Flavonoids-mediated TLR4 Inhibition as a Promising Therapy for Renal Diseases.

Toll-like receptors (TLRs) control both innate and adaptive immunity with a wide expression on renal epithelial cells and leukocytes. Activation of TLRs results in the production of cytokines, chemokines and interferons along with activation of the transcription factor NF-κB, resulting in inflammatory perturbations. TLR4 signaling pathway is the most extensively studied of TLRs. TLR4 is expressed on renal microvascular endothelial and tubular epithelial cells. So, targeting TLR4 modulation could be a therapeutic approach to attenuate kidney diseases that are underlined by inflammatory cascade. Medicinal plants with anti-inflammatory activities display valuable effects and are employed as alternative sources to alleviate renal disease linked with inflammation. Flavonoids and other phytochemicals derived from traditional medicines possess promising pharmacological activities owing to their relatively cheap and high safety profile. Our review focuses on the potent anti-inflammatory activities of twenty phytochemicals to verify if their potential promising renoprotective effects are related to suppression of TLR4 signaling in different renal diseases, including sepsis-induced acute kidney injury, renal fibrosis, chemotherapy-induced nephrotoxicity, diabetic nephropathy and renal ischemia/reperfusion injury. Additionally, molecular docking simulations were employed to explore the potential binding affinity of these phytochemicals to TLR4 as a strategy to attenuate renal diseases associated with activated TLR4 signaling.

Titania coating of mesoporous silica nanoparticles for improved biocompatibility and drug release within blood vessels.

Blood vessel disease is a major contributor to cardiovascular morbidity and mortality and is hallmarked by dysfunction of the lining endothelial cells (ECs). These cells play a significant role in vascular homeostasis, through the release of mediators to control vessel diameter, hence tissue perfusion. Mesoporous silica nanoparticles (MSNs) can be used as potential drug delivery platforms for vasodilator drugs. Here, using an ex vivo model of vascular function, we examine the use of titania coating for improved biocompatibility and release dynamics of MSN loaded sodium nitroprusside (SNP). MSNs (95 ±â€¯23 nm diameter; pore size 2.7 nm) were synthesised and fully characterised. They were loaded with SNP and coated with titania (TiO2), using the magnetron sputtering technique. Pre-constricted aortic vessels were exposed to drug loaded MSNs (at 1.96 × 1012 MSN mL-1) and the time course of vessel dilation observed, in real time. Exposure of viable vessels to MSNs lead to their internalization into the cytoplasm of ECs, while TiMSNs were also observed in the elastic lamina and smooth muscle cell layers. We demonstrate that titania coating of MSNs significantly improves their biocompatibility and alters the dynamics of drug release. A slow and more sustained relaxation was evident after uptake of TiMSN-SNP, in comparison to uncoated MSN-SNP (rate of dilation was 0.08% per min over a 2.5 h period). The use of titania coated MSNs for drug delivery to the vasculature may be an attractive strategy for therapeutic clinical intervention in cardiovascular disease. STATEMENT OF SIGNIFICANCE: Cardiovascular disease is a major cause of mortality and morbidity worldwide, with a total global cost of over $918 billion, by 2030. Mesoporous silica nanoparticles (MSNs) have great potential for the delivery of drugs that can treat vessel disease. This paper provides the first description for the use of titania coated MSNs with increased vascular penetration, for the delivery of vasodilator drugs, without compromising overall vessel function. We demonstrate that titania coating of MSNs significantly improves their biocompatibility and uptake within aortic blood vessels and furthermore, enables a slower and more sustained release of the vasodilator drug, sodium nitroprusside within the vessel, thus making them an attractive strategy for the treatment of vascular disease.

The influence of silica nanoparticles on small mesenteric arterial function.

AIM: To determine the influence of silica nanoparticles (SiNPs) on small arterial function; both ex vivo and in vivo. METHODS: Mono-dispersed dye-encapsulated SiNPs (97.85 ± 2.26 nm) were fabricated and vasoconstrictor and vasodilator responses of mesenteric arteries assessed. RESULTS: We show that while exposure to SiNPs under static conditions, attenuated endothelial dependent dilator responses ex vivo, attenuation was only evident at lower agonist concentrations, when exposed under flow conditions or after intravenous administration in vivo. Pharmacological inhibition studies suggest that SiNPs may interfere with the endothelial dependent hyperpolarizing factor vasodilator pathway. CONCLUSION: The dosage dependent influence of SiNPs on arterial function will help identify strategies for their safe clinical administration.

Altered sensitivity to nitric oxide donors, induced by intravascular infusion of quantum dots, in murine mesenteric arteries.

Quantum dots (QDs) are utilised in imaging diagnostics, tissue engineering and medical therapeutics, however, their influence on vascular function is not ascertained. Here, we examined small mesenteric arterial responses after acute intravascular exposure to QDs. Incubation in mercaptoundecanoic acid (MUA)-coated QDs (at 15 µg/mL) had no influence on endothelial-dependent dilator responses (Acetylcholine; Ach) but led to an attenuated relaxation to the nitric oxide donor, sodium nitroprusside (SNP). Conversely, incubation in POSS-PCU coated QDs (at 15 µg/mL) led to attenuated Ach responses (10(-11)-10(-3)M; n=5, P<0.05), but had no influence on SNP-induced relaxation. At lower concentrations of POSS-PCU coated QDs (5 µg/mL), Ach responses were preserved. We demonstrate that acute exposure to QDs, can attenuate vasodilation but not vasoconstriction, and is dependent on their surface coatings. Our findings have implications in QD use for imaging diagnostics in disease states, where SNP based drugs are used in therapeutic intervention. FROM THE CLINICAL EDITOR: In this paper, the influence of quantum dots on vascular function is investigated---an important aspect to consider with the growing utility of quantum dots in imaging diagnostics, tissue engineering and medical therapeutics.