Search

Asthma is a chronic airway inflammatory disease whose global incidence increases annually. The role of innate lymphoid cells (ILCs) is a crucial aspect of asthma research with respect to different endotypes of asthma. Based on its pathological and inflammatory features, asthma is divided into type 2 high and type 2 low endotypes. Type‐2 high asthma is distinguished by the activation of type 2 immune cells, including T helper 2 (Th2) cells and ILC2s; the production of cytokines interleukin (IL)‐4, IL‐5 and IL‐13; eosinophilic aggregation; and bronchial hyper‐responsiveness. Type‐2 low asthma represents a variety of endotypes other than type 2 high endotype such as the IL‐1β/ILC3/neutrophil endotype and a paucigranulocytic asthma, which may be insensitive to corticosteroid treatment and/or associated with obesity. The complexity of asthma is due to the involvement of multiple cell types, including tissue‐resident ILCs and other innate immune cells including bronchial epithelial cells, dendritic cells, macrophages and eosinophils, which provide immediate defence against viruses, pathogens and allergens. On this basis, innate immune cells and adaptive immune cells combine to induce the pathological condition of asthma. In addition, the plasticity of ILCs increases the heterogeneity of asthma. This review focuses on the phenotypes of tissue‐resident ILCs and their roles in the different endotypes of asthma, as well as the mechanisms of tissue‐resident ILCs and other immune cells. Based on the phenotypes, roles and mechanisms of immune cells, the therapeutic strategies for asthma are reviewed. [ABSTRACT FROM AUTHOR]

A novel levofloxacin (LVFX) molecularly imprinted two dimensional (2D) photonic crystal hydrogels (LVFX-MIPCH) sensor has been developed, which could be used for the visual monitoring of LVFX. The response performance of the MIPCH sensor would be explored by measuring the diameter of the Debye diffraction ring. In the presence of LVFX, the hydrogel volume shrinks, leads to the particle spacing of photonic crystal in the gel decreases, thus causes the diameter of the Debye diffraction ring increases. As the concentration of LVFX in the solution increases from 0 to 10−12 M, the diameter of the Debye diffraction ring increases by 2.5 mm, and the corresponding particle spacing of photonic crystal decreases by 3.16 nm. Then, with the concentration continues to increase to 10−3 M, the diameter of the Debye diffraction ring increases by 10.0 mm, and the corresponding particle spacing decreases by 32 nm. A linear relationship between the change of particle spacing of photonic crystal (Δ d) and the logarithm value of the LVFX concentration (lg c) in the range from 10−10 to 10−4 M. Besides, the diffraction peak wavelength of the sensor gradually blue-shifted, consistent with the sensor color change(from orange to blue) by naked eye. Besides, The LVFX-MIPCH sensor showed high sensitivity(as low as 10−12 M), excellent specific recognition and stable reusability. [Display omitted] • Levofloxacin molecularly imprinted two dimensional photonic crystal hydrogel sensor was successfully prepared. • By measuring the Debye ring diameter to explore the response performance of the sensor. • In the presence of LVFX, the hydrogel volume shrinks, the particle spacing decreases, the diameter increases. • The diffraction peak wavelength of the sensor blue-shifted while the sensor color changed by naked eye. • The change of particle spacing is linear to the logarithm of LVFX, and the LOD is 10−12 M. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the relationship of ficolin-3 with inflammatory and angiogenic factors, namely, vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF), in the vitreous of eyes with proliferative diabetic retinopathy (PDR). Design: Case-control study. Methods: Vitreous fluid and serum samples were obtained at the time of vitreoretinal surgery from 21 eyes of 21 patients with PDR and from 16 eyes of 16 nondiabetic patients with idiopathic macular hole. Ficolin-3, VEGF, and PEDF concentrations were determined by enzyme-linked immunosorbent assay. Results: Vitreous ficolin-3 levels were significantly higher in eyes with PDR than in eyes with idiopathic macular hole. Similarly, VEGF levels also were significantly higher in eyes with PDR than in eyes with idiopathic macular hole. In contrast, vitreous PEDF concentrations were significantly lower in eyes with PDR than in eyes with idiopathic macular hole, and the VEGF-to-PEDF ratio was higher in eyes with PDR than in eyes with idiopathic macular hole. Furthermore, a significant correlation between ficolin-3 and the VEGF-to-PEDF ratio was observed in the vitreous of eyes with PDR. In addition, serum ficolin-3 levels in eyes with PDR were higher than the levels in eyes with idiopathic macular hole, and the vitreous ficolin-3 levels also correlated with serum ficolin-3 levels. Conclusions: We found that ficolin-3 levels were elevated in the vitreous fluid of patients with PDR. Our results suggest that ficolin-3 may be used as a new therapeutic target for treatment of PDR. [ABSTRACT FROM AUTHOR]

NK cells play crucial roles in defending against persistent HBV. However, NK cells present dysfunction in chronic hepatitis B virus (CHB) infection, and the associated mechanism is still not fully understood. Except for the regulatory receptors, NK cells could also be regulated by the surface and intracellular pattern recognition receptors (PRRs). In the present study, we found that the level of the adaptor of DNA sensor STING in NK cells was significantly decreased in HBeAg-negative CHB patients, and it was positively associated with the degranulation ability of NK cells. Compared to NK cells from healthy donors, NK cells from HBeAg-negative CHB patients displayed a lower responsiveness to cGAMP stimulation. Further investigation showed that HBsAg could inhibit the STING expression in NK cells and suppress the response of NK cells to cGAMP. Significantly, STAT3 was identified to be a transcription factor that directly regulated STING transcription by binding to the promoter. In addition, STAT3 positively regulated the STING associated IFN-α response of NK cells. These findings suggested that STING is an important adaptor in NK cell recognition and activation, while HBsAg disturbs NK cell function by the STAT3-STING axis, providing a new mechanism of NK disability in HBeAg-negative CHB infection. [ABSTRACT FROM AUTHOR]

Lonicerae japonicae flos (LJF) is widely used for the treatment of inflammation-related diseases in traditional Chinese medicine (TCM). To clarify the anti-inflammatory mechanism of LJF, 29 compounds with high content in LJF were selected for network pharmacology. Then, a comprehensive network pharmacology strategy was implemented, which involved compound-inflammation-target construction, protein-protein interaction (PPI) network analysis, and enrichment analysis. Finally, molecular docking and in vitro experiments were performed to verify the anti-inflammatory activity and targets of the key compound. As a result, 279 inflammation-associated proteins were identified, which are mainly involved in the AGE/RAGE signaling pathway in diabetic complications, the HIF-1 signaling pathway, the PI3K-AKT signaling pathway, and EGFR tyrosine kinase inhibitor resistance. A total of 12 compounds were linked to more than 35 targets, including apigenin, kaempferol, quercetin, luteolin, and ferulic acid. The results of molecular docking showed that AKT has the most binding activity, exhibiting certain binding activity with 10 compounds, including vanillic acid, protocatechuic acid, secologanic acid, quercetin, and luteolin; the results of qRT-PCR and WB confirmed that two key compounds, secologanic acid and luteolin, could significantly decrease the secretion of TNF-α and the AKT expression of RAW264.7 murine macrophages stimulated by LPS (lipopolysaccharide). These results demonstrate that the comprehensive strategy can serve as a universal method to illustrate the anti-inflammatory mechanisms of traditional Chinese medicine by identifying the pathways or targets. [ABSTRACT FROM AUTHOR]

Aims: To assess the association between the NOS3 4b/a, T-786C and G894T polymorphisms and diabetic retinopathy (DR) susceptibility. Materials and Methods: Twenty-one studies covering 8,111 subjects were included. The fixed or random effect model used was based on heterogeneity. Results: A significant association of the intron 4a allele in the NOS3 4b/a polymorphism with reduced risk of DR was found in dominant (OR 0.778, 95% CI 0.654-0.926) and additive (OR 0.809, 95% CI 0.698-0.937) models. Subgroup analysis revealed that the intron 4a allele additive model (OR 0.807, 95% CI 0.697-0.935) was associated with DR risk in type 2 diabetic patients. We also found a marginally significant association of the C allele in the T-786C polymorphism with reduced risk of proliferative DR. In contrast, no statistically significant association was observed between the G894T polymorphism and DR risk, either in the overall or subgroup analyses. Conclusions: The intron 4a allele of the 4b/a polymorphism in the eNOS gene has protective effects against DR, especially in type 2 diabetic patients. The C allele of the T-786C polymorphism may be a protective factor for proliferative DR. However, the G894T polymorphism does not appear to influence the development of DR. This conclusion warrants confirmation by further studies. [ABSTRACT FROM AUTHOR]

Cellular metabolic memory occurs in diabetic microvascular and macrovascular complications, but the underlying mechanisms remain unclear. Here, we investigate the role of sirtuin 1 (SIRT1) and metformin in this phenomenon. In bovine retinal capillary endothelial cells (BRECs) and retinas of diabetic rats, the inflammatory gene, nuclear factor-κB (NF-κB), and the proapoptotic gene, Bax, induced by hyperglycemia, remained elevated after returning to normoglycemia. BRECs with small interfering RNA-mediated SIRT1 knockdown had increased sensitivity to hyperglycemia stress, whereas SIRT1 overexpression or activation by metformin inhibited the increase of mitochondrial reactive oxygen species-mediated glyceraldehyde-3-phosphate dehydrogenase by poly (ADP-ribose) polymerase (PARP) activity through the upregulation of liver kinase B1/AMP-activated protein kinase (LKB1/AMPK), ultimately suppressing NF-κB and Bax expression. Furthermore, we showed that hyperglycemia led to PARP activation, which in turn may have downregulated SIRT1. Of importance, this study also demonstrated that metformin suppressed the "memory" of hyperglycemia stress in the diabetic retinas, which may be involved in the SIRT1/LKB1/AMPK pathway. Our data suggest that SIRT1 is a potential therapeutic target for the treatment of the cellular metabolic memory, and the use of metformin specifically for such therapy may be a new avenue of investigation in the diabetes field. [ABSTRACT FROM AUTHOR]

Objective: Mitochondrial reactive oxygen species (ROS) plays a key role in diabetic retinopathy (DR) pathogenesis. However, whether simvastatin decreases diabetes-induced mitochondrial ROS production remains uncertain. The aim of this study was to clarify the beneficial effects and mechanism of action of simvastatin against diabetes-induced retinal vascular damage.Research Design and Methods: Diabetic rats and control animals were randomly assigned to receive simvastatin or vehicle for 24 weeks, and bovine retinal capillary endothelial cells (BRECs) were incubated with normal or high glucose with or without simvastatin. Vascular endothelial growth factor (VEGF) and peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) in the rat retinas or BRECs were examined by Western blotting and real-time RT-PCR, and poly (ADP-ribose) polymerase (PARP), and p38 MAPK were examined by Western blotting. Mitochondrial membrane potential (Deltapsim) and ROS production were assayed using the potentiometric dye 5,5',6,6'- Tetrachloro1,1',3,3'-tetraethyl-benzimidazolylcarbocyanine iodide (JC-1) or CM-H(2)DCFDA fluorescent probes.Results: Simvastatin significantly upregulated PGC-1alpha (P < 0.01), subsequently decreased Deltapsim (P < 0.05) and ROS generation (P < 0.01), inhibited PARP activation (P < 0.01), and further reduced VEGF expression (P < 0.01) and p38 MAPK activity (P < 0.01). Those changes were associated with the decrease of retinal vascular permeability, retinal capillary cells apoptosis, and formation of acellular capillaries.Conclusions: Simvastatin decreases diabetes-induced mitochondrial ROS production and exerts protective effects against early retinal vascular damage in diabetic rats in association with the inhibition of mitochondrial ROS/PARP pathway mediated by PGC-1alpha. The understanding of the mechanisms of action of statins has important implications in the prevention and treatment of mitochondrial oxidative stress-related illness such as DR. [ABSTRACT FROM AUTHOR]

Emerging evidence indicates that cancer cell-derived exosomes contribute to cancer progression through the modulation of tumor microenvironment, but the underlying mechanisms are not fully elucidated. Here, we reported that hepatocellular carcinoma (HCC)-derived exosomes could remodel macrophages by activating NF-κB signaling and inducing pro-inflammatory factors, and resulted in M2-polarized tumor-associated macrophages. In addition, the expression of IFN-γ and TNF-α was inhibited, while the expression of inhibitory receptors such as PD-1 and CTLA-4 was upregulated in T cells by HCC-derived exosome educated macrophages. Data also revealed that HCC exosomes were enriched with miR-146a-5p and promoted M2-polarization. Further investigation demonstrated that the transcription factor Sal-like protein-4 (SALL4) was critical for regulating miR-146a-5p in HCC exosomes and M2-polarization. Mechanistically, SALL4 could bind to the promoter of miR-146a-5p, and directly controlled its expression in exosomes. Blocking the SALL4/miR-146a-5p interaction in HCC reduced the expression of inhibitory receptors on T cells, reversed T cell exhaustion, and delayed HCC progression in DEN/CCL4-induced HCC mice. In conclusion, identification of a role of the exosomal SALL4/miR-146a-5p regulatory axis in M2-polarization as well as HCC progression provides potential targets for therapeutic and diagnostic applications in liver cancer. [ABSTRACT FROM AUTHOR]