Targeted-lung delivery of bardoxolone methyl using PECAM-1 antibody-conjugated nanostructure lipid carriers for the treatment of lung inflammation.

The effective treatment of acute lung injury (ALI) remains a significant challenge. Patients with ALI demonstrate an abundance of proinflammatory mediators in both bronchoalveolar lavage fluid (BALF) and circulating plasma. Bardoxolone methyl (BM) is a semi-synthetic triterpenoid derived from oleanolic acid, a natural product known for its ability to inhibit proinflammatory signaling. GSDMD is a signaling protein involved in pyroptosis, a form of programmed cell death. It has been reported that its upstream proteins play a role in the pathogenesis of ALI. However, there is currently no research examining whether the effect of BM on the occurrence and development of ALI is associated with changes in GSDMD protein. In this study, we prepared nanostructured lipid carriers loaded with BM and conjugated with anti-PECAM-1 antibody (PECAM@BM NLCs). PECAM@BM NLCs were designed to specifically bind to pulmonary vascular endothelial cells that highly express the PECAM-1 receptors. We also aimed to investigate the protective effects of PECAM@BM NLCs on ALI and elucidate the underlying molecular mechanisms. The results demonstrated that PECAM@BM NLCs accumulated in the lung tissues and significantly alleviated the inflammatory injury of ALI. This was evidenced by the changes in the lung wet/dry ratio, the total protein concentration, proinflammatory cytokines in BALF, and the histopathological progress. Additionally, we elucidated that PECAM@BM NLCs had the ability to inhibit the assembly of NLRP3 inflammasome and pro-caspase-1 complex, thereby suppressing the induction of pyroptosis. This mechanism resulted in the inhibition of N-terminal GSDMD expression and effectively prevented the progression of ALI.

Engineering of VCAM-1-targeted nanostructured lipid carriers for delivery of melatonin against acute lung injury through SIRT1/NLRP3 mediated pyroptosis signaling pathway.

Acute lung injury (ALI) is a prevalent and critical condition in clinical practice. Although certain pharmacological interventions have demonstrated benefits in preclinical studies, none have been proven entirely effective thus far. Therefore, the development of more efficient treatment strategies for ALI is imperative. In this study, we prepared nanostructured lipid carriers (NLCs) conjugated with anti-VCAM-1 antibodies to encapsulate melatonin (MLT), resulting in VCAM/MLT NLCs. This approach aimed to enhance the distribution of melatonin in lung vascular endothelial cells. The VCAM/MLT NLCs had an average diameter of 364 nm, high drug loading content, and a sustained drug release profile. Notably, the NLCs conjugated with anti-VCAM-1 antibodies demonstrated more specific cellular delivery mediated by the VCAM-1 receptors, increased cellular internalization, and enhanced accumulation in lung tissues. Treatment with VCAM/MLT NLCs effectively alleviated pulmonary inflammation by activating NLRP3 inflammasome-dependent pyroptosis through up-regulation of Sirtuin 1. Our findings suggest that VCAM/MLT NLCs demonstrate remarkable therapeutic effects on ALI in both in vitro and in vivo settings, making them a promising and efficient treatment strategy for ALI.

Correction: An E-selectin targeting and MMP-2-responsive dextran-curcumin polymeric prodrug for targeted therapy of acute kidney injury.

Correction for 'An E-selectin targeting and MMP-2-responsive dextran-curcumin polymeric prodrug for targeted therapy of acute kidney injury' by Jing-Bo Hu et al., Biomater. Sci., 2018, 6, 3397-3409, https://doi.org/10.1039/C8BM00813B.

Engineering of targeting antioxidant polypeptide nanopolyplexes for the treatment of acute lung injury.

The pathogenesis of acute lung injury (ALI) involves various mechanisms, such as oxidative stress, inflammation, and epithelial cell apoptosis. However, current drug therapies face limitations due to issues like systemic distribution, drug degradation in vivo, and hydrophobicity. To address these challenges, we developed a pH-responsive nano-drug delivery system for delivering antioxidant peptides to treat ALI. In this study, we utilized low molecular weight chitosan (LMWC) and hyaluronic acid (HA) as carrier materials. LMWC carries a positive charge, while HA carries a negative charge. By stirring the two together, the electrostatic adsorption between LMWC and HA yielded aggregated drug carriers. To specifically target the antioxidant drug WNWAD to lung lesions and enhance therapeutic outcomes for ALI, we created a targeted drug delivery system known as HA/LMWC@WNWAD (NPs) through a 12-h stirring process. In our research, we characterized the particle size and drug release of NPs. Additionally, we assessed the targeting ability of NPs. Lastly, we evaluated the improvement of lung injury at the cellular and animal levels to investigate the therapeutic mechanism of this drug targeting delivery system.

Synergy of Organic/Inorganic and Inner/Outer Cooperative Conductive Networks in Polydimethylsiloxane-Based Porous Foam on High-Performance Flexible Sensors.

The development of low-cost and high-performance flexible sensor materials is crucial for the advancement of wearable electronic devices, medical monitoring, and human-machine interfaces. In this study, a poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS)-coated multiwalled carbon nanotube (MWCNT)-reinforced polydimethylsiloxane (PDMS) composite foam with a uniform organic/inorganic and inner/outer cooperative conductive network was developed to detect tensile and compressive forces. The study demonstrates that the internally cross-linked MWCNTs and PEDOT:PSS coatings within the foam framework play a crucial role in the porous structure and sensing properties of the composite foam. Due to the excellent hierarchical pore structure and dual-channel electronic pathway of the PP@MWCNTs/PDMS foam, the sensor exhibited not only high sensitivity to small pressures but also notable perception capability within the stretchable range. It also maintained excellent stability during multiple stretching and compression loading cycles. In terms of applications, the sensor could be used not only to monitor external stimuli and detect subtle movements within the human body in the field of wearable monitoring but also to sense spatial pressure distribution, which validates its potential in the development of flexible wearable sensing devices.

Thermoelectric Properties of One-Pot Hydrothermally Synthesized Solution-Processable PEDOT:PSS/MWCNT Composite Materials.

The combination of organic and inorganic materials has been considered an effective solution for achieving ambient thermoelectric energy harvesting and has been developing rapidly. Here, PEDOT:PSS/MWCNT (PPM) composite hydrogels were synthesized using the self-assembled gelation process of poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) (PEDOT:PSS) and the interaction between PEDOT:PSS and multi-walled carbon nanotubes (MWCNTs) without the addition of any surfactant. After immersion in dimethyl sulfoxide and freeze-drying, the hydrogel is easily dispersed in water and used as a direct ink writing (DIW) 3D printing ink. At room temperature, the PPM-20 printed film with 20 wt% MWCNT solids achieved a maximum power factor of 7.37 µW m-1 K-2 and maintained stable thermoelectric properties during repeated bending cycles. On this basis, a thermoelectric generator (TEG) consisting of five legs was printed, which could be produced to generate an open circuit voltage of 6.4 mV and a maximum output power of 40.48 nW at a temperature gradient of 50 K, confirming its great potential for application in high-performance flexible organic/inorganic thermoelectric materials.

Combination of bioaffinity ultrafiltration-UFLC-ESI-Q/TOF-MS/MS, in silico docking and multiple complex networks to explore antitumor mechanism of topoisomerase I inhibitors from Artemisiae Scopariae Herba.

BACKGROUND: Artemisiae Scopariae Herba (ASH) has been widely used as plant medicine in East Asia with remarkable antitumor activity. However, the underlying mechanisms have not been fully elucidated. METHODS: This study aimed to construct a multi-disciplinary approach to screen topoisomerase I (topo I) inhibitors from ASH extract, and explore the antitumor mechanisms. Bioaffinity ultrafiltration-UFLC-ESI-Q/TOF-MS/MS was used to identify chemical constitution of ASH extract as well as the topo I inhibitors, and in silico docking coupled with multiple complex networks was applied to interpret the molecular mechanisms. RESULTS: Crude ASH extract exhibited toxicogenetic and antiproliferative activities on A549 cells. A series of 34 ingredients were identified from the extract, and 6 compounds were screened as potential topo I inhibitors. Docking results showed that the formation of hydrogen bond and π-π stacking contributed most to their binding with topo I. Interrelationships among the 6 compounds, related targets and pathways were analyzed by multiple complex networks model. These networks displayed power-law degree distribution and small-world property. Statistical analysis indicated that isorhamnetin and quercetin were main active ingredients, and that chemical carcinogenesis-reactive oxygen species was the critical pathway. Electrophoretic results showed a therapeutic effect of ASH extract on the conversion of supercoiled DNA to relaxed forms, as well as potential synergistic effect of isorhamnetin and quercetin. CONCLUSIONS: The results improved current understanding of Artemisiae Scopariae Herba on the treatment of tumor. Moreover, the combination of multi-disciplinary methods provided a new strategy for the study of bioactive constituents in medicinal plants.

Integrated morphological and transcriptome profiles reveal a highly-developed extrusome system associated to virulence in the notorious fish parasite, Ichthyophthirius multifiliis.

Ichthyophthirius multifiliis is an obligate parasitic ciliate that causes severe economic damage in aquaculture. The parasite contains numerous extrusive organelles (extrusomes) that assist in its pathogenesis and reproduction. However, the structure of these extrusomes and the molecular profiles involved in exocytosis remain unclear. In the present study, through comparative ultrastructural observations across the life cycle of I. multifiliis, we demonstrated that all three of its life stages (theront, trophont, and tomont) exhibited an abundance of extrusomes. In addition, two different types of extrusomes were identified according to their unique structures. Type I extrusomes (mucocysts) are crystalline, oval-shaped, 0.7-1.4 × 0.6-1.1 µm, and distributed as "rosettes" below the trophont membrane. Type II extrusomes, 2.0-3.0 × 0.2-0.3 µm, are rod-shaped with tubular cores and identified as toxicysts, the aggregation of which in the anterior part of the theront and cortex of the trophont revealed their potential roles in I. multifiliis invasion. This was confirmed by our transcriptome investigations of the three stages of I. multifiliis, which revealed that a set of genes involved in proteolysis and DNA/protein biogenesis was highly expressed in the theront and trophont. Furthermore, to map the molecular mechanisms of extrusome release, we characterized 25 Rab family genes in I. multifiliis and determined their expression profiles across the life cycle, reflecting the distribution patterns of the two extrusomes. Collectively, our data revealed that a highly developed extrusome system could play a potential role in the virulence of I. multifiliis, which facilitates a better understanding of the parasite's development.

Evaluation of the genotype I Japanese encephalitis virus as a stable viral vector for foreign gene expression.

Manipulation of the flavivirus genome to accommodate and express a heterologous gene of interest has become an attractive approach for gene delivery and the development of viral-vectored vaccines. However, due to the inherent genetic instability of the flavivirus genomes, the construction of recombinant viruses carrying a foreign gene could be problematic and heavily resistant. In this study, the possibility of the Japanese encephalitis virus (JEV) as a stable flavivirus vector for the expression of a foreign gene was assessed using reverse genetics. The full-length cDNA genome of genotype I (GI) JEV inherently possessed excellent stability and manipulability in a bacterial host, while mutations and deletions accumulated in the cDNA genomes of genotype Ⅲ (GⅢ) JEV strains. Using the GI JEV as backbones, we generate a panel of recombinant viruses expressing various foreign genes. All recombinant viruses exhibited excellent genetic stability and efficiently express foreign genes for at least ten serial passages in vitro. In application, a convenient, rapid and reliable image-based assay for neutralizing antibody testing and antiviral drug discovery was established with a mCherry-reporter recombinant virus (rBJ-mCherry). Meanwhile, the recombinant viruses expressing the antigens of the African swine fever virus (ASFV) or Classical swine fever virus (CSFV) could effectively induce antibody responses to the JEV vector and foreign antigens in a mouse vaccination model. Therefore, GI JEV strains could serve as viral vectors accommodating the expression of large foreign genes.

Allicin Inhibits Porcine Reproductive and Respiratory Syndrome Virus Infection In Vitro and Alleviates Inflammatory Responses.

Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most economically important pathogens to the swine industry worldwide over the past three decades. No approved effective antiviral drug is available to control this virus. The antiviral effects of allicin (diallyl thiosulfinate) on many human and animal viruses have been documented. However, the antiviral effect of allicin on PRRSV infection remains unknown. In this study, we found that allicin exhibited an inhibitory effect on HP-PRRSV and NADC30-like PRRSV in a dose-dependent manner by interfering with viral entry, replication, and assembly. Furthermore, allicin alleviated the expression of pro-inflammatory cytokines (IFN-ß, IL-6, and TNFα) induced by PRRSV infection. The pro-inflammatory signaling pathways, TNF signaling pathway and MAPK signaling pathway, up-regulated by PRRSV infection were restored by allicin treatment. Taken together, these results demonstrate that allicin has antiviral activity against PRRSV and ameliorates inflammatory responses induced by PRRSV infection, suggesting that allicin is a promising drug candidate for anti-PRRSV therapy in vivo.

Evaluation of high oleic sunflower oil oleogels with beeswax, beeswax-glyceryl monopalmitate, and beeswax-Span80 in cookie preparation.

BACKGROUND: Shortening is used widely in cookie preparation to improve quality and texture. However, large amounts of saturated and trans fatty acids present in shortening have adverse effects on human health, and much effort has been made to reduce the use of shortening. The use of oleogels might be a suitable alternative. In this study, the oleogels of high oleic sunflower oil with beeswax (BW), BW-glyceryl monopalmitate (BW-GMP), and BW-Span80 (BW-S80) were prepared and their suitability to replace shortening in cookie preparation was evaluated. RESULTS: The solid fat content of BW, BW-GMP, and BW-S80 oleogels was significantly lower than that of commercial shortening when the temperature was not higher than 35 °C. However, the oil-binding capacity of these oleogels was almost similar to that of shortening. The crystals in the shortening and oleogels were ß' form mainly; however, the morphology of crystal aggregates in these oleogels was different from that of shortening. The textural and rheological properties of doughs prepared with the oleogels were similar, and clearly different from those of dough with commercial shortening. The breaking strengths of cookies made with oleogels were lower than that of cookies prepared with shortening. However, cookies containing BW-GMP and BW-S80 oleogels were similar in density and color to those prepared with shortening. CONCLUSION: The textural properties and color of cookies with BW-GMP and BW-S80 oleogels were very similar to those of the cookies containing commercial shortening. The BW-GMP and BW-S80 oleogels could act as alternatives to shortening in the preparation of cookies. © 2023 Society of Chemical Industry.

Integrated analysis of topoisomerase I inhibitors from flavonoids of Scutellaria baicalensis Georgi using bioaffinity ultrafiltration UPLC-TripleTOF MS/MS, molecular docking and target-based multiple complex networks.

Scutellaria baicalensis Georgi (SBG) has been widely used as medical plant in East Asia with remarkable anti-cancer activity. However, the underlying mechanisms are still confused. In this study, an integrated analysis was conducted to screen topoisomerase I (topo I) inhibitors from flavonoids of SBG and investigate the anti-cancer mechanisms, containing bioaffinity ultrafiltration UPLC-ESI-TripleTOF-MS/MS, molecular docking, and multiple complex networks. The SBG extract exhibited notable cytotoxic activity on Hela cells. Five flavonoids were identified as potential topo I inhibitors, including skullcapflavone II, wogonin, chrysin, oroxylin A, and tenaxin I. Their ESI-MS/MS spectra showed that RDA reaction and neutral molecule loss were the main fragment patterns. Docking results demonstrated that π-π interaction and the formation of hydrogen bond contributed most to their binding with topo I. The selected compounds, related target proteins and pathways were integrated into target-based multiple complex networks, which consisted of three subnetworks. Statistical and topological analysis of these networks revealed a series of characteristics, including scale-free property with power-law degree distribution, Poisson degree distribution, and small-world property. Chrysin, wogonin, and oroxylin A exhibited as main active components with much higher degree values. Chemical carcinogenesis-receptor activation (hsa05207) was considered as critical pathway due to remarkable centrality indexes. Additionally, potential synergistic effect of wogonin and chrysin was observed on the conversion of supercoiled DNA to relaxed forms. These results improved current understanding of flavonoid-rich plants on the treatment of cancer. Moreover, the multi-disciplinary approach provided a new strategy for the research of natural products from medical plants.

Corrigendum: Advances in the research of nano delivery systems in ischemic stroke.

[This corrects the article DOI: 10.3389/fbioe.2022.984424.].

A Recombinant Genotype I Japanese Encephalitis Virus Expressing a Gaussia Luciferase Gene for Antiviral Drug Screening Assay and Neutralizing Antibodies Detection.

Japanese encephalitis virus (JEV) is the major cause of viral encephalitis in humans throughout Asia. In the past twenty years, the emergence of the genotype I (GI) JEV as the dominant genotype in Asian countries has raised a significant threat to public health security. However, no clinically approved drug is available for the specific treatment of JEV infection, and the commercial vaccines derived from the genotype III JEV strains merely provided partial protection against the GI JEV. Thus, an easy-to-perform platform in high-throughput is urgently needed for the antiviral drug screening and assessment of neutralizing antibodies specific against the GI JEV. In this study, we established a reverse genetics system for the GI JEV strain (YZ-1) using a homologous recombination strategy. Using this reverse genetic system, a gaussia luciferase (Gluc) expression cassette was inserted into the JEV genome to generate a reporter virus (rGI-Gluc). The reporter virus exhibited similar growth kinetics to the parental virus and remained genetically stable for at least ten passages in vitro. Of note, the bioluminescence signal strength of Gluc in the culture supernatants was well correlated with the viral progenies determined by viral titration. Taking advantage of this reporter virus, we established Gluc readout-based assays for antiviral drug screening and neutralizing antibody detection against the GI JEV. These Gluc readout-based assays exhibited comparable performance to the assays using an actual virus and are less time consuming and are applicable for a high-throughput format. Taken together, we generated a GI JEV reporter virus expressing a Gluc gene that could be a valuable tool for an antiviral drug screening assay and neutralization assay.

Advances in the research of nano delivery systems in ischemic stroke.

Ischemic stroke is the most common type of cerebrovascular disease with high disability rate and mortality. The blood-brain barrier (BBB) protects the homeostasis of the brain's microenvironment and impedes the penetration of 98% of drugs. Therefore, effective treatment requires the better drug transport across membranes and increased drug distribution. Nanoparticles are a good choice for drugs to cross BBB. The main pathways of nano delivery systems through BBB include passive diffusion, adsorption-mediated endocytosis, receptor-mediated transport, carrier-mediated transport, etc. At present, the materials used in brain-targeted delivery can be divided into natural polymer, synthetic polymers, inorganic materials and phospholipid. In this review, we first introduced several ways of nano delivery systems crossing the BBB, and then summarized their applications in ischemic stroke. Based on their potential and challenges in the treatment of ischemic stroke, new ideas and prospects are proposed for designing feasible and effective nano delivery systems.

Correction to "A Stepwise Targeting Curcumin Derivative, Ser@TPP@CUR, for Acute Kidney Injury".

[This corrects the article DOI: 10.1021/acsmedchemlett.1c00585.].

Enhanced efficiency of melatonin by stepwise-targeting strategy for acute lung injury.

Oxidative stress plays a key role in the progress of acute lung injury (ALI), which is an acute, progressive respiratory failure characterized by alveolar capillary injury caused by various external and internal factors other than cardiogenic factors. Pulmonary vascular endothelial cells are the main target cells during ALI, and therefore the mitochondrial targeting antioxidant derivative triphenylphosphine-melatonin (TPP-MLT) was encapsulated in VCAM-1 antibodies-conjugated nanostructured lipid carriers (VCAM@TPP-MLT NLCs) for lung targeting delivery. VCAM@TPP-MLT NLCs could be preferentially internalized by inflammatory endothelial cells in lung tissues, and then the released TPP-MLT from NLCs effectively eliminated the excessive reactive oxide species (ROS) and ameliorated cell apoptosis. Overall, the results suggested that VCAM@TPP-MLT NLCs exhibited remarkable in vitro and in vivo therapeutic effect on ALI, and could be a promising and efficient strategy for the treatment of ALI.