Compound Danshen dripping pills prevent early diabetic retinopathy: roles of vascular protection and neuroprotection.

Introduction: Diabetic retinopathy (DR) represents a major cause of adult blindness, and early discovery has led to significant increase in the number of patients with DR. The drugs currently used for treatment, such as ranibizumab, mainly focus on the middle and late periods of DR, and thus do not meet the clinical need. Here, the potential mechanisms by which compound Danshen Dripping Pills (CDDP) might protect against early DR were investigated. Methods: Db/db mice were used to establish a DR model. The initial weights and HbA1c levels of the mice were monitored, and retinal pathology was assessed by hematoxylin-eosin (HE) staining. The vascular permeability of the retina and thickness of each retinal layer were measured, and electroretinogram were performed together with fundus fluorescein angiography and optical coherence tomography. The levels of inflammatory factors were examined in retinal tissue, as well as those of intercellular adhesion molecule 1 (ICAM-1), IL-6, and monocyte chemoattractant protein 1 (MCP-1) in the serum using ELISA. Immunohistochemistry was used to evaluate levels of vascular endothelial growth factor (VEGF), B-cell lymphoma 2 (Bcl-2), and Bclassociated X protein (Bax). Retinal cell injury and apoptosis were examined by TdT-mediated dUTP Nick End Labeling (TUNEL) assays. Results: The data showed that CDDP significantly improved cellular disarrangement. Imaging data indicated that CDDP could reduce vascular permeability and the amplitude of oscillatory potentials (OPs), and restore the thickness of the ganglion cell layer. Moreover, CDDP reduced the expression levels of inflammatory factors in both the retina and serum. Conclusion: These findings strongly suggest that CDDP prevents early DR through vascular and neuroprotection.

NADase CD38 is a key determinant of ovarian aging.

The ovary ages earlier than most other tissues, yet the underlying mechanisms remain elusive. Here a comprehensive analysis of transcriptomic landscapes in different organs in young and middle-aged mice revealed that the ovaries showed earlier expression of age-associated genes, identifying increased NADase CD38 expression and decreased NAD+ levels in the ovary of middle-aged mice. Bulk and single-cell RNA sequencing revealed that CD38 deletion mitigated ovarian aging, preserving fertility and follicle reserve in aged mice by countering age-related gene expression changes and intercellular communication alterations. Mechanistically, the earlier onset of inflammation induced higher expression levels of CD38 and decreased NAD+ levels in the ovary, thereby accelerating ovarian aging. Consistently, pharmacological inhibition of CD38 enhanced fertility in middle-aged mice. Our findings revealed the mechanisms underlying the earlier aging of the ovary relative to other organs, providing a potential therapeutic target for ameliorating age-related female infertility.

Use of methylene blue and a spring microcoil in the preoperative localization of small pulmonary nodules under CT guidance: a meta-analysis.

OBJECTIVE: Methylene blue (MB) and spring microcoils are used for the preoperative localization of small pulmonary nodules (SPNs). We aimed to compare the efficacy and safety of these methods using published data. METHODS: We identified randomized controlled trials and observational studies that assessed preoperative SPN localization using MB or spring microcoil and compared these using a meta-analysis. RESULTS: Seven studies of 933 patients were identified, in whom 1081 SPNs were located. Four hundred twenty-four SPNs were located using MB (n = 359 participants), and 657 SPNs were located using the spring microcoil method (n = 574 participants). The prevalence of technical success of SPN localization was higher using MB (mean deviation [MD]: 0.43; 95% confidence interval [CI]: 0.20, 0.93); the incidence of postoperative complications was lower (MD: 1.70; 95% CI: 1.09, 2.65); and the time taken for removal was longer (MD: -12.37; 95% CI: -22.60, -2.13). There were no differences with respect to the successful wedge resection rate, the time taken for localization, the duration of the procedure, or the mean hospital stay. CONCLUSIONS: Both methods can detect SPNs; however, MB is associated with a higher success rate and fewer postoperative complications, while spring microcoil localization is associated with more rapid removal.

Shared diagnostic genes and potential mechanism between PCOS and recurrent implantation failure revealed by integrated transcriptomic analysis and machine learning.

Polycystic ovary syndrome (PCOS) is a complex endocrine metabolic disorder that affects 5-10% of women of reproductive age. The endometrium of women with PCOS has altered immune cells resulting in chronic low-grade inflammation, which attribute to recurrent implantation failure (RIF). In this study, we obtained three PCOS and RIF datasets respectively from the Gene Expression Omnibus (GEO) database. By analyzing differentially expressed genes (DEGs) and module genes using weighted gene co-expression networks (WGCNA), functional enrichment analysis, and three machine learning algorithms, we identified twelve diseases shared genes, and two diagnostic genes, including GLIPR1 and MAMLD1. PCOS and RIF validation datasets were assessed using the receiver operating characteristic (ROC) curve, and ideal area under the curve (AUC) values were obtained for each disease. Besides, we collected granulosa cells from healthy and PCOS infertile women, and endometrial tissues of healthy and RIF patients. RT-PCR was used to validate the reliability of GLIPR1 and MAMLD1. Furthermore, we performed gene set enrichment analysis (GSEA) and immune infiltration to explore the underlying mechanism of PCOS and RIF cooccurrence. Through the functional enrichment of twelve shared genes and two diagnostic genes, we found that both PCOS and RIF patients had disturbances in metabolites related to the TCA cycle, which eventually led to the massive activation of immune cells.

Non-coding RNAs in hepatocellular carcinoma: Insights into regulatory mechanisms, clinical significance, and therapeutic potential.

Hepatocellular carcinoma (HCC) is a complex and heterogeneous malignancy with high incidence and poor prognosis. In addition, owing to the lack of diagnostic and prognostic markers, current multimodal treatment options fail to achieve satisfactory outcomes. Tumor immune microenvironment (TIME), angiogenesis, epithelial-mesenchymal transition (EMT), invasion, metastasis, metabolism, and drug resistance are important factors influencing tumor development and therapy. The intercellular communication of these important processes is mediated by a variety of bioactive molecules to regulate pathophysiological processes in recipient cells. Among these bioactive molecules, non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), account for a large part of the human transcriptome, and their dysregulation affects the progression of HCC. The purpose of this review is to evaluate the potential regulatory mechanisms of ncRNAs in HCC, summarize novel biomarkers from somatic fluids (plasma/serum/urine), and explore the potential of some small-molecule modulators as drugs. Thus, through this review, we aim to contribute to a deeper understanding of the regulatory mechanisms, early diagnosis, prognosis, and precise treatment of HCC.

Defective STING expression potentiates IL-13 signaling in epithelial cells in eosinophilic chronic rhinosinusitis with nasal polyps.

BACKGROUND: Stimulator of interferon genes (STING) activation favors effective innate immune responses against viral infections. Its role in chronic rhinosinusitis with nasal polyps (CRSwNP) remains unknown. OBJECTIVE: Our aim was to explore the expression, regulation, and function of STING in CRSwNP. METHODS: STING expression in sinonasal mucosal samples was analyzed by means of quantitative RT-PCR, immunohistochemistry, flow cytometry, and Western blotting. Regulation and function of STING expression were explored by using cultured primary human nasal epithelial cells (HNECs) and cells of the line BEAS-2B in vitro. RESULTS: STING expression was reduced in eosinophilic nasal polyps compared with that in noneosinophilic nasal polyps and control tissues. STING was predominantly expressed by epithelial cells in nasal tissue and was downregulated by IL-4 and IL-13 in a signal transducer and activator of transcription 6 (STAT6)-dependent manner. HNECs derived from eosinophilic polyps displayed compromised STING-dependent type I interferon production but heightened IL-13-induced STAT6 activation and CCL26 production as compared with HNECs from noneosinophilic polyps and control tissues, which were rescued by exogenous STING overexpression. Knocking down or overexpressing STING decreased or enhanced expression of suppressor of cytokine signaling 1 (SOCS1) in BEAS-2B cells, respectively, independent of the canonic STING pathway elements TBK1 and IRF3. Knocking down SOCS1 abolished the inhibitory effect of STING on IL-13 signaling in BEAS-2B cells. STING expression was positively correlated with SOCS1 expression but negatively correlated with CCL26 expression in nasal epithelial cells from patients with CRSwNP. CONCLUSIONS: Reduced STING expression caused by the type 2 milieu not only impairs STING-dependent type I interferon production but also amplifies IL-13 signaling by decreasing SOCS1 expression in nasal epithelial cells in eosinophilic CRSwNP.

Deficiency in interleukin-10 production by M2 macrophages in eosinophilic chronic rhinosinusitis with nasal polyps.

BACKGROUND: M2 macrophages are characterized by high interleukin-10 (IL-10) expression and are critical for resolving inflammation. Although increased accumulation of M2 macrophages has been demonstrated in chronic rhinosinusitis with nasal polyps (CRSwNP), particularly the eosinophilic type, their functional relevance in CRSwNP remains poorly understood. METHODS: M1 and M2 macrophages and IL-10 expression in sinonasal tissues were detected by double-immunofluorescence staining. THP-1 cells, a human monocytic leukemia cell line, were stimulated with various cytokines to study macrophage polarization and IL-10 expression. Polyp size, computed tomography (CT) scans, and symptom severity were scored. RESULTS: Compared with numbers in control tissues, the numbers of total CD68+ macrophages, interferon regulatory factor 5-positive and CD68+ M1 macrophages, and CD163+ CD68+ and CD206+ CD68+ M2 macrophages were increased in both eosinophilic and non-eosinophilic polyps. However, compared with non-eosinophilic polyps, eosinophilic polyps contained fewer M1 macrophages and more M2 macrophages. Consistent with this, the M1/M2 macrophage ratio was increased in non-eosinophilic polyps, whereas it decreased in eosinophilic polyps. Strikingly, the numbers of IL-10+ CD68+ macrophages and the percentage of IL-10+ CD68+ macrophages relative to the total number of macrophages were decreased in eosinophilic polyps, despite the upregulation of M2 macrophages in this type of polyp. The number of IL-10+ CD68+ M2 macrophages correlated negatively with total symptoms scores, polyp sizes, total CT scores, and the total number of inflammatory cells in patients with eosinophilic CRSwNP. Poly I:C downregulated IL-10 expression in M2 macrophages differentiated from THP-1 cells in vitro. CONCLUSION: Impaired IL-10 production by M2 macrophages may contribute to sustained inflammation in eosinophilic CRSwNP.vv.

IgD-activated mast cells induce IgE synthesis in B cells in nasal polyps.

BACKGROUND: Although upregulated expression of local IgD has been reported in patients with chronic rhinosinusitis (CRS), its function is unclear. OBJECTIVE: We sought to explore the expression and function of soluble IgD in patients with CRS, particularly CRS with nasal polyps. METHODS: IgD levels in sinonasal mucosa were analyzed by using RT-PCR and ELISA. Numbers and phenotypes of IgD+ cells were studied by means of immunohistochemistry, immunofluorescence, and flow cytometry. HMC-1 cells, a human mast cell line, and mast cells purified from eosinophilic polyps were cultured alone or with naive B cells purified from peripheral blood. The antigen specificity of nasal IgD was investigated by using ELISA. RESULTS: The mRNA expression of immunoglobulin heavy constant delta gene, numbers of IgD+ cells, and protein levels of secretory IgD in sinonasal mucosa were increased in patients with CRS with or without nasal polyps compared with control subjects. Numbers of IgD+ plasmablasts were increased in both eosinophilic and noneosinophilic polyps, whereas numbers of IgD+ mast cells were only increased in eosinophilic polyps. Cross-linking IgD induced serum preincubated HMC-1 cells and polyp mast cells to produce B-cell activating factor, IL-21, IL-4, and IL-13 and to promote IgM, IgG, IgA, and IgE production from B cells. In eosinophilic polyps expression of those B cell-stimulating factors in mast cells and close contact between mast cells and B cells were found. Moreover, positive correlations of total IgD levels with total IgE levels and eosinophilia and upregulation of specific IgD against house dust mites were discovered in eosinophilic polyps. CONCLUSION: IgD-activated mast cells can facilitate IgE production and eosinophilic inflammation in patients with CRS with nasal polyps.

The association of Enamelin, Lactoferrin, and Tumour necrosis factor alpha gene polymorphisms with high caries susceptibility in Chinese children under 4 years old.

OBJECTIVE: The aim of this study was to assess the role of ENAM rs3796703, LTF rs1126478, and TNF-α rs1800629 in high caries susceptibility. DESIGN: The present case-control study included 1005 unrelated children under 4 years old: 505 with severe caries (dmft index ≥4) and 500 who were caries-free (dmft index=0 and without white-spot lesions). Questionnaires were obtained from parents and gardians about the children's diet and oral behavioural habits. All the children received dental examinations and oral swabbing for human genomic DNA collection. ENAM rs3796703, LTF rs1126478, and TNF-α rs1800629 were genotyped by Sanger sequencing. RESULTS: The frequency of the ENAM rs3796703T allele (6.7% in the caries group and 4.2% in the caries-free group), CT genotype (12.7% in the caries group and 8.4% in the caries-free group), TNF-α rs1800629 A allele (4.8% in the caries group and 6.8% in the caries-free group), and AG genotype (8.7% in the caries group and 13.2% in the caries-free group) were significantly different between the caries and caries-free groups (p<0.05). No significant difference was found in the LTF rs1126478 allele frequency and genotype distribution between the two groups. The ENAM rs3796703 CT genotype increased caries susceptibility by 60.9% compared to the CC genotype (ß=0.746, OR=1.609), and the TNF-α rs1800629 AG genotype reduced caries susceptibility by 47.4% compared to the GG genotype (ß=-0.642, OR=0.526). In terms of habits covariates, prolongation of night feeding time by 1 month increased caries susceptibility by 3.3% (ß=0.033, OR=1.033); additionally, sweets and acidic drinks consumption 1-2 times per day increased caries susceptibility by 218.2% (ß=1.158, OR=3.182), and consumption 3 or more times pe/r day increased susceptibility by 883.5% (ß=2.286, OR=9.835) compared to non-consumption. Topical fluoride application decreased caries susceptibility by 43.0% (ß=-0.562, OR=0.570). CONCLUSIONS: The ENAM and TNF-α genes are likely associated with caries experience in Chinese children. The ENAM rs3796703 CT genotype might be involved in caries susceptibility, while TNF-α rs1800629 AG genotype might be involved in caries protection.