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Abstract Retinal microaneurysm (MA) is a definite earliest clinical sigh of diabetic retinopathy (DR). Its automatic segmentation is key to realizing intelligent screening for early DR, which can significantly reduce the risk of visual impairment in patients. However, the minute scale and subtle contrast of MAs against the background pose challenges for segmentation. This paper focuses on automatic MA segmentation in fundus images. A novel pyramid feature fusion network (PFFNet) that progressively develops and fuses rich contextual information by integrating two pyramid modules is proposed. Multiple global pyramid scene parsing (GPSP) modules are introduced between the encoder and decoder to provide diverse global contextual information for the decoder through reconstructing skip connections. Additionally, a spatial scale‐aware pyramid (SSAP) module is introduced to dynamically fuse multi‐scale contextual information. This rich contextual information will help to identify MAs from low‐contrast background. Furthermore, to mitigate issue related to category imbalance, a combo loss function is introduced. Finally, to validate the effectiveness of the proposed method, experiments are conducted on two publicly available datasets, IDRiD and DDR, and PFFNet is compared with several state‐of‐the‐art models. The experimental results demonstrate the superiority of our PFFNet in the MA segmentation task.

Abstract Background: Nonspecific Orbital Inflammation (NSOI) remains a perplexing enigma among proliferative inflammatory disorders. Its etiology is idiopathic, characterized by distinctive and polymorphous lymphoid infiltration within the orbital region. Preliminary investigations suggest that PALMD localizes within the cytosol, potentially playing a crucial role in cellular processes, including plasma membrane dynamics and myogenic differentiation. The potential of PALMD as a biomarker for NSOI warrants meticulous exploration. Methods: PALMD was identified through the intersection analysis of common DEGs from datasets GSE58331 and GSE105149 from the GEO database, alongside immune-related gene lists from the ImmPort database, using Lasso regression and SVM-RFE analysis. GSEA and GSVA were conducted with gene sets co-expressed with PALMD. To further investigate the correlation between PALMD and immune-related biological processes, the CIBERSORT algorithm and ESTIMATE method were employed to evaluate immune microenvironment characteristics of each sample. The expression levels of PALMD were subsequently validated using GSE105149. Results: Among the 314 DEGs identified, several showed significant differences. Lasso and SVM-RFE algorithms pinpointed 15 hub genes. Functional analysis of PALMD emphasized its involvement in cell-cell adhesion, leukocyte migration, and leukocyte-mediated immunity. Enrichment analysis revealed that gene sets positively correlated with PALMD were enriched in immune-related pathways. Immune infiltration analysis indicated that resting dendritic cells, resting mast cells, activated NK cells, and plasma cells positively associate with PALMD expression. Conversely, naive B cells, activated dendritic cells, M0 and M1 macrophages, activated mast cells, activated CD4 memory T cells, and naive CD4 T cells showed a negative correlation with PALMD expression. PALMD demonstrated significant diagnostic potential in differentiating NSOI. Conclusions: This study identifies PALMD as a potential biomarker linked to NSOI, providing insights into its pathogenesis and offering new avenues for tracking disease progression.

Abstract Age-related macular degeneration (AMD) and diabetic macular edema (DME) are significant causes of blindness worldwide. The prevalence of these diseases is steadily increasing due to population aging. Therefore, early diagnosis and prevention are crucial for effective treatment. Classification of Macular Degeneration OCT Images is a widely used method for assessing retinal lesions. However, there are two main challenges in OCT image classification: incomplete image feature extraction and lack of prominence in important positional features. To address these challenges, we proposed a deep learning neural network model called MSA-Net, which incorporates our proposed multi-scale architecture and spatial attention mechanism. Our multi-scale architecture is based on depthwise separable convolution, which ensures comprehensive feature extraction from multiple scales while minimizing the growth of model parameters. The spatial attention mechanism is aim to highlight the important positional features in the images, which emphasizes the representation of macular region features in OCT images. We test MSA-NET on the NEH dataset and the UCSD dataset, performing three-class (CNV, DURSEN, and NORMAL) and four-class (CNV, DURSEN, DME, and NORMAL) classification tasks. On the NEH dataset, the accuracy, sensitivity, and specificity are 98.1%, 97.9%, and 98.0%, respectively. After fine-tuning on the UCSD dataset, the accuracy, sensitivity, and specificity are 96.7%, 96.7%, and 98.9%, respectively. Experimental results demonstrate the excellent classification performance and generalization ability of our model compared to previous models and recent well-known OCT classification models, establishing it as a highly competitive intelligence classification approach in the field of macular degeneration.

Abstract Idiopathic orbital inflammation, formerly known as NSOI (nonspecific orbital inflammation), is characterized as a spectrum disorder distinguished by the polymorphic infiltration of lymphoid tissue, presenting a complex and poorly understood etiology. Recent advancements have shed light on the HLF (Human lactoferrin), proposing its critical involvement in the regulation of hematopoiesis and the maintenance of innate mucosal immunity. This revelation has generated significant interest in exploring HLF's utility as a biomarker for NSOI, despite the existing gaps in our understanding of its biosynthetic pathways and operational mechanisms. Intersecting multi-omic datasets—specifically, common differentially expressed genes between GSE58331 and GSE105149 from the Gene Expression Omnibus and immune-related gene compendiums from the ImmPort database—we employed sophisticated analytical methodologies, including Lasso regression and support vector machine-recursive feature elimination, to identify HLF. Gene set enrichment analysis and gene set variation analysis disclosed significant immune pathway enrichment within gene sets linked to HLF. The intricate relationship between HLF expression and immunological processes was further dissected through the utilization of CIBERSORT and ESTIMATE algorithms, which assess characteristics of the immune microenvironment, highlighting a noteworthy association between increased HLF expression and enhanced immune cell infiltration. The expression levels of HLF were corroborated using data from the GSE58331 dataset, reinforcing the validity of our findings. Analysis of 218 HLF-related differentially expressed genes revealed statistically significant discrepancies. Fifteen hub genes were distilled using LASSO and SVM-RFE algorithms. Biological functions connected with HLF, such as leukocyte migration, ossification, and the negative regulation of immune processes, were illuminated. Immune cell analysis depicted a positive correlation between HLF and various cells, including resting mast cells, activated NK cells, plasma cells, and CD8 T cells. Conversely, a negative association was observed with gamma delta T cells, naive B cells, M0 and M1 macrophages, and activated mast cells. Diagnostic assessments of HLF in distinguishing NSOI showed promising accuracy. Our investigation delineates HLF as intricately associated with NSOI, casting light on novel biomarkers for diagnosis and progression monitoring of this perplexing condition.

Abstract Premature ovarian failure (POF), which is often comorbid with dry eye disease (DED) is a key issue affecting female health. Here, we explored the mechanism underlying comorbid POF and DED to further elucidate disease mechanisms and improve treatment. Datasets related to POF (GSE39501) and DED (GSE44101) were identified from the Gene Expression Omnibus (GEO) database and subjected to weighted gene coexpression network (WGCNA) and differentially expressed genes (DEGs) analyses, respectively, with the intersection used to obtain 158 genes comorbid in POF and DED. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses of comorbid genes revealed that identified genes were primarily related to DNA replication and Cell cycle, respectively. Protein–Protein interaction (PPI) network analysis of comorbid genes obtained the 15 hub genes: CDC20, BIRC5, PLK1, TOP2A, MCM5, MCM6, MCM7, MCM2, CENPA, FOXM1, GINS1, TIPIN, MAD2L1, and CDCA3. To validate the analysis results, additional POF- and DED-related datasets (GSE48873 and GSE171043, respectively) were selected. miRNAs-lncRNAs-genes network and machine learning methods were used to further analysis comorbid genes. The DGIdb database identified valdecoxib, amorfrutin A, and kaempferitrin as potential drugs. Herein, the comorbid genes of POF and DED were identified from a bioinformatics perspective, providing a new strategy to explore the comorbidity mechanism, opening up a new direction for the diagnosis and treatment of comorbid POF and DED.

Abstract Background Nonspecific Orbital Inflammation (NSOI) represents a persistent and idiopathic proliferative inflammatory disorder, characterized by polymorphous lymphoid infiltration within the orbit. The transcription factor Interferon Regulatory Factor 8 (IRF8), integral to the IRF protein family, was initially identified as a pivotal element for the commitment and differentiation of myeloid cell lineage. Serving as a central regulator of innate immune receptor signaling, IRF8 orchestrates a myriad of functions in hematopoietic cell development. However, the intricate mechanisms underlying IRF8 production remain to be elucidated, and its potential role as a biomarker for NSOI is yet to be resolved. Methods IRF8 was extracted from the intersection analysis of common DEGs of GSE58331 and GSE105149 from the GEO and immune- related gene lists in the ImmPort database using The Lasso regression and SVM-RFE analysis. We performed GSEA and GSVA with gene sets coexpressed with IRF8, and observed that gene sets positively related to IRF8 were enriched in immune-related pathways. To further explore the correlation between IRF8 and immune-related biological process, the CIBERSORT algorithm and ESTIMATE method were employed to evaluate TME characteristics of each sample and confirmed that high IRF8 expression might give rise to high immune cell infiltration. Finally, the GSE58331 was utilized to confirm the levels of expression of IRF8. Results Among the 314 differentially expressed genes (DEGs), some DEGs were found to be significantly different. With LASSO and SVM-RFE algorithms, we obtained 15 hub genes. For biological function analysis in IRF8, leukocyte mediated immunity, leukocyte cell-cell adhesion, negative regulation of immune system process were emphasized. B cells naive, Macrophages M0, Macrophages M1, T cells CD4 memory activated, T cells CD4 memory resting, T cells CD4 naive, and T cells gamma delta were shown to be positively associated with IRF8. While, Mast cells resting, Monocytes, NK cells activated, Plasma cells, T cells CD8, and T cells regulatory (Tregs) were shown to be negatively linked with IRF8. The diagnostic ability of the IRF8 in differentiating NSOI exhibited a good value. Conclusions This study discovered IRF8 that are linked to NSOI. IRF8 shed light on potential new biomarkers for NSOI and tracking its progression.

AimPrevious studies have demonstrated that Ras-related GTP-binding protein Rab10 (Rab10) plays a role in psychostimulant-induced behavioral effects. In this study, we showed that Rab10 in the nucleus accumbens (NAc) of male animals affects the development of cocaine-induced behavioral effects, which are associated with the plasma membrane expression of the GABAB heteroreceptor (GABABR).MethodsWe performed flow cytometry, immunoendocytosis, pHluorin activity analysis, electrophysiology analysis, and open-field testing to explore the role of Rab10 in modulating the membrane expression and function of GABABR and its regulatory effect on cocaine-induced behavioral effects.ResultsTranscriptomics analysis showed that Rab10 was elevated following acute cocaine treatment. Membrane levels of Rab10 increased within day 1 of the cocaine treatment, subsequently decreasing at later time points. Rab10 deficiency in NAc regions significantly increased cocaine-inhibited membrane GABABR levels and inhibited cocaine-induced hyperlocomotion and behavioral sensitization. In addition, GAD67+-expressing neurons from NAc regions treated with cocaine revealed a significant decrease in Rab10 membrane expression. Furthermore, NAc neuron-specific Rab10 knockout resulted in a significant increase in the cocaine-inhibited membrane expression of GABABR, along with increased miniature inhibitory postsynaptic current (mIPSC) amplitude and attenuation of baclofen-amplified Ca2+ influx.ConclusionThese results uncover a new mechanism in which Rab10-GABABR signaling may serve as a potential pathway for regulating cocaine-induced behavioral effects.

IntroductionNon-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease worldwide. Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide, with high morbidity and mortality. The rapidly increasing incidence of NAFLD is becoming an essential precursor of HCC globally. MicroRNAs (miRNAs) are involved in the progression of NAFLD and HCC.MethodPotential miRNAs associated with NAFLD in HCC tumorigenesis were identified through a systematic review, and their roles were evaluated by data mining analysis. The biological function of the potential miRNA and its target genes in NAFLD and HCC were evaluated by bioinformatic analysis.ResultMIR122 was identified as the potential miRNA associated with NAFLD and HCC. Then, MIR122 expression was significantly lower in HCC patients, and higher MIR122 levels were associated with significantly better overall survival. Next, the biological functions of MIR122 and target genes were predicted to be involved in inflammation, fibrosis, cell proliferation, invasion, metastasis, and apoptosis. In particular, the FOXO signaling pathway may regulate the above biological functions.ConclusionMIR122 was suggested to be involved in progressing from NAFLD to HCC through the PI3K/AKT/FOXO pathway.Systematic review registrationPROSPERO, identifier: CRD 42024517940.

Aims: Diabetic nephropathy (DN) is a major complication of diabetes mellitus (DM) without curative interventions currently. Huperzine A (Hup A), a natural alkaloid, has demonstrated significant hypoglycemic and anti-inflammatory effects. We aim to investigate the protective effects of Hup A on DN and explore the underlying mechanisms Methods: We applied STZ induced diabetic rats as DN model and leveraged combination analysis of the transcriptome, metabolome, microbiome, and network pharmacology (NP). The total effect of Hup A on DN was detected (i.e. urine protein, renal tissue structure) and the differential genes were further verified at the level of diabetic patients, db/db mice and cells. Clinical data and small interfering RNA (siRNA)-Apoe were adopted. Results: Hup A alleviated kidney injury in DN rats. Transcriptomics data and Western blot indicated that the improvement in DN was primarily associated with Apoe and Apoc2. Additionally, metabolomics data demonstrated that DN-induced lipid metabolism disruption was regulated by Hup A, potentially involving sphingosine. Hup A also enriched microbial diversity and ameliorated DN-induced microbiota imbalance. Spearman's correlation analysis demonstrated significant associations among the transcriptome, metabolome, and microbiome. Apoe level was positively correlated with clinical biomarkers in DN patients. Si-Apoe also played protective role in podocytes. NP analysis also suggested that Hup A may treat DN by modulating lipid metabolism, microbial homeostasis, and apoptosis, further validating our findings. Conclusions: Collectively, we provide the first evidence of the therapeutic effect of Hup A on DN, indicating that Hup A is a potential drug for the prevention and treatment of DN.

BackgroundLinarine is a natural chemical component widely found in Buddleja officinalis Maxim., Chrysanthemum indicum L., Mentha canadensis L., and other medicinal plants. Modern pharmacological studies have shown that linarine with good anti-inflammatory and antioxidant activities can inhibit the proliferation and induce apoptosis of many kinds of tumor cells. Moreover, linarine showed protective effect on the liver, kidneys, and other organs.MethodsInflammation model of human corneal epithelial cell (HCEC) was constructed using NaCl induction, and cytotoxicity was detected by the CCK8 assay. The levels of inflammatory factors tumor necrosis factor-α (TNF-α) and interleukin 1β (IL-1β) were measured using Enzyme-linked immunoassay (ELISA). Chronic painful stimulation (tail clamping) in combination with Benzalkonium Chloride Solution drops in a desiccator established a mouse model of dry eye disease (DED). The following parameters were recorded: body mass, anal temperature, tear secretion, tear film rupture time, and corneal fluorescein staining. The levels of inflammatory factors mitogen activated protein kinase (MAPK), nuclear factor kappa-B (NF-kB), c-Jun N-terminal kinase (JNK), IL-1β, Interleukin 18(IL-18), A2A, A3, P2X4, P2X7, P2Y1 were measured by using immunofluorescence (IF) staining.ResultsLinarine can inhibit the secreation of TNF-α, and IL-1β in HCECs. Linarine prolonged tear film rupture time, promoted tear secretion, repaired corneal damage, and reduced the levels of inflammatory factors of MAPK, NF-kB, JNK, IL-1β, IL-18, and modulated the levels of the purinergic receptor.ConclusionsLinarine is effective in treating dry eye in mice by inhibiting purinergic receptors-mediated inflammatory response.

BackgroundNon-specific Orbital Inflammation (NSOI) is a chronic idiopathic condition marked by extensive polymorphic lymphoid infiltration in the orbital area. The integration of metabolic and immune pathways suggests potential therapeutic roles for C-peptide and G protein-coupled receptor 146 (GPR146) in diabetes and its sequelae. However, the specific mechanisms through which GPR146 modulates immune responses remain poorly understood. Furthermore, the utility of GPR146 as a diagnostic or prognostic marker for NSOI has not been conclusively demonstrated.MethodsWe adopted a comprehensive analytical strategy, merging differentially expressed genes (DEGs) from the Gene Expression Omnibus (GEO) datasets GSE58331 and GSE105149 with immune-related genes from the ImmPort database. Our methodology combined LASSO regression and support vector machine-recursive feature elimination (SVM-RFE) for feature selection, followed by Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) to explore gene sets co-expressed with GPR146, identifying a significant enrichment in immune-related pathways. The tumor microenvironment’s immune composition was quantified using the CIBERSORT algorithm and the ESTIMATE method, which confirmed a positive correlation between GPR146 expression and immune cell infiltration. Validation of GPR146 expression was performed using the GSE58331 dataset.ResultsAnalysis identified 113 DEGs associated with GPR146, with a significant subset showing distinct expression patterns. Using LASSO and SVM-RFE, we pinpointed 15 key hub genes. Functionally, these genes and GPR146 were predominantly linked to receptor ligand activity, immune receptor activity, and cytokine-mediated signaling. Specific immune cells, such as memory B cells, M2 macrophages, resting mast cells, monocytes, activated NK cells, plasma cells, and CD8+ T cells, were positively associated with GPR146 expression. In contrast, M0 macrophages, naive B cells, M1 macrophages, activated mast cells, activated memory CD4+ T cells, naive CD4+ T cells, and gamma delta T cells showed inverse correlations. Notably, our findings underscore the potential diagnostic relevance of GPR146 in distinguishing NSOI.ConclusionOur study elucidates the immunological signatures associated with GPR146 in the context of NSOI, highlighting its prognostic and diagnostic potential. These insights pave the way for GPR146 to be a novel biomarker for monitoring the progression of NSOI, providing a foundation for future therapeutic strategies targeting immune-metabolic pathways.

Abstract Background Nonspecific orbital inflammation (NSOI) is an idiopathic, persistent, and proliferative inflammatory condition affecting the orbit, characterized by polymorphous lymphoid infiltration. Its pathogenesis and progression have been linked to imbalances in tumor metabolic pathways, with glutamine (Gln) metabolism emerging as a critical aspect in cancer. Metabolic reprogramming is known to influence clinical outcomes in various malignancies. However, comprehensive research on glutamine metabolism's significance in NSOI is lacking. Methods This study conducted a bioinformatics analysis to identify and validate potential glutamine-related molecules (GlnMgs) associated with NSOI. The discovery of GlnMgs involved the intersection of differential expression analysis with a set of 42 candidate GlnMgs. The biological functions and pathways of the identified GlnMgs were analyzed using GSEA and GSVA. Lasso regression and SVM-RFE methods identified hub genes and assessed the diagnostic efficacy of fourteen GlnMgs in NSOI. The correlation between hub GlnMgs and clinical characteristics was also examined. The expression levels of the fourteen GlnMgs were validated using datasets GSE58331 and GSE105149. Results Fourteen GlnMgs related to NSOI were identified, including FTCD, CPS1, CTPS1, NAGS, DDAH2, PHGDH, GGT1, GCLM, GLUD1, ART4, AADAT, ASNSD1, SLC38A1, and GFPT2. Biological function analysis indicated their involvement in responses to extracellular stimulus, mitochondrial matrix, and lipid transport. The diagnostic performance of these GlnMgs in distinguishing NSOI showed promising results. Conclusions This study successfully identified fourteen GlnMgs associated with NSOI, providing insights into potential novel biomarkers for NSOI and avenues for monitoring disease progression.

Abstract Thyroid eye disease (TED), an autoimmune inflammatory disorder affecting the orbit, exhibits a range of clinical manifestations. While the disease presentation can vary, cases that adhere to a prototypical pattern typically commence with mild symptoms that subsequently escalate in severity before entering a phase of stabilization. Notably, the metabolic activity of cells implicated in the disease substantially deviates from that of healthy cells, with purine metabolism representing a critical facet of cellular material metabolism by supplying components essential for DNA and RNA synthesis. Nevertheless, the precise involvement of Purine Metabolism Genes (PMGs) in the defensive mechanism against TED remains largely unexplored. The present study employed a bioinformatics approach to identify and validate potential PMGs associated with TED. A curated set of 65 candidate PMGs was utilized to uncover novel PMGs through a combination of differential expression analysis and a PMG dataset. Furthermore, GSEA and GSVA were employed to explore the biological functions and pathways associated with the newly identified PMGs. Subsequently, the Lasso regression and SVM-RFE algorithms were applied to identify hub genes and assess the diagnostic efficacy of the top 10 PMGs in distinguishing TED. Additionally, the relationship between hub PMGs and clinical characteristics was investigated. Finally, the expression levels of the identified ten PMGs were validated using the GSE58331 and GSE105149 datasets. This study revealed ten PMGs related with TED. PRPS2, PFAS, ATIC, NT5C1A, POLR2E, POLR2F, POLR3B, PDE3A, ADSS, and NTPCR are among the PMGs. The biological function investigation revealed their participation in processes such as RNA splicing, purine-containing chemical metabolism, and purine nucleotide metabolism. Furthermore, the diagnostic performance of the 10 PMGs in differentiating TED was encouraging. This study was effective in identifying ten PMGs linked to TED. These findings provide light on potential new biomarkers for TED and open up possibilities for tracking disease development.

Objective: To explore whether Lycium barbarum polysaccharide (LBP) can reduce the apoptosis of retinal photoreceptor cells in retinitis pigmentosa (RP) mice by inhibiting nuclear factor-kappa B (NF-κB)/NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) signaling pathway. Methods: (i) In vitro experiments, mouse retinal ganglion cells (661W cells) were divided into normal, model, LBP low-dose (LBP-L, 40 mg/L), LBP middle-dose (LBP-M, 80 mg/L), LBP high-dose (LBP-H, 160 mg/L), and positive drug control (NLRP3 inhibitor, 160 mg/L) groups. And the 661W cells were exposed to varying concentrations of H2O2 ranging from 50 to 400 μmol/L to determine the optimal concentration for inducing apoptosis (200 μmol/L). Then the cell viability was assessed using Cell Counting Kit-8 (CCK-8), while the apoptosis rate was detected by flow cytometry; the expression of NLRP3 was detected by immunofluorescence; and the expression of apoptosis markers was detected by enzyme-linked immunosorbent assay (ELISA) and Western blot (WB). (ii) In vivo assays were carried out with the use of C57/BL6 and Rd10 mice. The animal experimental groups were divided into normal, model, LBP-L, LBP-M, LBP-H, and NLRP3 inhibitor groups, in which the normal group was C57/BL6 mice and the other groups were Rd10 mice. Ten mice were included in each group, and the corresponding drugs were administered intragastrically for a duration of four weeks. NF-κB/NLRP3 pathway and the expression of apoptosis markers were observed by electroretinogram, histopathological examination, and WB to assess the effects of LBP on retinal photoreceptor cell apoptosis. Results: (i) In vitro experiments, compared with the normal group, the apoptosis rate of 661W cells in model group was significantly increased (P < 0.01), and the expression levels of key proteins of NF-κB/NLRP pathway, such as NLRP3, NF-κB, p-NF-κB, and pro-apoptotic protein caspase-3, were up-regulated (P < 0.01). The rate of Bax/Bcl-2 was increased (P < 0.01), and the concentrations of interleukin (IL)-1β and tumor necrosis factor (TNF)-α were significantly increased (P < 0.01). Compared with the model group, high dose of LBP decreased the apoptosis rate of 661W cells (P < 0.01), and down-regulated the expression levels of the key proteins of NF-κB/NLRP3 pathway, including NF-κB, NLRP3, p-NF-κB, and caspase-3 (P < 0.01). The rate of Bax/Bcl-2 was decreased (P < 0.01), and the concentrations of IL-1β and TNF-α were decreased (P < 0.01). (ii) In vivo experiments, high dose of LBP significantly increased morphological changes in the outer nuclear layer (ONL) thickness of Rd10 mice, as well as functional changes in the amplitudes of the a-wave and b-wave (P < 0.01), which also down-regulated the expression levels of NF-κB (P < 0.05), NLRP3, p-NF-κB, and caspase-3 (P < 0.01), reduced the Bax/Bcl-2 rate (P < 0.01), and decreased the concentrations of IL-1β (P < 0.01) and TNF-α (P < 0.05). Conclusion: LBP could improve both retinal morphology and function, providing protection to photoreceptors from apoptosis through the inhibition of the NF-κB/NLRP3 pathway.

Background: Oxidative stress plays a significant role in the pathogenesis of many retinal diseases. However, only a few systematic bibliometric studies have been conducted. This study aims to visualize research hotspots and developmental trends in oxidative stress in the retina from 2013 to 2023 by analyzing bibliometric data. Methods: We retrieved papers on oxidative stress in the retina published between 2013 and 2023 from the Web of Science Core Collection. The data were visually analyzed using CiteSpace and VOSviewer software. Results: The total number of 2100 publications were included in the analysis. An overall increasing trend in the number of publications is observed between 2013 and 2023. Chinese publications were the most contributive, but United States publications were the most influential. Shanghai Jiao Tong University was the most active and prolific institution. Antioxidants was the most productive journal, while Oxidative Medicine and Cellular Longevity were the journals with the most-cited articles. Kaarniranta K, from Finland, was the most productive and influential author. Examination of co-cited references revealed that researchers in the field are primarily focused on investigating the molecular mechanisms, preventive strategies, and utilization of antioxidants to address retinal oxidative damage. Diabetic retinopathy, endothelial growth factor, retinitis pigmentosa, retinal degeneration, antioxidant response, retinal ganglion cells, and genes are the research hotspots in this field. Metabolism, sodium iodate, and system are at the forefront of research in this field. Conclusion: Attention toward retinal oxidative stress has increased over the past decade. Current research focuses on the mechanisms of retinal diseases related to oxidative stress and the experimental study of antioxidants in retinal diseases, which may continue to be a trend in the future.

BackgroundNonspecific orbital inflammation (NSOI) represents a perplexing and persistent proliferative inflammatory disorder of idiopathic nature, characterized by a heterogeneous lymphoid infiltration within the orbital region. This condition, marked by the aberrant metabolic activities of its cellular constituents, starkly contrasts with the metabolic equilibrium found in healthy cells. Among the myriad pathways integral to cellular metabolism, purine metabolism emerges as a critical player, providing the building blocks for nucleic acid synthesis, such as DNA and RNA. Despite its significance, the contribution of Purine Metabolism Genes (PMGs) to the pathophysiological landscape of NSOI remains a mystery, highlighting a critical gap in our understanding of the disease’s molecular underpinnings.MethodsTo bridge this knowledge gap, our study embarked on an exploratory journey to identify and validate PMGs implicated in NSOI, employing a comprehensive bioinformatics strategy. By intersecting differential gene expression analyses with a curated list of 92 known PMGs, we aimed to pinpoint those with potential roles in NSOI. Advanced methodologies, including Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA), facilitated a deep dive into the biological functions and pathways associated with these PMGs. Further refinement through Lasso regression and Support Vector Machine-Recursive Feature Elimination (SVM-RFE) enabled the identification of key hub genes and the evaluation of their diagnostic prowess for NSOI. Additionally, the relationship between these hub PMGs and relevant clinical parameters was thoroughly investigated. To corroborate our findings, we analyzed expression data from datasets GSE58331 and GSE105149, focusing on the seven PMGs identified as potentially crucial to NSOI pathology.ResultsOur investigation unveiled seven PMGs (ENTPD1, POLR2K, NPR2, PDE6D, PDE6H, PDE4B, and ALLC) as intimately connected to NSOI. Functional analyses shed light on their involvement in processes such as peroxisome targeting sequence binding, seminiferous tubule development, and ciliary transition zone organization. Importantly, the diagnostic capabilities of these PMGs demonstrated promising efficacy in distinguishing NSOI from non-affected states.ConclusionsThrough rigorous bioinformatics analyses, this study unveils seven PMGs as novel biomarker candidates for NSOI, elucidating their potential roles in the disease’s pathogenesis. These discoveries not only enhance our understanding of NSOI at the molecular level but also pave the way for innovative approaches to monitor and study its progression, offering a beacon of hope for individuals afflicted by this enigmatic condition.

Abstract Background Diabetic retinopathy (DR) is a common cause of visual impairment. Apigenin has been shown to have antiangiogenic effects in various diseases. Our study aimed to investigate the role of apigenin in DR and elucidate the underlying mechanism. Methods Human retinal microvascular endothelial cells (HRMECs) were exposed to high glucose (HG) to establish a DR model. HRMECs were treated with apigenin. Then we knocked down or overexpressed miR-140-5p and HDAC3, and added PI3K/AKT inhibitor LY294002. The expression levels of miR-140-5p, HDAC3, and PTEN were measured using qRT-PCR. Western blot analysis was performed to assess the expression of HDAC3, PTEN, and PI3K/AKT pathway-related proteins. Finally, cell proliferation and migration were evaluated using MTT, wound-healing assay, and transwell assay, while angiogenesis was examined using the tube formation assay. Results HG treatment resulted in reduced miR-140-5p expression and overexpression of miR-140-5p suppressed proliferation, migration, and angiogenesis of the HG-induced HRMECs. Apigenin treatment significantly restored the decreased level of miR-140-5p caused by HG treatment and inhibited proliferation, migration, and angiogenesis of the HG-induced HRMECs by upregulating miR-140-5p. Moreover, miR-140-5p targeted HDAC3, and overexpression of miR-140-5p reversed the HG-inducted upregulation of HDAC3 expression. HDAC3 was found to bind to the promoter region of PTEN, inhibiting its expression. Knockdown of HDAC3 suppressed the PI3K/AKT pathway by elevating PTEN expression. Furthermore, apigenin inhibited angiogenesis in DR cell models through the regulating of the miR-140-5p/HDAC3-mediated PTEN/PI3K/AKT pathway. Conclusions Apigenin effectively suppressed angiogenesis in HG-induced HRMECs by modulating the miR-140-5p/HDAC3-mediated PTEN/PI3K/AKT pathway. Our study may contribute to the development of novel therapeutic approaches and identification of potential targets for the treatment of DR.

Transient electromagnetic method (TEM) is widely used in coalfield hydrogeological exploration and goaf investigation. However, given the limitations of the method, the vertical resolution of ground TEM is somewhat low for effectively detecting water-bearing coal goaf. Compared with ground TEM, ground-borehole TEM is characterized by a relatively better ability for detecting low-resistivity target bodies. In this study, a low-resistivity thin plate model was established, and the ground-borehole TEM electromagnetic responses of different points (within and without of the plate) were numerically simulated. We considered an exploration project in Datong City (Shanxi Province, China) as a study case, to conduct the field investigation, examine the characteristics of ground-borehole TEM electromagnetic responses under different situations, and validate the numerical model as well, including (a) water-bearing coal goaf and (b) solid coal. The result showed that, (a) the longer the sampling time is, the weaker the electromagnetic response of ground-borehole TEM will be; (2) ground-borehole TEM stands out with a high vertical resolution for water-bearing coal goaf; (c) the extreme points of the Z component and the polarity changing points of the X and Y components can indicate the interface where the physical properties alternated.

Abstract Background The highly heterogeneous nature of hepatocellular carcinoma (HCC) results in different responses and prognoses to the same treatment in patients with similar clinical stages. Aims Thus, it is imperative to investigate the association between HCC tumor heterogeneity and treatment response and prognosis. Methods and Results At first, we downloaded scRNA‐seq, bulk RNA‐seq, and clinical data from TCGA and GEO databases. We conducted quality control, normalization using SCTransform, dimensionality reduction using PCA, batch effect removal using Harmony, dimensionality reduction using UMAP, and cell annotation‐based marker genes on the scRNA‐seq data. We recognized tumor cells, identified tumor‐related genes (TRGs), and performed cell communication analysis. Next, we developed a prognostic model using univariable Cox, LASSO, and multivariate Cox analyses. The signature was evaluated using survival analysis, ROC curves, C‐index, and nomogram. Last, we studied the predictability of the signature in terms of prognosis and immunotherapeutic response for HCC, assessed a variety of drugs for clinical treatment, and used the qRT‐PCR analysis to validate the mRNA expression levels of prognostic TRGs. Conclusion To conclude, this study expounded upon the influence of tumor cell heterogeneity on the prediction of treatment outcomes and prognosis in HCC. This, in turn, enhances the predictive ability of the TNM staging system and furnishes novel perspectives on the prognostic assessment and therapy of HCC.

Schlemm’s canal (SC) is a small circular canal in the deep part of the sclera at the junction of the sclera and cornea. As an integral component of the aqueous humor outflow, its structure and function are essential in regulating intraocular pressure (IOP). If SC develops lesions, the drainage of aqueous humor would be obstructed, leading to increased intraocular pressure and injury to the optic nerve. With the rapid development of minimally invasive glaucoma surgery, an increasing number of surgeons became familiar with SC, and the area generated substantial academic attention. The pathological mechanism and the therapy for SC that had been studied in recent years are summarized in this article, hoping to provide ideas for the treatment of glaucoma in the future.

Ferroptosis has been observed during retinal photoreceptor cell death, suggesting that it plays a role in retinitis pigmentosa (RP) pathogenesis. Qi-Shen-Tang (QST) is a combination of two traditional Chinese medicines used for the treatment of ophthalmic diseases; however, its mechanism of action in RP and ferroptosis remains unclear. Therefore, this study aimed to explore the effect and potential molecular mechanisms of QST on RP. QST significantly improved tissue morphology and function of the retina in the RP model mice. A significant increase in retinal blood flow and normalization of the fundus structure were observed in mice in the treatment group. After QST treatment, the level of iron and the production of malondialdehyde decreased significantly; the levels of superoxide dismutase and glutathione increased significantly; and the protein expression of glutathione peroxidase 4 (GPX4), glutathione synthetase, solute carrier family 7 member 11, and nuclear factor erythroid 2-related factor 2 (NRF2) increased significantly. The molecular docking results demonstrated potential interactions between the small molecules of QST and the key proteins of NRF2/GPX4 signaling pathway. Our results indicate that QST may inhibit ferroptosis by inhibiting the NRF2/GPX4 signaling pathway, thereby reducing RP-induced damage to retinal tissue.

Dry eye disease (DED) is a multifactorial syndrome that commonly occurs with depression. However, therapies targeting depression-related dry eye disease are rare. In the current study, we studied the beneficial effect of a natural flavone, acacetin, in depression-associated dry eye disease by utilizing the chronic unpredictable mild stress (CUMS) depression model. Our data showed that acacetin improved the depressive behaviors in sucrose preference test (SPT), tail suspension test (TST) and forced swim test (FST); relieved the dry eye symptoms including corneal epithelial impairments, tear production decrease and goblet cell loss in CUMS mice. Acacetin also inhibited NOD-like receptor protein 3 (NLRP3) inflammasome expression levels and suppressed inflammatory responses via enhancing glycoprotein 78 (gp78)/Insulin induced gene-1 (Insig-1)-controlled NLRP3 ubiquitination in CUMS mice. Furthermore, knockdown of gp78 compromised acacetin-conferred protective efficacy in depression-related dry eye disease. In summary, our findings indicated that acacetin exerts beneficial effect in depression-associated dry eye disease, which is tightly related to gp78-mediated NLRP3 ubiquitination.

Background: Geleophysic dysplasia and Weill-Marchesani syndrome from the acromelic dysplasias group of genetic skeletal disorders share remarkable clinical and genetic overlap.Methods: Ophthalmological, physical, radiological examinations were conducted with a female patient in her early 30 s. Whole exome sequencing followed by Sanger sequencing validation was performed to identify the genetic cause.Results: The patient, born to consanguineous Chinese parents, presented with microspherophakia, lens subluxation, high myopia, short statue, small hands and feet, stiff joints, and thickened skin. A diagnosis of Weill-Marchesani syndrome was initially made for her. However, genetic testing reveals that the patient is homozygous for the c.1966G>A (p.Gly656Ser) variant in ADAMTSL2, and that the patient’s healthy mother and daughter are heterozygous for the variant. As mutations in ADAMTSL2 are known to cause autosomal recessive geleophysic dysplasia, the patient is re-diagnosed with geleophysic dysplasia in terms of her genotype and phenotype.Conclusion: The present study describes the clinical phenotype of the homozygous ADAMTSL2 p. Gly656Ser variant, which increases our understanding of the genotype-phenotype correlation in acromelic dysplasias.

IL-1β mediates inflammation and regulates immune responses, cell proliferation, and differentiation. Dysregulation of IL-1β is linked to inflammatory and autoimmune diseases. Elevated IL-1β levels are found in patients with severe COVID-19, indicating its excessive production may worsen the disease. Also, dry eye disease patients show high IL-1β levels in tears and conjunctival epithelium. Therefore, IL-1β signaling is a potential therapeutic targeting for COVID-19 and aforementioned diseases. No small-molecule IL-1β inhibitor is clinically approved despite efforts. Developing such inhibitors is highly desirable. Herein, a docking-based strategy was used to screen the TCM (Traditional Chinese Medicine) database to identify possible IL-1β inhibitors with desirable pharmacological characteristics by targeting the IL-1β/IL-1R interface. Primarily, the docking-based screening was performed by selecting the crucial residues of IL-1β interface to retrieve the potential compounds. Afterwards, the compounds were shortlisted on the basis of binding scores and significant interactions with the crucial residues of IL-1β. Further, to gain insights into the dynamic behavior of the protein–ligand interactions, MD simulations were performed. The analysis suggests that four selected compounds were stabilized in an IL-1β pocket, possibly blocking the formation of an IL-1β/IL-1R complex. This indicates their potential to interfere with the immune response, making them potential therapeutic agents to investigate further.

Background: The studies about the correlation between bone mineral density (BMD) and coronary arterial calcification (CAC) were still controversial. The aim of this study was to conduct a meta-analysis to evaluate the association between BMD and CAC. Methods: We systematically searched PubMed, Embase, Google scholar and Cochrane library for observational studies. We pooled odds ratio (OR) or correlation coefficient, and 95% confidence interval (CI) of the studies. Continuous data were pooled by mean difference (MD). Sub-group analysis was applied to investigate sources of heterogeneity. Funnel plots for publication bias was also performed. Results: Seventeen studies met the inclusion criteria. Pooled ORs for the prevalence of CAC in patients with low BMD versus patients with normal BMD was 2.11 (95% CI: 1.11 - 4.02, P = 0.02). The data pooled for comparing CAC score of low BMD and normal BMD patients is 33.77 (95% CI: 23.77 - 43.77, p = 0.000). The pooled ORs of multivariate logistic regression to predict the association were 1.00 (95% CI: 0.92 - 1.10, p = 0.95, age-adjusted), and 0.95 (95% CI: 0.86 - 1.05, p = 0.33, multivariable-adjusted). Cohort category and BMD assessment method were the main sources of heterogeneity. Conclusions: Low BMD is associated with higher prevalence and severity of CAC, especially in postmenopausal women. But the relation is not significant after adjusting age and other confounding variables. Low BMD and CAC may be two independent processes with aging. More large-scale studies with high-quality design are still needed to increase the understanding of them.

Background. Continuous wavelet transform (CWT) based scalogram can be used for photoplethysmography (PPG) signal transformation to classify blood pressure (BP) with deep learning. We aimed to investigate the determinants that can improve the accuracy of BP classification based on PPG and deep learning and establish a better algorithm for the prediction. Methods. The dataset from PhysioNet was accessed to extract raw PPG signals for testing and its corresponding BPs as category labels. The BP category of normal or abnormal followed the criteria of the 2017 American College of Cardiology/American Heart Association (ACC/AHA) Hypertension Guidelines. The PPG signals were transformed into 224 ∗ 224 ∗ 3-pixel scalogram via different CWTs and segment units. All of them are fed into different convolutional neural networks (CNN) for training and validation. The receiver-operating characteristic and loss and accuracy curves were used to evaluate and compare the performance of different methods. Results. Both wavelet type and segment length could affect the accuracy, and Cgau1 wavelet and segment-300 revealed the best performance (accuracy 90%) without obvious overfitting. This method performed better than previously reported MATLAB Morse wavelet transformed scalogram on both of our proposed CNN and CNN-GoogLeNet. Conclusions. We have established a new algorithm with high accuracy to predict BP classification from PPG via matching of CWT type and segment length, which is a promising solution for rapid prediction of BP classification from real-time processing of PPG signal on a wearable device.

Recently, the development of β-titanium (Ti) alloys with a low Young’s modulus as human implants has been the trend of research in biomedical materials. However, designing β-titanium alloys by conventional experimental methods is too costly and inefficient. Therefore, it is necessary to propose a method that can efficiently and reliably predict the microstructures and the mechanical properties of biomedical titanium alloys. In this study, a machine learning prediction method is proposed to accelerate the design of biomedical multi-component β-Ti alloys with low moduli. Prediction models of microstructures and Young’s moduli were built at first. The performances of the models were improved by introducing new experimental data. With the help of the models, a Ti–13Nb–12Ta–10Zr–4Sn (wt.%) alloy with a single β-phase microstructure and Young’s modulus of 69.91 GPa is successfully developed. This approach could also be used to design other advanced materials.

The purpose of this study was to investigate the effects of Buddleja officinalis Maxim eye drops on morphology and apoptosis in lacrimal glands of the experimental dry eye rabbit model. A total of thirty-six male rabbits were divided into six study groups, consisting of the control group and the dry eye rabbit model group (without any treatment), the dry eye rabbit model group treated with testosterone, and the dry eye rabbit model group treated with different concentrations of Buddleja officinalis Maxim eye drops (1.0 mg/ml, 1.5 mg/ml and 3.0 mg/ml). The lacrimal glands were evaluated by hematoxylin-eosin staining and immunohistochemistry. Buddleja officinalis Maxim eye drops can improve the morphological structure of the lacrimal gland in the dry eye model of castrated rabbits. The average optical density values of PI3K, Akt, and caspase-9 protein in the lacrimal gland tissue of the 3 mg/ml Buddleja officinalis Maxim eye drops group were significantly different from those in the model group (P0.05). Buddleja officinalis Maxim eye drops can improve the morphological structure of the lacrimal gland in the dry eye model of castrated rabbits.

Purpose. To investigate the characteristics of blood in nonsyndromic retinitis pigmentosa (RP) and reveal the pathogenesis of blood cells involved in blood stasis in RP. Design. This is a retrospective observational study. Methods. We collected vein blood from 101 cases of patients with nonsyndromic RP and 120 cases of normal individuals according to a single-blind study and used routine clinical examination to detect the indicators of blood. All the subjects were mainly from the central south of China. Data were analyzed statistically between the RP group and normal control. Results. The indicator of platelet distribution width (PDW) in patients with RP was higher than that in the normal group; the indicators of red blood cell (RBCs), hemoglobin (HGB), hematocrit (HCT), basophils (BASs), platelets (PLTs), and plateletcrit (PCT) in the RP group were lower than those in the normal control. The differences were statistically very significant between the RP group and normal group (p

Cocaine- and amphetamine-regulated transcript (CART) peptides are neuropeptides that are expressed in brain regions associated with reward, such as the nucleus accumbens (NAc), and play a role in cocaine reward. Injection of CART into the NAc can inhibit the behavioral effects of cocaine, and injecting CART into the ventral tegmental area (VTA) reduces cocaine-seeking behavior. However, the exact mechanism of these effects is not clear. Recent research has demonstrated that Ca2+/calmodulin-dependent protein kinase II (CaMKII) and inhibitory G-protein coupled receptor (GPCR) signaling are involved in the mechanism of the effect of CART on cocaine reward. Hence, we review the role of CaMKII and inhibitory GPCR signaling in the effect of CART on cocaine reward and provide a new insight into the mechanism of that effect. In this article, we will first review the biological function of CART and discuss the role of CART in cocaine reward. Then, we will focus on the role of CaMKII and inhibitory GPCR signaling in cocaine reward. Furthermore, we will discuss how CaMKII and inhibitory GPCR signaling are involved in the mechanistic action of CART in cocaine reward. Finally, we will provide our opinions regarding the future directions of research on the role of CaMKII and inhibitory GPCR signaling in the effect of CART on cocaine reward.