Phospholipid Type Regulates Protein Corona Composition and In Vivo Performance of Lipid Nanodiscs.

Over the years, there has been significant interest in PEGylated lipid-based nanocarriers within the drug delivery field. The inevitable interplay between the nanocarriers and plasma protein plays a pivotal role in their in vivo biological fate. Understanding the factors influencing lipid-based nanocarrier and protein corona interactions is of paramount importance in the design and clinical translation of these nanocarriers. Herein, discoid-shaped lipid nanodiscs (sNDs) composed of different phospholipids with varied lipid tails and head groups were fabricated. We investigated the impact of phospholipid components on the interaction between sNDs and serum proteins, particle stability, and biodistribution. The results showed that all of these lipid nanodiscs remained stable over a 15 day storage period, while their stability in the blood serum demonstrated significant differences. The sND composed of POPG exhibited the least stability due to its potent complement activation capability, resulting in rapid blood clearance. Furthermore, a negative correlation between the complement activation capability and serum stability was identified. Pharmacokinetic and biodistribution experiments indicated that phospholipid composition did not influence the capability of sNDs to evade the accelerated blood clearance phenomenon. Complement deposition on the sND was inversely associated with the area under the curve. Additionally, all lipid nanodiscs exhibited dominant adsorption of apolipoprotein. Remarkably, the POPC-based lipid nanodisc displayed a significantly higher deposition of apolipoprotein E, contributing to an obvious brain distribution, which provides a promising tool for brain-targeted drug delivery.

Utilizing network pharmacology and experimental validation to investigate the underlying mechanism of Denglao Qingguan decoction against HCoV-229E.

Background: Denglao Qingguan decoction (DLQGD) has been extensively utilized for the treatment of colds, demonstrating significant therapeutic efficacy. Human Coronavirus 229E (HCoV-229E) is considered a crucial etiological agent of influenza. However, the specific impact and underlying mechanisms of DLQGD on HCoV-229E remain poorly understood. Methods: Active ingredients and targets information of DLQGD were collected from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), literature search, and Swiss ADEM database. The Genecard database was used to collect HCoV-229E related targets. We built an "ingredient-target network" through Cytoscape. Protein - Protein interaction (PPI) networks were mapped using the String database. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) were enriched using the DAVID database. Then, we used molecular docking techniques to verify the binding activity between the core compounds and the core gene targets. Finally, in vitro experiments were conducted to validate DLQGD's antiviral activity against HCoV-229E and assess its anti-inflammatory effects. Results: In total, we identified 227 active components in DLQGD. 18 key targets involved in its activity against HCoV-229E. Notably, the core active ingredients including quercetin, luteolin, kaempferol, ß-sitosterol, and apigenin, and the core therapeutic targets were CXCL8, RELA, MAPK14, NFKB1, and CXCL10, all associated with HCoV-229E. KEGG enrichment results included IL-17 signaling pathway, Toll-like receptor signaling pathway, RIG-I-like receptor signaling pathway and so on. The core active ingredients and the core therapeutic targets and Human Aminopeptidase N (ANPEP) all showed good binding activity by molecular docking verification. In vitro, DLQGD exhibited anti-HCoV-229E activity and anti-inflammatory effects. Conclusion: Our study suggests that DLQGD has both effects of anti-HCoV-229E and anti-inflammatory. The core active ingredients (quercetin, luteolin, kaempferol, ß-sitosterol, apigenin) and the core therapeutic targets (CXCL8, RELA, MAPK14, NFKB1, CXCL10) may play key roles in the pharmacological action of DLQGD against HCoV-229E.

Dynamic performance of a membrane-based variable focus lens with a large aperture.

Dynamic performance is one of the most important characteristics of a variable focus lens. However, there are few studies investigating the dynamic response of a membrane-based variable focus lens. In this paper, we present a mathematical model to describe spring-damping phenomena in theory. The first order natural frequencies with different scales were confirmed via finite element analysis. We also built a dynamic response experiment platform with changeable optical apertures, which was driven by a high-speed piezo stack actuator. A photodiode module was placed behind the lens to measure the variation of light luminance as the lens changed, and a laser displacement sensor was used to measure the deformation of the membrane. A series of data was collected with different optical apertures (20 mm, 30 mm, 50 mm) and different pre-stretching ratios (200%, 300%) under different driving frequencies (from 5 Hz to 25 Hz in every 5 Hz step). The experimental results were consistent with the mathematical model, which showed that the first order natural frequency increased as the aperture decreased or the membrane stiffness increased. This frequency-dependent characteristic of the variable focus lens provides a basis for further research on its dynamic performance.

Phase wavefront perturbation calculation model for spectroscopic refractive index matching of hybrid materials.

A low-cost flexible spectroscopic refractive index matching (SRIM) material with bandpass filtering properties without incidence angle and polarization dependence by randomly dispersing inorganic C a F 2 particles in organic polydimethylsiloxane (PDMS) materials was proposed in our previous study. Since the micron size of the dispersed particles is much larger than the visible wavelength, the calculation based on the commonly used finite-difference time-domain (FDTD) method to simulate light propagation through the SRIM material is too bulky; however, on the other hand, the light tracing method based on Monte Carlo theory in our previous study cannot adequately explain the process. Therefore, a novel approximate calculation model, to the best of our knowledge, based on phase wavefront perturbation is proposed that can well explain the propagation of light through this SRIM sample material and can also be used to approximate the soft scattering of light through composite materials with small refractive index differences, such as translucent ceramics. The model simplifies the complex superposition of wavefront phase disturbances and the calculation of scattered light propagation in space. The scattered and nonscattered light ratios; the light intensity distribution after transmission through the spectroscopic material; and the influence of absorption attenuation of the PDMS organic material on the spectroscopic performance are also considered. The simulation results based on the model are in great agreement with the experimental results. This work is important to further improve the performance of SRIM materials.

Color tunable Ca8ZnM(PO4)7 (M = Lu/Tb, Lu/Eu, Tb/Eu) phosphors: luminescence, energy transfer and thermal stability studies for n-UV white LEDs.

A series of Tb3+- and Eu3+-doped Ca8ZnLu(PO4)7 (CZLP:Tb3+ and CZLP:Eu3+) as well as Ca8ZnTb(PO4)7:Eu3+ (CZTP:Eu3+) phosphors have been prepared via the traditional high-temperature solid-state reaction. X-ray powder diffraction (XRD) patterns of the as-prepared phosphors indicate that the introduction of Tb3+ or Eu3+ affects neither the phase impurity nor the crystal structure of the CZLP host lattice. The concentration dependent photoluminescence (PL) spectra reveal that even if Lu3+ was fully substituted by the dopants, Tb3+ or Eu3+, the phenomenon of concentration quenching would not occur. Color tunable emissions from green to red can be realized by adjusting the type of doping ion (Tb3+ and Eu3+) and their relative concentration. Furthermore, the energy transfer from Tb3+ to Eu3+ was confirmed and the mechanism was determined to be the dipole-quadrupole interaction. In addition, the quantum efficiencies were found to be 0.61, 0.58 and 0.85 for CZTP, CZTP:0.2Eu3+ and CaZnEu(PO4)7 (CZEP), respectively. As a result, a white light emitting diode (WLED) device was fabricated using the optimal CZTP:0.2Eu3+ yellow phosphor, the BaMgAl10O17:Eu2+ (BAM:Eu2+) blue phosphor and a 370 nm near-ultraviolet (n-UV) chip. The obtained device displays a suitable color rendering index (CRI, ∼81.3) and correlated color temperature (CCT, ∼2634 K) value, indicating its potential application in n-UV LEDs.

Antigenic Drift of the Hemagglutinin from an Influenza A (H1N1) pdm09 Clinical Isolate Increases its Pathogenicity In Vitro.

The influenza A (H1N1) pdm09 virus emerged in 2009 and has been continuously circulating in humans for over ten years. Here, we analyzed a clinical influenza A (H1N1) pdm09-infected patient case hospitalized for two months in Guangdong (from December 14, 2019 to February 15, 2020). This isolate, named A/Guangdong/LCF/2019 (LCF/19), was genetically sequenced, rescued by reverse genetics, and phylogenetically analyzed in the context of other relevant pdm09 isolates. Compared with earlier isolates, this pdm09 virus's genetic sequence contains four substitutions, S186P, T188I, D190A, and Q192E, of the hemagglutinin (HA) segment at position 186-192 (H3 numbering) in the epitope Sb, and two of which are located at the 190-helix. Phylogenetic analysis indicated that the epitope Sb started undergoing a rapid antigenic change in 2018. To characterize the pathogenicity of this novel substitution motif, a panel of reassortant viruses containing the LCF/2019 HA segment or the chimeric HA segment with the four substitutions were rescued. Kinetic growth data revealed that the reassortant viruses, including the LCF/2019 with the PTIAAQE substitution, propagated faster than those rescued ones having the STTADQQ motif in the epitope Sb in Madin-Darby Canine Kidney (MDCK) cells. The HI test showed that the binding activity of escape mutant to 2018 pdm09 sera was weaker than GLW/2018, suggesting that old vaccines might not effectively protect people from infection. Due to the difference in the selection of vaccine strains, people vaccinated in the southern hemisphere could still suffer a severe infection if infected with this antigenic drift pdm09 virus.

Generation of a pdmH1N1 2018 Influenza A Reporter Virus Carrying a mCherry Fluorescent Protein in the PA Segment.

Influenza A virus (IAV) is a major human pathogen associated with significant morbidity and mortality worldwide. Through serial passage in mice, we generated a recombinant pdmH1N1 2009 IAV, A/Guangdong/GLW/2018 (GLW/18-MA), which encodes an mCherry gene fused to the C-terminal of a polymerase acidic (PA) segment and demonstrated comparable growth kinetics to the wild-type. Nine mutations were identified in the GLW/18-MA genome: PA (I61M, E351G, and G631S), NP (E292G), HA1 (T164I), HA2 (N117S and P160S), NA (W61R), and NEP (K44R). The recombinant IAV reporter expresses mCherry, a red fluorescent protein, at a high level and maintains its genetic integrity after five generations of serial passages in Madin-Darby Canine Kidney cells (MDCK) cells. Moreover, the imaging is noninvasive and permits the monitoring of infection in living mice. Treatment with oseltamivir or baicalin followed by infection with the reporter IAV led to a decrease in fluorescent protein signal in living mice. This result demonstrates that the IAV reporter virus is a powerful tool to study viral pathogenicity and transmission and to develop and evaluate novel anti-viral drugs, inhibitors, and vaccines in the future.

Role of pericyte-derived SENP1 in neuronal injury after brain ischemia.

AIMS: SUMOylation is a posttranslational modification related to multiple human diseases. SUMOylation can be reversed by classes of proteases known as the sentrin/SUMO-specific proteases (SENPs). In the present study, we investigate the potential role of SENP1 in pericytes in the brain ischemia. METHODS: Pericyte-specific deletion of senp1 mice (Cspg4-Cre; senp1f/f ) were used for brain function and neuronal damage evaluation following brain ischemia. The cerebral blood vessels of diameter, velocity, and flux were performed in living mice by two-photon laser scanning microscopy (TPLSM). Biochemical analysis and immunohistochemistry methods were used to address the role and mechanism of pericyte-specific SENP1 in the pathological process of brain ischemia. A coculture model of HBVPs and HBMECs mimicked the BBB in vitro and was used to evaluate BBB integrity after glucose deprivation. RESULTS: Our results showed that senp1-specific deletion in pericytes did not affect the motor function and cognitive function of mice. However, the pericyte-specific deletion of senp1 aggravated the infarct size and motor deficit following focal brain ischemia. Consistently, the TPLSM data demonstrated that SENP1 deletion in pericytes accelerated thrombosis formation in brain microvessels. We also found that pericyte-specific deletion of senp1 exaggerated the neuronal damage significantly following brain ischemia in mice. Moreover, SENP1 knockdown in pericytes could activate the apoptosis signaling and disrupt the barrier integrity in vitro coculture model. CONCLUSIONS: Our findings revealed that targeting SENP1 in pericytes may represent a novel therapeutic strategy for neurovascular protection in stroke.