Circular RNA in Retina: A Potential Biomarker and Therapeutic Target.

Circular RNA (circRNA) is a newly discovered noncoding RNA, which forms a closed ring with more than 200 bases in length. CircRNA is formed by back splicing of precursor RNA, and its expression abundance in body fluid is up to 10 times that of homologous linear transcripts. Recently, novel activities for circRNA in various diseases have emerged, ranging from cancer therapy and neurodegenerative diseases. Here, we reviewed the literature on the biogenesis of circRNA and its relationship with retinal diseases in recent years. We first described the mechanism, existing form and main function of circRNA. Next, we also pinpoint that circRNA has great value in the diagnosis and treatment of retinal diseases represented by retinoblastoma, retinal degeneration, and diabetic retinopathy. By this review, we hope to explore more possibilities of circRNA in clinical diagnosis and treatment.

Kaempferol alleviates corneal transplantation rejection by inhibiting NLRP3 inflammasome activation and macrophage M1 polarization via promoting autophagy.

Corneal transplantation rejection remains a major threat to the success rate of high-risk patients. Given the many side effects presented by traditional immunosuppressants, there is an urgency to clarify the mechanism of corneal transplantation rejection and to identify new therapeutic targets. Kaempferol is a natural flavonoid that has been proven in various studies to possess anti-inflammatory, antioxidant, anticancer, and neuroprotective properties. However, the effect of Ka on corneal transplantation remains largely unexplored. To address this, both at the in vivo and in vitro levels, we established a model of corneal allograft transplantation in Wistar rats and an LPS-induced inflammatory model using human THP-1-derived macrophages. In the transplantation experiments, we observed an enhancement of mRNA and protein level in the NLRP3/IL-1 ß axis and in M1 macrophage polarization post-operation. In groups to which kaempferol intraperitoneal injections were administered, this response was effectively reduced. However, the effect of kaempferol was reversed after the application of autophagy inhibitors. Similarly, in the inflammatory model, we found that different concentrations of kaempferol reduced the LPS-induced M1 polarization and NLRP3 inflammasome activation. Moreover, we confirmed that kaempferol induced autophagy and that autophagy inhibitors reversed this effect in macrophages. In conclusion, we found that kaempferol can inhibit the activation of NLRP3 inflammasomes by inducing autophagy, thus inhibiting macrophage polarization, and ultimately alleviating corneal transplantation rejection. Thus, our study suggests that kaempferol is a potential therapeutic agent in the treatment of allograft rejection.

Planning mass eradication of Helicobacter pylori infection for indigenous Taiwanese peoples to reduce gastric cancer.

BACKGROUND AND AIM: The aim of this study is to identify gastric cancer burden in Indigenous Taiwanese peoples and conduct a project to evaluate how to reduce the disparities most effectively in Indigenous communities. METHODS: First, we quantified the health disparities in gastric cancer in Indigenous peoples using data from the cancer registries during the period of 2006-2014. Second, we identified parameters that might be associated with Helicobacter pylori infection or help identify a good eradication strategy. RESULTS: Gastric cancer incidence (24.4 vs 12.3 per 100 000 person-years) and mortality rates (15.8 vs 6.8 per 100 000 person-years) were higher in Indigenous than in non-Indigenous, with 2.19-fold (95% confidence interval [CI]: 2.06-2.33) and 2.47-fold (2.28-2.67) increased risk, respectively. In Indigenous communities, H. pylori infection was more prevalent in Indigenous than in non-Indigenous (59.4% vs 31.5%, P < 0.01). Regression analyses consistently showed that either the mountain or plain Indigenous had 1.89-fold (95% CI: 1.34-2.66) and 1.73-fold (95% CI: 1.24-2.41) increased risk for H. pylori infection, respectively, as compared with non-Indigenous, adjusting for other baseline characteristics. The high infection rates were similarly seen in young, middle-aged, and older adults. Program eradication rates using clarithromycin-based triple therapy were suboptimal (73.7%, 95% CI: 70.0-77.4%); the habits of smoking (1.70-fold, 95% CI: 1.01-2.39) and betel nut chewing (1.54-fold, 95% CI: 0.93-2.16) were associated with the higher risk of treatment failure. CONCLUSION: Gastric cancer burden is higher in Indigenous Taiwanese peoples than in their non-Indigenous counterparts. Eliminating the prevalent risk factor of H. pylori infection is a top priority to reduce this health disparity.

Prognostic value of extraocular muscles for intraocular pressure in thyroid-associated ophthalmopathy patients.

Background: Persistent increase in intraocular pressure (IOP) is often observed in eyes with thyroid-associated ophthalmopathy (TAO), which has irreversible effects on the visual function of patients. This retrospective cross-sectional study evaluated the value of magnetic resonance imaging (MRI) measurements of extraocular muscle (EOM) volume in prognosing IOP in patients with TAO. Methods: This single-center study was conducted in Beijing Friendship Hospital (Beijing, China), a tertiary hospital. From 35 participants, 70 eyes (normal IOP group: 50 eyes; high IOP group: 20 eyes; random samples) were enrolled in this study. Basic data from patients were collected and compared using 2-sample t-tests and chi-squared tests. The volume of the EOM, orbit fat, and whole orbit were measured by orbital MRI. Moreover, proptosis, optic nerve (ON) sheath diameter, optic nerve angle (ONA), and gaze angle were additionally measured with MRI. These parameters were compared between the two groups using 2-sample t-tests and chi-squared tests. Before and after post-methylprednisolone therapy, the MRI data of 20 eyes were obtained and compared with a paired t-test. Peripapillary retinal nerve fiber layer (RNFL) thickness was obtained using an optical coherence tomography (OCT) scan. Spearman rank correlation analysis, logistic regression analysis, and receiver operating characteristic (ROC) curves were performed to evaluate the role of these factors in IOP changes. Results: The EOM volume and axial and sagittal ONAs in the high-IOP group were significantly increased compared to the normal-IOP group (P<0.001, P=0.001, P=0.02, respectively). Logistic regression analysis indicate that the cutoff value for EOM volume for the diagnosis of high IOP was significantly larger than that of the other parameters except orbit volume (P=0.03, P=0.004, P=0.08, respectively). Spearman correlation analysis revealed a significant correlation between EOM volume and ON sheath diameter and average RNFL thickness (P=0.01, P=0.02, respectively). A paired t-test indicated a significant decrease of EOM volume and ON sheath diameter as well as a significant enlargement of the axial ONAs after methylprednisolone therapy (P=0.002, P=0.02, P=0.05, respectively). Conclusions: EOM volume was an effective diagnostic factor for tracking IOP changes and ON patterns in patients with TAO. Methylprednisolone therapy is recommended for patients with TAO with secondary glaucoma to quickly reduce the EOM volume.

Sulphate Corrosion Mechanism of Ultra-High-Performance Concrete (UHPC) Prepared with Seawater and Sea Sand.

The lack of river sand is becoming increasingly serious. In this study, we consider how to use sea sand to prepare innovative construction and building materials with excellent mechanical and durability properties. Sulphate corrosion causes expansion, cracking and spalling of concrete, resulting in the reduction or even loss of concrete strength and cementation force. In this paper, artificial seawater, sea sand, industrial waste, steel fiber and polycarboxylate superplasticizer were used to prepare ultra-high-performance polymer cement mortar (SSUHPC), and the sulphate corrosion mechanism was investigated. The strength and cementation force of mortar on the SSUHPC surface decreased and flaked off with the development of sulphate erosion, and the steel fiber rusted and fell off. A 3D model was established based on X-ray computed tomography (X-CT), and the results showed that SSUHPC maintained excellent internal structural characteristics despite severe sulphate erosion on the surface. Mercury intrusion porosimetry (MIP), scanning electron microscopy (SEM) and X-ray diffraction (XRD) techniques were adopted to investigate the sulphate corrosion mechanism of SSUHPC. We found a transition zone within 1-5 mm of the surface of SSUHPC. The Vickers hardness of mortar in this area was increased by 5~15%, and the porosity was reduced to 3.8489%. Obvious structural damage did not occur in this area, but a high content of gypsum appeared. UHPC prepared with seawater sea sand was found to have better sulphate resistance than that prepared with freshwater river sand, which supports the development and utilization of sea sand in concrete.

The Mechanism of Anticorrosion Performance and Mechanical Property Differences between Seawater Sea-Sand and Freshwater River-Sand Ultra-High-Performance Polymer Cement Mortar (UHPC).

There are abundant sea-sand resources on the earth. Traditional sea-sand concrete faced various problems relating to insufficient anticorrosion ability. In this paper, artificial seawater, sea sand, industrial waste, steel fiber, and polycarboxylate superplasticizer were used to prepare ultra-high-performance polymer cement mortar (SSUHPC). At the same time, freshwater river-sand ultra-high-performance polymer cement mortar (FRUHPC) with the same mixing ratio was prepared for comparative study. The compressive strength of SSUHPC reached 162.1 MPa, while the that of FRUHPC reached 173.3 MPa, which was slightly higher. Meanwhile, SSUHPC showed excellent anticorrosion characteristics in terms of carbonization, frost resistance and chloride resistance, and especially for sulfate resistance. The composition of SSUHPC was separated into three parts: mortar, pore and steel fiber, and the performance difference mechanisms of SSUHPC and FRUHPC were investigated by X-ray computed tomography (X-CT), mercury intrusion porosimetry (MIP), scanning electron microscopy (SEM), and X-ray diffraction (XRD). The hydration degree of mortar in SSUHPC was higher, with higher content of CSH and CH, and its better optimized gel pore characteristics gave SSUHPC better corrosion resistance. The mechanical properties of SSUHPC were slightly poor due to the uneven dispersion of steel fibers and air pores, with an- air pore porosity of 1.52% (above 200 µm) that was twice that of FRUHPC (0.6%). In this paper, the mechanics and anticorrosion performance of ultra-high-performance polymer cement mortar prepared with seawater sea sand were comprehensively evaluated, and the mechanism of performance difference between SSUHPC and FRUHPC was revealed, conducive to the targeted improvement of sea sand concrete.

Implications of macrophage polarization in corneal transplantation rejection.

Corneal transplantation rejection remains an urgent problem threatening the success rate of high-risk patients. Macrophages are involved in the rejection of corneal transplants. Macrophages have M1 and M2 phenotypes, classified according their response to external stimuli. Macrophage polarization, through which these distinct forms are activated, is not only involved in the occurrence and development of inflammation, tumors, and autoimmune and other diseases, but also participates in graft rejection. This study provides an overview of the types of macrophages and mechanisms of their polarization, and review current knowledge regarding their involvement in corneal transplantation and potential therapeutic applications. Consideration of the relationship between the direction of macrophage polarization and the determination of graft survival and how it can be modified, is important for the development of novel corneal anti-rejection therapies.

Research on the Effect of Desert Sand on Pore Structure of Fiber Reinforced Mortar Based on X-CT Technology.

Concrete is a multi-phase, porous system. The pore structure has an important influence on the properties of the concrete. In this paper, a kind of fiber reinforced mortar was prepared with desert sand and its pore structure was studied. The MIP technique was used to investigate the pore structure characteristics between 1 nm and 500 µm (in diameter). Meanwhile, the µX-CT technique was used to study the pore structure characteristics above 200 µm. It was found that the total porosity tends to decrease first and then increase as the dosage of desert sand increased. The porosity decreased gradually from the upper to bottom area inside the sample, and the diameter of the air voids near the upper area became larger. After curing for 28 days, the compressive strength of fiber reinforced mortar reached the maximum when the content of desert sand was 50%. In conclusion, the appropriate amount of desert sand can reduce the porosity of the fiber reinforced mortar to some extent and the number of large size air voids can be significantly reduced, which improves the pore structure and the mechanical properties of the fiber reinforced mortar.

Conformation-Specific Blockade of αIIbß3 by a Non-RGD Peptide to Inhibit Platelet Activation without Causing Significant Bleeding and Thrombocytopenia.

Bleeding and thrombocytopenia to readministration are the most serious side effects of clinical integrin αIIbß3 antagonists such as RGD-containing peptides. Here we show that a non-RGD peptide ZDPI, identified from skin secretions of Amolops loloensis, inhibited platelet aggregation induced by agonists, such as adenosine diphosphate, collagen, arachidonic acid, PAR1AP, and integrin αIIbß3 allosteric activator, and reduces soluble fibrinogen binding to activated platelets without perturbing adhesion numbers on immobilized fibrinogen. Further study showed that ZDPI preferred to bind to the active conformation of integrin αIIbß3, and thus inhibited c-Src-mediated integrin signaling transduction. In contrast to currently used clinical blockers of integrin αIIbß3, which are all conformation-unspecific blockers, ZDPI conformation specifically binds to activated integrin αIIbß3, subsequently suppressing platelet spreading. In vivo study revealed that ZDPI inhibited carotid arterial thrombosis with limited bleeding and thrombocytopenia. A non-RGD peptide which targets the active conformation of integrin αIIbß3, such as ZDPI, might be an excellent candidate or template to develop antithrombotics without significant bleeding and thrombocytopenia side effects.

Snake C-Type Lectins Potentially Contribute to the Prey Immobilization in Protobothrops mucrosquamatus and Trimeresurus stejnegeri Venoms.

Snake venoms contain components selected to immobilize prey. The venoms from Elapidae mainly contain neurotoxins, which are critical for rapid prey paralysis, while the venoms from Viperidae and Colubridae may contain fewer neurotoxins but are likely to induce circulatory disorders. Here, we show that the venoms from Protobothrops mucrosquamatus and Trimeresurus stejnegeri are comparable to those of Naja atra in prey immobilization. Further studies indicate that snake C-type lectin-like proteins (snaclecs), which are one of the main nonenzymatic components in viper venoms, are responsible for rapid prey immobilization. Snaclecs (mucetin and stejnulxin) from the venoms of P. mucrosquamatus and T. stejnegeri induce the aggregation of both mammalian platelets and avian thrombocytes, leading to acute cerebral ischemia, and reduced animal locomotor activity and exploration in the open field test. Viper venoms in the absence of snaclecs fail to aggregate platelets and thrombocytes, and thus show an attenuated ability to cause cerebral ischemia and immobilization of their prey. This work provides novel insights into the prey immobilization mechanism of Viperidae snakes and the understanding of viper envenomation-induced cerebral infarction.

Potential Role of Platelet-Activating C-Type Lectin-Like Proteins in Viper Envenomation Induced Thrombotic Microangiopathy Symptom.

Envenomation by viperid snakes may lead to severe bleeding, consumption coagulopathy, and thrombotic microangiopathy symptoms. The exact etiology or toxins responsible for thrombotic microangiopathy symptoms after snake envenomation remain obscure. Snake C-type lectin-like proteins (snaclecs) are one of the main non-enzymatic protein constituents in viper venoms, of which a majority are considered as modulators of thrombosis and hemostasis. In this study, we demonstrated that two snaclecs (mucetin and stejnulxin), isolated and identified from Protobothrops mucrosquamatus and Trimeresurus stejnegeri venoms, directly induced platelet degranulation and clot-retraction in vitro, and microvascular thrombosis has been confirmed in various organs in vivo. These snaclecs reduced cerebral blood flow and impaired motor balance and spatial memories in mice, which partially represent the thrombotic microangiopathy symptoms in some snakebite patients. The functional blocking of these snaclecs with antibodies alleviated the viper venom induced platelet activation and thrombotic microangiopathy-like symptoms. Understanding the pathophysiology of thrombotic microangiopathy associated with snake envenoming may lead to emerging therapeutic strategies.

Centipede KCNQ Inhibitor SsTx Also Targets KV1.3.

It was recently discovered that Ssm Spooky Toxin (SsTx) with 53 residues serves as a key killer factor in red-headed centipede's venom arsenal, due to its potent blockage of the widely expressed KCNQ channels to simultaneously and efficiently disrupt cardiovascular, respiratory, muscular, and nervous systems, suggesting that SsTx is a basic compound for centipedes' defense and predation. Here, we show that SsTx also inhibits KV1.3 channel, which would amplify the broad-spectrum disruptive effect of blocking KV7 channels. Interestingly, residue R12 in SsTx extends into the selectivity filter to block KV7.4, however, residue K11 in SsTx replaces this ploy when toxin binds on KV1.3. Both SsTx and its mutant SsTx_R12A inhibit cytokines production in T cells without affecting the level of KV1.3 expression. The results further suggest that SsTx is a key molecule for defense and predation in the centipedes' venoms and it evolves efficient strategy to disturb multiple physiological targets.

Probiotic Mixture Golden Bifido Prevents Neonatal Escherichia coli K1 Translocation via Enhancing Intestinal Defense.

Escherichia coli (E. coli) K1 sepsis and meningitis is a severe infection characterized by high mortality in neonates. Successful colonization and translocation across the intestinal mucosa have been regarded as the critical steps for E. coli K1 sepsis and meningitis. We recently reported that the probiotic mixture, Golden Bifido (containing live Lactobacillus bulgaricus, Bifidobacterium, and Streptococcus thermophilus, LBS) has a preventive role against neonatal E. coli K1 bacteremia and meningitis. However, the interaction between the neonatal gut barrier, probiotics and E. coli K1 is still not elucidated. The present study aims to investigate how LBS exerts its protective effects on neonatal gut barrier during E. coli K1 infection. The beneficial effects of LBS were explored in vitro and in vivo using human colon carcinoma cell lines HT-29 and rat model of neonatal E. coli K1 infection, respectively. Our results showed that stimulation with E. coli K1 was able to cause intestinal barrier dysfunction, which were reflected by E. coli K1-induced intestinal damage and apoptosis of intestinal epithelial cells, reduction of mucin, immunoglobulin A (IgA) and tight junction proteins expression, as well as increase in intestinal permeability, all these changes facilitate E. coli K1 intestinal translocation. However, these changes were alleviated when HT-29 cells were treated with LBS before E. coli K1 infection. Furthermore, we found that LBS-treated neonatal rats (without E. coli K1 infection) have showed higher production of mucin, ZO-1, IgA, Ki67 in intestinal mucosa as well as lower intestinal permeability than that of non-treated rats, indicating that LBS could accelerate the development of neonatal intestinal defense. Taken together, our results suggest that enhancement of the neonatal intestinal defense to fight against E. coli K1 translocation could be the potential mechanism to elucidate how LBS confers a protective effect against neonatal E. coli K1 bacteremia and meningitis. This indirect mechanism makes LBS exert preventive effect on most of gut-derived pathogenic infections rather than only E. coli.

[Lactobacillus rhamnosus GG conditioned medium prevents E. coli meningitis by inhibiting nuclear factor-κB pathway].

OBJECTIVE: To investigate whether Lactobacillus rhamnosus GG conditioned medium(LGG-CM)has preventive effect against E. coli K1-induced neuropathogenicity in vitro by inhibiting nuclear factor-κB (NF-κB) signaling pathway. METHODS: An in vitro blood-brain barrier (BBB) model was constructed using human brain microvascular endothelial cells (HBMECs). The effect of LGG-CM on E. coli-actived NF-κB signaling pathway was assayed using Western blotting. Invasion assay and polymorphonuclear leukocyte (PMN) transmigration assay were performed to explore whether LGG-CM could inhibit E. coli invasion and PMN transmigration across the BBB in vitro. The expressions of ZO-1 and CD44 were detected using Western blotting and immunofluorescence. The changes of trans-epithelial electric resistance (TEER) and bacterial translocation were determined to evaluate the BBB permeability. RESULTS: Pre-treament with LGG-CM inhibited E. coli-activated NF-κB signaling pathway in HBMECs and decreased the invasion of E. coli K1 and transmigration of PMN. Western blotting showed that LGG-CM could alleviate E. coli-induced up-regulation of CD44 and down-regulation of ZO-1 expressions in HBMECs. In addition, pre-treatment with LGG-CM alleviated E. coli K1-induced reduction of TEER and suppressed bacterial translocation across the BBB in vitro. CONCLUSION: LGG-CM can block E. coli-induced activation of NF-κB signaling pathway and thereby prevents E. coli K1-induced neuropathogenicity by decreasing E. coli K1 invasion rates and PMN transmigration.