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Free Radical Biology & Medicine May 2024Severe dry eye disease causes ocular surface damage, which is highly associated with mitochondrial dysfunction. Mitochondrial transcription factor A (TFAM) is essential...
Disrupted mitochondrial transcription factor A expression promotes mitochondrial dysfunction and enhances ocular surface inflammation by activating the absent in melanoma 2 inflammasome.
PURPOSE
Severe dry eye disease causes ocular surface damage, which is highly associated with mitochondrial dysfunction. Mitochondrial transcription factor A (TFAM) is essential for packaging mitochondrial DNA (mtDNA) and is crucial for maintaining mitochondrial function. Herein, we aimed to explore the effect of a decreased TFAM expression on ocular surface damage.
METHODS
Female C57BL/6 mice were induced ocular surface injury by topical administrating benzalkonium chloride (BAC). Immortalized human corneal epithelial cells (HCECs) were stimulated by tert-butyl hydroperoxide (t-BHP) to create oxidative stress damage. HCECs with TFAM knockdown were established. RNA sequencing was employed to analyze the whole-genome expression. Mitochondrial changes were measured by transmission electron microscopy, Seahorse metabolic flux analysis, mitochondrial membrane potential, and mtDNA copy number. TFAM expression and inflammatory cytokines were determined using RT-qPCR, immunohistochemistry, immunofluorescence, and immunoblotting.
RESULTS
In both the corneas of BAC-treated mice and t-BHP-induced HCECs, we observed impaired TFAM expression, accompanied by mitochondrial structure and function defects. TFAM downregulation in HCECs suppressed mitochondrial respiratory capacity, reduced mtDNA content, induced mtDNA leakage into the cytoplasm, and led to inflammation. RNA sequencing revealed the absent in melanoma 2 (AIM2) inflammasome was activated in the corneas of BAC-treated mice. The AIM2 inflammasome activation was confirmed in TFAM knockdown HCECs. TFAM knockdown in t-BHP-stimulated HCECs aggravated mitochondrial dysfunction and the AIM2 inflammasome activation, thereby further triggering the secretion of inflammatory factors such as interleukin (IL) -1β and IL-18.
CONCLUSIONS
TFAM reduction impaired mitochondrial function, activated AIM2 inflammasome and promoted ocular surface inflammation, revealing an underlying molecular mechanism for ocular surface disorders.
PubMed: 38797339
DOI: 10.1016/j.freeradbiomed.2024.05.032 -
Redox Biology May 2024Fungal keratitis is a severely vision-threatening corneal infection, where the prognosis depends on both fungal virulence and host immune defense. Inappropriate host...
Fungal keratitis is a severely vision-threatening corneal infection, where the prognosis depends on both fungal virulence and host immune defense. Inappropriate host responses can induce substantial inflammatory damage to the cornea. Therefore, in the treatment of fungal keratitis, it is important to concurrently regulate the immune response while efforts are made to eliminate the pathogen. Ebselen is a widely studied organo-selenium compound and has been demonstrated to have antifungal, antibacterial, anti-inflammatory, and oxidative stress-regulatory properties. The effectiveness of ebselen for the treatment of fungal keratitis remains unknown. In this study, ebselen was demonstrated to produce a marked inhibitory effect on Aspergillus fumigatus (A. fumigatus), including spore germination inhibition, mycelial growth reduction, and fungal biofilm disruption. The antifungal activity of ebselen was related to the cell membrane damage caused by thioredoxin (Trx) system inhibition-mediated oxidative stress. On the contrary, ebselen enhanced the antioxidation of Trx system in mammalian cells. Further, ebselen was proven to suppress the expressions of inflammatory mediators (IL-1β, IL-6, TNF-α, COX-2, iNOS, and CCL2) and reduce the production of oxidative stress-associated indicators (ROS, NO, and MDA) in fungi-stimulated RAW264.7 cells. In addition, ebselen regulated PI3K/Akt/Nrf2 and p38 MAPK signaling pathways, which contributed to the improvement of inflammation and oxidative stress. Finally, we verified the therapeutic effect of ebselen on mouse fungal keratitis. Ebselen improved the prognosis and reduced the fungal burden in mouse corneas. Expressions of inflammatory mediators, as well as the infiltration of macrophages and neutrophils in the cornea were also obviously decreased by ebselen. In summary, ebselen exerted therapeutic effects by reducing fungal load and protecting host tissues in fungal keratitis, making it a promising treatment for fungal infections.
PubMed: 38796864
DOI: 10.1016/j.redox.2024.103206 -
Microorganisms May 2024The emergence of antibiotic resistance poses a significant threat to public health worldwide, affecting various medical fields, including ophthalmology. Eye infections,...
The emergence of antibiotic resistance poses a significant threat to public health worldwide, affecting various medical fields, including ophthalmology. Eye infections, ranging from conjunctivitis to more severe conditions like keratitis, are commonly treated with antibiotics. However, the misuse and overuse of these drugs have led to the development of resistant strains of bacteria, allowing traditional treatments ineffective. This paper aims to examine the current situation of antibiotic resistance in eye infections globally, with a specific focus on a large group of hospitals located in Milan (Italy) with considerable experience in cataract and cornea surgery as well as in retinopathy. The results of the study show the prevalence of Gram-positives in the tested samples and a low resistance of fluoroquinolones and glycopeptides. The results also highlight the need to implement sample collection methods for ocular infections, as the quantity of positive samples is rather low compared to the total number of samples. In conclusion, the study, although with limited data, shows that resistance to aminoglycosides and cephalosporins is a situation to be monitored. These data also show the critical need to improve and guide the biological sample collection modalities in order to make the diagnosis more reliable.
PubMed: 38792813
DOI: 10.3390/microorganisms12050984 -
International Journal of Molecular... May 2024Corneal neovascularization can impair vision and result in a poor quality of life. The pathogenesis involves a complex interplay of angiogenic factors, notably vascular... (Review)
Review
Corneal neovascularization can impair vision and result in a poor quality of life. The pathogenesis involves a complex interplay of angiogenic factors, notably vascular endothelial growth factor (VEGF). This review provides a comprehensive overview of potential therapies for corneal neovascularization, covering tissue inhibitors of metalloproteinases (TIMPs), transforming growth factor beta (TGF-β) inhibitors, interleukin-1L receptor antagonist (IL-1 Ra), nitric oxide synthase (NOS) isoforms, galectin-3 inhibitors, retinal pigment epithelium-derived factor (PEDF), platelet-derived growth factor (PDGF) receptor inhibitors, and surgical treatments. Conventional treatments include anti-VEGF therapy and laser interventions, while emerging therapies such as immunosuppressive drugs (cyclosporine and rapamycin) have been explored. Losartan and decorin are potential antifibrotic agents that mitigate TGF-β-induced fibrosis. Ocular nanosystems are innovative drug-delivery platforms that facilitate the targeted release of therapeutic agents. Gene therapies, such as small interfering RNA and antisense oligonucleotides, are promising approaches for selectively inhibiting angiogenesis-related gene expression. Aganirsen is efficacious in reducing the corneal neovascularization area without significant adverse effects. These multifaceted approaches underscore the corneal neovascularization management complexity and highlight ideas for enhancing therapeutic outcomes. Furthermore, the importance of combination therapies and the need for further research to develop specific inhibitors while considering their therapeutic efficacy and potential adverse effects are discussed.
Topics: Humans; Corneal Neovascularization; Animals; Genetic Therapy; Angiogenesis Inhibitors; Transforming Growth Factor beta
PubMed: 38791518
DOI: 10.3390/ijms25105479 -
Bioengineering (Basel, Switzerland) May 2024Organ-on-chip (OOC) technology has gained importance for biomedical studies and drug development. This technology involves microfluidic devices that mimic the structure... (Review)
Review
Organ-on-chip (OOC) technology has gained importance for biomedical studies and drug development. This technology involves microfluidic devices that mimic the structure and function of specific human organs or tissues. OOCs are a promising alternative to traditional cell-based models and animals, as they provide a more representative experimental model of human physiology. By creating a microenvironment that closely resembles in vivo conditions, OOC platforms enable the study of intricate interactions between different cells as well as a better understanding of the underlying mechanisms pertaining to diseases. OOCs can be integrated with other technologies, such as sensors and imaging systems to monitor real-time responses and gather extensive data on tissue behavior. Despite these advances, OOCs for many organs are in their initial stages of development, with several challenges yet to be overcome. These include improving the complexity and maturity of these cellular models, enhancing their reproducibility, standardization, and scaling them up for high-throughput uses. Nonetheless, OOCs hold great promise in advancing biomedical research, drug discovery, and personalized medicine, benefiting human health and well-being. Here, we review several recent OOCs that attempt to overcome some of these challenges. These OOCs with unique applications can be engineered to model organ systems such as the stomach, cornea, blood vessels, and mouth, allowing for analyses and investigations under more realistic conditions. With this, these models can lead to the discovery of potential therapeutic interventions. In this review, we express the significance of the relationship between mucosal tissues and vasculature in organ-on-chip (OOC) systems. This interconnection mirrors the intricate physiological interactions observed in the human body, making it crucial for achieving accurate and meaningful representations of biological processes within OOC models. Vasculature delivers essential nutrients and oxygen to mucosal tissues, ensuring their proper function and survival. This exchange is critical for maintaining the health and integrity of mucosal barriers. This review will discuss the OOCs used to represent the mucosal architecture and vasculature, and it can encourage us to think of ways in which the integration of both can better mimic the complexities of biological systems and gain deeper insights into various physiological and pathological processes. This will help to facilitate the development of more accurate predictive models, which are invaluable for advancing our understanding of disease mechanisms and developing novel therapeutic interventions.
PubMed: 38790343
DOI: 10.3390/bioengineering11050476 -
Bioengineering (Basel, Switzerland) Apr 2024This study aimed to employ the incremental digital image correlation (DIC) method to obtain displacement and strain field data of the cornea from Corvis ST (CVS)...
PURPOSE
This study aimed to employ the incremental digital image correlation (DIC) method to obtain displacement and strain field data of the cornea from Corvis ST (CVS) sequences and access the performance of embedding these biomechanical data with machine learning models to distinguish forme fruste keratoconus (FFKC) from normal corneas.
METHODS
100 subjects were categorized into normal (N = 50) and FFKC (N = 50) groups. Image sequences depicting the horizontal cross-section of the human cornea under air puff were captured using the Corvis ST tonometer. The high-speed evolution of full-field corneal displacement, strain, velocity, and strain rate was reconstructed utilizing the incremental DIC approach. Maximum (max-) and average (ave-) values of full-field displacement V, shear strain γxy, velocity VR, and shear strain rate γxyR were determined over time, generating eight evolution curves denoting max-V, max-γxy, max-VR, max-γxyR, ave-V, ave-γxy, ave-VR, and ave-γxyR, respectively. These evolution data were inputted into two machine learning (ML) models, specifically Naïve Bayes (NB) and Random Forest (RF) models, which were subsequently employed to construct a voting classifier. The performance of the models in diagnosing FFKC from normal corneas was compared to existing CVS parameters.
RESULTS
The Normal group and the FFKC group each included 50 eyes. The FFKC group did not differ from healthy controls for age ( = 0.26) and gender ( = 0.36) at baseline, but they had significantly lower bIOP ( < 0.001) and thinner central cornea thickness (CCT) ( < 0.001). The results demonstrated that the proposed voting ensemble model yielded the highest performance with an AUC of 1.00, followed by the RF model with an AUC of 0.99. Radius and A2 Time emerged as the best-performing CVS parameters with AUC values of 0.948 and 0.938, respectively. Nonetheless, no existing Corvis ST parameters outperformed the ML models. A progressive enhancement in performance of the ML models was observed with incremental time points during the corneal deformation.
CONCLUSION
This study represents the first instance where displacement and strain data following incremental DIC analysis of Corvis ST images were integrated with machine learning models to effectively differentiate FFKC corneas from normal ones, achieving superior accuracy compared to existing CVS parameters. Considering biomechanical responses of the inner cornea and their temporal pattern changes may significantly improve the early detection of keratoconus.
PubMed: 38790296
DOI: 10.3390/bioengineering11050429 -
Heliyon May 2024Dehiscence is a common complication of corneal transplant surgery involving separating the graft from the host eye. The present article aims to investigate fundamental...
Dehiscence is a common complication of corneal transplant surgery involving separating the graft from the host eye. The present article aims to investigate fundamental insights into the mechanical and structural aspects of the graft-host junction (GHJ) of a graft that survived in a patient for 13 years after penetrating keratoplasty (PK). Additionally, it adopts the sutur retention strength (SRS) test procedure defined in ISO:7198-2016 and aims to provide a comprehensive test protocol to study the biomechanics of the GHJ in extracted PK buttons. A 9 mm corneal button with GHJ was extracted from a 46-year-old patient who underwent PK 13 years back. The strength of the GHJ was quantified using the SRS test. Corresponding control results were obtained from the SRS tests of a corneoscleral button with no history of any refractive procedure. Birefringence, histological, and scanning electron microscopy (SEM) imaging were used to visualize the microstructural details of the GHJ. The strength of the GHJ was observed to be ten times lower than the native cornea. Histopathological features, such as fragmented Bowman's layer, and fibrosis with a clear demarcation line between host and graft tissue, were observed at the GHJ, suggesting a weak bond across the GHJ. The low strength of the GHJ in PK indicates the high susceptibility of the GHJ towards wound dehiscence.
PubMed: 38784531
DOI: 10.1016/j.heliyon.2024.e30871 -
Clinical Ophthalmology (Auckland, N.Z.) 2024To evaluate both the early experience of real-world patients treated with dexamethasone ophthalmic insert (0.4 mg; DEXTENZA), hereafter referred to as DEX, after...
PURPOSE
To evaluate both the early experience of real-world patients treated with dexamethasone ophthalmic insert (0.4 mg; DEXTENZA), hereafter referred to as DEX, after cataract surgery as well as staff/practice integration of DEX relative to eyedrops.
PATIENTS AND METHODS
This was a cross-sectional survey study of 23 cataract practices in the United States. Respondents were patients and practice staff who had experience with DEX following cataract surgery. Both patients and practice staff completed an online survey. Descriptive statistics summarized the survey responses to portray the experience of the respondents.
RESULTS
Surveys were completed by 62 patients and 19 practice staff. Almost all patients (93%) were satisfied or extremely satisfied with DEX. Patients highly preferred DEX (93%) to topical steroid drops (7%) based on past experiences with topical steroid drops. Most practice staff (95%) were satisfied or highly satisfied with DEX, reporting a 45% reduction in time spent educating patients on postoperative drop use and a 46% decrease in time spent addressing calls from pharmacies regarding postoperative medications.
CONCLUSION
Incorporating the DEX insert into clinical practice in cataract surgery practices can improve patient adherence, while potentially providing significant savings to practices in terms of time spent educating patients and responding to patient and pharmacy call-backs.
PubMed: 38784434
DOI: 10.2147/OPTH.S448973 -
Investigative Ophthalmology & Visual... May 2024The purpose of this study was to analyze human corneal endothelial cells (HCECs) morphology and ocular biometrics in premature (PM) children with or without retinopathy...
PURPOSE
The purpose of this study was to analyze human corneal endothelial cells (HCECs) morphology and ocular biometrics in premature (PM) children with or without retinopathy of prematurity (ROP).
METHODS
Retrospective data on patient demographics, HCECs status, and ocular biometrics with at least 2 visits between 2016 and 2021 were reviewed. The main outcomes were endothelial cell density (ECD), coefficient of variation (CV), hexagonal cell ratio (HEX), central corneal thickness (CCT), axial length, anterior chamber depth, keratometry, corneal diameter, pupil diameter, and refraction status. Generalized estimating equation was used to evaluate the differences between PM no-ROP and ROP groups. We also analyzed the trend of ECD, CV, HEX, and CCT change with age between groups.
RESULTS
The study included 173 PM patients without ROP and 139 patients with ROP. A total of 666 and 544 measurements were recorded in the PM no-ROP and ROP groups, respectively. The ROP group had higher spherical power, myopic spherical equivalent (SE), and steeper steep keratometry (K; P < 0.05). The ROP group had higher CV (P = 0.0144), lower HEX (P = 0.0012) and thicker CCT (P = 0.0035). In the HCECs parameters, the ROP group had slower ECD decrement (P < 0.0001), faster CV decrement (P = 0.0060), and faster HEX increment (P = 0.0001). A difference in corneal morphology changes between the ROP and PM no-ROP groups were prominent in patients with lower gestational age (GA) in the subgroup analysis.
CONCLUSIONS
Worse HCECs morphology and higher myopic status were initially observed in patients with prior ROP but not in PM patients with no-ROP. ECD and HCECs morphology improved with age, especially in patients with low GA.
Topics: Humans; Retinopathy of Prematurity; Retrospective Studies; Male; Female; Biometry; Infant, Newborn; Endothelium, Corneal; Gestational Age; Infant, Premature; Refraction, Ocular; Cell Count; Infant; Child, Preschool; Axial Length, Eye; Child
PubMed: 38780946
DOI: 10.1167/iovs.65.5.37 -
Craniomaxillofacial Trauma &... Jun 2024Retrospective analysis at a tertiary care center.
STUDY DESIGN
Retrospective analysis at a tertiary care center.
OBJECTIVE
This study describes a method of analyzing postoperative results using lateral view clinical photographs to create normalized projection ratios of the glabella and radix.
METHODS
We reviewed preoperative and postoperative photographs of 15 patients. All photographs were in the lateral view Frankfort horizontal plane. We calculated the distances between the (a) tragus and cornea, (b) cornea and radix, (c) cornea and glabella, and the (θ) nasofrontal angle.
RESULTS
Fifteen sets of patient photographs were analyzed and found that there was a favorable 14% reduction at the radix and an even greater reduction (78.9%) at the glabella. The nasofrontal angle was improved to a more feminine range from 131.84° preoperatively to 145.86° postoperatively.
CONCLUSIONS
Normalized projection ratios of the glabella and radix, along with the nasofrontal angle, can be used to objectively measure outcomes of frontal feminizing cranioplasty.
PubMed: 38779400
DOI: 10.1177/19433875221143609