Search

Considering that the precise delivery of Celastrol (Cst) into mitochondria to induce mitochondrial dysfunction may be a potential approach to improve the therapeutic outcomes of Cst on TNBC, a novel tumor mitochondria dual-targeted mixed-micelle nano-system was fabricated via self-synthesized triphenylphosphonium-modified cholesterol (TPP-Chol) and hyaluronic acid (HA)-modified cholesterol (HA-Chol). The Cst-loaded mixed micelles (Cst@HA/TPP-M) exhibited the characteristics of a small particle size, negative surface potential, high drug loading of up to 22.8%, and sustained drug release behavior. Compared to Cst-loaded micelles assembled only by TPP-Chol (Cst@TPP-M), Cst@HA/TPP-M decreased the hemolysis rate and upgraded the in vivo stability and safety. In addition, a series of cell experiments using the triple-negative breast cancer cell line MDA-MB-231 as a cell model proved that Cst@HA/TPP-M effectively increased the cellular uptake of the drug through CD44-receptors-mediated endocytosis, and the uptake amount was three times that of the free Cst group. The confocal results demonstrated successful endo-lysosomal escape and effective mitochondrial transport triggered by the charge converse of Cst@HA/TPP-M after HA degradation in endo-lysosomes. Compared to the free Cst group, Cst@HA/TPP-M significantly elevated the ROS levels, reduced the mitochondrial membrane potential, and promoted tumor cell apoptosis, showing a better induction effect on mitochondrial dysfunction. In vivo imaging and antitumor experiments based on MDA-MB-231-tumor-bearing nude mice showed that Cst@HA/TPP-M facilitated drug enrichment at the tumor site, attenuated drug systemic distribution, and polished up the antitumor efficacy of Cst compared with free Cst. In general, as a target drug delivery system, mixed micelles co-constructed by TPP-Chol and HA-Chol might provide a promising strategy to ameliorate the therapeutic outcomes of Cst on TNBC. [ABSTRACT FROM AUTHOR]

Reactive astrocytes are important pathophysiologically and synthesize neurosteroids. We observed that LPS increased immunoreactive TLR4 and key steroidogenic enzymes in cortical astrocytes of rats and investigated whether corticosteroids are produced and mediate astrocytic TLR4‐dependent innate immune responses. We found that LPS increased steroidogenic acute regulatory protein (StAR) and StAR‐dependent aldosterone production in purified astrocytes. Both increases were blocked by the TLR4 antagonist TAK242. LPS also increased 11β‐hydroxysteroid dehydrogenase type 1 (11β‐HSD1) and corticosterone production, and both were prevented by TAK242 and by siRNAs against 11β‐HSD1, StAR, or aldosterone synthase (CYP11B2). Knockdown of 11β‐HSD1, StAR, or CYP11B2 or blocking either mineralocorticoid receptors (MR) or glucocorticoid receptors (GR) prevented dephosphorylation of p‐Ser9GSK‐3β, activation of NF‐κB, and the GSK‐3β‐dependent increases of C3, IL‐1β, and TNF‐α caused by LPS. Exogenous aldosterone mimicked the MR‐ and GSK‐3β‐dependent pro‐inflammatory effects of LPS in astrocytes, but corticosterone did not. Supernatants from astrocytes treated with LPS reduced MAP2 and viability of cultured neurons except when astrocytic StAR or MR was inhibited. In adrenalectomized rats, intracerebroventricular injection of LPS increased astrocytic TLR4, StAR, CYP11B2, and 11β‐HSD1, NF‐κB, C3 and IL‐1β, decreased astrocytic p‐Ser9GSK‐3β in the cortex and was neurotoxic, except when spironolactone was co‐injected, consistent with the in vitro results. LPS also activated NF‐κB in some NeuN+ and CD11b+ cells in the cortex, and these effects were prevented by spironolactone. We conclude that intracrine aldosterone may be involved in the TLR4‐dependent innate immune responses of astrocytes and can trigger paracrine effects by activating astrocytic MR/GSK‐3β/NF‐κB signaling. [ABSTRACT FROM AUTHOR]

Collagen plays a crucial role in cancer development and migration. However, the impact of changes in the collagen molecular structure on its interaction with cancer cells remains unclear. In this study, natural bovine tendon collagen was heat-treated to obtain collagen samples with different triple helix dissociation degrees. Three methods, including cell adhesion assay, fluorescence labeling assay, and cancer cell capture assay, were employed to compare the binding efficiency of collagen samples to both breast cancer cells (MCF-7) and human umbilicus vein endothelial cells (HUVECs). The results demonstrated that collagen samples exhibited stronger binding efficiency to cancer cells than to normal cells. Additionally, untreated collagen samples showed higher cell binding efficiency compared to heat-treated collagen samples. Furthermore, by comparing the differences in the binding efficiency of collagen samples with different triple helix dissociation degrees to cancer cells and normal cells, it was confirmed that untreated collagen samples exhibited the greatest disparity in binding efficiency with both cell types. Moreover, a strong linear relationship was observed between the triple helix dissociation degree of collagen and the capture rate of cancer cells in the co-culture system. These findings provide important insights into the role of collagen in cancer development. [ABSTRACT FROM AUTHOR]

In order to precisely deliver celastrol into mitochondria of tumor cells, improve antitumor efficacy of celastrol and overcome its troublesome problems in clinical application, a novel multistage-targeted celastrol delivery system (C-TL/HA) was developed via electrostatic binding of hyaluronic acid (HA) to celastrol-loaded cationic liposomes composed of natural soybean phosphatidylcholine and cholesterol modified with mitochondrial targeting molecular TPP. Study results in this article showed that C-TL/HA successfully transported celastrol into mitochondria, effectively activated apoptosis of mitochondrial pathway, exerted higher tumor inhibition efficiency and lower toxic side effects compared with free celastrol. More importantly, HA coating not only enabled this delivery system to have good stability and safety in vivo, but also increased drug uptake and facilitated tumor targeting through recognizing CD44 receptors rich on the surface of tumor cells. Conclusively, this HA-coated mitochondrial targeting liposomes may provide a prospect for the clinical application of celastrol in tumor therapy. [ABSTRACT FROM AUTHOR]

Background Obesity is a major health problem worldwide, and non-alcoholic fatty pancreas disease (NAFPD) and non-alcoholic fatty liver disease (NAFLD) are obesity-associated complications. Liraglutide, a glucagon-like peptide-1 (GLP-1) agonist, has been approved for treatment of obesity. We aimed to evaluate the therapeutic effects of liraglutide on the complications through its regulation of endoplasmic reticulum (ER) stress. Methods A high-fat diet mouse model was established in C57BL/6J mice. Two groups of mice were fed a high-fat diet with 60% fat for 16 weeks and control mice were fed standard chow. A four-week 0.6 mg/kg/day liraglutide treatment was started in one high-fat diet group after 12 weeks of the high-fat diet. After sacrificing the mice, pancreatic and hepatic tissues were prepared for western blot and immunohistochemistry for ER stress proteins, including activating transcription factor 4 (ATF4), caspase 12, C/EBP homologous protein (CHOP) eukaryotic initiation factor 2 α (eIF2α), glucose regulated protein (GRP) 78 and protein kinase RNA-like endoplasmic reticulum kinase (PERK). Results Liraglutide significantly decreased body weight gained by mice consuming a high-fat diet (27.6 g vs. 34.5 g, P<0.001), and levels of all ER proteins increased significantly in both the pancreas and liver (all P<0.05). Expression of most ER stress proteins in pancreatic tissue correlated with disease scores of NAFLD (all P<0.05). However, no significant differences were found in pancreatic ATF 4 expression between mice without NAFLD, and those with early non-alcoholic steatohepatitis (NASH) and fibrotic NASH (P=0.122). Conclusion Liraglutide may reduce the severity of NAFPD and NAFLD through regulating the ER stress pathway and downstream apoptosis signaling. [ABSTRACT FROM AUTHOR]

The migration and deposition processes of fine particles under the influence of temperature gradients and fluid flow are widely prevalent. Investigating the mechanisms of particle interactions in these processes contributes to the development of efficient dust removal techniques. In this work, experimental and numerical studies of particle motion in temperature gradient fields are conducted. The research encompasses both qualitative and quantitative analyses of particle motion influenced by thermophoresis and particle diameter. Qualitative analysis reveals that the motion characteristics of particles are jointly determined by gravity, drag force, and thermophoretic force, and the diameter range that exhibiting a notable influence of the thermophoretic force is 20–30 μm. Quantitative analysis shows that the manifestations of deposition and diffusion become more evident with an increasing temperature gradient. For instance, in comparison to the working condition with Δ T = 0 K and d p = 20 μm, the deposition mass increases by approximately 23% when Δ T = -15 K; conversely, it diminishes by about 11% when Δ T = 15 K. Additionally, the Discrete Phase Model (DPM) is employed to simulate the motion of gas-solid flow. This study presents a novel visualization system to observe particle motion in gas-solid systems to elucidate the mechanisms underlying the thermophoretic effect and establish a robust theoretical foundation for thermophoretic dust removal technology. [ABSTRACT FROM AUTHOR]