IL-17A enhances the inflammatory response of glaucoma through Act1/TRAF6/NF-κB pathway.

OBJECTIVES: To investigate the possible roles of Interleukin 17A (IL-17A) and IL-17A neutralizing antibodies (IL-17Ab) in glaucoma and the potential mechanisms. METHODS: The two glaucoma animal models, chronic ocular hypertension (COH) and N-methyl-D-aspartate (NMDA)-induced retinal ganglion cell (RGC) damage, were established and treated with intravitreal injection of IL-17A or IL-17Ab. Intraocular pressure (IOP) was measured by a rebound tonometer. The retina and RGC injury were evaluated by HE staining, TUNLE assay and Brn3a immunofluorescence staining. The frequency of IL-17A+CD4+T cells in peripheral blood was detected by flow cytometry. The expression of glial fibrillary acidic protein (GFAP) was detected by immunofluorescence staining, Western Blot and qPCR in retina. The RNA and protein expression of Act1/TRAF6/NF-κB were detected by Western Blot and qPCR in retina. RESULTS: The expression of IL-17A increased in glaucoma models. After intravitreal injection of IL-17A, in the retina, the number of RGCs decreased, the apoptosis of RGCs increased, the Müller cell gliosis was more obvious. In addition, peripheral inflammation aggravated. Whereas the intravitreal injection of IL-17Ab alleviated the relevant manifestations and peripheral inflammation, reduced the gliosis of Müller cells. In the COH model, IOP increased after the injection of IL-17A, while the intravitreal injection of IL-17Ab led to a decrease in IOP. Furthermore, IL-17A promotes the apoptosis of RGCs by binding to IL-17A receptor, activating Act1/TRAF6/NF-κB pathways. CONCLUSION: IL-17A plays a role in and aggravates RGC damage in glaucoma. IL-17Ab can neutralize the pro-inflammatory effect of IL-17A and have a protective function in glaucoma. These findings reveal the importance of IL-17A in the pathogenesis of glaucoma, which will shed light on a novel direction for the prevention and treatment of glaucoma, and also provide a reference for further research on other retinal diseases.

Identification of immune-related biomarkers for glaucoma using gene expression profiling.

Introduction: Glaucoma, a principal cause of irreversible vision loss, is characterized by intricate optic neuropathy involving significant immune mechanisms. This study seeks to elucidate the molecular and immune complexities of glaucoma, aiming to improve our understanding of its pathogenesis. Methods: Gene expression profiles from glaucoma patients were analyzed to identify immune-related differentially expressed genes (DEGs). Techniques used were weighted gene co-expression network analysis (WGCNA) for network building, machine learning algorithms for biomarker identification, establishment of subclusters related to immune reactions, and single-sample gene set enrichment analysis (ssGSEA) to explore hub genes' relationships with immune cell infiltration and immune pathway activation. Validation was performed using an NMDA-induced excitotoxicity model and RT-qPCR for hub gene expression measurement. Results: The study identified 409 DEGs differentiating healthy individuals from glaucoma patients, highlighting the immune response's significance in disease progression. Immune cell infiltration analysis revealed elevated levels of activated dendritic cells, natural killer cells, monocytes, and immature dendritic cells in glaucoma samples. Three hub genes, CD40LG, TEK, and MDK, were validated as potential diagnostic biomarkers for high-risk glaucoma patients, showing increased expression in the NMDA-induced excitotoxicity model. Discussion: The findings propose the three identified immune-related genes (IRGs) as novel diagnostic markers for glaucoma, offering new insights into the disease's pathogenesis and potential therapeutic targets. The strong correlation between these IRGs and immune responses underscores the intricate role of immunity in glaucoma, suggesting a shift in the approach to its diagnosis and treatment.

Activation of Sonic Hedgehog Signaling Pathway Regulates Human Trabecular Meshwork Cell Function.

Purpose: To investigate the effects of Sonic hedgehog (Shh) signaling on primary human trabecular meshwork (HTM) cells. Methods: Primary HTM cells were isolated from healthy donors and cultured. Recombinant Shh (rShh) protein and cyclopamine were used to activate and inhibit the Shh signaling pathway, respectively. A cell viability assay was performed to assess the effects of rShh on the activity of primary HTM cells. Functional assessment of cell adhesion and phagocytosis was also performed. The proportion of apoptotic cells was examined using flow cytometry. Fibronectin (FN) and transforming growth factor beta2 (TGF-ß2) protein were detected to assess the influence of rShh on the metabolism of the extracellular matrix (ECM). Real-time polymerase chain reaction (RT-PCR) and western blot analyses were used to examine mRNA and protein expression of Shh signaling pathway-associated factors GLI Family Zinc Finger 1 (GLI1) and Suppressor of Fused (SUFU). Results: rShh significantly enhanced primary HTM cell viability at a concentration of 0.5 µg/mL. rShh increased the adhesion and phagocytic abilities of primary HTM cells, and decreased cell apoptosis. FN and TGF-ß2 protein expression increased in primary HTM cells treated with rShh. rShh upregulated the transcriptional activity and protein levels of GLI1, and downregulated those of SUFU. Correspondingly, the rShh-induced GLI1 upexpression was partially blocked by pretreatment with the Shh pathway inhibitor cyclopamine at a concentration of 10 µM. Conclusions: Activation of Shh signaling can regulate the function of primary HTM cells through GLI1. Regulation of Shh signaling may be a potential target for attenuating cell damage in glaucoma.

The effect of diet and exercise on climacteric symptomatology.

BACKGROUND AND OBJECTIVES: This study aimed to explore the effects of health education, diet and exercise interventions on the climacteric symptoms of perimenopausal women. METHODS AND STUDY DESIGN: A total of 78 perimenopausal women in a gynaecological clinic from June 2018 to August 2018 were recruited and divided randomly into the following three groups: A (centralised education alone), B (health education + per-sonalised diet guidance) and C (health education + personalised diet guidance + intensive resistance exercise). The changes in diet score, exercise habits and climacteric symptoms were observed after 3 months. RESULTS: There was no difference between groups in food intake scores and total scores before the interventions. After the interventions, the total diet score of group C was higher than in groups A and B, and the red meat score decreased significantly (p<0.05). After the interventions, the number of resistance exercises per week in group B increased significantly. The number of aerobic exercises and resistance exercises per week in group C also increased significantly (p<0.05). The total score for climacteric symptoms in the three groups decreased significantly before and after the interventions (p<0.05), and the scores for insomnia and sexual disorders in group A decreased significantly (p<0.01). In group B, there was a significant effect on the improvement of moderate and severe climacteric symptoms (p<0.01), and the scores for seven other common symptoms (i.e. hot flushes, sweating, irritability, depression, suspicion, fatigue, joint pain, muscle pain, palpitations and sexual disorders) decreased significantly (p<0.05). CONCLUSIONS: Centralised health education, personalised dietary guidance and intensive resistance exercise improved the menopausal symptoms experienced by peri-menopausal women; the most indicative changes of this improvement were obtained using combined health education and personalised dietary guidance.

Lithocholic acid inhibits dendritic cell activation by reducing intracellular glutathione via TGR5 signaling.

Dendritic cells (DCs) are the major antigen-presenting cells and play an important role in autoimmune uveitis. Emerging evidence suggests that bile acids (BAs) regulate DCs maturation. However, the underlying mechanisms by which BAs regulate the function of DCs still need to be clarified. Here, we demonstrate that lithocholic acid (LCA) inhibits the production of pro-inflammatory cytokines and the expression of surface molecules in bone marrow-derived dendritic cells (BMDCs). LCA attenuates the severity of EAU by modulating the maturation of splenic CD11C+MHCIIhigh DCs. Notably, Takeda G-protein coupled receptor 5 (TGR5) deficiency partially reverses the inhibitory effect of LCA on DCs in vitro and in vivo. TGR5 activation also downregulates the NF-κB and MAPK pathways by inhibiting glutathione production and inducing oxidative stress in DCs, which leads to apoptosis and autophagy in DCs. In addition, LCA or INT-777 treatment increases the TGR5 expression in monocyte-derived dendritic cells (MD-DCs) of patients with active BD, whereas both LCA and TGR5 agonists inhibit the activation of MD-DCs. These results suggest that LCA and TGR5 agonists might be potential therapeutic drugs for the treatment of autoimmune uveitis.

NEDD9 Mediates the FAK/Src Signaling Pathway to Promote the Adhesion of Human Trabecular Meshwork Cells after Dexamethasone Treatment.

PURPOSE: The differential gene expression of neural precursor cell expressed developmentally downregulated 9 (NEDD9) in human trabecular meshwork (HTM) cells after dexamethasone (Dex) treatment was confirmed through gene expression profiling. However, the regulatory mechanism of NEDD9 expression in HTM cells remains unknown. In this study, we investigated NEDD9 expression in HTM cells and gained a better understanding of glucocorticoid-induced glaucoma (GIG) pathophysiology. METHODS: The Gene Expression Omnibus database and GEO2R tool were used to identify differentially expressed genes in the GSE37474 and GSE124114 datasets, and NEDD9 gene expression was found to be upregulated. Human corneoscleral segments and HTM cells were treated with 100 nM Dex or an equal volume of ethanol (0.01%) for 7 days. NEDD9 expression in TM tissues was evaluated by immunohistochemistry, and NEED9 expression in HTM cells was confirmed by RT-qPCR and western blotting. HTM cell adhesive behaviors were assessed with a cell adhesion detection kit. NEDD9 expression was knocked down with short hairpin RNA in HTM cells, and FAK/Src signaling pathway activation was found to be regulated by NEDD9. RESULTS: After 7 days of HTM cell Dex treatment, NEDD9 expression was upregulated to be approximately twice that of control. FAK, Src, phospho-FAK, and phospho-Src expression in Dex-treated HTM cells was markedly increased. Downregulation of NEDD9 expression reduced HTM cell adhesion to the surface of culture wells and simultaneously led to a reduction in FAK, Src, phospho-FAK and phospho-Src expression. CONCLUSIONS: NEDD9 expression is upregulated in HTM cells after Dex treatment and promotes HTM cell adhesion. These findings underscore the contribution of NEDD9 overexpression to altered HTM cell adhesion during glucocorticoid therapy and may play a key role in GIG pathological progression. Considering the similarity between GIG and primary open-angle glaucoma (POAG), our findings suggest that targeting NEDD9 may be a new therapeutic strategy for POAG patients.

Dietary and exercise interventions for metabolic health in perimenopausal women in Beijing.

BACKGROUND AND OBJECTIVES: This study aims to investigate the effects of individualised dietary guidance and anti-resistance exercise intervention on blood pressure and metabolic indexes of perimenopausal women. METHODS AND STUDY DESIGN: Between June 2018 to August 2018, 78 perimenopausal women were recruited at the Gynaecological Outpatient Department of Beijing Pinggu District Hospital. After coding, they were randomly divided into three groups, A, B and C, by lottery. Group A was required to participate in educational seminars. Group B was required to participate in educational seminars and received individualised dietary guidance from professional nutritionists. Group C had the same intensive education classes and individualised dietary guidance as Group B, along with intensive resistance exercise. The difference in the various observation indexes was reviewed after three months of intervention. RESULTS: The number of patients with abnormal metabolic indexes in the diet and comprehensive groups decreased significantly after intervention, compared with the statistics before intervention. The number of patients with a waist circumference ≥80 cm in the diet and comprehensive groups decreased significantly, and the difference was statistically significant (χ2=5.976, p=0.014; χ2=4.433, p=0.035). Before and after observation, the control and diet groups had a higher incidence of HDL <1.29 mmol/L than the comprehensive group, and the difference was statistically significant (p<0.05). After intervention, TGs in the comprehensive group were significantly lower than the control group (≥1.7 mmol/L), and the difference was statistically significant. CONCLUSIONS: Individualised dietary intervention combined with anti-resistance exercise can significantly improve eating and exercise habits, correct metabolic disorders and reduce the occurrence of metabolic syndrome.

Dietary and Exercise Interventions for Perimenopausal Women: A Health Status Impact Study.

PURPOSE: To explore the impact of different intervention methods on physical health indexes of perimenopausal women. METHODS: Seventy-eight perimenopausal women were divided into three groups. Group A received routine gynecological diagnosis and treatment and participated in centralized lifestyle health education. Group B was required to participate in all intensive education content, and professional dietitians gave individualized dietary guidance. Group C received intensive education, individualized diet intervention and intensified resistance exercise. Dietary scores, exercise habits, waist circumference, body mass index, fat and muscle mass were observed after three months. RESULTS: After the intervention, the total diet score of group C was higher than groups A and B, and the red meat score was significantly reduced. The number of patients in groups B and C who exercised >3 times per week and the number of resistance exercises were significantly increased, while the number of aerobic exercises per week in group C was significantly increased. The body fat and waist circumference were significantly reduced, and skeletal muscle weight was significantly increased. Body mass index, trunk fat ratio and waist-to-hip ratio were significantly decreased in groups B and C, while trunk muscle was significantly increased in group C. CONCLUSION: The combined intervention of the three methods can give full play to the synergistic effect of various interventions. The improvement effect of increasing the appropriate amount of resistance exercise is more obvious, which is worthy of further promotion and application.

Ultra-broadband spatiotemporal sweeping device for high-speed optical imaging.

In this work, we propose and demonstrate a spatiotemporal sweeping fiber bundle for ultra-fast optical diagnoses over a multioctave wavelength span, ranging from ∼400 nm to ∼2000 nm. This all-optical spatiotemporal sweeping is realized by precisely controlling the length increment between individual fibers in the fiber bundle. Here, a 200-ps pixel delay increment specifically enables a pixel readout rate of up to 5 GHz. Depending on different configurations of the fiber bundle, either 1D or 2D spatiotemporal sweeping can be realized. Moreover, the high peak power of the short pulse in each pixel can facilitate the highly sensitive optical detection. To showcase its ultra-broadband operation capability, we here perform ultra-fast optical microscopy at three distinctive wavelengths, which are 710 nm, 1030 nm, and 1600 nm, and achieve tens of MHz line-scan rate and few-micrometers resolution for all three experiments. It is anticipated that this inertia-free spatiotemporal sweeping device with ultra-broad bandwidth, GHz pixel readout rate, and high detection sensitivity is promising for ultra-fast optical diagnosis, particularly when hyperspectral characteristics are desired.

Ultrafast optical imaging at 2.0 µm through second-harmonic-generation-based time-stretch at 1.0 µm.

The performance of ultrafast time-stretch imaging at long wavelengths (beyond 1.5 µm) has suffered from low detection sensitivity due to the increasing loss of optical dispersive fibers. Here, we report an ultrafast optical imaging system with a line scan rate of ∼19 MHz at the 2.0-µm wavelength window by combining second-harmonic generation (SHG) with the highly sensitive time-stretch detection at 1.0 µm. In this imaging system, the sample is illuminated by the pulsed laser source at 2.0 µm in the spectrally encoding manner. After SHG, the encoded spectral signal at 2.0 µm is converted to 1.0 µm and then mapped to the time domain through a highly dispersive fiber at 1.0 µm, which provides a superior dispersion-to-loss ratio of ∼53 ps/nm/dB, ∼50 times larger than that of the standard fibers at 2.0 µm (typically ∼1.1 ps/nm/dB). These efforts make it possible for time-stretch technology not only being translated to longer wavelengths, where unique optical absorption contrast exists, but also benefitting from the high detection sensitivity at shorter wavelengths.

Flexible pulse-stretching for a swept source at 2.0 µm using free-space angular-chirp-enhanced delay.

Dispersive pulse-stretching at 2.0 µm has long been hindered by the high intrinsic optical loss from conventional dispersive media. Here a flexible pulse-stretching technique at 2.0 µm is demonstrated over a broad bandwidth with large-scale dispersion and low intrinsic optical loss. The technique employs the newly proposed pulse-stretching scheme, namely, free-space angular-chirp-enhanced delay. Both normal and anomalous temporal dispersion (up to ±500 ps/nm) with low intrinsic loss (<6 dB) over a spectral bandwidth of ∼84 nm at 2.0 µm is obtained with low nonlinear effects. Based on this method, an optical wavelength-swept source at 2.0 µm is realized and applied to spectrally encoded imaging at a line scan rate of ∼19 MHz, proving the potential of this pulse-stretching technique for continuous single-shot measurements at the 2.0 µm wavelength regime, particularly for optical microscopy and spectroscopy.

Optical receiver sensitivity enhancement by single- and dual-band fiber optical parametric amplifier.

A semi-classical model is proposed theoretically and demonstrated experimentally on the optical receiver sensitivity enhancement by single-band (signal or idler) and dual-band (signal and idler) fiber optical parametric amplifier (FOPA). The sensitivity enhancement by single-band is determined by the gain of FOPA and the transmission loss of signal and idler, and it can be further improved by up to 3-dB using amplified signal and phase-conjugated idler together at dual-band configuration. The theoretical results are experimentally verified in both fiber communication and biomedical imaging applications. This detection sensitivity enhancement scheme can be potentially applied in the scenarios where ultrafast broadband signal at low-power level is being handled.

High-speed wavelength-swept source at 2.0 µm and its application in imaging through a scattering medium.

We report a high-speed wavelength-swept source operating at 2.0 µm through advanced time-stretch technology. It sweeps over 30 nm at a speed of 3.3×109 nm/s and a repetition rate of ∼19 MHz. To the best of our knowledge, this is the first time that a megahertz-stable swept source has been implemented at such a long wavelength. A wide bandwidth is enabled by a simple mode-locked fiber laser that covers a wavelength range of ∼60 nm. The all-optical wavelength sweeping is realized by a chirped fiber Bragg grating (CFBG), which shows a superior temporal stability and power efficiency, compared with commonly used dispersive fibers, particularly in the 2.0 µm wavelength window. To showcase its specialties, here we employ it to perform high-speed spectrally-encoded microscopy (i.e., time-stretch imaging) through a scattering medium at a line-scan rate of up to ∼19 MHz. Better image quality is achieved, compared with a conventional imaging window at 1.0 µm. It is believed that the potential applications of this new high-speed swept source will benefit the transient diagnosis that requires deep penetration through a scattering medium.

High-power widely tunable all-fiber thulium-assisted optical parametric oscillator at SWIR band.

A novel short-wave infrared (SWIR) all-fiber thulium-assisted optical parametric oscillator (TAOPO) that exploits jointly optical parametric conversion and thulium amplification in a highly nonlinear fiber (HNLF) and thulium-doped fiber (TDF) is demonstrated. This is implemented through constructing a joint fiber line by directly fusion splicing 50 m HNLF with 1.5 m TDF. Incorporating a bidirectional-pumping scheme, i.e., forward-pumped by a step-tuned C-band pulsed laser, and simultaneously backward-pumped by an L-band continuous-wave laser, this TAOPO produces a pulsed SWIR laser at output power higher than 200 mW, signal-to-noise ratio over 40 dB, and wavelength tuning range beyond 150 nm from 1815 to 1968 nm. Via separate characterization of the HNLF and TDF joint fiber line, the tunability of the current TAOPO to shorter wavelength is only limited by the employed fiber components, while higher power could be realized by increasing the backward pump power. This TAOPO could be a promising platform for the generation of a highly functional SWIR source that facilitates applications such as bond-selective imaging of deep tissue.

Sensitivity enhancement in swept-source optical coherence tomography by parametric balanced detector and amplifier.

We proposed a sensitivity enhancement method of the interference-based signal detection approach and applied it on a swept-source optical coherence tomography (SS-OCT) system through all-fiber optical parametric amplifier (FOPA) and parametric balanced detector (BD). The parametric BD was realized by combining the signal and phase conjugated idler band that was newly-generated through FOPA, and specifically by superimposing these two bands at a photodetector. The sensitivity enhancement by FOPA and parametric BD in SS-OCT were demonstrated experimentally. The results show that SS-OCT with FOPA and SS-OCT with parametric BD can provide more than 9 dB and 12 dB sensitivity improvement, respectively, when compared with the conventional SS-OCT in a spectral bandwidth spanning over 76 nm. To further verify and elaborate their sensitivity enhancement, a bio-sample imaging experiment was conducted on loach eyes by conventional SS-OCT setup, SS-OCT with FOPA and parametric BD at different illumination power levels. All these results proved that using FOPA and parametric BD could improve the sensitivity significantly in SS-OCT systems.

Compact and stable temporally magnified tomography using a phase-locked broadband source.

The temporally magnified tomography system is further improved in terms of resolution and imaging stability. We simplify the system configuration and improve the axial resolution simultaneously by utilizing a stabilized all-fiber broadband source. The highly stable spectrum of the source assisted by a phase-locked loop guarantees an improved imaging quality. In addition, the impact of the repetition-rate fluctuation of the source to the system stability is analyzed, which also applies to other temporal imaging systems. Achieving a 90-µm in-air resolution at 89-MHz A-scan rate and improved stability, we are taking one major step toward the practical application of this new optical tomographic modality.

110 nm versatile fiber optical parametric amplifier at 1.0 µm.

The fiber optical parametric amplifier (FOPA) has been well investigated and widely adopted at the telecommunication window, and outstanding progress has been achieved in areas such as high gain, wide bandwidths, and even flexible gain-spectrum shape. In contrast, a FOPA at the bio-favorable window, 1.0 µm, has been largely underexploited, especially for its relatively limited bandwidth. Here, we demonstrate an all-fiber single-pump FOPA at 1.0 µm with versatile performances, including ultrahigh gain (∼52 dB), wide bandwidth (∼110 nm), and good gain-spectrum flatness (∼3 dB). To showcase the practical applications, the FOPA is utilized to amplify the broadband optical image signal from a spectrally encoded microscopy, yielding a sensitivity enhancement of 47 dB. Thus, it is promising that this all-fiber versatile FOPA works well as an add-on module in boosting sensitivity for existing optical systems at a 1.0 µm window.

109 MHz optical tomography using temporal magnification.

Ultrafast optical tomographic imaging with a 109 MHz A-scan rate is achieved by using temporal magnification. Based on two four-wave mixing (FWM) time lenses with carefully designed group delay dispersion, we construct a temporal imaging system with a magnification factor of 48.3×. The two time-lens scheme not only relaxes the requirement for the pump source but also facilitates the application for tomographic imaging. As a proof-of-concept demonstration, our system achieves an axial resolution of 140 µm in air (∼105 µm in biosample) over a 28 mm depth range with sensitivity up to 55 dB. We then evaluate the imaging performance using a fish-eye lens at a 109 MHz A-scan rate. Utilizing better dispersion-engineered nonlinear media, resolution of less than 5 µm in the biosample with higher sensitivity may be achieved. We believe this scheme will provide a promising solution for video-rate 3D tomographic imaging.

Experimental observation of optical differentiation and optical Hilbert transformation using a single SOI microdisk chip.

Optical differentiation and optical Hilbert transformation play important roles in communications, computing, information processing and signal analysis in optical domain offering huge bandwidth. Meanwhile, silicon-based photonic integrated circuit is one of the most promising candidates for all-optical signal processing due to its intrinsic advantages of low power consumption, compact footprint, ultra-high speed and compatibility with electronic integrated circuits. In this study, we analyze the interrelation between first-order optical differentiation and optical Hilbert transformation and then experimentally demonstrate a feasible integrated scheme which can simultaneously function as first-order optical differentiation and optical Hilbert transformation based on a single microdisk resonator. This finding may motivate the development of integrated optical signal processors.

High-order all-optical differential equation solver based on microring resonators.

We propose and experimentally demonstrate a feasible integrated scheme to solve all-optical differential equations using microring resonators (MRRs) that is capable of solving first- and second-order linear ordinary differential equations with different constant coefficients. Employing two cascaded MRRs with different radii, an excellent agreement between the numerical simulation and the experimental results is obtained. Due to the inherent merits of silicon-based devices for all-optical computing, such as low power consumption, small size, and high speed, this finding may motivate the development of integrated optical signal processors and further extend optical computing technologies.