coupling with ACs could be increased in myopia development of the cone-dominated chicken retina.

Elevated intraocular pressure (IOP) is a major risk factor for glaucoma that results from impeded fluid drainage. The increase in outflow resistance is caused by trabecular meshwork (TM) cell dysfunction and excessive extracellular matrix (ECM) deposition. Baicalein (Ba) is a natural flavonoid and has been shown to regulate cell contraction, fluid secretion, and ECM remodeling in various cell types, suggesting the potential significance of regulating outflow resistance and IOP. We demonstrated that Ba significantly lowered the IOP by about 5 mmHg in living mice. Consistent with that, Ba increased the outflow facility by up to 90% in enucleated mouse eyes. The effects of Ba on cell volume regulation and contractility were examined in primary human TM (hTM) cells. We found that Ba (1–100 µM) had no effect on cell volume under iso-osmotic conditions but inhibited the regulatory volume decrease (RVD) by up to 70% under hypotonic challenge. In addition, Ba relaxed hTM cells via reduced myosin light chain (MLC) phosphorylation. Using iTRAQ-based quantitative proteomics, 47 proteins were significantly regulated in hTM cells after a 3-h Ba treatment. Ba significantly increased the expression of cathepsin B by 1.51-fold and downregulated the expression of D-dopachrome decarboxylase and pre-B-cell leukemia transcription factor-interacting protein 1 with a fold-change of 0.58 and 0.40, respectively. We suggest that a Ba-mediated increase in outflow facility is triggered by cell relaxation via MLC phosphorylation along with inhibiting RVD in hTM cells. The Ba-mediated changes in protein expression support the notion of altered ECM homeostasis, potentially contributing to a reduction of outflow resistance and thereby IOP.

Retinal ischemia is a common cause of many retinal diseases, leading to irreversible vision impairment and blindness. Excessive neuroinflammation, including microglial activation and T-cell responses, has been identified as a critical factor associated with neurodegeneration in retinal ischemia. Baicalein is a natural flavonoid reported to have broad anti-inflammatory and neuroprotective bioactivities. Herein, the effects of baicalein on microglia activation in vitro and in vivo were investigated. We found that baicalein exhibited robust anti-inflammatory effect on cultured human and mouse microglia, as demonstrated by decreased induction of pro-inflammatory cytokines and the phosphorylation of phosphoinositide 3-kinase (PI3K) and nuclear factor kappa B (NFκB). Proteomic analysis further unraveled baicalein’s effect on modulating IL-17 signaling pathways and its upstream regulator IL-1β. Intravitreal administration of baicalein in the mouse model of retinal ischemia/reperfusion (I/R) injury attenuated microglial activation and retinal T-cell infiltration, particularly the T helper 17 cells. Additionally, baicalein was shown to exert neuroprotective effects by significantly reducing the retinal ganglion cell (RGC) loss after I/R injury, leading to an improved retinal function and spatial vision. These results suggest that baicalein, a natural flavonoid, acts as a negative regulator of activated microglia and immune responses both in vitro and in vivo , effectively alleviating neurodegeneration in retinal I/R injury. This finding indicates that baicalein could be a potential therapeutic agent against currently incurable degenerative retinal diseases.

To explore the temporal profile of retinal proteomes specific to primary and secondary retinal ganglion cell (RGC) loss. Unilateral partial optic nerve transection (pONT) was performed on the temporal side of the rat optic nerve. Temporal and nasal retinal samples were collected at 1, 4 and 8 weeks after pONT (n = 4 each) for non-biased profiling with a high-resolution hybrid quadrupole time-of-flight mass spectrometry running on label-free SWATHTM acquisition (SCIEX). An information-dependent acquisition ion library was generated using ProteinPilot 5.0 and OneOmics cloud bioinformatics. Combined proteome analysis detected 2531 proteins with a false discovery rate of <1%. Compared to the nasal retina, 10, 25 and 61 significantly regulated proteins were found in the temporal retina at 1, 4, and 8 weeks, respectively (p < 0.05, FC ≥ 1.4 or ≤0.7). Eight proteins (ALDH1A1, TRY10, GFAP, HBB-B1, ALB, CDC42, SNCG, NEFL) were differentially expressed for at least two time points. The expressions of ALDH1A1 and SNCG at nerve fibers were decreased along with axonal loss. Increased ALDH1A1 localization in the inner nuclear layer suggested stress response. Increased GFAP expression demonstrated regional reactivity of astrocytes and Muller cells. Meta-analysis of gene ontology showed a pronounced difference in endopeptidase and peptidase inhibitor activity. Temporal proteomic profiling demonstrates established and novel protein targets associated with RGC damage.

The corneal epithelium serves as the front barrier against environmental stimuli and pathogens on the ocular surface. A comprehensive protein profile of the corneal epithelium would be crucial for understanding the molecular mechanisms that are related to corneal disease. This work demonstrated a library-free data-independent acquisition (DIA) approach across different mass spectrometers and proteomic software to build a comprehensive proteomic dataset for human corneal epithelial cells (HCECs). With the combinational use of different data-independent acquisition technologies of multiple mass spectrometers, including Sciex ZenoTOF 7600 (DIA-SWATH), Bruker TimsTOF Pro2 (DIA-PASEF), and ThermoFisher Orbitrap Fusion Lumos (DIA-HRMS1), protein identification and quantification were performed with superior sensitivity and resolution. By using a library-free DIA approach, this study constructed a more diverse and unbiased proteomic profile of human corneal epithelial cells (HCECs), comprising 11,954 protein groups (1% FDR). This represents the largest corneal proteome reported to date. All raw proteomic data were deposited to ProteomeXchange Consortium via Proteomics Identifications database (PRIDE) with the dataset identifier accession number PXD059451. Our findings hold the potential to enhance future understanding of corneal pathologies and transformative therapeutics.

Glaucoma, a form of progressive optic neuropathy, is the second leading cause of blindness worldwide. Being a prominent disease affecting vision, substantial efforts are being made to better understand glaucoma pathogenesis and to develop novel treatment options including neuroprotective and neuroregenerative approaches. Cell transplantation has the potential to play a neuroprotective and/or neuroregenerative role for various ocular cell types (e.g., retinal cells, trabecular meshwork). Notably, glaucoma is often associated with elevated intraocular pressure, and over the past 2 decades, several rodent models of chronic ocular hypertension (COH) have been developed that reflect these changes in pressure. However, the underlying pathophysiology of glaucoma in these models and how they compare to the human condition remains unclear. This limitation is the primary barrier for using rodent models to develop novel therapies to manage glaucoma and glaucoma-related blindness. Here, we review the current techniques used to induce COH-related glaucoma in various rodent models, focusing on the strengths and weaknesses of the each, in order to provide a more complete understanding of how these models can be best utilized. To so do, we have separated them based on the target tissue (pre-trabecular, trabecular, and post-trabecular) in order to provide the reader with an encompassing reference describing the most appropriate rodent COH models for their research. We begin with an initial overview of the current use of these models in the evaluation of cell transplantation therapies.