The causal relationship between vitiligo and autoimmune thyroid diseases: A bidirectional two-sample Mendelian randomization analysis.

BACKGROUND: Vitiligo is an acquired autoimmune depigmented disorder characterized by the presence of white and well-defined patches on the skin, mucous membrane, or both. It is associated with a significant disease burden and has a profoundly impacts patients' quality of life. Autoimmune thyroid diseases (AITDs) result from an autoimmune system dysregulation, leading to an erroneous immune attack on the thyroid gland. Previous observational and epidemiological studies have suggested the association between vitiligo and AITDs. However, the bidirectional cause-effect relationship between vitiligo and AITDs has not been formally assessed. METHOD: Two-sample bidirectional Mendelian randomization (MR) analysis was conducted to explore potential causal relationships between genetically increased risk of vitiligo and AITDs, using summary statistics from genome-wide association studies in European populations. Causal effects were primarily estimated using the inverse variance weighted method, and additional quality control was performed using the MR-Egger, weighted median, simple mode, and weight mode methods. Sensitivity analysis was conducted to assess the robustness of the results. RESULTS: The forward MR analysis showed a positive causal relationship between vitiligo and autoimmune thyroiditis (AIT), autoimmune hyperthyroidism (AIH), and Graves' disease (GD). The odds ratio (OR) were 1.17 (95% CI, 1.01-1.35; p = 0.04), 1.12 (95% CI, 1.03-1.22; p = 0.01), and 1.13 (95% CI, 1.06-1.20; p < 0.01), respectively. In the reverse MR analysis, a positive causal relationship was found between AIT and vitiligo, with an OR of 1.10 (95% CI, 1.01-1.35; p = 0.04). However, no causal relationship was observed between AIH (p = 0.10) or GD (p = 0.61) and vitiligo. Sensitivity analysis revealed no evidence of horizontal pleiotropy or heterogeneity. CONCLUSIONS: The genetic-level investigation provides evidence of a genetic causal association between susceptibility to vitiligo and an increased risk of AITDs. Additionally, the results demonstrate a genetic causal association between susceptibility to AIT and an increased risk of vitiligo, while not indicating a similar association with susceptibility to AIH or GD.

In Vitro Anti-Inflammatory Study of Limonoids Isolated from Chisocheton Plants.

Chisocheton plants from the family Meliaceae have traditionally been used to treat several diseases; however, scientific evidence is limited. The most abundant chemical constituents of this plant are the limonoids, which are known for their various biological activities, including anti-inflammatory effects. However, the anti-inflammatory effects and underlying mechanisms of action of the constituents of Chisocheton plants have not been fully explored. In this report, we evaluated the anti-inflammatory activity of 17 limonoid compounds from Chisocheton plant primarily by measuring their inhibitory effects on the production of pro-inflammatory cytokines, including TNF-α, IL-6, IL-1ß, and MCP-1, in LPS-stimulated THP-1 cells using an ELISA assay. Compounds 3, 5, 9, and 14-17 exhibited significant activity in inhibiting the evaluated pro-inflammatory markers, with IC50 values less than 20 µM and a high selectivity index (SI) range. Compounds 3, 5, 9, and 15 significantly suppressed the expression of phosphorylated p38 MAPK in THP-1 cells stimulated with LPS. These findings support the use of limonoids from Chisocheton plants as promising candidates for anti-inflammatory therapy.

Antigen/Adjuvant-Displaying Enveloped Viral Replica as a Self-Adjuvanting Anti-Breast-Cancer Vaccine Candidate.

We report a promising cancer vaccine candidate comprising antigen/adjuvant-displaying enveloped viral replica as a novel vaccine platform. The artificial viral capsid, which consists of a self-assembled ß-annulus peptide conjugated with an HER2-derived antigenic CH401 peptide, was enveloped within a lipid bilayer containing the lipidic adjuvant α-GalCer. The use of an artificial viral capsid as a scaffold enabled precise control of its size to ∼100 nm, which is generally considered to be optimal for delivery to lymph nodes. The encapsulation of the anionically charged capsid by a cationic lipid bilayer dramatically improved its stability and converted its surface charge to cationic, enhancing its uptake by dendritic cells. The developed CH401/α-GalCer-displaying enveloped viral replica exhibited remarkable antibody-production activity. This study represents a pioneering example of precise vaccine design through bottom-up construction and opens new avenues for the development of effective vaccines.

Reactive oxygen species are associated with the inhibitory effect of N-(4-hydroxyphenyl)-retinamide on the entry of the severe acute respiratory syndrome-coronavirus 2.

N-(4-hydroxyphenyl)-retinamide (4-HPR) inhibits the dihydroceramide Δ4-desaturase 1 (DEGS1) enzymatic activity. We previously reported that 4-HPR suppresses the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) spike protein-mediated membrane fusion through a decrease in membrane fluidity in a DEGS1-independent manner. However, the precise mechanism underlying the inhibition of viral entry by 4-HPR remains unclear. In this study, we examined the role of reactive oxygen species (ROS) in the inhibition of membrane fusion by 4-HPR because 4-HPR is a well-known ROS-inducing agent. Intracellular ROS generation was found to be increased in the target cells in a cell-cell fusion assay after 4-HPR treatment, which was attenuated by the addition of the antioxidant, α-tocopherol (TCP). The reduction in membrane fusion susceptibility by 4-HPR treatment in the cell-cell fusion assay was alleviated by TCP addition. Furthermore, fluorescence recovery after photobleaching analysis showed that the lateral diffusion of glycosylphosphatidylinositol-anchored protein and SARS CoV-2 receptor was reduced by 4-HPR treatment and restored by TCP addition. These results indicate that the decrease in SARS-CoV-2 spike protein-mediated membrane fusion and membrane fluidity by 4-HPR was due to ROS generation. Taken together, these results demonstrate that ROS production is associated with the 4-HPR inhibitory effect on SARS-CoV-2 entry.

Astatine-211-Labeled Gold Nanoparticles for Targeted Alpha-Particle Therapy via Intravenous Injection.

Alpha-particle radiotherapy has gained considerable attention owing to its potent anti-cancer effect. 211At, with a relatively short half-life of 7.2 h, emits an alpha particle within a few cell diameters with high kinetic energy, which damages cancer cells with high biological effectiveness. In this study, we investigated the intravenous injection of 211At-labeled gold nanoparticles (AuNPs) for targeted alpha-particle therapy (TAT). Different kinds of surface-modified gold nanoparticles can be labeled with 211At in high radiochemical yield in 5 min, and no purification is necessary. The in vivo biodistribution results showed the accumulation of 5 nm 211At-AuNPs@mPEG at 2.25% injection dose per gram (% ID/g) in tumors within 3 h via the enhanced permeability and retention (EPR) effect. Additionally, we observed a long retention time in tumor tissues within 24 h. This is the first study to demonstrate the anti-tumor efficacy of 5 nm 211At-AuNPs@mPEG that can significantly suppress tumor growth in a pancreatic cancer model via intravenous administration. AuNPs are satisfactory carriers for 211At delivery, due to simple and efficient synthesis processes and high stability. The intravenous administration of 5 nm 211At-AuNPs@mPEG has a significant anti-tumor effect. This study provides a new framework for designing nanoparticles suitable for targeted alpha-particle therapy via intravenous injection.

A Simulation Analysis of Maternal Pelvic Floor Muscle.

Pelvic floor disorder (PFD) is a common disease affecting the quality of life of middle-aged and elderly women. Pelvic floor muscle (PFM) damage is related to delivery mode, fetal size, and parity. Spontaneous vaginal delivery causes especially great damage to PFM. The purpose of this study was to summarize the characteristics of PFM action during the second stage of labor by collecting female pelvic MRI (magnetic resonance imaging) data and, further, to try to investigate the potential pathogenetic mechanism of PFD. A three-dimensional model was established to study the influence factors and characteristics of PFM strength. In the second stage of labor, the mechanical responses, possible damage, and the key parts of postpartum lesions of PFM due to the different fetal biparietal diameter (BPD) sizes were analyzed by finite element simulations. The research results showed that the peak stress and strain of PFM appeared at one-half of the delivery period and at the attachment point of the pubococcygeus to the skeleton. In addition, during the simulation process, the pubococcygeus was stretched by about 1.2 times and the levator ani muscle was stretched by more than two-fold. There was also greater stress and strain in the middle area of the levator ani muscle and pubococcygeus. According to the statistics, either being too young or in old maternal age will increase the probability of postpartum PFM injury. During delivery, the entire PFM underwent the huge deformation, in which the levator ani muscle and the pubococcygeus were seriously stretched and the attachment point between the pubococcygeus and the skeleton were the places with the highest probability of postpartum lesions.

Intratumoral administration of astatine-211-labeled gold nanoparticle for alpha therapy.

BACKGROUND: 211At is a high-energy α-ray emitter with a relatively short half-life and a high cytotoxicity for cancer cells. Its dispersion can be imaged using clinical scanners, and it can be produced in cyclotrons without the use of nuclear fuel material. This study investigated the biodistribution and the antitumor effect of 211At-labeled gold nanoparticles (211At-AuNP) administered intratumorally. RESULTS: AuNP with a diameter of 5, 13, 30, or 120 nm that had been modified with poly (ethylene glycol) methyl ether (mPEG) thiol and labeled with 211At (211At-AuNP-S-mPEG) were incubated with tumor cells, or intratumorally administered to C6 glioma or PANC-1 pancreatic cancers subcutaneously transplanted into rodent models. Systemic and intratumoral distributions of the particles in the rodents were then evaluated using scintigraphy and autoradiography, and the changes in tumor volumes were followed for about 40 days. 211At-AuNP-S-mPEG was cytotoxic when it was internalized by the tumor cells. After intratumoral administration, 211At-AuNP-S-mPEG became localized in the tumor and did not spread to systemic organs during a time period equivalent to 6 half-lives of 211At. Tumor growth was strongly suppressed for both C6 and PANC-1 by 211At-AuNP-S-mPEG. In the C6 glioma model, the strongest antitumor effect was observed in the group treated with 211At-AuNP-S-mPEG with a diameter of 5 nm. CONCLUSIONS: The intratumoral single administration of a simple nanoparticle, 211At-AuNP-S-mPEG, was shown to suppress the growth of tumor tissue strongly in a particle size-dependent manner without radiation exposure to other organs caused by systemic spread of the radionuclide.

Geometric Non-Linear Analysis of Auxetic Hybrid Laminated Beams Containing CNT Reinforced Composite Materials.

In the current work, a novel hybrid laminate with negative Poisson's ratio (NPR) is developed by considering auxetic laminate which is composed of carbon nanotube-reinforced composite (CNTRC) and fiber-reinforced composite (FRC) materials. The maximum magnitude of out-of-plane NPR is identified in the case of (20 F/20 C/-20 C/20 C) S laminate as well. Meanwhile, a method for the geometric non-linear analysis of hybrid laminated beam with NPR including the non-linear bending, free, and forced vibrations is proposed. The beam deformation is modeled by combining higher-order shear-deformation theory (HSDT) and large deflection theory. Based on a two-step perturbation approach, the asymptotic solutions of the governing equations are obtained to capture the linear and non-linear frequencies and load-deflection curves. Moreover, a two-step perturbation methodology in conjunction with fourth-order Runge-Kutta method is employed to solve the forced-vibration problem. Several key factors, such as CNT distribution, variations in the elastic foundation, and thermal stress, are considered in the exhaustive analysis. Theoretical results for some particular cases are given to examine the geometric non-linearity behavior of hybrid beam with NPR as well as positive Poisson's ratio (PPR).