Background Silver nanoparticles (AgNP) are widely used in medical practices owing to their distinct antibacterial, antiviral and anticancer activities. However, with increasing use of AgNP, concerns over its potential toxicity are also escalating. Here, we demonstrated the potential thrombotic effect of AgNP which was mediated by the procoagulant activity of red blood cells (RBCs). Results In freshly isolated human RBCs, AgNP, but not silver microparticles (AgMP), elicited morphological changes, phosphatidylserine (PS) exposure and microvesicles (MV) generation, the key indicators of procoagulant activity in RBCs at concentration ranges (≤ 100 μg/mL) that were free of significant hemolysis. In line with this, AgNP potentiated thrombin generation and adherence of RBCs to endothelial cells, while AgMP did not. Oxidative stress, intracellular calcium increase and ATP depletion were found to underlie the procoagulant effects of AgNP, which led to altered activity of membrane aminophospholipid translocases. These in vitro findings were well reproduced in rat in vivo, where intravenously exposure to AgNP promoted venous thrombosis significantly. Of note, RBCs isolated from cancer patients, who inherently convey the risk of thrombogenesis, were more sensitive to the procoagulant effects of AgNP. In addition, AgNP significantly potentiated the procoagulant effects of a chemotherapeutic drug, paclitaxel. Conclusion Collectively, these results suggest that AgNP may have prothrombotic risks by promoting procoagulant activity of RBCs and caution shall be taken for its use in the population sensitive to thrombosis like cancer patients. Electronic supplementary material The online version of this article (10.1186/s12989-019-0292-6) contains supplementary material, which is available to authorized users.

The purpose of the present study was to optimize the formulations of the thermoresponsive ophthalmic in situ gels of a poorly water-soluble drug fluconazole (FLU) and evaluate the in vitro and in vivo properties of the formulations. The thermoresponsive ophthalmic FLU in situ gels were prepared by mixing FLU, Poloxamer407, Tween80, benzalkonium chloride and carbopol934 in borate buffer solution. The in vivo eye irritation tests and ophthalmic absorption were carried out in rabbits. The formulation compositions influenced the physicochemical properties of FLU in situ gels. The amount of poloxamer407 in the formulation was the main factor that affected the sol-gel transition temperature of the products. Tween80 not only improved the solubility of the FLU but also affected the products' sol-gel transition temperature. In this study, sol-gel transition temperature was not affected by carbopol934. However, carbopol934 affected pH value, transparency and gelling capacity of the products. The product of the optimized formulation was a pseudoplastic fluid and its sol-gel transition temperature was 30.6 ± 1.2 °C. The autoclaving test showed that the sol-gel transition temperature, the flow ability and the flow behavior of the test samples did not change obviously after autoclaving sterilization at 121 °C and 15 psi for 20 min, thus the autoclaving was an acceptable sterilization method for this preparation. The thermoresponsive ophthalmic FLU in situ gels' in vivo ophthalmic absorption was superior to the conventional FLU eye drop. In conclusion, the thermoresponsive ophthalmic FLU in situ gel is a better alternative than the FLU eye drop.

Antiplatelet agents are important in the pharmacotherapeutic regime for many cardiovascular diseases, including thrombotic disorders. However, bleeding, the most serious adverse effect associated with current antiplatelet therapy, has led to many efforts to discover novel anti-platelet drugs without bleeding issues. Of note, shear stress-induced platelet aggregation (SIPA) is a promising target to overcome bleeding since SIPA happens only in pathological conditions. Accordingly, this study was carried out to discover antiplatelet agents selectively targeting SIPA. By screening various herbal extracts, Paeonia suffruticosa and its major bioactive constituent, paeoniflorin, were identified to have significant inhibitory effects against shear-induced aggregation in human platelets. The effects of paeoniflorin on intraplatelet calcium levels, platelet degranulation, and integrin activation in high shear stress conditions were evaluated by a range of in vitro experiments using human platelets. The inhibitory effect of paeoniflorin was determined to be highly selective against SIPA, through modulating von Willebrand Factor (vWF)-platelet glycoprotein Ib (GP Ib) interaction. The effects of paeoniflorin on platelet functions under high shear stress were confirmed in the ex vivo SIPA models in rats, showing the good accordance with the anti-SIPA effects on human platelets. Treatment with paeoniflorin significantly prevented arterial thrombosis in vivo from the dose of 10 mg/kg without prolonging bleeding time or blood clotting time in rats. Collectively, our results demonstrated that paeoniflorin can be a novel anti-platelet agent selectively targeting SIPA with an improved safety profile.

Adipocytes play pivotal roles in maintaining energy homeostasis by storing lipids in adipose tissue (AT), regulating the flux of lipids between AT and the circulation in response to the body's energy requirements and secreting a variety of hormones, cytokines and other factors. Proper AT development and function ensure overall metabolic health. Nuclear factor erythroid 2-related factor 1 (NFE2L1, also known as NRF1) belongs to the CNC-bZIP family and plays critical roles in regulating a wide range of essential cellular functions and varies stress responses in many cells and tissues. Human and rodent Nfe2l1 genes can be transcribed into multiple splice variants resulting in various protein isoforms, which may be further modified by a variety of post-translational mechanisms. While the long isoforms of NFE2L1 have been established as master regulators of cellular adaptive antioxidant response and proteasome homeostasis, the exact tissue distribution and physiological function of NFE2L1 isoforms, the short isoforms in particular, are still under intense investigation. With regard to key roles of NFE2L1 in adipocytes, emerging data indicates that deficiency of Nfe2l1 results in aberrant adipogenesis and impaired AT functioning. Intriguingly, a single nucleotide polymorphism (SNP) of the human NFE2L1 gene is associated with obesity. In this review, we summarize the most significant findings regarding the specific roles of the multiple isoforms of NFE2L1 in AT formation and function. We highlight that NFE2L1 plays a fundamental regulatory role in the expression of multiple genes that are crucial to AT metabolism and function and thus could be an important target to improve disease states involving aberrant adipose plasticity and lipid homeostasis.