Polystyrene nanoplastics induce apoptosis, autophagy, and steroidogenesis disruption in granulosa cells to reduce oocyte quality and fertility by inhibiting the PI3K/AKT pathway in female mice.

BACKGROUND: Nanoplastics (NPs) are emerging pollutants that pose risks to living organisms. Recent findings have unveiled the reproductive harm caused by polystyrene nanoparticles (PS-NPs) in female animals, yet the intricate mechanism remains incompletely understood. Under this research, we investigated whether sustained exposure to PS-NPs at certain concentrations in vivo can enter oocytes through the zona pellucida or through other routes that affect female reproduction. RESULTS: We show that PS-NPs disrupted ovarian functions and decreased oocyte quality, which may be a contributing factor to lower female fertility in mice. RNA sequencing of mouse ovaries illustrated that the PI3K-AKT signaling pathway emerged as the predominant environmental information processing pathway responding to PS-NPs. Western blotting results of ovaries in vivo and cells in vitro showed that PS-NPs deactivated PI3K-AKT signaling pathway by down-regulating the expression of PI3K and reducing AKT phosphorylation at the protein level, PI3K-AKT signaling pathway which was accompanied by the activation of autophagy and apoptosis and the disruption of steroidogenesis in granulosa cells. Since PS-NPs penetrate granulosa cells but not oocytes, we examined whether PS-NPs indirectly affect oocyte quality through granulosa cells using a granulosa cell-oocyte coculture system. Preincubation of granulosa cells with PS-NPs causes granulosa cell dysfunction, resulting in a decrease in the quality of the cocultured oocytes that can be reversed by the addition of 17ß-estradiol. CONCLUSIONS: This study provides findings on how PS-NPs impact ovarian function and include transcriptome sequencing analysis of ovarian tissue. The study demonstrates that PS-NPs impair oocyte quality by altering the functioning of ovarian granulosa cells. Therefore, it is necessary to focus on the research on the effects of PS-NPs on female reproduction and the related methods that may mitigate their toxicity.

Design, Synthesis, Antibacterial, and Antitumor Activity of Linear Polyisocyanide Quaternary Ammonium Salts with Different Structures and Chain Lengths.

The development of organic polymer materials for disinfection and sterilization is thought of as one of the most promising avenues to solve the growth and spread of harmful microorganisms. Here, a series of linear polyisocyanide quaternary ammonium salts (L-PQASs) with different structures and chain lengths were designed and synthesized by polymerization of phenyl isocyanide monomer containing a 4-chloro-1-butyl side chain followed by quaternary amination salinization. The resultant compounds were characterized by 1H NMR and FT-IR. The antibacterial activity of L-PQASs with different structures and chain lengths against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) was evaluated by determining the minimum inhibitory concentrations (MICs). The L-POcQAS-M50 has the strongest antimicrobial activity with MICs of 27 µg/mL against E. coli and 32 µg/mL against S. aureus. When the L-PQASs had the same polymerization degree, the order of the antibacterial activity of the L-PQASs was L-POcQAS-Mn > L-PBuQAS-Mn > L-PBnQAS-Mn > L-PDBQAS-Mn (linear, polyisocyanide quaternary ammonium salt, monomer, n = 50,100). However, when L-PQASs had the same side chain, the antibacterial activity reduced with the increase of the molecular weight of the main chain. These results demonstrated that the antibacterial activity of L-PQASs was dependent on the structure of the main chain and the length of the side chain. In addition, we also found that the L-POcQAS-M50 had a significant killing effect on MK-28 gastric cancer cells.

[Detection of aspiration of nasopharyngeal secretion and the relationship between the aspiration of nasopharyngeal secretion and the incidence of pneumonia].

OBJECTIVE: To establish a method to detect aspiration of nasopharyngeal secretion and to explore the relationship between aspiration of nasopharyngeal secretion and pneumonia. METHOD: Thirty-two patients with pulmonary infection [(30 males, 2 females; mean age (73 ± 8) years] were recruited from the First Affiliated Hospital of Guangzhou Medical University during the period between June 2014 and August 2014, and 9 age-matched healthy volunteers [(7 males, 2 females; mean age (73 ± 6) years] as the control group. A dose of 74.0 MBq 99Tc(m)-sulfur colloid was diluted in 12 ml of saline, and then the mixture was dripped into the nasal pharynx of volunteers by 24 ml/h. Dynamic imaging from the mouth to the stomach was acquired by SPECT/CT. Two experienced physicians assessed all examination results and reached consensus for final diagnosis. Radioactivity detected at either the bronchi or within the lung fields was reported as positive for aspiration. RESULTS: In the test group, 19 of 32 patients with pneumonia had a history of suffering from upper respiratory tract symptoms such as runny or blocked nose, and 21 of 32 patients were detected to have aspiration. However, none of the healthy people had aspiration (χ² = 9.624, P=0.002). In 21 patients with pneumonia, 14 showed respiratory aspirations in areas corresponding to the lesions, i.e. bilateral lungs, the right lung and the left lung in 6/10, 6/8, and 2/3 cases respectively (P=0.067). CONCLUSION: 99Tc(m)-sulfur colloid imaging is effective to detect the aspiration of nasopharyngeal secretions in the elderly people. Besides, the incidence rate of aspiration in the patients was higher than that in healthy people, which suggests that aspiration of nasopharyngeal secretion is the cause of pulmonary infection.

Preparation and evaluation of solid dispersions of a new antitumor compound based on early-stage preparation discovery concept.

Ensuring sufficient drug solubility is a crucial problem in pharmaceutical-related research. For water-insoluble drugs, various formulation approaches are employed to enhance the solubility and bioavailability of lead compounds. The goal of this study was to enhance the dissolution and absorption of a new antitumor lead compound, T-OA. Early-stage preparation discovery concept was employed in this study. Based on this concept, a solid dispersion system was chosen as the method of improving drug solubility and bioavailability. Solid dispersions of T-OA in polyvinylpyrrolidone (PVP) K30 were prepared by the solvent evaporation method. Dissolution testing determined that the ideal drug-to-PVP ratio was 1:5. X-ray diffraction, Fourier transform infrared spectroscopy, and differential scanning calorimetry were employed to confirm the formation of solid dispersions. Scanning electron microscopy demonstrated that T-OA was converted into an amorphous form. Both in vitro dissolution testing and the in vivo studies demonstrated that the solubility and bioavailability of T-OA were significantly improved when formulated in a solid dispersion with PVP. The dissolution rate of the T-OA/PVP solid dispersion was greatly enhanced relative to the pure drug, and the relative bioavailability of T-OA solid dispersions was found to be 392.0%, which is 4-fold higher than the pure drug.

Multiphysics modeling and simulation of local transport and absorption kinetics of intramuscularly injected lipid nanoparticles.

Recent clinical applications of mRNA vaccines highlight the critical role of drug delivery, especially when using lipid nanoparticles (LNPs) as the carrier for genetic payloads. However, kinetic and transport mechanisms for locally injected LNPs, such as lymphatic or cellular uptake and drug release, remain poorly understood. Herein, we developed a bottom-up multiphysics computational model to simulate the injection and absorption processes of LNPs in muscular tissues. Our purpose was to seek underlying connections between formulation attributes and local exposure kinetics of LNPs and the delivered drug. We were also interested in modeling the absorption kinetics from the local injection site to the systemic circulation. In our model, the tissue was treated as the homogeneous, poroelastic medium in which vascular and lymphatic vessel densities are considered. Tissue deformation and interstitial fluid flow (modeled using Darcy's Law) were also implemented. Transport of LNPs was described based on diffusion and advection; local disintegration and cellular uptake were also integrated. Sensitivity analyses of LNP and drug properties and tissue attributes were conducted using the simulation model. It was found that intrinsic tissue porosity and lymphatic vessel density affect the local transport kinetics; diffusivity, lymphatic permeability, and intracellular update kinetics also play critical roles. Simulated results were commensurate with experimental observations. This study could shed light on the development of LNP formulations and enable further development of whole-body pharmacokinetic models.

Glucagon-modified Liposomes Delivering Thyroid Hormone for Anti-obesity Therapy.

BACKGROUND: Thyroid hormones (active form T3) are naturally potent compounds that influence energy expenditure, cholesterol metabolism, and fat oxidation. T3 would be an effective anti-obesity drug if it would not be delivered to the heart and bones, which leads to serious side effects, such as cardiovascular and bone thyrotoxicity, muscle wasting, and so on. METHODS: In this study, we designed a targeted drug delivery system that is a glucagon-modified liposome to deliver T3 to the liver and adipose tissues. RESULTS: The liposomes exhibited excellent properties, including uniform nanoscale particle size, good physicochemical stability, and adequate drug release behavior. More importantly, the glucagon-modified liposomes were enriched in the liver, which minimized the undesired bone and cardiovascular thyrotoxicity of T3. Compared to the control group, T3-loading glucagon-modified liposomes could effectively decrease body weight, reverse hepatic steatosis, and correct hyperlipidemia and hyperglycemia in ob/ob mice, without the undesired cardiovascular and bone thyrotoxicity. CONCLUSION: These findings indicate that delivery of thyroid hormone by glucagon-modified liposomes may provide an effective strategy for anti-obesity therapy.

Reducing plastic film mulching and optimizing agronomic management can ensure food security and reduce carbon emissions in irrigated maize areas.

Increasing crop yields to ensure food security while also reducing agriculture's environmental impacts to ensure green sustainable development are great challenges for global agriculture. Plastic film, widely used to improve crop yield, also creates plastic film residue pollution and greenhouse gas emissions that restricts the development of sustainable agriculture. So, one of those challenges is to reduce plastic film use while also ensuring food security, and thus promote green and sustainable development. A field experiment was conducted during 2017-2020 at 3 farmland areas, each with different altitudes and climate conditions, in northern Xinjiang, China. We investigated the effects on maize yield, economic returns, and greenhouse gas (GHG) emissions of plastic film mulching (PFM) versus no mulching (NM) methods in drip-irrigated maize production. We also chose maize hybrids with 3 different maturation times and used 2 planting densities to further investigate how those differences more specifically affect maize yield, economic returns, and greenhouse gas (GHG) emissions under each mulching method. We found that by using maize varieties with a utilization rate of accumulated temperature (URAT) <86.6 % with NM, and increasing the planting density by 3 plants m-2, yields and economic returns improved and GHG emissions reduced by 33.1 %, compared to those of PFM maize. The maize varieties with URATs between 88.2 % to 89.2 %, had the lowest GHG emissions. We discovered that by matching the required accumulated temperatures of various maize varieties to environmental accumulated temperatures, along with filmless and higher density planting, and modern irrigation and fertilization practices, yields increased and residual plastic film pollution and carbon emissions reduced. Therefore, these advances in agronomic management are important steps toward reducing pollution and achieving carbon peak and carbon neutrality goals.

The synthesis and characterization of polymer-coated FeAu multifunctional nanoparticles.

We report the one-pot nanoemulsion synthesis of FeAu magnetic-optical multifunctional nanoparticles coated by the biocompatible triblock copolymer, poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) (PEO-PPO-PEO). The FTIR study confirms the PEO-PPO-PEO molecules on the surface of the resulting nanoparticles. The structural characterization identifies the crystallographic parameter 4.072 A of the cubic phase and the morphology analysis gives the nanoparticle shape, size and size distribution, showing the high crystallinity of the FeAu nanoparticles and an average particle size of approximately 6.5 nm. In addition there is direct confirmation of the alloying by elemental point probing of an individual nanoparticle. Following the visual demonstration of a rapid, efficient and reversible dispersion-collection process of the nanoparticles in solution, the magnetic measurement manifests a soft ferromagnetic behavior of the nanoparticles with a small coercivity of approximately 60 Oe at room temperature. The corresponding magnetic hysteresis curves were effectively assessed by modified bi-phase Langevin equations, which were satisfactorily explained in terms of a bimodal particle size distribution. The UV-vis studies display the broadband absorption of the PEO-PPO-PEO-coated nanoparticles with the maximum surface plasmon resonance around 585 nm. The characterization and analysis, therefore, shows the unification of iron and gold into one alloy nanostructure entity covered by the biocompatible triblock copolymer thin film, preserving the optical and magnetic properties of the individual constituents. This gives the prospect of enhanced performance in applications.

A lanthanide-peptide-derived bacterium-like nanotheranostic with high tumor-targeting, -imaging and -killing properties.

Nanostructures formed with bioactive peptides offer an exciting prospect in clinical oncology as a novel class of therapeutic agents for human cancers. Despite their therapeutic potential, however, peptide-based nanomedicines are often inefficacious in vivo due to low cargo-loading efficiency, poor tumor cell-targeting specificity and limited drug accumulation in tumor tissues. Here, we describe the design, via assembly of a p53-activating peptide termed PMI, functionalized PEG and fluorescent lanthanide oxyfluoride nanocrystals, of a novel nanotheranostic shaped in flexible rods. This lanthanide-peptide nanorod or LProd of bionic nature exhibited significantly enhanced tumor-targeting and -imaging properties compared to its spherical counterpart. Importantly, LProd potently inhibited tumor growth in a mouse model of human colon cancer through activating tumor suppressor protein p53 via MDM2/MDMX antagonism, while maintaining a highly favorable biosafety profile. Our data demonstrate that LProd as a multifunctional theranostic platform is ideally suited for tumor-specific peptide drug delivery with real-time disease tracking, thereby broadly impacting clinical development of antitumor peptides.

Synthesis and characterization of biocompatible Fe3O4 nanoparticles.

In this study, magnetite (Fe3O4) nanoparticles with a size range of 8-20 nm were prepared by the modified controlled chemical coprecipitation method from the solution of ferrous/ferric mixed salt-solution in alkaline medium. In the process, two kinds of surfactant (sodium oleate and polyethylene glycol) were studied; then, sodium oleate was chosen as the apt surfactant to attain ultrafine, nearly spherical and well-dispersed (water-base) Fe3O4 nanoparticles, which had well magnetic properties. The size and size distribution of nanoparticles were determined by particle size analyzer. And the magnetite nanoparticles was characterized by X-ray powder diffraction (XRD) analysis, transmission electron microscopy (TEM), electron diffraction (ED) photography, Fourier transform infrared spectrometer (FT-IR), and vibrating-sample magnetometer (VSM). Also the effect of many parameters on the Fe3O4 nanoparticles was studied, such as reaction temperature, pH of the solution, stirring rate and concentration of sodium oleate. And the 5-dimethylthiazol-2-yl-2,5- diphenyltetrazolium bromide (MTT) assay was performed to evaluate the biocompatibility of magnetite nanoparticles. The results showed that the Fe3O4 nanoparticles coated by sodium oleate had a better biocompatibility, better magnetic properties, easier washing, lower cost, and better dispersion than the magnetite nanoparticles coated by PEG.

Ag-Incorporated FHA Coating on Pure Mg: Degradation and in Vitro Antibacterial Properties.

Fluoridated hydroxyapatite (FHA) coating can help retard the degradation of magnesium, and possess good biocompatibility. However, the antibacterial property of FHA is very limited. In this work, we aimed to incorporate silver into FHA structure to fabricate biocompatible and antibacterial coatings with enhanced anticorrosion property. The results showed that the Ag-FHA coating prepared by electrochemical deposition and subsequent immersion in AgNO3 solution was superior to the Ag-FHA coating prepared by coelectrodeposition in terms of crystal structure, surface morphology and corrosion resistance. The release of Ag(+) ion causing high antiplanktonic bacterial rate and excellent antiadherence property to MRSA. Meanwhile, good cell compatibility of MC3T3-E1 including cell viability, cell adhesion, and cell morphology was achieved under the controlled degradation. The balance of degradation and antimicrobial property of Ag-incorporated FHA coating made it an alternative in the application of surface modification for biodegradable Mg.

Reduced antibacterial property of metallic magnesium in vivo.

Magnesium and its alloys have drawn interest as antibacterial biomaterials, owing to their ability to alkalize the surrounding medium during degradation. The antibacterial effect of pure Mg and Mg alloys in vitro has previously been reported. However, the antibacterial property of Mg in vivo might be different because of the apparently dissimilar corrosion characteristics. In this study, pure Mg rods were implanted and bacterial suspension were injected into rat femurs to investigate the antibacterial property of Mg in vivo. The results showed that contrary to the high antibacterial rate in vitro, Mg exhibited a dramatic drop in antibacterial effect in vivo. Bacteria proliferated on the surface of the Mg rods as well as in the femur. Inflammatory cells filled cavities in the cortical bone of the femur, which was demonstrated by histological and micro-CT examination after 2 and 4 weeks of implantation. It is suggested that a reduced corrosion rate in vivo would result in insufficient pH value. In addition, the deposition layer would prevent further corrosion of Mg and provide a favorite site for bacteria adhesion. Hence, the dramatically reduced antibacterial property of Mg needs to be noticed when it is used as a biomaterial.

In vitro and in vivo studies on the degradation of high-purity Mg (99.99wt.%) screw with femoral intracondylar fractured rabbit model.

High-purity magnesium (HP Mg) takes advantage in no alloying toxic elements and slower degradation rate in lack of second phases and micro-galvanic corrosion. In this study, as rolled HP Mg was fabricated into screws and went through in vitro immersion tests, cytotoxicity test and bioactive analysis. The HP Mg screws performed uniform corrosion behavior in vitro, and its extraction promoted cell viability, bone alkaline phosphatase (ALP) activity, and mRNA expression of osteogenic differentiation related gene, i.e. ALP, osteopontin (OPN) and RUNX2 of human bone marrow mesenchymal stem cells (hBMSCs). Then HP Mg screws were implanted in vivo as load-bearing implant to fix bone fracture and subsequently gross observation, range of motion (ROM), X-ray scanning, qualitative micro-computed tomography (µCT) analysis, histological analysis, bending-force test and SEM morphology of retrieved screws were performed respectively at 4, 8, 16 and 24 weeks. As a result, the retrieved HP Mg screws in fixation of rabbit femoral intracondylar fracture showed uniform degradation morphology and enough bending force. However, part of PLLA screws was broken in bolt, although its screw thread was still intact. Good osseointegration was revealed surrounding HP Mg screws and increased bone volume and bone mineral density were detected at fracture gap, indicating the rigid fixation and enhanced fracture healing process provided by HP Mg screws. Consequently, the HP Mg showed great potential as internal fixation devices in intra-articular fracture operation.

Preparation and physicochemical characterization of a solid dispersion of (3, 5, 6-trimethylpyrazin-2-yl) methyl 3-methoxy-4-[(3, 5, 6-trimethylpyrazin-2-yl) methoxy] benzoate (VA-T) and polyvinylpyrrolidone.

Ischemic brain injury is a major disease which threatens human health and safety. (3, 5, 6-trimethylpyrazin-2-yl) methyl 3-methoxy-4-[(3, 5, 6-trimethylpyrazin-2-yl) methoxy] benzoate (VA-T), a newly discovered lead compound, is effective for the treatment of ischemic brain injury and its sequelae. But the poor solubility of VA-T leads to poor dissolution and limited clinical application. In order to improve the dissolution of VA-T, the pharmaceutical technology of solid dispersions was used in the present study. VA-T/polyvinylpyrrolidone (PVP) solid dispersion was prepared by the solvent method. The dissolution studies were carried out and solid state characterization was evaluated by differential scanning calorimetry (DSC), infrared spectroscopy (IR), x-ray diffraction (XRD) and scanning electron microscopy (SEM). The dissolution rate of VA-T was significantly improved by solid dispersion compared to that of the pure drug and physical mixture. The results of DSC and XRD indicated that the VA-T solid dispersion was amorphous. The IR spectra showed the possible interaction between VA-T and PVP was the formulation of hydrogen bonding. The SEM analysis demonstrated that there was no VA-T crystal observed in the solid dispersions. The ideal drug-to-PVP ratio was 1:5. In conclusion, the solid dispersion technique can be successfully used for the improvement of the dissolution profile of VA-T.