Electroacupuncture regulates the P2X7R-NLRP3 inflammatory cascade to relieve decreased sensation on ocular surface of type 2 diabetic rats with dry eye.

Dry eye (DE) is a prevalent ocular surface disease in patients with type 2 diabetes (T2DM). However, current medications are ineffective against decreased sensation on the ocular surface. While electroacupuncture (EA) effectively alleviates decreased sensation on ocular surface of DE in patients with T2DM, the neuroprotective mechanism remains unclear. This study explored the pathogenesis and therapeutic targets of T2DM-associated DE through bioinformatics analysis. It further investigated the underlying mechanism by which EA improves decreased sensation on the ocular surface of DE in rats with T2DM. Bioinformatic analysis was applied to annotate the potential pathogenesis of T2DM DE. T2DM and DE was induced in male rats. Following treatment with EA and fluorometholone, comprehensive metrics were assessed. Additionally, the expression patterns of key markers were studied. Key targets such as NLRP3, Caspase-1, and NOD-like receptor signaling may be involved in the pathogenesis of T2DM DE. EA treatment improved ocular measures. Furthermore, EA potently downregulated P2X7R, NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), and Caspase-1 expression within the trigeminal ganglion and spinal trigeminal nucleus caudalis. Targeted P2X7R antagonist (A-438079) and agonist (BzATP) employed as controls to decipher the biochemistry of the therapeutic effects of EA showed an anti-inflammatory effect with A-438079, while BzATP blocked the anti-inflammatory effect of EA. EA relieved DE symptoms and attenuated inflammatory damage to sensory nerve pathways in T2DM rats with DE. These findings suggest a crucial role of EA inhibition of the P2X7R-NLRP3 inflammatory cascade to provide these benefits.

Electroacupuncture Alleviates Dry Eye Ocular Pain Through TNF-ɑ Mediated ERK1/2/P2X3R Signaling Pathway in SD Rats.

Purpose: This study aimed to examine electroacupuncture's influence on ocular pain and its potential modulation of the TNF-ɑ mediated ERK1/2/P2X3R signaling pathway in dry eye-induced rat models. Methods: Male Sprague-Dawley rats with induced dry eye, achieved through extraorbital lacrimal gland removal, were treated with electroacupuncture. Comprehensive metrics such as the corneal mechanical perception threshold, palpebral fissure height, eyeblink frequency, eye wiping duration, behavioral changes in the open field test, and the forced swimming test were employed. Additionally, morphological changes in microglia and neurons were observed. Expression patterns of key markers, TNF-ɑ, TNFR1, p-ERK1/2, and P2X3R, in the trigeminal ganglion (TG) and spinal trigeminal nucleus caudalis (SpVc) regions, were studied with etanercept serving as a control to decipher the biochemistry of electroacupuncture's therapeutic effects. Results: Electroacupuncture treatment demonstrated a notable decrease in the corneal mechanical perception threshold, improvement in palpebral fissure height, and significant reductions in both eyeblink frequency and eye wiping duration. Moreover, it exhibited a promising role in anxiety alleviation. Notably, the technique effectively diminished ocular pain by curbing microglial and neuronal activation in the TG and SpVc regions. Furthermore, it potently downregulated TNF-ɑ, TNFR1, p-ERK1/2, and P2X3R expression within these regions. Conclusion: Electroacupuncture attenuated damage to sensory nerve pathways, reduced pain, and eased anxiety in dry eye-afflicted rats. The findings suggest a crucial role of TNF-ɑ mediated ERK1/2/P2X3R signaling pathway inhibition by electroacupuncture in these benefits.

Electroacupuncture Reduces Ocular Surface Neuralgia in Dry-Eyed Guinea Pigs by Inhibiting the Trigeminal Ganglion and Spinal Trigeminal Nucleus Caudalis P2X3R-PKC Signaling Pathway.

PURPOSE: To observe the effects of electroacupuncture on ocular surface neuralgia and the P2X3R-PKC signaling pathway in guinea pigs with dry eye. METHODS: A dry eye guinea pig model was established by subcutaneous injection of scopolamine hydrobromide. Guinea pigs were monitored for body weight, palpebral fissure height, number of blinks, corneal fluorescein staining score, phenol red thread test, and corneal mechanical perception threshold. Histopathological changes and mRNA expression of P2X3R and protein kinase C in the trigeminal ganglion and spinal trigeminal nucleus caudalis were observed. We performed a second part of the experiment, which involved the P2X3R-specific antagonist A317491 and the P2X3R agonist ATP in dry-eyed guinea pigs to further validate the involvement of the P2X3R-protein kinase C signaling pathway in the regulation of ocular surface neuralgia in dry eye. The number of blinks and corneal mechanical perception threshold were monitored before and 5 min after subconjunctival injection and the protein expression of P2X3R and protein kinase C was detected in the trigeminal ganglion and spinal trigeminal nucleus caudalis of guinea pigs. RESULTS: Dry-eyed guinea pigs showed pain-related manifestations and the expression of P2X3R and protein kinase C in the trigeminal ganglion and spinal trigeminal nucleus caudalis was upregulated. Electroacupuncture reduced pain-related manifestations and inhibited the expression of P2X3R and protein kinase C in the trigeminal ganglion and spinal trigeminal nucleus caudalis. Subconjunctival injection of A317491 attenuated corneal mechanoreceptive nociceptive sensitization in dry-eyed guinea pigs, while ATP blocked the analgesic effect of electroacupuncture. CONCLUSIONS: Electroacupuncture reduced ocular surface sensory neuralgia in dry-eyed guinea pigs, and the mechanism of action may be associated with the inhibition of the P2X3R-protein kinase C signaling pathway in the trigeminal ganglion and spinal trigeminal nucleus caudalis by electroacupuncture.

Nitric Oxide-Driven Nanomotor for Deep Tissue Penetration and Multidrug Resistance Reversal in Cancer Therapy.

Poor permeation of therapeutic agents and multidrug resistance (MDR) in solid tumors are the two major challenges that lead to the failure of the current chemotherapy methods. Herein, a zero-waste doxorubicin-loaded heparin/folic acid/l-arginine (HFLA-DOX) nanomotor with motion ability and sustained release of nitric oxide (NO) to achieve deep drug penetration and effective reversal of MDR in cancer chemotherapy is designed. The targeted recognition, penetration of blood vessels, intercellular penetration, special intracellular distribution (escaping from lysosomes and accumulating in Golgi and nucleus), 3D multicellular tumor spheroids (3D MTSs) penetration, degradation of tumor extracellular matrix (ECM), and reversal of MDR based on the synergistic effects of the motion ability and sustained NO release performance of the NO-driven nanomotors are investigated in detail. Correspondingly, a new chemotherapy mode called recognition-penetration-reversal-elimination is proposed, whose effectiveness is verified by in vitro cellular experiments and in vivo animal tumor model, which can not only provide effective solutions to these challenges encountered in cancer chemotherapy, but also apply to other therapy methods for the special deep-tissue penetration ability of a therapeutic agent.

A Safe and Efficient Strategy for the Rapid Elimination of Blood Lead In†Vivo Based on a Capture-Fix-Separate Mechanism.

Lead poisoning is an important problem because of its serious effects on human health. Yet a solution is not available due to an incomplete understanding of the state of lead ions in blood. Since most blood lead binds to hemoglobin (Hb) in red blood cells, identifying and capturing lead-contaminated Hb in RBCs is important. Herein, a magnetic blood lead remover with hyperbranched poly(amidoamine)s (HPAM) as template/co-adsorbent and core-shell mesoporous structure was synthesized. Lead-containing Hb was selectively captured and then fixed by mesoporous channels. The magnetic separation technology was used to separate the magnetic remover from blood. A related blood lead clean-up apparatus was used to remove lead from the blood of a pig in vivo. Results of physical/chemical characterizations, biocompatibility experiments, animal tests, and theoretical simulation verify the safety and efficiency of this removal strategy and the high efficiency of the blood lead clean-up apparatus.

Multiple Drug Delivery from Mesoporous Coating Realizing Combination Therapy for Bare Metal Stents.

The simultaneous loading of multifunctional drugs has been regarded as one of the major challenges in the drug delivery system. Herein, a mesoporous silica coating was constructed on a bare metal stent surface by an evaporation-induced self-assembly method, in which both hydrophilic and hydrophobic drugs (heparin and rapamycin) were encapsulated by a one-pot method for the first time, and the release behaviors of these drugs were studied. The releasing mechanisms of these drugs were investigated in detail. Rapid release of heparin can achieve anticoagulation and endothelialization, whereas slow release of rapamycin can realize antiproliferative therapy for long term. In vitro hemocompatibility and promotion for proliferation of vein endothelial cells and the inhibition of smooth muscle cells were conducted. In vivo stent implantation results verify that the mesoporous silica coating with both heparin and rapamycin can successfully accelerate the endothelialization process and realize the antiproliferative therapy for as long as 3 months. These results indicate that this multifunctional mesoporous coating containing both hydrophilic and hydrophobic drugs might be a promising stent coating in the future.

In Situ Loading of Drugs into Mesoporous Silica SBA-15.

In a new strategy for loading drugs into mesoporous silica, a hydrophilic (heparin) or hydrophobic drug (ibuprofen) is encapsulated directly in a one-pot synthesis by evaporation-induced self-assembly. In situ drug loading significantly cuts down the preparation time and dramatically increases the loaded amount and released fraction of the drug, and appropriate drug additives favor a mesoporous structure of the vessels. Drug loading was verified by FTIR spectroscopy and release tests, which revealed much longer release with a larger amount of heparin or ibuprofen compared to postloaded SBA-15. Besides, the in vitro anticoagulation properties of the released heparin and the biocompatibility of the vessels were carefully assessed, including activated partial thromboplastin time, thrombin time, hemolysis, platelet adhesion experiments, and the morphologies of red blood cells. A concept of new drug-release agents with soft core and hard shell is proposed and offers guidance for the design of novel drug-delivery systems.

Facilely Fabricating Multifunctional N-Enriched Carbon.

A new synthetic strategy, named "carbonization in limited space" and based on the specific interaction between eutectic salt and dual-ionic liquids (dual-ILs), is reported in this article. N-Containing dual-ILs (1,4-diethyl-1,4-diazaniabicyclo[2,2,2]octane imidazolide-4,5-dicyanoiazolide, [2C2DABCO](2+)[Im](-)[CN-Im](-)) were synthesized as new carbon-nitrogen precursors, while eutectic salt was chosen as a reuseable template in order to facilely fabricate the N-doped porous carbon with sheetlike morphology. Nitrogen can be directly and efficiently incorporated into the porous carbon, resulting in the materials with suitable N content, tunable pore structure, and controllable thickness of sheet as well as high surface area. They exhibited good performance as electrodes for supercapacitors, photocatalysts in degradation of methyl orange (MO) under visible light, and the sorbent to capture tobacco-specific N-nitrosamines (TSNAs) in solution, offering a new simplified but effective method to prepare versatile carbon material.

Novel CO2-capture derived from the basic ionic liquids orientated on mesoporous materials.

Two new basic ionic liquids (ILs) are designed and synthesized in order to conquer the challenge arising from the capture of CO2 in flue gas whose temperature is over 373 K, and they possess a suitable basic strength to adsorb CO2 at 393 K with the capacity of 22-49 mg g(-1). After these ILs are immobilized on mesoporous alumina or silica, equimolar CO2 capture is realized at 393 K for the first time. Besides, these adsorbents can be regenerated at 443 K to form a feasible cycle for controlling CO2 emission in flue gas. Theoretical calculations indicated the key role played by the mesoporous support in promoting CO2 adsorption via electrostatic interactions between support and ILs. An unwonted promotion of the support's ζ-potential on the performance of ILs is revealed, which induces the immobilized ILs to be oriented in a favorable dispersion, enhancing the efficiency of ILs in the CO2 adsorption at elevated temperature. This study proposes a new strategy for the sustainable development of novel adsorbent.

Fabricating a sustained releaser of heparin using SBA-15 mesoporous silica.

The sustained release of heparin in sufficient amounts and over long time is a challenge to drive the development of functional materials. In this paper SBA-15 mesoporous silica is selected in the search for a favorable morphology and optimized surface state for the sustained release of heparin. In situ carbonization of the template in the as-synthesized sample enables SBA-15 to possess narrowed channels with rougher surfaces, while modification with (aminopropyl)triethoxysilane (APTES) through a one-pot synthesis offers SBA-15 with positive charges to attract heparin through electro-static interactions. The structure of modified SBA-15 samples is assessed with XRD (powder X-ray diffraction analysis), nitrogen adsorption-desorption and electron microscopy techniques, and their performance is evaluated in adsorption and release of heparin. These modifications improve the heparin adsorption in SBA-15 and thus promote its sustained release, prolonging the release-equilibrium time up to 60 days. Among them, the SBA-15 sample modified with APTES can trap three times as much heparin as the parent SBA-15, and the release ratio is elevated to 80% (that of SBA-15 is 38%), realizing the best performance of controlling heparin release to date.

One-pot synthesis of a hierarchical PMO monolith with superior performance in enzyme immobilization.

A novel hierarchical periodic mesoporous organosilica (PMO) monolith is synthesized by using N,S-bis[3-(triethoxysilyl)propyl]-carbamothioic acid for the first time, in order to fabricate a highly efficient enzyme immobilizer. The hierarchical monolith is spontaneously formed with mild shearing force without further additives, in which the primary particles can be selectively prepared to be inter-connected with each other end to end to form a net-like framework throughout the whole monolith, and the inorganic/organic composition is finely controlled by adjusting the initial composition of the silica precursors. As the result, an ordered net framework with micrometer sized macropores and large mesopores is simultaneously obtained together with a high organic content, favoring high enzyme immobilization, in which they demonstrate an enhanced adsorption capacity, superior immobilization stability and good reusability. Especially, the PMO monolith can adsorb 126 mg g-1 of horseradish peroxidase (HRP), higher than double that of the power-like analogue (38 mg g-1); and the bioactivity is three times higher than that of the free enzyme, indicating the strong advantages of morphology assistance in enzyme immobilization.

Multiple functionalization of SBA-15 mesoporous silica in one-pot: fabricating an aluminum-containing plugged composite for sustained heparin release.

To fabricate an efficient releaser of heparin, which is an extensively used anticoagulant, aluminum containing plugged mesoporous silica SBA-15 is prepared using a one-pot synthesis process. A suitable aluminum additive in the starting mixture enables plugs to be formed inside hexagonal channels and Al species to be incorporated into the mesostructure, evidence for which is provided by powder X-ray diffraction analysis (XRD), transmission electron microscopy (TEM), N2 sorption measurements and 27Al MAS NMR tests. Incorporation of aluminum in SBA-15 reduces the negative charge (Zeta-potential) and tailors the surface roughness of the channel through forming plugs, and the former significantly improves heparin adsorption while the latter retards heparin release. As a result, these modified composites adsorb 2-4 times more heparin than parent SBA-15 and release 60-130% more of the drug over several weeks; the sample possessing both an Al-component and plug structure can sustain release of heparin for 6 weeks, demonstrating the increased efficiency of multiply functionalized SBA-15 in the controllable release of heparin and offering a valuable clue for design of novel drug releasers.

Sustained release of heparin on enlarged-pore and functionalized MCM-41.

Mesoporous silica MCM-41 and SBA-15 were chosen to study the adsorption and release of bulky biomolecule heparin, in order to develop new heparin controlled delivery system and expand the application of mesoporous materials in life science. To explore how the structure of support such as pore size and surface state affects the accommodation and release of heparin, we used decane as swelling agent to enlarge pores of MCM-41, introduced amino groups for improving the biocompatibility of support, and controllably retained templates in the as-synthesized sample. The influence of modification on the structure of samples was investigated by XRD and N(2) adsorption-desorption, whereas their performance of adsorbing and releasing heparin was assessed with that of toluidine blue method. Both enlarged pore and organic modification significantly promoted the adsorption and prolonged the release of heparin in MCM-41, and the release was characterized with a three-stage release model. The mechanism of heparin release from mesoporous material was studied by fitting the release profiles to the theoretical equation. As expected, some mesoporous composites could release heparin in the long term with tuned dosage.

Promoting immobilization and catalytic activity of horseradish peroxidase on mesoporous silica through template micelles.

New concept on the promotion of immobilization and catalytic activity of enzyme on mesoporous silica through template micelles is proposed and realized in this paper. Proper P123 templates are controllable retained in the as-synthesized SBA-15, not only to anchor the horseradish peroxidase (HRP) guest, but also to establish the crowding-like microenvironment around the enzyme. The influence of retaining templates on the pore structure of SBA-15, immobilization, and catalytic activity of HRP is studied, and the possible process of template removal is proposed. Ethanol refluxing of 6 h is conformable to prepare the optimal mesoporous support characterized with the retained templates of about 8%. With the assistance of retained templates in SBA-15, up to 49 mg g(-1) of HRP can be immobilized, 100% more than that on calcined SBA-15. Furthermore, the thermal stability, the resistance of pH variation and denaturing agent urea, and the recycle usage of HRP immobilized are obviously elevated, paving a novel and low-cost route to develop enzyme catalysts.

Novel phenol capturer derived from the as-synthesized MCM-41.

Novel phenol-capturer was prepared by modifying the as-synthesized mesoporous silica MCM-41 with tetraethylenepentamine (TEPA), not only saving the energy and time for removal of template, but also opening the way to utilize the micelles for adsorption. Once the organic modifier was distributed in the template micelle of MCM-41 to form a web within the mesoporous channel, the composite could adsorb more phenols in gas stream than activated carbon for the first time. With an unwanted high adsorption capacity, this mesoporous silica-amine composite represented potential application for trapping phenols, especially in tobacco smoke to protect environment.